678 PART X REPRODUCTIVE PHYSIOLOGY levels are low in response to the removal of negative feed- occurs before the LH surge. This rise is important for aug- back by estrogen, progesterone, and inhibin. A few days menting the LH surge and, together with estradiol, pro- later, however, LH levels slowly begin to rise. FSH acts on motes a concomitant surge in FSH. There are indications a cohort of follicles recruited 20 to 25 days earlier from a that the midcycle FSH surge is important for inducing resting pool of smaller follicles. The follicles on days 3 to 5 enough LH receptors on granulosa cells for luteinization, average 4 to 6 mm in diameter, and they are stimulated by stimulating plasminogen activator for follicular rupture, FSH to grow into the preantral stages. In response to FSH, and activating a cohort of follicles destined to develop in the granulosa cells proliferate, aromatase activity increases, the next cycle. and plasma estradiol levels rise slightly between days 3 and The LH surge reduces the concentration of 17-hy- 7. The designated dominant follicle is selected between droxylase and subsequently decreases androstenedione days 5 and 7, and increases in size and steroidogenic activ- production by the dominant follicle. Estradiol levels de- ity. Between days 8 and 10, plasma estradiol levels rise cline, 17-hydroxyprogesterone increases, and progesterone sharply, reaching peak levels above 200 pg/mL on day 12, levels plateau. The prolonged exposure to high LH levels the day before the LH surge. during the surge down-regulates the ovarian LH receptors, During the early follicular phase, LH pulsatility is of low accounting for the immediate postovulatory suppression of amplitude and high frequency (about every hour). Coin- estradiol. As the corpus luteum matures, it increases prog- ciding pulses of GnRH are released about every hour. As esterone production and reinitiates estradiol secretion. estradiol levels rise, the pulse frequency in GnRH further Both reach high plasma concentrations on days 20 to 23, increases, without a change in amplitude. The mean plasma about 1 week after ovulation. LH level increases and further supports follicular steroido- During the luteal phase, circulating FSH levels are sup- genesis, especially since FSH has increased the number of pressed by the elevated steroids. The LH pulse frequency is LH receptors on growing follicles. During the midfollicular reduced during the early luteal phase, but the amplitude is to late follicular phase, rising estradiol and inhibin from the higher than that during the follicular phase. LH is impor- dominant follicle suppress FSH release. The decline in tant at this time for maintaining the function of the corpus FSH, together with an accumulation of nonaromatizable luteum and sustaining steroid production. In the late luteal androgens, induces atresia in the nonselected follicles. The phase, both LH pulse frequency and amplitude are reduced dominant follicle is saved by virtue of its high density of by a progesterone-dependent, opioid-mediated suppres- FSH receptors, the accumulation of FSH in its follicular sion of the GnRH pulse generator. fluid (see Table 38.2), and the acquisition of LH receptors After the demise of the corpus luteum on days 24 to 26, by the granulosa cells. estradiol and progesterone levels plunge, causing the The midcycle surge of LH is rather short (24 to 36 withdrawal of support of the uterine endometrium, culmi- hours) and is an example of positive feedback. For the LH nating within 2 to 3 days in menstruation. The reduction surge to occur, estradiol must be maintained at a critical in ovarian steroids acts centrally to remove feedback inhi- concentration (about 200 pg/mL) for a sufficient duration bition. The FSH level begins to rise and a new cycle is ini- (36 to 48 hours) prior to the surge. Any reduction of the tiated. estradiol rise or a rise that is too small or too short elimi- nates or reduces the LH surge. In addition, in the presence of elevated progesterone, high concentrations of estradiol Estradiol and Progesterone Influence Cyclic do not induce an LH surge. Paradoxically, although it ex- erts negative feedback on LH release most of the time, pos- Changes in the Reproductive Tract itive feedback by estradiol is required to generate the mid- The female reproductive tract undergoes cyclic alterations cycle surge. in response to the changing levels of ovarian steroids. The Estrogen exerts its effects directly on the anterior pitu- most notable changes occur in the function and histology itary, with GnRH playing a permissive, albeit mandatory, of the oviduct and uterine endometrium, the composition role. This concept is derived from experiments in monkeys of cervical mucus, and the cytology of the vagina whose medial basal hypothalamus, including the GnRH- (Fig. 38.7). At the time of ovulation, there is also a small but producing neurons, was destroyed by lesioning, resulting in detectable rise in basal body temperature, caused by prog- a marked decrease in plasma LH levels. The administration esterone. All of the above parameters are clinically useful of exogenous GnRH at a fixed frequency restored LH re- for diagnosing menstrual dysfunction and infertility. lease. When estradiol was given at an optimal concentration The oviduct is a muscular tube lined internally with a cil- for an appropriate time, an LH surge was generated, in spite iated, secretory, columnar epithelium with a deeper stromal of maintaining steady and unchanging pulses of GnRH. tissue. Fertilization occurs in the oviduct, after which the The mechanism that transforms estradiol from a nega- zygote enters the uterus; therefore, the oviduct is involved tive to a positive regulator of LH release is unknown. One in transport of the gametes and provides a site for fertiliza- factor involves an increase in the number of GnRH recep- tion and early embryonic development. Estrogens maintain tors on the gonadotrophs, increasing pituitary responsive- the ciliated nature of the epithelium, and ovariectomy ness to GnRH. Another factor is the conversion of a stor- causes a loss of the cilia. Estrogens also increase the motil- age pool of LH (perhaps within a subpopulation of ity of the oviducts. Exogenous estrogen given around the gonadotrophs) to a readily releasable pool. Estrogen may time of fertilization can cause premature expulsion of the also increase GnRH release, serving as a fine-tuning or fail- fertilized egg, whereas extremely high doses of estrogen safe mechanism. A small but distinct rise in progesterone can cause “tube locking,” the entrapment of the fertilized
CHAPTER 38 The Female Reproductive System 679 egg and an ectopic pregnancy. Progesterone opposes these receptors. Under the combined action of progesterone and actions of estrogen. estrogen, the endometrial glands become coiled, store The endometrium (also called uterine mucosa) is com- glycogen, and secrete large amounts of carbohydrate-rich posed of a superficial layer of epithelial cells and an under- mucus. The stroma increases in vascularity and becomes lying stromal layer. The epithelial layer contains glands edematous, and the spiral arteries become tortuous (see that penetrate the stromal layer. The glands are lined by a Fig. 38.7). Peak secretory activity, edema formation, and secretory columnar epithelium. overall thickness of the endometrium are reached on days 6 The endometrial cycle consists of four phases. The pro- to 8 after ovulation in preparation for implantation of the liferative phase coincides with the midfollicular to late fol- blastocyst. Progesterone antagonizes the effect of estrogen licular phase of the menstrual cycle. Under the influence of on the myometrium and reduces spontaneous myometrial the rising plasma estradiol concentration, the stromal and contractions. epithelial layers of the uterine endometrium undergo hy- The ischemic phase, generally not depicted graphically, perplasia and hypertrophy and increase in size and thick- occurs immediately before the menses and is initiated by ness. The endometrial glands elongate and are lined with the declining levels of progesterone and estradiol caused by columnar epithelium. The endometrium becomes vascular- regression of the corpus luteum. Necrotic changes and ized, and more spiral arteries, a rich blood supply to this re- abundant apoptosis occur in the secretory epithelium as it gion, develop. Estradiol also induces the formation of collapses. The arteries constrict, reducing the blood supply progesterone receptors and increases myometrial excitabil- to the superficial endometrium. Leukocytes and ity and contractility. macrophages invade the stroma and begin to phagocytose The secretory phase begins on the day of ovulation and the ischemic tissue. Leukocytes persist in large numbers coincides with the early to midluteal phase of the menstrual throughout menstruation, providing resistance against in- cycle. The endometrium contains numerous progesterone fection to the denuded endometrial surface. Ovulation Proliferative phase Secretory phase Days 0481216202428 32 Plasma level Progesterone Estradiol Degrees (F) 99 Basal body temperature 98 97 100 Vaginal cornification and 50 pyknotic index 0 3 Cervical mucus 2 ferning 1 0 Glycogen vacuoles 4 Gland Endometrium Cyclic changes in the uterus, mm 3 FIGURE 38.7 cervix, vagina, and body tempera- 2 Artery ture in relationship to estradiol, progesterone, and ovulation during the menstrual cycle. (Modified 1 from Odell WD. The reproductive system in women. 0 In: Degroot LJ, et al, eds. Endocrinology. Vol 3. New Menses Menses York: Grune & Stratton, 1979.)
680 PART X REPRODUCTIVE PHYSIOLOGY Desquamation and sloughing of the entire functional The most important progestin is progesterone. It is se- layer of the endometrium occurs during the menstrual creted in significant amounts during the luteal phase of the phase (menses). The mechanism leading to necrosis is only menstrual cycle. During pregnancy, the corpus luteum se- partly understood. The reduction in steroids destabilizes cretes progesterone throughout the first trimester, and the lysosomal membranes in endometrial cells, resulting in the placenta continues progesterone production until parturi- liberation of proteolytic enzymes and increased production tion. Small amounts of 17-hydroxyprogesterone are se- of vasoconstrictor prostaglandins (e.g., PGF 2 ). The creted along with progesterone. Progesterone binds prostaglandins induce vasospasm of the spiral arteries, and equally to albumin and to a plasma protein called corticos- the proteolytic enzymes digest the tissue. Eventually, the teroid-binding protein (transcortin). Progesterone is me- blood vessels rupture and blood is released, together with tabolized in the liver to pregnanediol and, subsequently, cellular debris. The endometrial tissue is expelled through excreted in the urine as a glucuronide conjugate. the cervix and vagina, with blood from the ruptured arter- Circulating androgens in the female originate from the ies. The menstrual flow lasts 4 to 5 days and averages 30 to ovaries and adrenals and from peripheral conversion. An- 50 mL in volume. It does not clot because of the presence drostenedione and dehydroepiandrosterone (DHEA) orig- of fibrinolysin, but the spiral arteries constrict, resulting in inate from the adrenal cortex (see Chapter 34), and ovarian a reduction in bleeding. theca and stroma cells. Peripheral conversion from an- Changes in the properties of the cervical mucus promote drostenedione provides an additional source of testos- the survival and transport of sperm and, thus, can be im- terone. Testosterone can also be converted in peripheral portant for normal fertility. The cervical mucus undergoes tissues to dihydrotestosterone (DHT) by 5-reductase. cyclic changes in composition and volume. During the fol- However, the primary biologically active androgen in licular phase, estrogen increases the quantity, alkalinity, women is testosterone. Androgens bind primarily to SHBG viscosity, and elasticity of the mucus. The cervical muscles and bind to albumin by about half as much. Androgens are relax, and the epithelium becomes secretory in response to also metabolized to water-soluble forms by oxidation, sul- estrogen. By the time of ovulation, elasticity of the mucus fation, or glucuronidation and excreted in the urine. or spinnbarkeit is greatest. Sperm can readily pass through the estrogen-dominated mucus. With progesterone rising either after ovulation, during pregnancy, or with low-dose progestogen administration during the cycle, the quantity PUBERTY and elasticity of the mucus decline; it becomes thicker (low During the prepubertal period, the hypothalamic-pituitary- spinnbarkeit) and does not form a ferning pattern when ovarian axis becomes activated—an event known as go- dried on a microscope slide. With these conditions, the nadarche—and gonadotropins increase in the circulation mucus provides better protection against infections and and stimulate ovarian estrogen secretion. The increase in go- sperm do not easily pass through. nadotropins is a direct result of increased secretion of GnRH. The vaginal epithelium proliferates under the influence Factors stimulating the secretion of GnRH include gluta- of estrogen. Basophilic cells predominate early in the fol- mate, norepinephrine, and neuropeptide Y emanating from licular phase. The columnar epithelium becomes cornified synaptic inputs to GnRH-producing neurons. In addition, a (keratinized) under the influence of estrogen and reaches decrease in -aminobutyric acid (GABA), an inhibitor of its peak in the periovulatory period. During the postovula- GnRH secretion, may occur at this time. It is also known that tory period, progesterone induces the formation of thick the response of the pituitary to GnRH increases at the time mucus, the epithelium becomes infiltrated with leukocytes, of puberty. Collectively, numerous factors control the rise in and cornification decreases (see Fig. 38.7). ovarian estradiol secretion that triggers the development of physical characteristics of sexual maturation. Estradiol induces the development of secondary sex ESTROGEN, PROGESTIN, AND ANDROGEN: characteristics, including the breasts and reproductive TRANSPORT AND METABOLISM tract, and increased fat in the hips. Estrogens also regulate the growth spurt at puberty, induce closure of the epi- The principal sex steroids in the female are estrogen, prog- physes, have a positive effect in maintaining bone forma- estin, and androgen. Three estrogens are present in signif- tion, and can antagonize the degrading actions of icant quantities—estradiol, estrone, and estriol. Estradiol is parathyroid hormone on bone. Therefore, estrogens have the most abundant and is 12 and 80 times more potent than a positive effect on bone maintenance, and later in life, ex- estrone and estriol, respectively. Much of estrone is derived ogenous estrogens oppose the osteoporosis often associ- from peripheral conversion of either androstenedione or ated with menopause. estradiol (see Fig 37.9). During pregnancy, large quantities As mentioned earlier, the first menstruation is called of estriol are produced from dehydroepiandrosterone sul- menarche and occurs around age 12. The first ovulation fate after 16-hydroxylation by the fetoplacental unit (see does not occur until 6 to 9 months after menarche be- Chapter 39). Most estrogens are bound to either albumin cause the hypothalamic-pituitary axis is not fully respon- (60%) with a low affinity or to sex hormone-binding sive to the feedback effects of estrogen. During the pu- globulin (SHBG) (40%) with high affinity. Estrogens are bertal period, the development of breasts, under the metabolized in the liver through oxidation or conversion to influence of estrogen, is known as thelarche. At this time, glucuronides or sulfates. The metabolites are then ex- the appearance of axillary and pubic hair occurs, a devel- creted in the urine. opment known as pubarche, controlled by adrenal an-
CHAPTER 38 The Female Reproductive System 681 drogens. The adrenals begin to produce significant through 1,25-dihydroxyvitamin D 3 . amounts of androgens (dehydroepiandrosterone and an- Menopausal symptoms are often treated with hormone drostenedione) 4 to 5 years prior to menarche, and this replacement therapy (HRT), which includes estrogens and event is called adrenarche. The adrenal androgens are re- progestins. HRT is not an uncommon treatment to improve sponsible in part for pubarche. Adrenarche is independ- the quality of life. In some patients, treatment with estro- ent of gonadarche. gen can cause adverse effects, such as vaginal bleeding, nausea, and headache. Estrogen therapy is contraindicated in cases of existing reproductive tract carcinomas or hyper- tension and other cardiovascular disease. The prevailing MENOPAUSE opinion is that the benefit of treating postmenopausal Menopause is the time after which the final menses occurs. women with estrogens for limited periods outweighs any It is associated with the cessation of ovarian function and risk of developing breast or endometrial carcinomas. reproductive cycles. Generally, menstrual cycles and bleed- ing become irregular, and the cycles become shorter from the lack of follicular development (shortened follicular INFERTILITY phases). The ovaries atrophy and are characterized by the presence of few, if any, healthy follicles. One of five women in the United States will be affected by The decline in ovarian function is associated with a de- infertility. A thorough understanding of female endocrinol- crease in estrogen secretion and a concomitant increase in ogy, anatomy, and physiology are critical to gaining in- LH and FSH, which is characteristic of menopausal women sights into solving this major health problem. Infertility can (Table 38.3). It is used as a diagnostic tool. The elevated be caused by several factors. Environmental factors, disor- LH stimulates ovarian stroma cells to continue producing ders of the central nervous system, hypothalamic disease, androstenedione. Estrone, derived almost entirely from the pituitary disorders, and ovarian abnormalities can interfere peripheral conversion of adrenal and ovarian androstene- with follicular development and/or ovulation. If a normal dione, becomes the dominant estrogen (see Fig. 37.9). Be- ovulation occurs, structural, pathological, and/or endocrine cause the ratio of estrogens to androgens decreases, some problems associated with the oviduct and/or uterus can pre- women exhibit hirsutism, which results from androgen ex- vent fertilization, impede the transport or implantation of cess. The lack of estrogen causes atrophic changes in the the embryo, and, ultimately, interfere with the establish- breasts and reproductive tract, accompanied by vaginal ment or maintenance of pregnancy. dryness, which often causes pain and irritation. Similar changes in the urinary tract may give rise to urinary distur- Amenorrhea Is Caused by Endocrine Disruption bances. The epidermal layer of the skin becomes thinner and less elastic. Menstrual cycle disorders can be divided into two cate- Hot flashes, as a result of the loss of vasomotor tone, os- gories: amenorrhea, the absence of menstruation, and teoporosis, and an increased risk of cardiovascular disease are oligomenorrhea, infrequent or irregular menstruation. Pri- not uncommon. Hot flashes are associated with episodic in- mary amenorrhea is a condition in which menstruation has creases in upper body and skin temperature, peripheral va- never occurred. An example is Turner’s syndrome, also sodilation, and sweating. They occur concurrently with LH called gonadal dysgenesis, a congenital abnormality caused pulses but are not caused by the gonadotropins because they by a nondisjunction of one of the X chromosomes, resulting are evident in hypophysectomized women. Hot flashes, con- in a 45 X0 chromosomal karyotype. Because the two X chro- sisting of episodes of sudden warmth and sweating, reflect mosomes are necessary for normal ovarian development, temporary disturbances in the hypothalamic thermoregula- women with this condition have rudimentary gonads and do tory centers, which are somehow linked to the GnRH pulse not have a normal puberty. Because of ovarian steroid defi- generator. ciency (lack of estrogen), secondary sex characteristics re- Osteoporosis increases the risk of hip fractures and es- main prepubertal, and plasma LH and FSH are elevated. trogen replacement therapy reduces the risk. Estrogen an- Other abnormalities include short stature, a webbed neck, a tagonizes the effects of PTH on bone but enhances its ef- coarctation of the aorta, and renal disorders. fect on kidney, i.e., it stimulates retention of calcium. Another congenital form of primary amenorrhea is hy- Estrogen also promotes the intestinal absorption of calcium pogonadotropism with anosmia, similar to Kallmann’s syn- TABLE 38.3 Serum Gonadotropin and Steroid Levels in Premenopausal and Postmenopausal Women Menstrual Cycle Hormone Units Follicular Preovulatory Luteal Postmenopausal LH mIU/mL 2.5–15 15–100 2.5–15 20–100 FSH mIU/mL 2–10 10–30 2–6 20–140 Estradiol pg/mL 70–200 200–500 75–300 Progesterone ng/mL 0.5 1.5 4–20 0.5
682 PART X REPRODUCTIVE PHYSIOLOGY drome in males (see Chapter 37). Patients do not progress ies reveal that exogenous TRH increases the secretion of through normal puberty and have low and nonpulsatile LH PRL. The mechanism by which elevated PRL levels sup- and FSH levels. However, they can have normal stature, press ovulation is not entirely clear. It has been postulated female karyotype, and anosmia. The disorder is caused by a that PRL may inhibit GnRH release, reduce LH secretion in failure of olfactory lobe development and GnRH defi- response to GnRH stimulation, and act directly at the level ciency. Primary amenorrhea can also be caused by a con- of the ovary by inhibiting the action of LH and FSH on fol- genital malformation of reproductive tract structures origi- licle development. nating from the müllerian duct, including the absence or Oligomenorrhea can be caused by excessive exercise obstruction of the uterus, cervix, or upper vagina. and by nutritional, psychological, and social factors. Secondary amenorrhea is the cessation of menstrua- Anorexia nervosa, a severe behavioral disorder associated tion for longer than 6 months. Pregnancy, lactation, and with the lack of food intake, is characterized by extreme menopause are common physiological causes of second- malnutrition and endocrine changes secondary to psycho- ary amenorrhea. Other causes are premature ovarian fail- logical and nutritional disturbances. About 30% of patients ure, polycystic ovarian syndrome, hyperprolactinemia, develop amenorrhea that is not alleviated by weight gain. and hypopituitarism. Strenuous exercise, especially by competitive athletes and Premature ovarian failure is characterized by amenor- dancers, frequently causes menstrual irregularities. Two rhea, low estrogen levels, and high gonadotropin (LH and main factors are thought to be responsible: a low level of FSH) levels before age 40. The symptoms are similar to body fat, and the effect of stress itself through endorphins those of menopause, including hot flashes and an in- that are known to inhibit the secretion of LH. Other types creased risk of osteoporosis. The etiology is variable, in- of stress, such as relocation, college examinations, general cluding chromosomal abnormalities; lesions resulting illness, and job-related pressures, have been known to in- from irradiation, chemotherapy, or viral infections; and duce some forms of oligomenorrhea. autoimmune conditions. Polycystic ovarian syndrome, also called Stein-Leven- thal syndrome, is a heterogeneous group of disorders char- Female Infertility Is Caused by acterized by amenorrhea or anovulatory bleeding, an ele- Endocrine Malfunction and Abnormalities vated LH/FSH ratio, high androgen levels, hirsutism, and in the Reproductive Tract obesity. Although the etiology is unknown, the syndrome The diagnosis and treatment of amenorrhea present a chal- may be initiated by excessive adrenal androgen production, lenging problem. The amenorrhea must first be classified as during puberty or following stress, that deranges the hypo- primary or secondary, and menopause, pregnancy, and lac- thalamic-pituitary axis secretion of LH. Androgens are con- tation must be excluded. The next step is to determine verted peripherally to estrogens and stimulate LH release. whether the disorder originates in one of the following ar- Excess LH, in turn, increases ovarian stromal and thecal an- eas: the hypothalamus and central nervous system, the an- drogen production, resulting in impaired follicular matura- terior pituitary, the ovary, and/or the reproductive tract. tion. The LH-stimulated ovaries are enlarged and contain Several treatments can alleviate infertility problems; for many small follicles and hyperplastic and luteinized theca example, some success has been achieved in hypothalamic cells (the site of LH receptors). The elevated plasma an- disease with pulsatile administration of GnRH. When hy- drogen levels cause hirsutism, increased activity of seba- pogonadotropism is the cause of infertility, sequential ad- ceous glands, and clitoral hypertrophy, which are signs of ministration of FSH and hCG is a common treatment for virilization in females. inducing ovulation, although the risk of ovarian hyperstim- Hyperprolactinemia is also a cause of secondary amen- ulation and multiple ovulations is increased. Hyperpro- orrhea. Galactorrhea, a persistent milk-like discharge from lactinemia can be treated surgically by removing the pitu- the nipple in nonlactating individuals, is a frequent symp- itary adenoma containing numerous lactotrophs tom and is due to the excess prolactin (PRL). The etiology (prolactin-secreting cells). It can also be treated pharmaco- of hyperprolactinemia is variable. Pituitary prolactinomas logically with bromocriptine, a dopaminergic agonist that account for about 50% of cases. Other causes are hypo- reduces the size and number of the lactotrophs and PRL se- thalamic disorders, trauma to the pituitary stalk, and psy- cretion. Treatment with clomiphene, an antiestrogen that chotropic medications, all of which are associated with a binds to and blocks estrogen receptors, can induce ovula- reduction in dopamine release, resulting in an increased tion in women with endogenous estrogens in the normal PRL secretion. Hypothyroidism, chronic renal failure, and range. Clomiphene reduces the negative feedback effects hepatic cirrhosis are additional causes of hyperprolactine- of estrogen and thus increases endogenous FSH and LH se- mia. In some forms of hypothyroidism, increased hypo- cretion. When reproductive tract lesions are the cause of thalamic thyrotropin-releasing hormone (TRH) is thought infertility, corrective surgery or in vitro fertilization is the to contribute to excess PRL secretion, as experimental stud- treatment of choice.
CHAPTER 38 The Female Reproductive System 683 REVIEW QUESTIONS DIRECTIONS: Each of the numbered (E) Increased secretion of FSH (A) The oviduct and has entered the items or incomplete statements in this 5. The theca interna cells of the graafian second meiotic division section is followed by answers or by follicle are distinguished by (B) The uterus and has completed the completions of the statement. Select the (A) Their capacity to produce first meiotic division ONE lettered answer or completion that is androgens from cholesterol (C) Metaphase of mitosis BEST in each case. (B) The lack of cholesterol side-chain (D) The graafian follicle, which then cleavage enzyme enters the oviduct 1. Estradiol synthesis in the graafian (C) Aromatization of testosterone to (E) The uterus, extruding the second follicle involves estradiol polar body and implanting (A) Activation of LH-stimulated (D) The lack of a blood supply 10.The enzyme, 5-reductase is granulosa production of androgen (E) The production of inhibin responsible for (B) Stimulation of aromatase in the 6. Disruption of the hypothalamic- (A) Conversion of cholesterol to granulosa cell by FSH pituitary portal system will lead to pregnenolone and enhancing (C) Decreased secretion of (A) High circulating levels of PRL, low steroidogenesis progesterone from the corpus luteum, levels of LH and FSH, and ovarian (B) Conversion of testosterone to resulting in increased LH atrophy dihydrotestosterone (D) Inhibition of the LH surge during (B) Enhanced follicular development as (C) Aromatization of testosterone to the preovulatory period a result of increased circulating levels estradiol (E) Synergy between FSH and of PRL (D) Increasing the synthesis of LH progesterone (C) Ovulation, followed by increased (E) Female secondary sex 2. Granulosa cells do not produce circulating levels of progesterone characteristics estradiol from cholesterol because they (D) A reduction of ovarian inhibin do not have an active levels, followed by increased SUGGESTED READING (A) 17-Hydroxylase circulating FSH Carr BR, Blackwell RE. Textbook of Re- (B) Aromatase (E) Excessive androgen production by productive Medicine. Norwalk, CT: (C) 5-Reductase the ovaries Appleton & Lange, 1998. (D) Sulfatase 7. Inhibin is an ovarian hormone that Griffin JE, Ojeda, SR. Textbook of En- (E) Steroidogenic acute regulatory (A) Inhibits the secretion of LH and docrine Physiology. 4th Ed. New York: protein PRL Oxford University Press, 2000. 3. A clinical sign indicating the onset of (B) Is produced by granulosa cells and Johnson MH, Everitt BJ. Essential Repro- the menopause is inhibits the secretion of FSH duction. Oxford: Blackwell Science, (A) The onset of menses near age 50 (C) Only has local ovarian effects and 2000. (B) An increase in plasma FSH levels no effect on the secretion of FSH Kettyle WM, Arky RA. Endocrine Patho- (C) An excessive presence of corpora (D) Has two forms, A and B, with the physiology. Philadelphia: Lippincott- lutea same subunits but distinct subunits Raven, 1998. (D) An increased number of cornified (E) Binds activin and increases FSH Van Voorhis BJ. Follicular development. cells in the vagina secretion In: Knobil E, Neill JD, eds. The En- (E) Regular menstrual cycles 8. Spinnbarkeit formation is induced by cyclopedia of Reproduction. New 4. Increased progesterone during the (A) Secretory endometrium York: Academic Press, postovulatory period is associated with (B) Progesterone action on the uterus 1999;376–389. (A) Proliferation of the uterine (C) Androgen production from the Van Voorhis BJ. Follicular steroidogenesis. endometrium ovaries In: Knobil E, Neill JD, eds. The Ency- (B) Enhanced development of graafian (D) Estrogen action on the vaginal clopedia of Reproduction. New York: follicles secretions Academic Press, 1999;389–395. (C) Luteal regression (E) Prolactin secretion Yen SSC, Jaffe RB, Barbieri RL. Reproduc- (D) An increase in basal body 9. Successful fertilization is most likely to tive Endocrinology. 4th Ed. Philadel- temperature by 0.5 to 1.0C occur when the oocyte is in phia: WB Saunders, 1999.
Fertilization, Pregnancy, CHAPTER 39 39 and Fetal Development Paul F. Terranova, Ph.D. CHAPTER OUTLINE ■ OVUM AND SPERM TRANSPORT, FERTILIZATION, ■ FETAL DEVELOPMENT AND PARTURITION AND IMPLANTATION ■ POSTPARTUM AND PREPUBERTAL PERIODS ■ PREGNANCY KEY CONCEPTS 1. Fertilization of the ovum occurs in the oviduct. Proges- 7. The termination of pregnancy is initiated by strong uterine terone and estrogen released from the ovary prepare the contractions induced by oxytocin. Estrogens, relaxin, and oviduct and uterus for receiving the developing embryo. prostaglandins are involved in softening and dilating the 2. The blastocyst enters the uterus, leaves the surrounding uterine cervix so that the fetus may exit. zona pellucida, and implants into the uterine wall on day 7 8. Lactogenesis is milk production, which requires prolactin of gestation. (PRL), insulin, and glucocorticoids. Galactopoiesis is the 3. Human chorionic gonadotropin (hCG), produced by tro- maintenance of an established lactation and requires PRL phoblast cells of the developing embryo, activates the cor- and numerous other hormones. Milk ejection is the pus luteum to continue producing progesterone and estra- process by which stored milk is released; “milk letdown” is diol beyond its normal life span to maintain pregnancy. regulated by oxytocin, which contracts the myoepithelial 4. Shortly after the embryo implants into the uterine wall, a pla- cells surrounding the alveoli and ejects milk into the ducts. centa develops from embryonic and maternal cells and be- 9. Lactation is associated with the suppression of menstrual comes the major steroid-secreting organ during pregnancy. cycles and anovulation due to the inhibitory actions of 5. Major hormones produced by the fetoplacental unit are PRL on GnRH release and the hypothalamic-pituitary- progesterone, estradiol, estriol, hCG, and human placental ovarian axis. lactogen. Elevated estriol levels indicate fetal well-being, 10. The hypothalamic-pituitary axis becomes activated during whereas low levels might indicate fetal stress. Human pla- the late prepubertal period, resulting in increased fre- cental lactogen has a role in preparing the breasts for milk quency and amplitude of GnRH pulses, increased LH and production. FSH secretion, and increased steroid output by the gonads. 6. The pregnant woman becomes insulin-resistant during the 11. Most disorders of sexual development are caused by chro- latter half of pregnancy in order to conserve maternal glu- mosomal or hormonal alterations, which may result in in- cose consumption and make glucose available for the de- fertility, sexual dysfunction, or various degrees of intersex- veloping fetus. uality (hermaphroditism). mother is considered pregnant at the moment of fertil- by gonadal steroids and is, therefore, receptive to accepting Aization—the successful union of a sperm and an egg. the blastocyst. At the time of implantation, the trophoblast The life span of the sperm and an ovum is less than 2 days, cells of the early embryonic placenta begin to produce a so their rapid transport to the oviduct is required for fertil- hormone, human chorionic gonadotropin (hCG), which ization to occur. Immediately after fertilization, the zygote signals the ovary to continue to produce progesterone, the or fertilized egg begins to divide and a new life begins. The major hormone required for the maintenance of pregnancy. cell division produces a morula, a solid ball of cells, which As a signal from the embryo to the mother to extend the life then forms a blastocyst. Because the early embryo contains of the corpus luteum (and progesterone production), hCG a limited energy supply, the embryo enters the uterus prevents the onset of the next menstruation and ovulatory within a short time and attaches to the uterine en- cycle. The placenta, an organ produced by the mother and dometrium, a process that initiates the implantation phase. fetus, exists only during pregnancy; it regulates the supply Implantation occurs only in a uterus that has been primed of oxygen and the removal of wastes and serves as an en- 684
CHAPTER 39 Fertilization, Pregnancy, and Fetal Development 685 ergy supply for the fetus. It also produces protein and favorable environment, enabling sperm survival for sev- steroid hormones, which duplicate, in part, the functions of eral hours. Under estrogen dominance, mucin molecules the pituitary gland and gonads. Some of the fetal endocrine in the cervical mucus become oriented in parallel and fa- glands have important functions before birth, including cilitate sperm migration. Sperm stored in the cervical sexual differentiation. crypts constitute a pool for slow release into the uterus. Parturition, the expulsion of the fully formed fetus from Sperm survival in the uterine lumen is short because of the uterus, is the final stage of gestation. The onset of par- phagocytosis by leukocytes. The uterotubal junction also turition is triggered by signals from both the fetus and the presents an anatomic barrier that limits the passage of mother and involves biochemical and mechanical changes sperm into the oviducts. Abnormal or dead spermatozoa in the uterine myometrium and cervix. After delivery, the may be prevented from entry to the oviduct. Of the mil- mother’s mammary glands must be fully developed and se- lions of sperm deposited in the vagina, only 50 to 100, usu- crete milk in order to provide nutrition to the newborn ally spaced in time, will reach the oviduct. Major losses of baby. Milk is produced and secreted in response to suck- sperm occur in the vagina, uterus, and at the uterotubal ling. The act of suckling, through neurohormonal signals, junction. Spermatozoa that survive can reach the ampulla prevents new ovulatory cycles. Suckling acts as a natural within 5 to 10 minutes after coitus. The motility of sperm contraceptive until the baby stops suckling. Thereafter, the largely accounts for this rapid transit. However, transport is mother regains metabolic balance, which has been reduced assisted by muscular contractions of the vagina, cervix, and by the nutritional demands of pregnancy and lactation, and uterus; ciliary movement; peristaltic activity; and fluid flow ovulatory cycles return. Sexual maturity of the offspring is in the oviducts. Semen samples with low sperm motility can attained during puberty, at approximately 12 years of age. be associated with male infertility. The onset of puberty requires changes in the sensitivity, ac- There is no evidence for chemotactic interactions be- tivity, and function of several endocrine organs, including tween the egg and sperm, although evidence exists for spe- those of the hypothalamic-pituitary-gonadal axis. cific ligand-receptor binding between egg and sperm. Sperm arrive in the vicinity of the egg at random, and some exit into the abdominal cavity. Although sperm remain OVUM AND SPERM TRANSPORT, motile for up to 4 days, their fertilizing capacity is limited FERTILIZATION, AND IMPLANTATION to 1 to 2 days in the female reproductive tract. Sperm can be cryopreserved for years, if agents such as glycerol are Sperm deposited in the female reproductive tract swim up used to prevent ice crystal formation during freezing. the uterus and enter the oviduct where fertilization of the Freshly ejaculated sperm cannot immediately penetrate ovum occurs. The developing embryo transits the oviduct, an egg. During maturation in the epididymis, the sperm ac- enters the uterus, and implants into the endometrium. quire surface glycoproteins that act as stabilizing factors but also prevent sperm-egg interactions. To bind to and penetrate the zona pellucida, the sperm must undergo ca- The Egg and Sperm Enter the Oviduct pacitation, an irreversible process that involves an increase A meiotically active egg is released from the ovary in a in sperm motility, the removal of surface proteins, a loss of cyclical manner in response to the LH surge. For a suc- lipids, and merging of the acrosomal and plasma mem- cessful fertilization, fresh sperm must be present at the branes of the sperm head. The uniting of these sperm mem- time the ovum enters the oviduct. To increase the proba- branes and change in acrosomal structure is called the acro- bility that the sperm and egg will meet at an optimal time, some reaction. The reaction occurs when the sperm cell the female reproductive tract facilitates sperm transport binds to the zona pellucida of the egg. It involves a redis- during the follicular phase of the menstrual cycle, prior to tribution of membrane constituents, increased membrane ovulation (see Chapter 38). However, during the luteal fluidity, and a rise in calcium permeability. Capacitation phase, after ovulation, sperm survival and access to the takes place along the female genital tract and lasts 1 hour to oviduct are decreased. If fertilization does not occur, the several hours. Sperm can be capacitated in a chemically de- egg and sperm begin to exhibit signs of degeneration fined medium, a fact that has enabled in vitro fertilization within 24 hours after release. (see Clinical Focus Box 39.1). In vitro fertilization may be The volume of semen (ejaculatory fluids and sperm) in used in female infertility as well. fertile men is 2 to 6 mL, and it contains some 20 to 30 mil- Because the ovary is not entirely engulfed by the lion sperm per milliliter, which are deposited in the oviduct, an active “pickup” of the released ovum is required. vagina. The liquid component of the semen, called semi- The ovum is grasped by the fimbria, ciliated finger-like nal plasma, coagulates after ejaculation but liquefies projects of the oviducts. The grasping of the egg is facili- within 20 to 30 minutes from the action of proteolytic en- tated by ciliary movement and muscle contractions, under zymes secreted by the prostate gland. The coagulum the influence of estrogen secreted during the periovulatory forms a temporary reservoir of sperm, minimizing the ex- period. Because the oviduct opens into the peritoneal cav- pulsion of semen from the vagina. During intercourse, ity, eggs that are not picked up by the oviducts can enter some sperm cells are immediately propelled into the cer- the abdominal cavity. An ectopic pregnancy may result if vical canal. Those remaining in the vagina do not survive an abdominal ovum is fertilized. Egg transport from the long because of the acidic environment (pH 5.7), al- fimbria to the ampulla, the swollen end of the oviduct, is though some protection is provided by the alkalinity of accomplished by coordinated ciliary activity and depends the seminal plasma. The cervical canal constitutes a more on the presence of granulosa cells surrounding the egg.
686 PART X REPRODUCTIVE PHYSIOLOGY CLINICAL FOCUS BOX 39.1 In Vitro Fertilization transvaginal approach. Oocyte maturity is judged from the Candidates for in vitro fertilization (IVF) are women with dis- morphology of the cumulus (granulosa) cells and the pres- ease of the oviducts, unexplained infertility, or endometrio- ence of the germinal vesicle and first polar body. The ma- sis (occurrence of endometrial tissue outside the endome- ture oocytes are then placed in culture media. trial cavity, a condition that reduces fertility), and those The donor’s sperm are prepared by washing, centrifug- whose male partners are infertile (e.g., low sperm count). ing, and collecting those that are most motile. About Follicular development is induced with one or a combina- 100,000 spermatozoa are added for each oocyte. After 24 tion of GnRH analogs, clomiphene, recombinant FSH, and hours, the eggs are examined for the presence of two menopausal gonadotropins (a combination of LH and FSH). pronuclei (male and female). Embryos are grown to the Follicular growth is monitored by measuring serum estra- four- to eight-cell stage, about 60 to 70 hours after their re- diol concentration and by ultrasound imaging of the devel- trieval from the follicles. Approximately three embryos are oping follicles. When the leading follicle is 16 to 17 mm in di- often deposited in the uterine lumen in order to increase ameter and/or the estradiol level is greater than 300 pg/mL, the chance for a successful pregnancy. To ensure a recep- hCG is injected to mimic an LH surge and induce final follic- tive endometrium, daily progesterone administrations be- ular maturation, including maturation of the oocyte. Ap- gin on the day of retrieval. A successful pregnancy rate of proximately, 34 to 36 hours later, oocytes are retrieved from 15 to 25% has been reported by many groups, which com- the larger follicles by aspiration using laparoscopy or a pares favorably with that of natural human pregnancy. The fertilizable life of the human ovum is about 24 head becomes anchored to the membrane surface of the hours, and fertilization occurs usually by 2 days after ovu- egg, and microvilli protruding from the oolemma (plasma lation. The fertilized ovum remains in the oviduct for 2 to membrane of the egg) extend and clasp the sperm. The 3 days, develops into a solid ball of cells called a morula, oolemma engulfs the sperm, and eventually, the whole and by day 3 or 4 enters the uterus. While in the uterus, the head and then the tail are incorporated into the ooplasm. morula further develops into a blastocyst, the zona pellu- Shortly after the sperm enters the egg, cortical granules, cida is shed, and the blastocyst implants into the wall of the which are lysosome-like organelles located underneath the uterus on day 7. The movement of the developing embryo oolemma, are released. The cortical granules fuse with the from the oviduct to the uterus is largely regulated by prog- oolemma. Fusion starts at the point of sperm attachment and esterone and estrogen. propagates over the entire egg surface. The content of the granules is released into the perivitelline space and diffuses into the zona pellucida, inducing the zona reaction, which Fertilization Is Accompanied by a is characterized by sperm receptor inactivation and a hard- Multitude of Cellular Events ening of the zona. Consequently, once the first spermato- The initial stage of fertilization is the attachment of the zoon triggers the zona reaction, other sperm cannot pene- sperm head to the zona pellucida of the egg. A successful trate the zona, and therefore, polyspermia is prevented. fertilization restores the full complement of 46 chromo- An increase in intracellular calcium initiated by sperm in- somes and subsequently initiates the development of an corporation into the egg triggers the next event, which is embryo. Fertilization involves several steps. Recognition of the activation of the egg for completion of the second mei- the egg by the sperm occurs first. The next step is the reg- otic division. The chromosomes of the egg separate and half ulation of sperm entry into the egg. A series of key molec- of the chromatin is extruded with the small second polar ular events, collectively called polyspermy block, prevent body. The remaining haploid nucleus with its 23 chromo- multiple sperm from entering the egg. Coupled with fertil- somes is transformed into a female pronucleus. Soon after ization is the completion of the second meiotic division of being incorporated into the ooplasm, the nuclear envelope the egg, which extrudes the second polar body. At this of the sperm disintegrates; the male pronucleus is formed point, the male and female pronuclei unite, followed by ini- and increases 4 to 5 times in size. The two pronuclei, which tiation of the first mitotic cell division (Fig. 39.1). are visible 2 to 3 hours after the entry of the sperm into the The zona pellucida contains specific glycoproteins that egg, are moved to the center of the cell by contractions of serve as sperm receptors. They selectively prevent the fu- microtubules and microfilaments. Replication of the haploid sion of inappropriate sperm cells (e.g., from a different chromosomes begins in both pronuclei. Pores are formed in species) with the egg. Contact between the sperm and egg their nuclear membranes, and the pronuclei fuse. The zy- triggers the acrosome reaction, which is required for sperm gote (fertilized egg) then enters the first mitotic division penetration. Sperm proteolytic enzymes are released that (cleavage) producing two unequal sized cells called blas- dissolve the matrices of the cumulus (granulosa) cells sur- tomeres within 24 to 36 hours after fertilization. Develop- rounding the egg, enabling the sperm to move through this ment proceeds with four-cell and eight-cell embryos and a densely packed group of cells. The sperm penetrates the morula, still in the oviduct, forming at approximately 48, 72, zona pellucida, aided by proteolytic enzymes and the and 96 hours, respectively. The morula enters the uterine propulsive force of the tail; this process may take up to 30 cavity at around 4 days after fertilization, and subsequently, minutes. After entering the perivitelline space, the sperm a blastocyst develops at approximately 6 days after fertiliza-
CHAPTER 39 Fertilization, Pregnancy, and Fetal Development 687 First polar body Sperm Metaphase spindle A Egg H Spindle of Granulosa first mitotic division (cumulus cells) (cleavage) Zona pellucida B G Perivitelline space Ooplasm C F The FIGURE 39.1 Oolemma Male pronucleus process of Female pronucleus fertilization. A, A sperm cell approaches an egg. B, Con- tact between the sperm and Second polar body the zona pellucida. C, The entry of the sperm and con- tact with the oolemma. D, The resumption of the second meiotic division. E, The com- DE pletion of meiosis. F, The for- mation of male and female pronuclei. G, The migration of the pronuclei to center of cell. H, The zygote is ready for the first mitotic division. tion. The blastocyst implants into the uterine wall on ap- for embryo transport, protection against mechanical dam- proximately day 7 after fertilization. age or adhesion to the oviduct wall, and prevention of im- munological rejection by the mother. At the 20- to 30-cell stage, a fluid-filled cavity (blasto- coele) appears and enlarges until the embryo becomes a Implantation Requires the Interaction of the Uterine Endometrium and the Embryo hollow sphere, the blastocyst. The cells of the blastocyst have undergone significant differentiation. A single outer Cell division of the fertilized egg occurs without growth. layer of the blastocyst consists of extraembryonic ectoder- The cells of the early embryo become progressively mal cells called the trophoblast, which will participate in smaller, reaching the dimension of somatic cells after sev- implantation, form the embryonic contribution to the pla- eral cell divisions. The embryonic cells continue to cleave centa and embryonic membranes, produce hCG, and pro- as the embryo moves from the ampulla toward the uterus vide nutrition to the embryo. A cluster of smaller centrally (Fig. 39.2). Until implantation, the embryo is enclosed in located cells comprises the embryoblast or inner cell mass the zona pellucida. Retention of an intact zona is necessary and will give rise to the fetus.
688 PART X REPRODUCTIVE PHYSIOLOGY Blastocyst Two-cell stage Uterus Morula First cleavage Early stage of implantation Fimbria Fertilization (pronuclei stage) Transport of the developing embryo from the oviduct, the site of fertilization, to FIGURE 39.2 the uterus, the site of implantation. The morula reaches the uterus about 4 days after fertil- dometrial glandular and epithelial cells (Fig. 39.3). The ex- ization. It remains suspended in the uterine cavity for 2 to act embryonic signals that trigger this reaction are unclear, 3 days while developing into a blastocyst and is nourished but histamine, catechol estrogens, steroids, prostaglandins, by constituents of the uterine fluid during that time. Im- leukemia inhibitory factor, epidermal growth factor, trans- plantation of the blastocyst, which is attachment to the forming growth factor , platelet-derived growth factor, surface endometrial cells of the uterine wall, begins on days placental growth factor, and several other pregnancy-asso- 7 to 8 after fertilization and requires proper priming of the ciated proteins have been proposed. uterus by estrogen and progesterone. In preparing for im- Invasion of the endometrium is mediated by the release plantation, the blastocyst escapes from the zona pellucida. of proteases produced by trophoblast cells adjacent to the The zona is ruptured by expansion of the blastocyst and uterine epithelium. By 8 to 12 days after ovulation, the hu- lysed by enzymes. The denuded trophoblast cells become man conceptus has penetrated the uterine epithelium and is negatively charged and adhere to the endometrium via sur- embedded in the uterine stroma (see Fig. 39.3). The tro- face glycoproteins. Microvilli from the trophoblast cells in- phoblast cells have differentiated into large polyhedral cy- terdigitate with and form junctional complexes with the totrophoblasts, surrounded by peripheral syncytiotro- uterine endometrial cells. phoblasts lacking distinct cell boundaries. Maternal blood In the presence of progesterone emanating from the cor- vessels in the endometrium dilate and spaces appear and pus luteum, the endometrium undergoes decidualization, fuse, forming blood-filled lacunae. Between weeks 2 and 3, which involves the hypertrophy of endometrial cells that villi, originating from the embryo, are formed that protrude contain large amounts of glycogen and lipid. In some cases, into the lacunae, establishing a functional communication the cells are multinucleated. This group of decidualized between the developing embryonic vascular system and the cells is called the decidua, which is the site of implantation maternal blood (see Fig. 17.6). At this time, the embry- and the maternal contribution to the placenta. In the ab- oblast has differentiated into three layers: sence of progesterone, decidualization does not occur and • Ectoderm, destined to form the epidermis, its ap- implantation would fail. As the blastocyst implants into the pendages (nails and hair), and the entire nervous system decidualizing uterus, a decidual reaction occurs involving • Endoderm, which will give rise to the epithelial lining of the dilation of blood vessels, increased capillary permeabil- the digestive tract and associated structures ity, edema formation, and increased proliferation of en- • Mesoderm, which will form the bulk of the body, in-
CHAPTER 39 Fertilization, Pregnancy, and Fetal Development 689 cluding connective tissue, muscle, bone, blood, and and maternal circulations do not mix. The human placenta lymph. is a hemochorial type, in which the fetal endothelium and fetal connective tissues are surrounded by maternal blood. The chorionic villi aggregate into groups known as cotyle- PREGNANCY dons and are surrounded by blood from the maternal spiral arteries that course through the decidua. Pregnancy is maintained by protein and steroid hormones Major functions of the placenta are the delivery of nu- from the mother’s ovary and the placenta. The maternal en- trients to the fetus and the removal of its waste products. docrine system adapts to allow optimum growth of the fetus. Oxygen diffuses from maternal blood to the fetal blood down an initial gradient of 60 to 70 mm Hg. The oxygen- transporting capacity of fetal blood is enhanced by fetal The Mother and Fetus Contribute to the Placenta hemoglobin, which has a high affinity for oxygen. The In the human placenta, the maternal and fetal components P CO2 of fetal arterial blood is 2 to 3 mm Hg higher than are interdigitated. The functional units of the placenta, the that of maternal blood, allowing the diffusion of carbon chorionic villi (see Fig. 17.6), form on days 11 to 12 and ex- dioxide toward the maternal compartment. Other com- tend tissue projections into the maternal lacunae that form pounds, such as glucose, amino acids, free fatty acids, elec- from endometrial blood vessels immediately after implan- trolytes, vitamins, and some hormones, are transported by tation. By week 4, the villi are spread over the entire surface diffusion, facilitated diffusion, or pinocytosis. Waste prod- of the chorionic sac. As the placenta matures, it becomes ucts, such as urea and creatinine, diffuse away from the fe- discoid in shape. During the third month, the chorionic tus down their concentration gradients. Large proteins, in- villi are confined to the area of the decidua basalis. The de- cluding most polypeptide hormones, do not readily cross cidua basalis and chorionic plate together form the pla- the placenta, whereas the lipid-soluble steroids pass centa proper (Fig. 39.4). through quite easily. The blood-placental barrier allows The decidua capsularis around the conceptus and the the transfer of some immunoglobulins, viruses, and drugs decidua parietalis on the uterine wall fuse and occlude the from the mother to the fetus (Fig. 39.5). uterine cavity. The yolk sac becomes vestigial and the am- niotic sac expands, pushing the chorion against the uterine The Recognition and Maintenance of Pregnancy wall. From the fourth month onward, the fetus is enclosed Depend on Maternal and Fetal Hormones within the amnion and chorion and is connected to the pla- centa by the umbilical cord. Fetal blood flows through two The placenta is an endocrine organ that produces proges- umbilical arteries to capillaries in the villi, is brought into terone and estrogens, hormones essential for the continu- juxtaposition with maternal blood in the sinuses, and re- ance of pregnancy. The placenta also produces protein hor- turns to the fetus through a single umbilical vein. The fetal mones unique to pregnancy, such as human placental Trophoblast Cytotrophoblast Blastocoele Embryoblast Uterine epithelium Multinucleated giant cells Fibrin plug (syncytium) Cytotrophoblast Amniotic cavity Yolk sac Decidua Uterine stroma Syncytiotrophoblast Endometrial vessel Lacuna (Maternal) The process of embryo implantation and the decidual reaction. FIGURE 39.3
690 PART X REPRODUCTIVE PHYSIOLOGY Cavity of uterus Yolk sac Decidua basalis Placenta Allantoic vessels Umbilical cord Amnion Extraembryonic coelom Chorion Decidua capsularis Decidua parietalis Chorionic plate Decidua basalis Remnants of yolk sac Amniotic cavity Amnion Remnant of extraembryonic coelom Chorion Myometrium Cervical canal Two stages in the develop- FIGURE 39.4 ment of the placenta, showing the origin of the membranes around the fetus. lactogen (hPL) and human chorionic gonadotropin Human chorionic gonadotropin is a glycoprotein made (hCG). Several peptides and polypeptides, including corti- of two dissimilar subunits, and . It belongs to the same cotropin-releasing hormone (CRH), GnRH, and insulin- hormone family as luteinizing hormone (LH), follicle-stim- like growth factors, are also synthesized by the placenta ulating hormone (FSH), and thyroid-stimulating hormone and function as paracrine factors. (TSH). The subunit is made of the same 92 amino acids During the menstrual cycle, the corpus luteum forms as the other glycoprotein hormones. The subunit is made shortly after ovulation and produces significant amounts of of 145 amino acids, with six N- and O-linked oligosaccha- progesterone and estrogen to prepare the uterus for receiv- ride units. It resembles the LH subunit but has a 24-amino ing a fertilized ovum. If the egg is not fertilized, the corpus acid extension at the C-terminal end. Because of extensive luteum regresses at the end of the luteal phase, as indicated glycosylation, the half-life of hCG in the circulation is by declining levels of progesterone and estrogen in the cir- longer than that of LH. Like LH, the major function of culation. After losing ovarian steroidal support, the superfi- hCG in early pregnancy is the stimulation of luteal cial endometrial layer of the uterus is expelled, resulting in steroidogenesis. Both bind to the same or similar membrane menstruation. If the egg is fertilized, the developing em- receptors and increase the formation of pregnenolone from bryo signals its presence by producing hCG, which extends cholesterol by a cAMP-dependent mechanism. the life of the corpus luteum. This signaling process is The hCG level in plasma doubles about every 2 to 3 called the maternal recognition of pregnancy. Syncytiotro- days in early pregnancy and reaches peak levels at about 10 phoblast cells produce hCG 6 to 8 days after ovulation (fer- to 15 weeks of gestation. It is reduced by about 75% by 25 tilization), and hCG enters the maternal and fetal circula- weeks and remains at that level until term (Fig. 39.6). Fetal tions. Very similar to LH, hCG has a molecular weight of concentrations of hCG follow a similar pattern. The hCG approximately 38 kDa, binds LH receptors on the corpus levels are higher in pregnancies with multiple fetuses. Dur- luteum, stimulates luteal progesterone production, and pre- ing the first trimester, GnRH locally produced by cytotro- vents menses at the end of the anticipated cycle. It can be phoblasts appears to regulate hCG production by a detected in the pregnant woman’s urine using commercial paracrine mechanism. The suppression of hCG release dur- colorimetric kits. ing the second half of pregnancy is attributed to negative
CHAPTER 39 Fertilization, Pregnancy, and Fetal Development 691 Placenta is not established. Human placental lactogen (hPL) has lactogenic and Mother Fetus growth hormone-like actions. As a result, it is also called human chorionic somatomammotropin and chorionic Oxygen growth hormone. This hormone is synthesized by syncy- tiotrophoblasts and secreted into the maternal circulation, CO 2 where its levels gradually rise from the third week of preg- Water, electrolytes nancy until term. Although hPL is produced by the same cells as hCG, its pattern of secretion is different, indicating the possibility of control by different regulatory mecha- Water, urea Carbohydrates, nisms. The hormone is composed of a single chain of 191 lipids, amino acids, amino acids with two disulfide bridges and has a molecular vitamins weight of about 22 kDa. Its structure and function resemble Waste products those of prolactin (PRL) and growth hormone (GH). Hormones (some) Human placental lactogen promotes cell specialization in the mammary gland but is less potent than PRL in stim- ulating milk production and is much less potent than GH in Antibodies stimulating growth. Its main function is to alter fuel avail- Hormones ability by antagonizing maternal glucose consumption and Drugs (some) enhancing fat mobilization. This ensures adequate fuel sup- plies for the fetus. Its effects on carbohydrate, protein, and Viruses (most) fat metabolism are similar to those of GH. The amniotic fluid also contains large amounts of PRL produced mainly by the decidual compartments. Decidual PRL is indistin- Role of the placenta in exchanges between FIGURE 39.5 guishable from pituitary PRL, but its function and regula- the fetal and maternal compartments. The size of the arrows indicates the amount of exchange between the tion are unclear. compartments. Steroid Production During Pregnancy Involves the Ovary and Fetoplacental Unit feedback by placental progesterone or other steroids pro- duced by the fetus. Progesterone secretion by the corpus Progesterone is required to maintain normal human preg- luteum is maximal 4 to 5 weeks after conception and de- nancy. During the early stages of pregnancy (approxi- clines, although hCG levels are still rising. Corpus luteum mately the first 8 weeks), the ovaries produce most of the refractoriness to hCG results from receptor desensitization sex steroids; the corpus luteum produces primarily proges- and the rising levels of placental estrogens. From week 7 to terone and estrogen. As the placenta develops, trophoblast 10 of gestation, steroid production by the corpus luteum is cells gradually take over a major role in the production of gradually replaced by steroid production by the placenta. progesterone and estrogen. Although the corpus luteum Removal of the corpus luteum after week 10 does not ter- continues to secrete progesterone, the placenta secretes minate the pregnancy. Other placental-derived growth most of the progesterone. Progesterone levels gradually regulators affecting hCG production are activin, inhibin, rise during early pregnancy and plateau during the transi- and transforming growth factors and . tion period from corpus luteal to placental production (see Human chorionic gonadotropin has been shown to in- Fig. 39.6). Thereafter, plasma progesterone levels continue crease progesterone production by the trophoblast. There- fore, hCG may have a critical role in maintaining placental steroidogenesis throughout pregnancy and replacing luteal 100 Total 20 progesterone secretion after week 10 when the ovaries are hCG estrogen PRL (mg/mL) no longer needed to maintain pregnancy. Another impor- tant function of hCG is in sexual differentiation of the male fetus, which depends on testosterone production by the fe- 200 tal testes. Peak production of testosterone occurs 11 to 17 hCG (IU/mL) 50 10 Progesterone and total estrogen (µg/dL) weeks after conception. This timing coincides with peak hCG production and predates the functional maturity of Progesterone 100 the fetal hypothalamic-pituitary axis (fetal LH levels are PRL low). Human chorionic gonadotropin appears to regulate fetal Leydig cell proliferation as well as testosterone 0 biosynthesis, especially because LH/hCG receptors are 0 0 present in the early fetal testes. The role of hCG in fetal 010203040 ovarian development is less clear since LH/hCG receptors Weeks of gestation are not present on fetal ovaries. There are some indications Profiles of hCG, progesterone, total estro- that increased levels of hCG and thyroxine accompany ma- FIGURE 39.6 gens, and PRL in the maternal blood ternal morning sickness, but a cause-and-effect relationship throughout gestation.
692 PART X REPRODUCTIVE PHYSIOLOGY to rise and reach about 150 ng/mL near the end of preg- pregnenolone or progesterone to androgens (the precur- nancy. Two major estrogens, estradiol and estriol, gradu- sors of the estrogens). Maternal 17-hydroxyprogesterone ally rise during the first half of pregnancy and steeply in- can be measured during the first trimester and serves as a crease in the latter half of pregnancy to more than 25 marker of corpus luteum function, since the placenta can- ng/mL near term. not make this steroid. The production of estrogens (estra- Progesterone and estrogen have numerous functions diol, estrone, and estriol) during gestation requires cooper- throughout gestation. Estrogens increase the size of the ation between the maternal compartment and the placental uterus and uterine blood flow, are critical in the timing of and fetal compartments, referred to as the fetoplacental implantation of the embryo into the uterine wall, induce unit (Fig. 39.7). To produce estrogens, the placenta uses an- the formation of uterine receptors for progesterone and drogenic substrates derived from both the fetus and the oxytocin, enhance fetal organ development, stimulate ma- mother. The primary androgenic precursor is dehy- ternal hepatic protein production, and increase the mass of droepiandrosterone sulfate (DHEAS), which is produced breast and adipose tissues. Progesterone is essential for by the fetal zone of the fetal adrenal gland. The fetal adre- maintaining the uterus and early embryo, inhibits myome- nal gland is extremely active in the production of steroid trial contractions, and suppresses maternal immunological hormones, but because it lacks 3-hydroxysteroid dehy- responses to fetal antigens. Progesterone also serves as a drogenase, it cannot make progesterone. Therefore, the fe- precursor for steroid production by the fetal adrenal glands tal adrenals use progesterone from the placenta to produce and plays a role in the onset of parturition. androgens, which are ultimately sulfated in the adrenal Beginning at approximately week 8 of gestation, proges- glands. The conjugation of androgenic precursors to sul- terone production is carried out by the placenta, but its syn- fates ensures greater water solubility, aids in their transport, thesis requires cholesterol, which is contributed from the and reduces their biological activity while in the fetal cir- mother. The placenta cannot make significant amounts of culation. DHEAS diffuses into the placenta and is cleaved cholesterol from acetate and obtains it from the maternal by a sulfatase to yield a nonconjugated androgenic precur- blood via LDL cholesterol. Trophoblast cells have LDL re- sor. The placenta has an active aromatase that converts an- ceptors, which bind the LDL cholesterol and internalize it. drogenic precursors to estradiol and estrone. Free cholesterol is released and used by cholesterol side- The major estrogen produced during human pregnancy chain cleavage enzyme to synthesize pregnenolone. Preg- is estriol, which has relatively weak estrogenic activity. Es- nenolone is converted to progesterone by 3-hydroxys- triol is produced by a unique biosynthetic pathway (see teroid dehydrogenase. Fig. 39.7). DHEAS from the fetal adrenal is converted to The placenta lacks the 17-hydroxylase for converting 16-hydroxydehydroepiandrosterone sulfate by 16-hy- Maternal Compartment Fetoplacental unit Placenta Fetus Acetate Cholesterol Cholesterol Pregnenolone Pregnenolone Pregnenolone sulfate sulfate Adrenal PROGESTERONE Adrenal Dehydroepiandrosterone Dehydroepiandrosterone Dehydroepiandrosterone sulfate sulfate Androstenedione-Testosterone Liver ESTRONE-ESTRADIOL 16-Hydroxydehydroepiandrosterone 16-Hydroxydehydroepiandrosterone sulfate 16-Hydroxyandrostenedione ESTRIOL The fetoplacental unit and steroidogene- (Modified from Goodman HM. Basic Medical Endocrinology. FIGURE 39.7 sis. Note that estriol is the product of reac- New York: Raven, 1988.) tions occurring in the fetal adrenal, fetal liver, and placenta.
CHAPTER 39 Fertilization, Pregnancy, and Fetal Development 693 droxylation in the fetal liver and, to a lesser extent, the fe- the high levels of steroids during pregnancy. However, the tal adrenal gland. This step is followed by desulfation using placenta can produce ACTH, so plasma levels tend to rise a placental sulfatase and conversion by 3-hydroxysteroid throughout pregnancy because placental secretion (unlike dehydrogenase to 16-hydroxyandrostenedione, which is pituitary hormone secretion) is not regulated by the high subsequently aromatized in the placenta to estriol. Al- level of steroids. though 16-OH-DHEAS can be made in the maternal adre- Maternal metabolism responds in several ways to the in- nal from maternal DHEAS, the levels are low. It has been creasing nutritional demands of the fetus. The major net estimated that 90% of the estriol is derived from the fetal weight gain of the mother occurs during the first half of 16-OH-DHEAS. Therefore, the levels of estriol in plasma, gestation, mostly resulting from fat deposition. This re- amniotic fluid, or urine are used as an index of fetal well-be- sponse is attributed to progesterone, which increases ap- ing. Low levels of estriol would indicate potential fetal dis- petite and diverts glucose into fat synthesis. The extra fat tress, although rare inherited sulfatase deficiencies can also stores are used as an energy source later in pregnancy, when lead to low estriol. the metabolic requirements of the fetus are at their peak, and also during periods of starvation. Several maternal and placental hormones act together to provide a constant sup- Maternal Physiology Changes ply of metabolic fuels to the fetus. Toward the second half Throughout Gestation of gestation, the mother develops a resistance to insulin. This is brought about by combined effects of hormones an- The pregnant woman provides nutrients for her growing fe- tus, is the sole source of fetal oxygen, and removes fetal tagonistic to insulin action, such as GH, PRL, hPL, waste products. These functions necessitate significant ad- glucagon, and cortisol. As a result, maternal glucose use de- justments in her pulmonary, cardiovascular, renal, meta- clines and gluconeogenesis increases, maximizing the avail- bolic, and endocrine systems. Among the most notable ability of glucose to the fetus. changes during pregnancy are hyperventilation, reduced arterial blood P CO2 and osmolality, increased blood volume and cardiac output, increased renal blood flow and FETAL DEVELOPMENT AND PARTURITION glomerular filtration rate, and substantial weight gain. These are brought about by the rising levels of estrogens, At fertilization, genetic sex is determined; subsequently, progesterone, hPL, and other placental hormones and by sexual differentiation is controlled by gonadal hormones. mechanical factors, such as the expanding size of the uterus The fetal endocrine system participates in growth and de- and the development of uterine and placental circulations. velopment of the fetus, and parturition is regulated by in- The maternal endocrine system undergoes significant teractions of fetal and maternal factors. adaptations. The hypothalamic-pituitary-ovarian axis is suppressed by the high levels of sex steroids. Conse- The Fetal Endocrine System Gradually Matures quently, circulating gonadotropins are low, and ovulation does not occur during pregnancy. In contrast, the rising The protective intrauterine environment postpones the ini- levels of estrogens stimulate PRL release. PRL levels begin tiation of some physiological functions that are essential for to rise during the first trimester, increasing gradually to life after birth. For example, the fetal lungs and kidneys do reach a level 10 times higher near term (see Fig. 39.6). Pi- not act as organs of gas exchange and excretion because tuitary lactotrophs undergo hyperplasia and hypertrophy their functions are carried out by the placenta. Constant and mostly account for the enlargement of the pregnant isothermal surroundings alleviate the need to expend calo- woman’s pituitary gland. However, somatotrophs that pro- ries to maintain body temperature. The gastrointestinal duce growth hormone are reduced, and GH levels are low tract does not carry out digestive activities, and fetal bones throughout pregnancy. and muscles do not support weight or locomotion. Being The thyroid gland enlarges, but TSH levels are in the exposed to low levels of external stimuli and environmental normal nonpregnant range. T 3 and T 4 increase, but thyrox- insults, the fetal nervous and immune systems develop ine-binding globulin (TBG) also increases in response to slowly. Homeostasis in the fetus is regulated by hormones. the rising levels of estrogen, which are known to stimulate The fetal endocrine system plays a vital role in fetal growth TBG synthesis. Therefore, the pregnant woman stays in an and development. euthyroid state. The parathyroid glands and their hor- Given that most protein and polypeptide hormones are mone, PTH, increase mostly during the third trimester. excluded from the fetus by the blood-placental barrier, the PTH enhances calcium mobilization from maternal bone maternal endocrine system has little direct influence on the stores in response to the fetus’s growing demands for cal- fetus. Instead, the fetus is almost self-sufficient in its hor- cium. The rate of adrenal secretion of mineralocorticoids monal requirements. Notable exceptions are some of the and glucocorticoids increases, and plasma free cortisol is steroid hormones, which are produced by the fetoplacental higher because of its displacement from transcortin, the unit; they cross easily between the different compartments cortisol-binding globulin, by progesterone, but hypercorti- and carry out integrated functions in both the fetus and the solism is not apparent during pregnancy. mother. By and large, fetal hormones perform the same func- Changes in maternal ACTH levels throughout preg- tions as in the adult, but they also subserve unique processes, nancy are variable, although there is a significant increase such as sexual differentiation and the initiation of labor. at the time of parturition. Current reports indicate that ma- The fetal hypothalamic nuclei, including their releasing ternal pituitary secretion of ACTH may be suppressed by hormones such as TRH, GnRH, and several of the neuro-
694 PART X REPRODUCTIVE PHYSIOLOGY transmitters, are well developed by 12 weeks of gestation. At deposition. It does not control the supply of glucose, how- about week 4, the anterior pituitary begins its development ever; this is determined by maternal gluconeogenesis and from Rathke’s pouch, an ectodermal evagination from the placental glucose transport. The release of insulin in the fe- roof the fetal mouth (stomodeum), and by week 8, most an- tus is relatively constant, increasing only slightly in re- terior pituitary hormones can be identified. The posterior pi- sponse to a rapid rise in blood glucose levels. When blood tuitary or neurohypophysis is an evagination from the floor glucose levels are chronically elevated, as in diabetic of the primitive hypothalamus, and its nuclei, supraoptic and women, the fetal pancreas becomes enlarged and circulat- paraventricular with AVP and oxytocin, can be detected ing insulin levels increase. Consequently, fetal growth is around week 14. The hypothalamic-pituitary axis is well de- accelerated, and infants of uncontrolled diabetic women veloped by midgestation, and well-differentiated hormone- are overweight (Fig. 39.8). producing cells in the anterior pituitary are also apparent at Calcium is in large demand because of the fetus’s rapid this time. Whether the fetal pituitary is tightly regulated by growth and large amount of bone formation during preg- hypothalamic hormones or possesses some autonomy is un- nancy. Maternal calcium is highly important for meeting clear. However, the release of pituitary hormones can occur this fetal requirement. During pregnancy, maternal calcium prior to the establishment of the portal system, indicating intake increases, and 1,25 dihydroxyvitamin D 3 and PTH that the hypothalamic-releasing hormones may diffuse down increase to meet the increased calcium demands of the fe- to the pituitary from the hypothalamic sites. tus. In the mother, total plasma calcium and phosphate de- Experiments with long-term catheterization of monkey cline without affecting free calcium. The placenta has a fetuses indicate that by the last trimester, both LH and specialized calcium pump that transfers calcium to the fe- testosterone increase in response to GnRH administration. tus, resulting in sustained increases in calcium and phos- In the adult, GH largely regulates the secretion of the in- phate throughout pregnancy. Although PTH and calci- sulin-like growth factors (IGF-I and IGF-II) from the liver. tonin are evident in the fetus near week 12 of gestation, In the fetus, this may not be the case, since newborns with their role in regulating fetal calcium is unclear. In addition, low GH have normal birth size; therefore, other mecha- the placenta has 1-hydroxylase and can convert 25-hy- nisms may control the secretion of IGFs in the fetus. GH droxyvitamin D 3 to 1,25 dihydroxyvitamin D 3 . At the end levels increase in the fetus until midgestation and decline of gestation, calcium and phosphate levels in the fetus are thereafter when fetal weight is increasing significantly, rep- higher than in the mother. However, after delivery, neona- resenting another dichotomy in GH and IGF in the fetus tal calcium levels decrease and PTH levels rise to raise the versus postnatal life. PRL levels increase in the fetus levels of serum calcium. throughout gestation and can be inhibited by an exogenous dopamine agonist. Although the role of PRL in fetal growth is unclear, it has been implicated in adrenal and lung func- The Sex Chromosomes Dictate the tion, as well as in the regulation of amniotic fluid volume. Development of the Fetal Gonads The fetal adrenal glands are unique in both structure and Sexual differentiation begins at the time of fertilization by function. At month 4 of gestation, they are larger than the a random unification of an X-bearing egg with either an X- kidneys, as a result of the development of a fetal zone that or Y-bearing spermatozoon and continues during early em- constitutes 75 to 80% of the whole gland. The outer defini- tive zone will form the adult adrenal cortex, whereas the deeper fetal zone involutes after birth; the reason for the in- Placenta volution is unknown, but it is not caused by the withdrawal Mother Fetus of ACTH support. The fetal zone produces large amounts of DHEAS and provides androgenic precursors for estrogen synthesis by the placenta (see Fig. 39.7). The definitive zone produces cortisol, which has multiple functions during fetal Pancreas Pancreas life, including the promotion of pancreas and lung matura- tion, the induction of liver enzymes, the promotion of intes- tinal tract cytodifferentiation and, possibly, the initiation of labor. ACTH is the main regulator of fetal adrenal steroido- Plasma Defect in genesis, partly evidenced by the observation that anen- insulin action insulin cephalic fetuses have low ACTH and the fetal zone is small. The adrenal medulla develops by about week 10 and is capa- ble of producing epinephrine and norepinephrine. The rate of fetal growth increases significantly during Growth the last trimester. Surprisingly, growth hormone of mater- nal, placental, or fetal origin has little effect on fetal growth, as judged by the normal weight of hypopituitary Plasma Plasma dwarfs or anencephalic fetuses. Fetal insulin is the most im- glucose glucose portant hormone in regulating fetal growth. Glucose is the main metabolic fuel for the fetus. Fetal insulin, produced by the pancreas by week 12 of gestation, regulates tissue glu- FIGURE 39.8 Effects of maternal diabetes on fetal cose use, controls liver glycogen storage, and facilitates fat growth.
CHAPTER 39 Fertilization, Pregnancy, and Fetal Development 695 bryonic life with the development of male or female go- the yolk sac to the genital ridges. Depending on genetic nads. Therefore, at the time of fertilization, chromosomal programming, the inner medullary tissue will become the sex or genetic sex is determined. Sexual differentiation is testicular components, and the outer cortical tissue will de- controlled by gonadal hormones that act at critical times velop into an ovary. The primordial germ cells will become during organogenesis. Testicular hormones induce mas- oogonia or spermatogonia. In an XY fetus, the testes differ- culinization, whereas feminization does not require (fe- entiate first. Between weeks 6 and 8 of gestation, the cortex male) hormonal intervention. The process of sexual devel- regresses, the medulla enlarges, and the seminiferous opment is incomplete at birth; the secondary sex tubules become distinguishable. Sertoli cells line the base- characteristics and a functional reproductive system are not ment membrane of the tubules, and Leydig cells undergo fully developed until puberty. rapid proliferation. Development of the ovary begins at Human somatic cells have 44 autosomes and 2 sex chro- weeks 9 to 10. Primordial follicles, composed of oocytes mosomes. The female is homogametic (having two X chro- surrounded by a single layer of granulosa cells, are dis- mosomes) and produces similar X-bearing ova. The male is cernible in the cortex between weeks 11 and 12 and reach heterogametic (having one X and one Y chromosome) and maximal development by weeks 20 to 25. generates two populations of spermatozoa, one with X chromosomes and the other with Y chromosomes. The X chromosome is large, containing 80 to 90 genes responsi- Differentiation of the Genital Ducts Is ble for many vital functions. The Y chromosome is much Determined by Hormones smaller, carrying only few genes responsible for testicular development and normal spermatogenesis. Gene mutation During the indifferent stage, the primordial genital ducts of genes on an X chromosome results in the transmission of are the paired mesonephric (wolffian) ducts and the paired X-linked traits, such as hemophilia and color-blindness, to paramesonephric (müllerian) ducts. In the normal male fe- male offspring, which, unlike females, cannot compensate tus, the wolffian ducts give rise to the epididymis, vas def- with an unaffected allele. erens, seminal vesicles, and ejaculatory ducts, while the Theoretically, by having two X chromosomes, the fe- müllerian ducts become vestigial. In the normal female fe- male has an advantage over the male, who has only one. tus, the müllerian ducts fuse at the midline and develop into However, because one of the X chromosomes is inactivated the oviducts, uterus, cervix, and upper portion of the at the morula stage, the advantage is lost. Each cell ran- vagina, while the wolffian ducts regress (Fig. 39.9). The domly inactivates either the paternally or the maternally mesonephros is the embryonic kidney. derived X chromosome, and this continues throughout the The fetal testes differentiate between weeks 6 and 8 of cell’s progeny. The inactivated X chromosome is recog- gestation. Leydig cells, either autonomously or under regu- nized cytologically as the sex chromatin or Barr body. In lation by hCG, start producing testosterone. Sertoli cells males, with more than one X chromosome, or in females, produce two nonsteroidal compounds. One is the antimül- with more than two extra X chromosomes are inactivated lerian hormone (AMH), also known as müllerian inhibit- and only one remains functional. This does not apply to the ing substance, a large glycoprotein with a sequence ho- germ cells. The single active X chromosome of the sper- mologous to inhibin and transforming growth factor , matogonium becomes inactivated during meiosis, and a which inhibits cell division of the müllerian ducts. The sec- functional X chromosome is not necessary for the forma- ond is androgen-binding protein (ABP), which binds tion of fertile sperm. The oogonium, however, reactivates testosterone. Peak production of these compounds occurs its second X chromosome, and both are functional in between weeks 9 and 12, coinciding with the time of dif- oocytes and important for normal oocyte development. ferentiation of the internal genitalia along the male line. Testicular differentiation requires a Y chromosome and The ovary, which differentiates later, does not produce occurs even in the presence of two or more X chromo- hormones and has a passive role. somes. Gonadal sex determination is regulated by a testis- The primordial external genitalia include the genital tu- determining gene designated SRY (sex-determining region, bercle, genital swellings, urethral folds, and urogenital si- Y chromosome). Located on the short arm of the Y chro- nus. Differentiation of the external genitalia also occurs mosome, SRY encodes a DNA-binding protein, which between weeks 8 and 12 and is determined by the presence binds to the target DNA in a sequence-specific manner. or absence of male sex hormones. Differentiation along The presence or absence of SRY in the genome determines the male line requires active 5-reductase, the enzyme whether male or female gonadal differentiation takes place. that converts testosterone to DHT. Without DHT, re- Thus, in normal XX (female) fetuses, which lack a Y chro- gardless of the genetic, gonadal, or hormonal sex, the ex- mosome, ovaries, rather than testes, develop. ternal genitalia develop along the female pattern. The Whether possessing the XX or the XY karyotype, every structures that develop from the primordial structures are embryo goes initially through an ambisexual stage and has illustrated in Figure 39.10, and a summary of sexual differ- the potential to acquire either masculine or feminine char- entiation during fetal life is shown in Figure 39.11. Andro- acteristics. A 4- to 6-week-old human embryo possesses in- gen-dependent differentiation occurs only during fetal life different gonads, and undifferentiated pituitary, hypothal- and is thereafter irreversible. However, the exposure of fe- amus, and higher brain centers. males to high androgens either before or after birth can The indifferent gonad consists of a genital ridge, de- cause clitoral hypertrophy. Testicular descent into the rived from coelomic epithelium and underlying mes- scrotum, which occurs during the third trimester, is also enchyme, and primordial germ cells, which migrate from controlled by androgens.
696 PART X REPRODUCTIVE PHYSIOLOGY Gonad Mesonephros Müllerian duct Wolffian duct Urogenital sinus Indifferent stage Ovary Testis Epididymis Vas deferens Fallopian tube Bladder Seminal vesicle Differentiation of FIGURE 39.9 the internal geni- Uterus Prostate talia and the primordial ducts. (Modified from George FW, Wilson JD. Embryology of the urinary tract. Bulbourethral gland Vagina In: Walsh PC, Retik AB, Stamey TA, et al., eds. Campbell’s Urology. 6th Female Male Ed. Philadelphia: WB Saunders, 1992;1496.) A Complex Interplay Between Maternal and quiescence throughout gestation, preventing premature de- Fetal Factors Induces Parturition livery, is called the progesterone block. In many species, a sharp decline in the circulating levels of progesterone and The duration of pregnancy in women averages 270 14 a concomitant rise in estrogen precede birth. In humans, days from the time of fertilization. Parturition or the onset progesterone does not fall significantly before delivery. of birth is regulated by the interactions of fetal and mater- However, its effective concentration may be altered by a nal factors. Uncoordinated uterine contractions start about rise in placental progesterone-binding protein or by a de- 1 month before the end of gestation. The termination of cline in the number of myometrial progesterone receptors. pregnancy is initiated by strong rhythmic contractions that Prostaglandins F 2A and E 2 are potent stimulators of uter- may last several hours and eventually generate enough ine contractions and also cause significant ripening of the force to expel the conceptus. The contraction of the uter- cervix and its dilation. They increase intracellular calcium ine muscle is regulated by hormones and by mechanical concentrations of myometrial cells and activate the actin- factors. The hormones include progesterone, estrogen, myosin contractile apparatus. Shortly before the onset of prostaglandins, oxytocin, and relaxin. The mechanical fac- parturition, the concentration of prostaglandins in amni- tors include distension of the uterine muscle and stretching otic fluid rises abruptly. Prostaglandins are produced by the or irritation of the cervix. myometrium, decidua, and chorion. Aspirin and in- Progesterone hyperpolarizes myometrial cells, lowers domethacin, inhibitors of prostaglandin synthesis, delay or their excitability, and suppresses uterine contractions. It prolong parturition. also prevents the release of phospholipase A 2 , the rate-lim- Oxytocin is also a potent stimulator of uterine contrac- iting enzyme in prostaglandin synthesis. Estrogen, in gen- tions, and its release from both maternal and fetal pitu- eral, has the opposite effects. The maintenance of uterine itaries increases during labor. Oxytocin is used clinically to
CHAPTER 39 Fertilization, Pregnancy, and Fetal Development 697 Indifferent drogen precursors. Injections of ACTH and cortisol in late stages pregnancy do not induce labor. Interestingly, the adminis- tration of estrogens to the cervix causes ripening, probably by increasing the secretion of prostaglandins. Genital fold Genital swelling POSTPARTUM AND PREPUBERTAL PERIODS Genital tubercle Lactation is controlled by pituitary and ovarian hormones, requires suckling for continued milk production, and is the major source of nutrition for the newborn. As the child grows, puberty will occur around age 10 to 11 because the hypothalamus activates secretion of pituitary hormones that cause secretion of estrogens and androgens from the Male Female Glans gonads and adrenals during that time. Alterations in hor- Glans Fused mone secretion lead to abnormal onset of puberty and go- urogenital Urethral groove nadal development. folds Anus Anus Urethral Mammogenesis and Lactogenesis Are groove Regulated by Multiple Hormones Labia minora Scrotum Lactation (the secretion of milk) occurs at the final phase of Labia majora the reproductive process. Several hormones participate in Prepuce mammogenesis, the differentiation and growth of the mam- Body of Clitoris mary glands, and in the production and delivery of milk. Lac- penis togenesis is milk production by alveolar cells. Galac- Urethral orifice Scrotal topoiesis, the maintenance of lactation, is regulated by PRL. raphe Hymen Milk ejection is the process by which stored milk is released from the mammary glands by the action of oxytocin. Differentiation of the external genitalia Mammogenesis occurs at three distinct periods: embry- FIGURE 39.10 from bipotential primordial structures. onic, pubertal, and gestational. The mammary glands begin to differentiate in the pectoral region as an ectodermal thickening on the epidermal ridge during weeks 7 to 8 of induce labor (see Clinical Focus Box 39.2). The functional fetal life. The prospective mammary glands lie along bilat- significance of oxytocin is that it helps expel the fetus from eral mammary ridges or milk lines extending from axilla to the uterus, and by contracting uterine muscles, it reduces groin on the ventral side of the fetus. Most of the ridge dis- uterine bleeding when bleeding may be significant after de- integrates except in the axillary region. However, in mam- livery. Interestingly, oxytocin levels do not rise at the time mals with serially repeated nipples, a distinct milk line with of parturition. several nipples persists, accounting for the accessory nip- Relaxin, a large polypeptide hormone produced by the ples that can occur in both sexes, although rarely. Mam- corpus luteum and the decidua, assists parturition by soft- mary buds are derived from surface epithelium, which in- ening the cervix, permitting the eventual passage of the vades the underlying mesenchyme. During the fifth month, fetus, and by increasing oxytocin receptors. However, the the buds elongate, branch, and sprout, eventually forming relative role of relaxin in parturition in humans is unclear, the lactiferous ducts, the primary milk ducts. They con- as its levels do not rise toward the end of gestation. Re- tinue to branch and grow throughout life. The ducts unite, laxin reaches its peak during the first trimester, declines to grow, and extend to the site of the future nipple. The pri- about half, and remains unchanged throughout the re- mary buds give rise to secondary buds, which are separated mainder of pregnancy. into lobules by connective tissue. These become sur- The fetus may play a role in initiating labor. In sheep, the rounded by myoepithelial cells derived from epithelial pro- concentration of ACTH and cortisol in the fetal plasma rise genitors. In response to oxytocin, myoepithelial cells will during the last 2 to 3 days of gestation. Ablation of the fetal contract, and expel milk from the duct. The nipple and are- lamb pituitary or removal of the adrenals prolongs gestation, ola, which are first recognized as circular areas, are formed while administration of ACTH or cortisol leads to premature during the eighth month of gestation. The development of delivery. Cortisol enhances the conversion of progesterone the mammary glands in utero appears to be independent of to estradiol, changing the progesterone-to-estrogen ratio, hormones but is influenced by paracrine interactions be- and increases the production of prostaglandins. The role of tween the mesenchyme and epithelium. cortisol and ACTH, however, has not been established in The mammary glands of male and female infants are humans. Anencephalic or adrenal-deficient fetuses, which identical. Although underdeveloped, they have the capacity lack a pituitary and have atrophied adrenal glands, have an to respond to hormones, revealed by the secretion of small unpredictable length of gestation. Those pregnancies also amounts of milk (witch’s milk) in many newborns. Witch’s exhibit low estrogen levels because of the lack of adrenal an- milk results from the responsiveness of the fetal mammary
698 PART X REPRODUCTIVE PHYSIOLOGY Gestational Age Fertilization Male Female XY XX/XO SRY positive SRY negative 6 weeks Testis Ovary 8 weeks Antimüllerian Testosterone DHT Estradiol Absent antimüllerian hormone hormone No müllerian Wolffian duct Müllerian duct duct 8-10 weeks No uterus Vas deferens Uterus Epididymis Fallopian tube Seminal vesicles Upper vagina 10-12 weeks 12-14 weeks Penis (genital tubercle) Clitoris Penile urethra (urogenital folds) Labia minora Scrotum (labioscrotal swellings) Labia majora (vaginal cord) Lower vagina The process of sex- FIGURE 39.11 ual differentiation 15-18 weeks and its time course. tissue to lactogenic hormones of pregnancy and the with- ciation with menstrual cycles, estrogen stimulates the drawal of placental steroids at birth. Sexual dimorphism in growth and branching of the ducts, whereas progesterone breast development begins at the onset of puberty. The acts primarily on the alveolar components. The action of male breast is fully developed at about age 20 and is similar both hormones, however, requires synergism with PRL, to the female breast at an early stage of puberty. GH, insulin, cortisol, and thyroxine. In females, estrogen exerts a major influence on breast The mammary glands undergo significant changes during growth at puberty. The first response to estrogen is an in- pregnancy. The ducts become elaborate during the first crease in size and pigmentation of the areola and acceler- trimester, and new lobules and alveoli are formed in the sec- ated deposition of adipose and connective tissues. In asso- ond trimester. The terminal alveolar cells differentiate into CLINICAL FOCUS BOX 39.2 Pharmacological Induction and Augmentation of Labor have also been used to induce and augment labor and cer- Several drugs are currently used to assist in the thera- vical ripening. Prostaglandins promote dilatation and ef- peutic induction and augmentation of labor. Therapeutic facement of the cervix and can be used for various reasons induction implies that labor is initiated by the use of a intravaginally, intravenously, or intra-amniotically. An- drug. Augmentation indicates that labor has started and other therapeutic agent being tested for efficacy in labor that the process is further stimulated by a therapeutic induction and augmentation is mifepristone (RU-486), a agent. progesterone receptor blocker. It is used to induce labor Oxytocin, the natural hormone produced from the pos- and to increase the sensitivity of the uterus to oxytocin and terior pituitary, is widely used to induce and augment la- prostaglandins. An additional and interesting feature of bor. Several synthetic forms of oxytocin can be used by in- these drugs is that they reduce postpartum hemorrhage by travenous routes. Recently, the prostaglandins (F 2 and E 2) causing muscle contractions.
CHAPTER 39 Fertilization, Pregnancy, and Fetal Development 699 secretory cells, replacing most of the connective tissue. The Arterial blood development of the secretory capability requires estrogen, progesterone, PRL, and placental lactogen. Their action is supported by insulin, cortisol, and several growth factors. Lactogenesis begins during the fifth month of gestation, but Capillaries Myoepithelial cell only colostrum (initial milk) is produced. Full lactation dur- ing pregnancy is prevented by elevated progesterone levels, which antagonize the action of PRL. The ovarian steroids synergize with PRL in stimulating mammary growth but an- tagonize its actions in promoting milk secretion. Lactogenesis is fully expressed only after parturition, on the withdrawal of placental steroids. Lactating women Lumen produce up to 600 mL of milk each day, increasing to 800 to 1,100 mL/day by the sixth postpartum month. Milk is isosmotic with plasma, and its main constituents include Milk-secreting proteins, such as casein and lactalbumin, lipids, and lac- alveolar cell tose. The composition of milk changes with the stage of lactation. Colostrum, produced in small quantities during Venous blood the first postpartum days, is higher in protein, sodium, Capillary milk duct and chloride content and lower in lactose and potassium than normal milk. Colostrum also contains immunoglob- ulin A, macrophages, and lymphocytes, which provide Lobuloalveolar duct passive immunity to the infant by acting on its GI tract. During the first 2 to 3 weeks, the protein content of milk decreases, whereas that of lipids, lactose, and water-solu- FIGURE 39.12 The structure of a mammary alveolus. Milk- producing cells are surrounded by a meshwork ble vitamins increases. of contractile myoepithelial cells. The milk-secreting alveolar cells form a single layer of epithelial cells, joined by junctional complexes (Fig. 39.12). The bases of the cells abut on the contractile myoepithelial cells, and their luminal surface is enriched with microvilli. ling reflex is neural and the efferent arc is hormonal. The They have a well-developed endoplasmic reticulum and suckling reflex increases the release of PRL, oxytocin, and Golgi apparatus and numerous mitochondria and lipid ACTH and inhibits the secretion of gonadotropins droplets. Alveolar cells contain plasma membrane receptors (Fig. 39.13). The neuronal component is composed of sen- for PRL, which can be internalized after binding to the sory receptors in the nipple that initiate nerve impulses in hormone. In synergism with insulin and glucocorticoids, response to breast stimulation. These impulses reach the PRL is critical for lactogenesis, promotes mammary cell di- hypothalamus via ascending fibers in the spinal cord and vision and differentiation, and increases the synthesis of then via the mesencephalon. Eventually, fibers terminating milk constituents. This hormone also stimulates the syn- in the supraoptic and paraventricular nuclei trigger the re- thesis of casein by increasing its transcription rate and sta- lease of oxytocin from the posterior pituitary into the gen- bilizing its mRNA, and stimulates enzymes that regulate eral circulation (see Chapter 32). On reaching the mam- the production of lactose. mary glands, oxytocin induces the contraction of myoepithelial cells, increasing intramammary pressure and forcing the milk into the main collecting ducts. The milk The Suckling Reflex Maintains Lactation and Inhibits Ovulation ejection reflex can be conditioned; milk ejection can occur because of anticipation or in response to a baby’s cry. The suckling reflex is central to the maintenance of lacta- PRL levels, which are elevated by the end of gestation, tion in that it coordinates the release of PRL and oxytocin decline by 50% within the first postpartum week and de- and delays the onset of ovulation. Lactation involves two crease to near pregestation levels by 6 months. Suckling components, milk secretion (synthesis and release) and elicits a rapid and significant rise in plasma PRL. The milk removal, which are regulated independently. Milk se- amount released is determined by the intensity and dura- cretion is a continuous process, whereas milk removal is in- tion of nipple stimulation. The exact mechanism by which termittent. Milk secretion involves the synthesis of milk suckling triggers PRL release is unclear, but the suppres- constituents by the alveolar cells, their intracellular trans- sion of dopamine, the major inhibitor of PRL release, and port, and the subsequent release of formed milk into the the stimulation of prolactin-releasing factor(s) have been alveolar lumen (see Fig. 39.12). PRL is the major regulator considered. Lactation can be terminated by dopaminergic of milk secretion in women and most other mammals. Oxy- agonists that reduce PRL or by the discontinuation of tocin is responsible for milk removal by activating milk suckling. Swollen alveoli can depress milk production by ejection or letdown. exerting local pressure, resulting in vascular stasis and The stimulation of sensory nerves in the breast by the in- alveolar regression. fant initiates the suckling reflex. Unlike ordinary reflexes Lactation is associated with the suppression of cyclic- with only neural components, the afferent arc of the suck- ity and anovulation. The contraceptive effect of lactation
700 PART X REPRODUCTIVE PHYSIOLOGY Hypothalamus GnRH CRH DA PRF Anterior pituitary Posterior pituitary Suckling stimulus Effect of suckling on hypothalamic, pi- FIGURE 39.13 OT FSH LH ACTH PRL tuitary, and adrenal hormones. GnRH, gonadotropin-releasing hormone; CRH, corticotropin-re- leasing hormone; DA, dopamine; PRF, prolactin-releasing factor; FSH, follicle-stimulating hormone; LH, luteinizing Ovary Adrenal Cortisol Breast hormone; ACTH, adrenocorticotropic hormone; PRL, pro- lactin; OT, oxytocin. Plus and minus signs indicate positive Suckling and negative effects. CLINICAL FOCUS BOX 39.3 Contraceptive Methods in excessive menstrual bleeding, alleviation of premenstrual Fertility can be controlled by interfering with the associa- syndrome, and some protection against pelvic inflammatory tion between the sperm and ovum, by preventing ovula- disease. Adverse effects include nausea, headache, breast tion or implantation, or by terminating an early pregnancy. tenderness, water retention, and weight gain, some of which Contraceptive methods may also be categorized as re- disappear after prolonged use. There is no evidence that fer- versible and irreversible. Most current methods regulate tility is reduced after discontinuation of the pill. fertility in women, with only a few contraceptives available Several contraceptives act by interfering with zygote for men (Table 39.A). transport or implantation and cause early pregnancy ter- Methods based on preventing contact between the mination. Among these are long-acting progesterone germ cells include coitus interruptus (withdrawal before preparations, high doses of estrogen, and progesterone ejaculation), the rhythm method (no intercourse at times receptor antagonists, such as RU-486 (also called mifepri- of the menstrual cycle, especially when an ovum is pres- stone). RU-486 blocks the action of the progesterone re- ent in the oviduct), and barriers. Barrier methods include quired for early pregnancy. Prostaglandins are given in condoms, diaphragms, and cervical caps. When com- combination with RU-486 to assist in the expulsion of the bined with spermicidal agents, barrier methods ap- products of conception. The intrauterine device (IUD) also proach the high success rate of oral contraceptives. Con- prevents implantation by provoking sterile inflammation doms are the most widely used reversible contraceptives of the endometrium and prostaglandin production. The for men. Because they also provide protection against contraceptive efficacy of IUDs, especially those impreg- the transmission of venereal diseases and AIDS, their nated with progestins, copper, or zinc, is high. The draw- use has increased in recent years. Diaphragms and cer- backs include a high rate of expulsion, uterine cramps, vical caps seal off the opening of the cervix. Spermicides excessive bleeding, perforation of the uterus, and in- are inserted into the vagina. Postcoital douching is not an creased incidence of ectopic pregnancy. Established effective contraceptive because some sperm enter the pregnancy can be interrupted by surgical means (dilata- uterus and oviduct very rapidly. tion and curettage). Vasectomy is cutting of the two vasa deferentia, and it prevents sperm from passing into the ejaculate. An in- creased incidence of sperm antibodies occurs following Contraceptive Use and Efficacy Rates TABLE 39.A vasectomy, but its consequences are unknown. Tubal liga- in the United States tion is the closure or ligation of the oviducts. Restorative surgery for the reversal of a tubal ligation and a vasectomy Accidental can be performed; its success is limited. Estimated Use Pregnancy Oral contraceptive steroids prevent ovulation by reduc- Method (%) in Year 1 (%) ing LH and FSH secretion through negative feedback. Re- duced secretion of LH and FSH retard follicular develop- Pill 32 3 ment. The pill’s effectiveness is also increased by Female sterilization 19 0.4 adversely affecting the environment within the reproduc- Condom 17 12 tive tract, making it unlikely for pregnancy to result even if Male sterilization 14 0.15 fertilization were to occur. Exogenous estrogen and prog- Diaphragm 4–6 2–23 esterone are likely to alter normal endometrial develop- Spermicides 5 20 ment and may contribute to their detrimental effects in the Rhythm 4 20 early establishment of pregnancy. Progesterone thickens Intrauterine device 3 6 cervical mucus and reduces oviductal peristalsis, imped- ing gamete transport. From Developing New Contraceptives: Obstacles and Opportuni- ties. Washington, DC: National Academy Press, 1990. Noncontraceptive benefits of the pill include a reduction
CHAPTER 39 Fertilization, Pregnancy, and Fetal Development 701 is moderate in humans. In non-breast-feeding women, the reduction in the effectiveness of intrinsic CNS inhibition menstrual cycle may return within 1 month after delivery, over the GnRH pulse generator. The mechanisms underly- whereas fully lactating women have a period of several ing these changes are unclear but might involve endoge- months of lactational amenorrhea, with the first few men- nous opioids. As a result of disinhibition, the frequency and strual cycles being anovulatory. The cessation of cyclicity amplitude of GnRH pulses increase. Initially, pulsatility is results from the combined effects of the act of suckling most prominent at night, entrained by deep sleep; later it and elevated PRL levels. PRL suppresses ovulation by in- becomes established throughout the 24-hour period. hibiting pulsatile GnRH release, suppressing pituitary re- GnRH acts on the gonadotrophs of the anterior pituitary as sponsiveness to GnRH, reducing LH and FSH, and de- a self-primer. It increases the number of GnRH receptors creasing ovarian activity. It is also possible that PRL may (up-regulation) and augments the synthesis, storage, and inhibit the action of the low circulating levels of go- secretion of the gonadotropins. The increased responsive- nadotropins on ovarian cells. Thus, follicular develop- ness of FSH to GnRH in females occurs earlier than that of ment would be suppressed by a direct inhibitory action of LH, accounting for a higher FSH/LH ratio at the onset of PRL on the ovary. Although fertility is reduced by lacta- puberty than during late puberty and adulthood. A reversal tion, there are numerous other methods of contraception of the ratio is seen again after menopause. (see Clinical Focus Box 39.3). The increased pulsatile GnRH release initiates a cascade of events. The sensitivity of gonadotrophs to GnRH is in- creased, the secretion of LH and FSH is augmented, the go- The Onset of Puberty Depends on Maturation nads become more responsive to the gonadotropins, and of the Hypothalamic GnRH Pulse Generator the secretion of gonadal hormones is stimulated. The rising The onset of puberty depends on a sequence of matura- circulating levels of gonadal steroids induce progressive de- tional processes that begin during fetal life. The hypothal- velopment of the secondary sex characteristics and estab- amic-pituitary-gonadal axis undergoes a prolonged and lish an adult pattern of negative feedback on the hypothal- multiphasic activation-inactivation process. By midgesta- amic-pituitary axis. Activation of the positive-feedback tion, LH and FSH levels in fetal blood are elevated, reach- mechanism in females and the capacity to exhibit an estro- ing near adult values. Experimental evidence suggests that gen-induced LH surge is a late event, expressed in midpu- the hypothalamic GnRH pulse generator is operative at this berty to late puberty. time, and gonadotropins are released in a pulsatile manner. The onset of puberty in humans begins at age 10 to 11. The levels of FSH are lower in males than in females, prob- Lasting 3 to 5 years, the process involves the development ably because of suppression by fetal testosterone at midges- of secondary sex characteristics, a growth spurt, and the ac- tation. As the levels of placental steroids increase, they ex- ert negative feedback on GnRH release, lowering LH and FSH to very low levels toward the end of gestation. Ovulation Girls After birth, the newborn is deprived of maternal and pla- Breast bud begins cental steroids. The reduction in steroidal negative feed- back stimulates gonadotropin secretion, which stimulates Pubic hair begins the gonads, resulting in transient increases in serum testos- terone in male infants and estradiol in females. FSH levels Peak height spurt in females are usually higher than those in males. At ap- proximately 3 months of age, the levels of both go- Menarche nadotropins and gonadal steroids are in the low-normal adult range. Circulating gonadotropins decline to low lev- Pubic hair adult els by 6 to 7 months in males and 1 to 2 years in females and remain suppressed until the onset of puberty. Breast adult Throughout childhood, the gonads are quiescent and plasma steroid levels are low. Gonadotropin release is also suppressed. The prepubertal restraint of gonadotropin secre- Genital development begins Boys tion is explained by two mechanisms, both of which affect the hypothalamic GnRH pulse generator. One is a sex steroid-de- Pubic hair begins pendent mechanism that renders the pulse generator ex- tremely sensitive to negative feedback by steroids. The other Peak height spurt is an intrinsic central nervous system (CNS) inhibition of the GnRH pulse generator. Together, they suppress the ampli- Genitalia adult tude, and probably the frequency, of GnRH pulses, resulting Spermatogenesis in diminished secretion of LH, FSH, and gonadal steroids. begins Pubic hair adult Throughout this period of quiescence, the pituitary and the gonads can respond to exogenous GnRH and gonadotropins, 8121620 but at a relatively low sensitivity. Age (years) The hypothalamic-pituitary axis becomes reactivated during the late prepubertal period. This response involves a FIGURE 39.14 Peripubertal maturation of secondary sex decrease in hypothalamic sensitivity to sex steroids and a characteristics in girls and boys.
702 PART X REPRODUCTIVE PHYSIOLOGY quisition of fertility. The timing of puberty is determined and growth hormone. The principal mediator of GH is in- by genetic, nutritional, climatic, and geographic factors. sulin-like growth factor-I (IGF-I). Plasma concentration of Over the last 150 years, the age of puberty has declined by IGF-I increases significantly during puberty, with peak lev- 2 to 3 months per decade; this pattern appears to correlate els observed earlier in girls than in boys. IGF-I is essential with improvements in nutrition and general health in for accelerated growth. The gonadal steroids appear to act Americans. primarily by augmenting pituitary growth hormone release, The first physical signs of puberty in girls are breast bud- which stimulates the production of IGF-I in the liver and ding, thelarche, and the appearance of pubic hair. Axillary other tissues. hair growth and peak height spurt occur within 1 to 2 years. Menarche, the beginning of menstrual cycles, occurs at a Disorders of Sexual Development Can Manifest median age of 12.8 years in American girls. The first few cycles are usually anovulatory. The first sign of puberty in Before or After Birth boys is enlargement of the testes, followed by the appear- Normal sexual development depends on a complex, orderly ance of pubic hair and enlargement of the penis. The peak sequence of events that begins during early fetal life and is growth spurt and appearance of axillary hair in boys usually completed at puberty. Any deviation can result in infertil- occurs 2 years later than in girls. The growth of facial hair, ity, sexual dysfunction, or various degrees of intersexuality deepening of the voice, and broadening of the shoulders or hermaphroditism. A true hermaphrodite possesses both are late events in male pubertal maturation (Fig. 39.14). ovarian and testicular tissues, either separate or combined Puberty is also regulated by hormones other than go- as ovotestes. A pseudohermaphrodite has one type of go- nadal steroids. The adrenal androgens DHEA and DHEAS nads but a different degree of sexuality of the opposite sex. are primarily responsible for the development of pubic and Sex is normally assigned according to the type of gonads. axillary hair. Adrenal maturation or adrenarche precedes Disorders of sexual differentiation can be classified as go- gonadal maturation or gonadarche by 2 years. The puber- nadal dysgenesis, female pseudohermaphroditism, male tal growth spurt requires a concerted action of sex steroids pseudohermaphroditism, or true hermaphroditism. Se- Hypothalamus Hypothalamus CRH GnRH CRH GnRH Anterior pituitary ACTH LH, FSH ACTH LH, FSH Adrenal Cortisol androgens Estrogen Cortisol Adrenal Estrogen androgens Adrenal Adrenal cortex Ovaries cortex Ovaries Normal female Adrenal virilism Hormonal interactions along the ovarian indicate low production of the hormone. Heavy arrows indicate FIGURE 39.15 and adrenal axes during normal female de- increased hormone production. Plus and minus signs indicate posi- velopment, compared with adrenal virilism. Dashed arrows tive and negative effects.
CHAPTER 39 Fertilization, Pregnancy, and Fetal Development 703 Normal male Urinary bladder Seminal vesicle Prostate Vas deferens Urethra Epididymis Testis Male with 5-reductase deficiency Urinary bladder Seminal vesicle Small Vas deferens prostate Urethra Testis Micropenis Epididymis Urogenital sinus Effects of 5-reductase deficiency FIGURE 39.16 Blind-ending on differentiation of the internal and vagina external genitalia. lected cases and their manifestations are briefly discussed have very low levels of estrogens, primary amenorrhea, and here, as are disorders of pubertal development (see also do not undergo normal pubertal development. Chapters 37 and 38). Female pseudohermaphrodites are 46,XX females with Gonadal dysgenesis refers to incomplete differentiation normal ovaries and internal genitalia but a different degree of the gonads and is usually associated with sex chromo- of virilization of the external genitalia, resulting from ex- some abnormalities. These result from errors in the first or posure to excessive androgens in utero. The most common second meiotic division and occur by chromosomal nondis- cause is congenital adrenal hyperplasia, an inherited ab- junction, translocation, rearrangement, or deletion. The normality in adrenal steroid biosynthesis, with most cases two most common disorders are Klinefelter’s syndrome of virilization resulting from 21-hydroxylase or 11-hy- (47,XXY) and Turner’s syndrome (45,XO). Because of a Y droxylase deficiency (see Chapter 34). In such cases, corti- chromosome, an individual with a 47,XXY karyotype has sol production is low, causing increased production of normal testicular function in utero in terms of testosterone ACTH by activating the hypothalamic-pituitary axis and AMH production and no ambiguity of the genitalia at (Fig. 39.15). The elevated ACTH levels induce adrenal hy- birth. The extra X chromosome, however, interferes with perplasia and an abnormal production of androgens and the development of the seminiferous tubules, which show corticosteroid precursors. These infants are born with am- extensive hyalinization and fibrosis, whereas the Leydig biguous external genitalia (i.e., clitoromegaly, labioscrotal cells are hyperplastic. Such males have small testes, are fusion, or phallic urethra). The degree of virilization de- azoospermic, and often exhibit some eunuchoidal features. pends on the time of onset of excess fetal androgen pro- Because of having only one X chromosome, an individual duction. When aldosterone levels are also affected, a life- with a 45,XO karyotype will have no gonadal development threatening salt-wasting disease results. Untreated patients during fetal life and is presented at birth as a phenotypic fe- with congenital adrenal virilism develop progressive mas- male. Given the absence of ovarian follicles, such patients culinization, amenorrhea, and infertility.
704 PART X REPRODUCTIVE PHYSIOLOGY Male pseudohermaphrodites are 46,XY individuals with in utero causes regression of the müllerian ducts. These in- differentiated testes but underdeveloped and/or absent dividuals have neither male nor female internal genitalia wolffian-derived structures and inadequate virilization of and phenotypic female external genitalia, with the vagina the external genitalia. These effects result from defects in ending in a blind pouch. They are reared as females and un- testosterone biosynthesis, metabolism, or action. The 5- dergo feminization during puberty because of the periph- reductase deficiency is an autosomal recessive disorder eral conversion of testosterone to estradiol. caused by the inability to convert testosterone to DHT. Disorders of puberty are classified as precocious pu- Such infants have ambiguous or female external genitalia berty, defined as sexual maturation before the age of 8 and normal male internal genitalia (Fig. 39.16). They are years, and delayed puberty, in which menses does not start often raised as females but undergo a complete or partial by age 17 or testicular development is delayed beyond age testosterone-dependent puberty, including enlargement of 20. True precocious puberty results from premature activa- the penis, testicular descent, and the development of male tion of the hypothalamic-pituitary-gonadal axis, leading to psychosexual behavior. Azoospermia is common. the development of secondary sex characteristics as well as The testicular feminization syndrome is an X-linked re- gametogenesis. The most frequent causes are CNS lesions cessive disorder caused by end-organ insensitivity to an- or infections, hypothalamic disease, and hypothyroidism. drogens, usually because of absent or defective androgen Pseudoprecocious puberty is the early development of receptors. These 46,XY males have abdominal testes that secondary sex characteristics without gametogenesis. It can secrete normal testosterone levels. Because of androgen in- result from the abnormal exposure of immature boys to an- sensitivity, the wolffian ducts regress, and the external gen- drogens and of immature girls to estrogens. Augmented italia develop along the female line. The presence of AMH steroid production can be of gonadal or adrenal origin. REVIEW QUESTIONS DIRECTIONS: Each of the numbered 4. The next ovulatory cycle after (A) Androgens produced from items or incomplete statements in this implantation is postponed because of cholesterol in the placenta section is followed by answers or by (A) High levels of PRL (B) Estradiol as a precursor from the completions of the statement. Select the (B) The production of hCG by mother’s ovary ONE lettered answer or completion that is trophoblast cells (C) Androgenic substrates from the BEST in each case. (C) The production of prostaglandins fetus by the corpus luteum (D) Androgens from the ovary of the 1. The suckling reflex (D) The depletion of oocytes in the mother (A) Has afferent hormonal and efferent ovary (E) Estradiol to be produced in the neuronal components (E) Low levels of progesterone placenta (B) Increases placental lactogen 5. Polyspermy block occurs as a result of 9. One benefit of insulin resistance in the secretion the mother during pregnancy is (C) Increases the release of dopamine (A) Cortical reaction (A) A reduction of her plasma glucose from the arcuate nucleus (B) Enzyme reaction concentrations (D) Triggers the release of oxytocin by (C) Acrosome reaction (B) The blockage of the development stimulating the supraoptic nuclei (D) Decidual reaction of diabetes mellitus in later life (E) Reduces PRL secretion from the (E) Inflammatory reaction (C) The increased availability of pituitary 6. Oral steroidal contraceptives are most glucose to the fetus 2. Implantation occurs effective in preventing pregnancy by (D) A reduction of pituitary function (A) On day 4 after fertilization (A) Blocking ovulation (E) Increased appetite (B) After the endometrium undergoes a (B) Altering the uterine environment 10.The primary reason that the female decidual reaction (C) Thickening the cervical mucus phenotype develops in an XY male is (C) When the embryo is at the morula (D) Reducing sperm motility (A) The secretion of progesterone stage (E) Inducing a premature LH surge (B) Adrenal insufficiency (D) Only after priming of the uterine 7. The maternal recognition of pregnancy (C) The lack of testosterone action endometrium by progesterone and occurs as a result of the (D) Increased inhibin secretion estrogen (A) Prolonged secretion of estrogen by (E) The secretion of antimüllerian (E) On the first day after entry of the the placenta hormone (AMH) embryo into the uterus (B) Production of human placental 3. Upon contact between the sperm head lactogen and the zona pellucida, penetration of (C) Increased secretion of SUGGESTED READING the sperm into the egg is allowed progesterone by the corpus luteum Carr BR. Fertilization, implantation, and because of (D) Secretion of hCG by the endocrinology of pregnancy. In: Griffin (A) The acrosome reaction trophoblast JE, Ojeda SR, eds. Textbook of En- (B) The zona reaction (E) Activation of an inflammatory docrine Physiology. 4th Ed. New York: (C) The perivitelline space reaction at implantation Oxford University Press, 2000;265–285. (D) Pronuclei formation 8. Estriol production during pregnancy Hay WW Jr. Metabolic changes in preg- (E) Cumulus expansion requires nancy. In: Knobil E, Neill JD, eds. The
CHAPTER 39 Fertilization, Pregnancy, and Fetal Development 705 Encyclopedia of Reproduction. New nancy. In: Carr BR, Blackwell RE, eds. encyclopedia of reproduction. New York: Academic Press, 1999;106–1026. Textbook of Reproductive Medicine. York: Academic Press, 1999;986–991. Johnson MH, Everitt BJ. Essential Repro- East Norwalk, CT: Appleton & Lange, Spencer TE: Maternal recognition of preg- duction. Oxford, UK: Blackwell Sci- 1993;17–40. nancy. In: Knobil E, Neill JD, eds. The ence, 2000. Regan CL. Overview, pregnancy in hu- Encyclopedia of Reproduction. New Parker CR Jr. The endocrinology of preg- mans. In Knobil E, Neill JD, eds. The York: Academic Press, 1999;1006–1015. CASE STUDIES FOR PART X • • • CASE STUDY FOR CHAPTER 37 3. What are some theoretical treatment options for this patient? Answers to Case Study Questions for Chapter 38 Steroid Abuse 1. There are two laboratory tests that indicate a problem, the A 30-year-old man and his 29-year-old wife have been try- low late follicular phase plasma estradiol concentration and ing to have a baby. She has been having regular menstrual the low midluteal phase plasma progesterone concentra- cycles. They have intercourse 2 to 3 times a week, with no tion. physical problems, and try to time intercourse around the 2. The low estradiol could be due to the development of a time of her ovulation. small dominant graafian follicle with insufficient numbers of Physical examination and history for the wife are normal. granulosa cells. The reduced number of granulosa cells The husband’s physical examination reveals a muscular would not contain sufficient aromatase to synthesize the man with an excellent physique who works out regularly to high levels of estradiol required during the late follicular build his body. His testes are small and soft. Laboratory re- phase. In addition, low estradiol could be due to inadequate sults indicate that his plasma testosterone is 1850 ng/dL FSH receptors on the granulosa cells or inadequate FSH se- (normal, 300 to 100 ng/dL) and LH 2 U/mL (normal, 3 to cretion. The low estradiol could also be explained by a lack 18 U/mL). His semen analysis reveals a sperm count of 1.2 of LH stimulation of thecal androgen production from the 6 6 10 /mL (normal, 20 10 /mL) small dominant follicle, possibly the result of inadequate LH Questions receptors on theca cells or low LH levels. 1. What is the major reason for the failure of the wife to get The low progesterone during the luteal phase might be due pregnant? to the ovulation of a small follicle or premature ovulation of a 2. What is a reasonable explanation for the abnormal hor- follicle that was not fully developed. The number of LH recep- mone levels? tors on the luteinized granulosa cells in the graafian follicle and developing corpus luteum may be insufficient, or LH se- Answers to Case Study Questions for Chapter 37 cretion may be deficient. LH receptors mediate the action of 1. He has an extremely low sperm count. LH, which stimulates progesterone secretion. An insufficient 2. Since he is a body builder with small, soft testes, high number of LH receptors could be due to insufficient priming testosterone levels, and low LH levels, the physician should of the developing follicle with FSH. Finally, the LH surge may suspect androgen abuse or possibly androgen-producing be insufficient for maximal progesterone secretion. tumor (extremely rare). The high androgen levels would 3. Theoretical treatment options for the patient include exoge- suppress LH secretion and reduce intratesticular testos- nous progesterone during the luteal phase, which would terone levels. The low LH and intratesticular testosterone raise the overall circulating progesterone to levels compati- would correlate well with small testes and low sperm count, ble with maintaining pregnancy, allowing implantation of respectively. the embryo. Another option would be to use exogenous FSH to stimulate follicular development to produce larger follicle(s) with suffi- CASE STUDY FOR CHAPTER 38 cient estradiol secretion and LH receptors. Follicles with ade- Early Spontaneous Pregnancy Termination quate LH receptors would respond to an LH surge with in- creased progesterone in the normal range. Another option is A 35-year-old woman visited her obstetrician/gynecolo- the administration of hCG during the periovulatory period for gist and complained that she was unable to get pregnant. inducing ovulation and full luteinization. The latter would Upon taking a medical history, the physician notes that the overcome any deficiency in the endogenous LH surge. Finally, patient had regular 28- to 30-day cycles during the past year, the use of clomiphene, an antiestrogen, would increase FSH during which time she had regular unprotected intercourse. (and LH) secretion in the follicular phase and, subsequently, She does not smoke and does not use caffeine, drugs, or al- induce follicular development with sufficient estradiol to in- cohol. She appears to be in good health. Her ovaries and duce a full LH surge. Exogenous hCG could be given during uterus appear normal in size for her age. Laboratory tests in- the ovulatory phase to ensure full luteinization of the corpus dicate that her preovulatory (late follicular phase) estradiol is luteum with sufficient progesterone to maintain pregnancy. 40 pg/mL (normal, 200 to 500 pg/mL) and midluteal phase progesterone is 3 ng/mL (normal, 4 to 20 ng/mL). Her hus- CASE STUDY band’s sperm count is 30 million/mL. Female Infertility Questions 1. What are the clinical indications of a fertility problem with A 25-year-old woman and her 29-year-old husband this patient? have been trying to have a baby for one year. She has reg- 2. Based on the clinical signs, what basic physiological princi- ular menstrual cycles of 26 to 28 days in length. They have ples provide insight into the infertility? intercourse three times a week, with no physical problems,
706 PART X REPRODUCTIVE PHYSIOLOGY and they try to time intercourse around the time of her cate that a dominant follicle has been recruited and is ac- ovulation. tive; low levels would indicate a subnormal dominant folli- Physical examination and history for the wife are normal. cle or lack of a dominant follicle; this could be verified by ul- The husband’s physical examination is normal. The hus- trasound of the ovaries. Serum LH should be measured band’s semen analysis reveals a semen volume of 4 mL; pH during the anticipated preovulatory period. High serum lev- 7.5; sperm count of 30 million/mL; and normal morphology els of LH would indicate that the dominant follicle is getting and motility of the sperm. Because of the short cycles (24 to the signal to ovulate. Low levels of LH may lead to an un- 26 days versus 28 days), the wife’s plasma progesterone ruptured dominant follicle that fails to ovulate but luteinizes, level during the midluteal phase is assessed and determined leading to progesterone levels in the normal range for the to be 10 ng/mL, which is considered normal (4 to 20 ng/mL, luteal phase. Plasma concentrations of hCG could be deter- see Table 38.3). mined during the midluteal to late luteal phase to determine whether she was pregnant. Questions 2. Low estradiol indicates a lack of development of a dominant 1. What hormones can be measured in the blood to determine follicle. Therapies such as gonadotropins and clomiphene why the patient is not able to get pregnant? 2. Based on the hormone measurements, what treatment (see Chapter 38) would be appropriate to stimulate follicular development, estradiol secretion, and ovulation. If a domi- would likely result in a successful pregnancy? nant follicle is present, then hCG can be given to induce fol- Answers to Case Study for Chapter 39 licular rupture. hCG binds to the LH receptor and is pre- 1. Estradiol should be measured at the end of the anticipated ferred over LH and GnRH for ovulation induction because of follicular phase. High serum levels of estradiol would indi- its longer half-life.
APPENDIX A Answers to Review Questions the action of either adenylyl or guanylyl cyclase on ATP or GTP, respectively. Cyclic AMP and cGMP ac- tivate distinct signaling pathways. For example, cAMP Chapter 1 can activate protein kinase A, which will phosphory- 1. The answer is C. In a steady state, the amount or con- late its substrates; cGMP activates protein kinase G, centration of a substance in a compartment does not which phosphorylates a different set of substrates. Al- change with respect to time. Although there may be though signal transduction in sensory tissues involves considerable movements into and out of the compart- both cAMP and cGMP, cGMP has a more important ment, there is no net gain or loss. Steady states in the role in signal transduction than cAMP. Phospholipase body often do not represent an equilibrium condition, C activation is coupled to the activation of a G protein but they are displaced from equilibrium by the con- (G q ), not to cAMP or cGMP. stant expenditure of metabolic energy. 6. The answer is D. Steroid hormone receptors are tran- 2. The answer is D. The increase in plasma insulin lowers scriptional regulators found in the cytoplasm or in the the plasma glucose concentration back to normal and nucleus. These receptors are activated by the binding is an example of negative feedback. Negative feedback of steroid ligands that diffuse through lipid bilayers opposes change and results in stability. Positive feed- and enter the cytosol. Activated steroid receptors me- back would produce a further increase in plasma glu- diate their effects by direct interaction with gene reg- cose concentration. Chemical equilibrium indicates a ulatory elements and do not activate G proteins or condition in which the rates of reactions in forward cause binding of IP 3 to the IP 3 -gated calcium release and backward directions are equal. End-product inhi- channel in the sarcoplasmic reticulum. Steroid hor- bition occurs when the products of a chemical reaction mone receptors do not have tyrosine kinase activity slow the reaction (for example, by inhibiting an en- and do not cause the phosphorylation of tyrosine zyme) that produces them. Feedforward control in- residues in these receptors. Steroid hormone receptors volves a command signal and does not directly sense are not linked to activation of the MAP kinase path- the regulated variable (plasma glucose concentration). way. Estrogen receptors are located in the cytoplasm 3. The answer is E. The EGF receptor is a tryosine kinase of cells; upon binding of estrogen, they move to the receptor; therefore, an inhibitor of tyrosine kinases nucleus to bind to estrogen response elements to acti- should have the desired effect. An adenylyl cyclase vate gene transcription. stimulator or phosphodiesterase inhibitor would in- 7. The answer is E. Cardiac muscle cells have many gap crease intracellular levels of cAMP, but this is not the junctions that allow the rapid transmission of electrical second messenger problem here. An EGF agonist activity and the coordination of heart muscle contrac- would increase signaling along the EGF pathway and tion. Gap junctions are pores composed of paired con- would increase the problem, causing an undesired ef- nexons that allow the passage of ions, nucleotides, and fect. Likewise, a phosphatase inhibitor would slow the other small molecules between cells. hydrolysis of phosphorylated intermediates and main- 8. The answer is E. Inositol trisphosphate (IP 3 ) and dia- tain the activated state of the EGF pathway. cylglycerol (DAG) are generated by the action of 4. The answer is D. Second messengers are a class of sig- phospholipase C (PLC) on PIP 2 , phosphatidylinositol naling molecules generated inside cells in response to 4,5-bisphosphate. IP 3 and DAG are second messen- the activation of a receptor. If second messengers were gers, not first messengers. DAG is important for the ac- always available, signal transduction pathways could tivation of protein kinase C, not PLC. Tyrosine kinase not be regulated. The response to a second messenger receptors are activated by the binding of ligands, such varies depending on the cell type because each cell as hormones or growth factors, not by IP 3 or DAG. IP 3 type differs with respect to the number and comple- can indirectly activate calcium-calmodulin-dependent ment of receptors, effectors, and downstream targets. protein kinases by causing the release of calcium from Second messengers include nucleotides such as cAMP intracellular stores; DAG has no direct effect on these or cGMP, ions such as calcium, and gases such as nitric kinases. oxide. Many different plasma membrane receptors, not 9. The answer is C. The activation of tyrosine kinase re- only tyrosine kinase receptors, are coupled to second ceptors often results in a cellular response that is in- messenger generating systems. volved in growth or differentiation. Tyrosine kinase re- 5. The answer is B. Cyclic nucleotides are generated by ceptors do not have constitutively active receptors; if 707
708 APPENDICES this were true, there could be no regulation of signal- 7. The answer is A. Cyclic GMP is the ligand that opens ing. The activation of ras occurs indirectly by the acti- the ion channel in this example. Ion pumps and Na vation of adapter molecules (Grb2 and SOS) that asso- solute-coupled transporters are examples of active ciate with phosphorylated tyrosine residues in the transport systems, not Na channels. The process is cytoplasmic tail of the receptor. The activation of ty- unrelated to receptor-mediated endocytosis. rosine kinase receptors usually involves multimeriza- 8. The answer is C. K is the major intracellular ion; ef- tion into dimers or trimers. flux of K will produce an osmotic flow of water out of 10. The answer is B. If it is unable to hydrolyze GTP, the the cell. Water exit will lead to a decrease in cell vol- G s subunit remains in its active form and results in in- ume. An influx of Na and synthesis of sorbitol do not creases in adenylyl cyclase activity, intracellular occur during this process because both processes cAMP, and release of growth hormone. If G i is acti- would increase intracellular osmolytes and drive water vated, adenylyl cyclase activity will be decreased. A into the cell, increasing cell volume. lack of GHRH receptors should produce decreased, 9. The answer is D. By substituting in the Nernst equa- not increased, growth hormone secretion. tion (equation 7): E i E o 61/–1 log 10 120/8 Chapter 2 61 1.176 71.7 mV inside the cell. 1. The answer is D. Phospholipids have both a polar hy- drophilic head group and a hydrophobic region be- Note that for Cl , the value for z (valence) is 1. cause of the long hydrocarbon chains of the two fatty 10. The answer is E. By using the van’t Hoff equation: acids. Since the hydrophilic and hydrophobic regions are present within the same molecule, phospholipids n R T ? C are described as amphipathic. Phospholipids are not 3 0.0821 300 0.86 0.1 soluble in water and do not have a steroid structure. 6.35 atm 2. The answer is B. Phospholipid molecules can rotate and move laterally within the plane of the lipid bilayer, Chapter 3 but movement from one half of the bilayer to the other is slow because it is an energetically unfavorable 1. The answer is B. Potassium ion concentration is high process. Cholesterol is an example of a separate class of in the intracellular fluid relative to the extracellular lipids that do not contain fatty acids. Many phospho- fluid. The opposite is true for sodium ion concentra- lipids are distributed unequally between the two halves tion; therefore, there is a strong driving force for potas- of the lipid bilayer. In the red blood cell membrane, for sium to leave the cell and sodium to enter the cell. If example, most of the phosphatidylcholine is in the the permeability to K increases, more potassium outer half. Both ion channels and symporters are mem- would leave the cell, and the cell would become more brane proteins, not phospholipids. negative (hyperpolarize). If the permeability to Na 3. The answer is A. Membrane-spanning segments of in- decreases, less sodium would enter the cell, and the cell tegral proteins frequently adopt an -helical confor- would become less positive (hyperpolarize). mation because this structure maximizes the opportu- 2. The answer is C. Voltage-gated potassium channels nities for the polar peptide bonds to form hydrogen open with a delay relative to voltage-gated sodium bonds with one another in the hydrophobic interior of channels in response to depolarization. Concomi- the lipid bilayer. These segments are composed largely tantly, there is a delay in their closing relative to the of amino acids with nonpolar hydrophobic side chains sodium channels. During the afterhyperpolarization that interact with the surrounding lipids. There are no phase of the action potential, the sodium channels are covalent bonds with cholesterol or phospholipids, and closed, but the potassium channels remain open. Be- the peptide bonds are not unusually strong. cause there is a strong driving force for K to leave the 4. The answer is D. The Nernst equation calculates the cell, the cell hyperpolarizes. An outward calcium cur- membrane potential that develops when a single ion is rent, an outward sodium current, or an inward chloride distributed at equilibrium across a membrane. The current could conceivably hyperpolarize the cell, but Goldman equation gives the value of the membrane these currents are not the basis for this phase of the ac- potential when all permeable ions are accounted for. tion potential. The van’t Hoff equation calculates the osmotic pres- 3. The answer is D. A specialization occurs in myelinated sure of a solution, and Fick’s law refers to the diffu- axons in which the voltage-gated sodium channels are sional movement of solute. The permeability coeffi- preferentially distributed to the axonal membrane be- cient accounts for several factors that determine the neath the nodes of Ranvier. Since these channels are ease with which a solute can cross a membrane. required for the generation of an action potential, the 5. The answer is B. Intracellular K is high compared action potential jumps from node to node. This with all other intracellular ions. process is facilitated by an increased membrane resist- 6. The answer is C. Active transport always moves solute ance and a decreased capacitance associated with the against its electrochemical gradient. All the other op- myelinated regions of the axon, both of which pro- tions are shared by both active transport and equili- mote the electrotonic spread of the positive charge brating carrier-mediated transport systems. that accumulates beneath one node of Ranvier at the
APPENDIX A Answers to Review Questions 709 peak of the action potential. Nongated ion channels available at the terminals, using enzymes that reside in are not involved in the generation of action potential. the terminals. However, peptides must be synthesized 4. The answer is C. Myelin contributes substantially to by ribosomes, which are not found in axons or termi- the effective membrane resistance, R m . The space con- nals. The supply of peptide transmitters in the axon stant increases as R m increases because it is more diffi- terminal must be continuously replenished via axoplas- cult for ions to flow across the membrane relative to mic transport from the cell body. Microtubules are an the ease with which they flow within the axon. When essential component of axoplasmic transport; disrupt- an axon demyelinates, its space constant decreases and ing their integrity would diminish axonal transport and conduction velocity is slowed. This slowing of the deplete the peptide transmitter from the terminal. conduction velocity is the basis for the neurological 11. The answer is B. GABA is the major inhibitory trans- deficits associated with multiple sclerosis. mitter in the brain. The activation of GABA receptors 5. The answer is C. SNARES are the group of proteins re- hyperpolarizes neurons. Activity of the GABA system sponsible for docking and binding synaptic vesicles to is widespread in the brain, and a disruption of GABA the presynaptic membrane to prepare them for release. signaling results in a hyperexcitability of neurons that If the vesicles cannot dock, they cannot fuse with the can lead to seizures. membrane to release their neurotransmitter. Disrup- 12. The answer is B. The acute onset of symptoms in both tion of SNARES has no direct effect on other compo- people suggests food poisoning and not a chronic dis- nents of neurochemical transmission, including action order or a stroke. A toxin that blocked nerve-muscle potential propagation, transmitter-receptor interac- transmission would produce muscle paralysis or weak- tion, or uptake mechanisms. ness and no sensory disturbances. The tingling feeling 6. The answer is A. Spatial summation of synaptic poten- suggests abnormally high excitability and firing of sen- tials can occur if they are close enough that the space sory nerves. Ciguatera toxin, the product of a dinofla- constant spans the two synapses; therefore, properties gellate that sometimes contaminates red snapper and of the cell that increase the space constant would opti- other reef fishes, is probably the cause of the sensory mize the effectiveness of the two synapses. The space abnormality and gastrointestinal symptoms. Ciguatera constant increases with increasing membrane resist- toxin binds to voltage-gated sodium channels and re- ance or decreasing cytoplasmic resistance. Cytoplas- sults in their persistent activation. mic resistance decreases as the cross-sectional area in- 13. The answer is C. Loss of myelin will result in a lower creases. Temporal summation could also increase the conduction velocity because the action potential will effectiveness of the two synapses; this would be facili- no longer “jump” from node to node. The compound tated by a large time constant. action potential (the sum of many individual action po- 7. The answer is C. Acetylcholinesterase is the enzyme tentials) will be more spread out and will have a slower that breaks acetylcholine down into acetate and rate of rise than normal. The afterhyperpolarization choline. The acetate diffuses away, and choline is will last longer. taken back up into the presynaptic nerve terminal for 14. The answer is C. Release of transmitter depends on the synthesis of more ACh. Blocking the function of opening of voltage-gated calcium channels and entry acetylcholinesterase would prevent the breakdown of of extracellular calcium into the nerve terminals. Defi- ACh, which would accumulate in the cleft because cient acetylcholine release by motor nerve terminals there is no uptake mechanism for ACh and it diffuses could explain muscle weakness. Nerve conduction ve- away more slowly than acetate. locity is not dependent on calcium channels. The re- 8. The answer is C. Catecholaminergic transmission is ef- polarization phase of the nerve action potential de- ficient, in part, because there is a significant reuptake pends on voltage-gated potassium channels. The of the catecholamines for repackaging into synaptic upstroke of the nerve action potential depends on volt- vesicles to use again. MAO and COMT are not found age-gated sodium channels. Nerve excitability (and, in the cleft and do not aid in the removal of the cate- hence, nerve firing) is affected by extracellular calcium cholamines from the cleft. The postsynaptic cell may concentration (hypocalcemia results in increased ex- have an uptake mechanism (not endocytosis) for the citability), but this is because of an effect on sodium catecholamines, but the efficacy of this mechanism is channels, not calcium channels. substantially lower than the reuptake mechanism. 9. The answer is A. Dopamine plays a major role in two Chapter 4 functional systems of the brain, the motor system and the limbic system. Within the limbic system, DA is as- 1. The answer is A. The intensity of sensory information sociated with affect. Too much dopaminergic trans- is encoded in the action potential frequency. Cessation mission can result in psychotic disorders, such as schiz- of the stimulus would lead to a rapid decrease in the ac- ophrenia. A blockade of dopaminergic transmission tion potential frequency, and adaptation of the recep- ameliorates psychosis. Cholinergic transmission is in- tor would also lead to a decrease in frequency. With a volved in cognitive function and motor control. The constant and maintained stimulus, at least some adap- role of nitrergic transmission in cognition and behav- tation would take place, and the frequency would fall ior is unknown. somewhat (and certainly not increase). The action po- 10. The answer is D. Most neurotransmitters are synthe- tential velocity is a property of the nerve—not the re- sized locally within the axon terminals from precursors ceptor—and it would not be affected.
710 APPENDICES 2. The answer is C. Rods and cones are absent from the tended limb are best sensed by receptors that adapt area of the retina where the optic nerve exits. The slowly. Likewise, sensors that adapt quickly would not blind spot is of appreciable size, but because its loca- be well suited for detecting the continued presence of tion is off-center and the eyeballs are mirror images, a chemical stimulus. (Our rapidly adapting olfactory each eye fills in the information missing from the sensors can sometimes fail to provide information other, even when the gaze is fixed at a point. There are about a continuing hazard.) no connections from lateral cells to the blind spot be- 9. The answer is D. Reduction in the intensity of a sensa- cause nerves are exiting there and do not make tion is largely the result of a decline in the generator synapses. potential. In this sense, it mimics the effects of a re- 3. The answer is C. Presbyopia is the age-related inabil- duction in the stimulus intensity. Because the action ity of the eye to focus on close objects. The decreased potentials arising in a sensory nerve are all-or-none, compliance of the lens prevents it from assuming a suf- their velocity of conduction, amplitude, and duration ficiently curved state, and the focal point is behind the of depolarization are not affected by the stimulus in- retina. As a person ages, only minor changes occur in tensity; rather, they are properties of the nerve cell. the shape of the eyeball. Age-related changes in the 10. The answer is C. The transfer of energy through the opacity of structures through which light must pass, middle ear from the relatively large eardrum to the while they can impair vision, have little effect on the smaller oval window by the ossicular chain increases the focal point of the light rays. efficiency of the mechanical transduction process. The 4. The answer is B. A myopic eyeball is too long, and bones do not support the membrane structures but allow light rays coming from great distances focus in front of them to move relatively freely. Interference with the os- the retina. The range of motion available to the lens is sicular transmission process by external influences (as by not sufficient to provide accommodation regardless of the stapedius and tensor tympani muscles) or by disease the effort made. A negative lens placed in front of the processes, acts to reduce the vibration transfer effi- eye corrects the eye’s refractive power, and the rays ciency, a change that can be either protective or harm- will now focus on the retina. A positive lens would only ful. The function of the eustachian tube is independent worsen matters, and a cylindrical lens (which has two of the ossicles. While the bones themselves are passive, foci, depending on the orientation considered) would they are essential to the process of sound conduction. not compensate satisfactorily. Reducing the light in- 11. The answer is B. The cone cells, which are responsible tensity also would not help; the pupils would dilate and for color vision, are located at the point of sharpest fo- admit more peripheral rays that would be further out of cus, but they do not function if the light intensity too focus. low. In such cases, the single-pigment rod cells (with 5. The answer is A. The frequency response of the basi- greater sensitivity, but with less advantageous location lar membrane changes steadily from high to low along and interconnection) provide monochromatic but dif- its length, so that high frequencies are detected close fuse vision. The color composition of light does not to the oval window and low frequencies are detected at depend on its intensity, and dark adaptation does not the other end, near the helicotrema. change the spectral sensitivity of the individual pig- 6. The answer is C. Relative motion between the en- ments. While focusing mechanisms may be less effec- dolymph and the cupulae of the semicircular canals is tive with low light, they still function. due to the inertia of the endolymph, whether the body motion is starting or stopping. As the fluid continues to Chapter 5 move when the head has stopped moving, the cupulae will be stimulated, producing the sensation of rotary 1. The answer is A. The maintenance of posture requires motion. Moving in a straight line, without accelera- continuous muscle action. The low threshold for acti- tion, will produce no fluid movement and no sensation. vation, fatigue-resistant motor units are the type active The sensation of static body position is accomplished in postural control. Intrafusal muscle fibers do not con- by the maculae, which are sensitive to gravity but not tribute to force generation. endolymph motion. 2. The answer is C. The Golgi tendon organ senses the 7. The answer is A. When a receptor adapts, the sensa- force of muscular contraction. The nuclear chain and tion decreases although the stimulus may be un- bag fibers, along with type Ia endings, are all compo- changed. Adaptation is largely a result of the fall in nents of the muscle spindle which reports muscle magnitude of the generator potential and is not due to length and velocity of muscle shortening. fatigue. Sensory responses are graded in response to 3. The answer is D. Motor neurons controlling axial mus- changes in stimulus intensity regardless of the level of cles are positioned most medially in the ventral horn adaptation, and the phenomenon of compression al- area. An enlarged central canal would impinge on that lows a wide range of environmental intensities to be pool of motor neurons first. translated into a much more narrow range of sensory 4. The answer is C. Muscle spindles monitor muscle responses. length. If the muscle is suddenly stretched, the spindle 8. The answer is B. Rapidly adapting sensory receptors produces action potentials that activate homonymous are best suited for detecting motion and change. Ac- motor neurons to contract the stretched muscle and re- tions such as holding a steady weight and sensing the sist the length change. resting position of the body or the position of an ex- 5. The answer is E. The spinal cord has the intrinsic cir-
APPENDIX A Answers to Review Questions 711 cuitry in the form of central pattern generators to pro- 5. The answer is E. Sweat glands are controlled by the duce the basic motions of walking. All the other listed sympathetic nervous system. areas may influence the local pattern generators. 6. The answer is B. Postsynaptic neurons are about a 100- 6. The answer is D. The rubrospinal tract descends in the fold more numerous than the presynaptic neurons. lateral spinal cord and influences distal muscle func- This divergence is why presynaptic neuron activation tion. This is also the function of the corticospinal tract. can produce a widespread sympathetic response. The vestibulospinal and reticulospinal tracts descend 7. The answer is D. Bright light would cause constriction medially and influence proximal muscle action. The of the pupil as a result of parasympathetic activation. spinocerebellar tract is an ascending pathway. Medications that inhibit the action of acetylcholine 7. The answer is C. The primary motor area is located (anticholinergic drugs) could impair pupillary con- along the precentral gyrus. The supplementary motor striction. Inhibition of adrenergic action might assist in area is located on the medial aspect of the hemisphere. pupillary constriction, but the primary constrictor ac- The other areas have sensory and association functions tion is cholinergic. that influence the motor areas. 8. The answer is D. Muscarinic receptors at the synapse 8. The answer is E. The supplementary motor area tends between the postganglionic axon and the target tissue to produce bilateral motor responses when stimulated. are of the indirect ligand-gated type, which utilizes a G The other areas would tend to produce unilateral re- protein. This type synapse alters the function of sponses. adenylyl cyclase and produces changes in cyclic AMP 9. The answer is C. The neurons of the primary motor levels. The preganglionic to postganglionic sympa- cortex contribute about one-third of the axons that thetic and parasympathetic synapses are directly gated make up the corticospinal tract. Other tracts, such as by acetylcholine. Curare blocks the receptor at the the rubrospinal, do not sprout additional axons. The neuromuscular junction but not at the direct ligand- alpha motor neurons do not atrophy if deprived of cor- gated cholinergic autonomic synapses. ticospinal input. 9. The answer is E. The medullary reticular formation is 10. The answer is C. Decreased inhibitory input to the the anatomic site for coordination of cardiac sympa- GPi from the putamen, would enhance inhibitory out- thetic and parasympathetic activity. put from the GPi to the thalamus. The result is inhibi- tion of excitatory output from the thalamus back to the Chapter 7 cortex. 11. The answer is B. Spinal input, such as from the spin- 1. The answer is A. Alpha waves are noted in the EEG in ocerebellar tracts, enters the cerebellum on the mossy a relaxed, awake person whose eyes are closed. An alert fibers. The climbing fibers originate from the inferior state is indicated by beta waves. Theta and delta waves olivary nucleus of the medulla. The other components are noted during sleep. Variability in the wave forms are intrinsic to the cerebellum. might indicate a seizure or damage locus. 2. The answer is D. Dreams are associated with REM Chapter 6 sleep. Normally, a person does not “act out” his or her dream because all of the motor neurons to muscles 1. The answer is D. Pupillary dilation is a function of the other than those for respiration, the middle ear, and sympathetic innervation that originates from the upper the extraocular eye muscles are inhibited, abolishing thoracic spinal cord. The preganglionic axons pass up muscle tone. If this inhibition does not occur, a person the paravertebral sympathetic chain to the superior exhibits marked and often dangerous movement dur- cervical ganglion from which the postganglionic axons ing dreaming. Muscle tone is reduced but not abol- arise. These axons then ascend in the pericarotid ished during slow-wave sleep; however, movements plexus to the eye. are not an issue, presumably because dreaming does 2. The answer is D. Destruction of the lumbar paraverte- not occur. (Note, however, that sleepwalking occurs in bral ganglia would impair sympathetic function to the slow-wave sleep.) Increased activity in motor areas of leg on that side. This would result in skin dryness from the cortex (or other areas) during REM sleep normally the absence of sweating and warmth from persistent would not cause movement because motor neurons are vasodilation. There should be no alteration of sensa- inhibited. tion or skeletal muscle function. 3. The answer is D. Melatonin is secreted by the pineal 3. The answer is D. Muscarine is an exogenous agonist gland. Adrenaline is secreted by the adrenal medulla, that acts at postganglionic synapses. All the other leptin by adipocytes, and melanocyte-stimulating hor- agents are neurotransmitters used at autonomic mone and vasopressin by the pituitary. synapses. 4. The answer is D. The basal forebrain nuclei and the pe- 4. The answer is A. The muscarinic parasympathetic and dunculopontine nuclei are major sources of distributed adrenergic sympathetic receptors are both G protein- cholinergic innervation in the CNS. These cell groups linked and share a seven-membrane-spanning segment are functionally dissimilar. Neither is a major input to configuration. The parasympathetic and sympathetic the striatum or involved in language construction. preganglionic synapses are both of the direct ligand- Only the basal forebrain nuclei receive input from the gated type, which is similar in configuration to the re- cingulate gyrus. Although not known for certain, it is ceptor at the neuromuscular junction. unlikely that either of these cell groups is atrophied in
712 APPENDICES schizophrenia, which appears to be a disorder of out the hippocampus, short-term memory is intact but dopaminergic function. the conversion to long-term does not take place. The 5. The answer is A. Circulating leptin levels are sensed by retrieval of stored declarative memory does not require neurons in the arcuate nucleus, which does not possess the hippocampus. The hippocampus is not needed for a blood-brain barrier. While some other regions of the the formation or retrieval of procedural memory. hypothalamus also lack a blood-brain barrier, these re- 13. The answer is E. Wernicke’s area is responsible for the gions do not contain leptin-sensing cells. recognition and construction of words and language; 6. The answer is B. Circadian rhythms are entrained by when it is damaged, the individual speaks but the con- the SCN to the external day/night cycle. This external tent is nonsensical. Damage to Broca’s area results in an information reaches the SCN directly by an optic inability to speak clearly because it controls the motor nerve projection from the retina. The internal clock re- patterns required to speak; the little speech that is pro- sides in the SCN and regulates the production of mela- duced is grammatically and syntactically correct. The tonin by the pineal gland. Reticular formation and vi- hippocampus and corpus callosum are not involved in sual cortical inputs are not directly involved in the the generation of speech. Damage to the arcuate fasci- regulation of circadian rhythms. culus would result in a loss of speech because language 7. The answer is C. Magnocellular neurons of the par- generated in the Wernicke’s area would not be con- aventricular and supraoptic nuclei of the hypo- veyed to Broca’s area. thalamus, whose axons reach the posterior pituitary via 14. The answer is D. Mania is an affective disorder char- the hypothalamo-hypophyseal tract, secrete the poste- acterized by increased transmission through noradren- rior pituitary hormones. The portal capillary system ergic pathways. Other transmitter systems may play a from the hypothalamus to the pituitary gland is associ- role, but effective treatments are targeted at the nora- ated with the anterior pituitary. While pituitary func- drenergic system. tion may be altered by the fight-or-flight response, the 15. The answer is A. Acetylcholine is critical for cognitive reticular activating system, or emotional state, none of function because of the cholinergic neurons in the these directly mediates posterior pituitary hormone se- basal forebrain that relay hippocampal information to cretion. the rest of the cortex. Nicotine activates cholinergic 8. The answer is E. The arcuate fasciculus is the fiber bun- receptors. The only effective drugs for the treatment of dle connecting Broca’s and Wernicke’s areas. The cognitive deficits in Alzheimer’s disease are choliner- fornix connects the hippocampus with the hypothala- gic, although cognition clearly involves neurons in mus and basal forebrain. The thalamocortical tract many regions of the brain that utilize a variety of trans- connects the thalamus with the cortex and the reticu- mitters. lar activating system connects the brainstem with the thalamus and cortex. The prefrontal cortex is not a Chapter 8 fiber bundle. 9. The answer is B. Neuroleptics drugs ameliorate the 1. The answer is C. In all muscle types, the interaction be- symptoms of psychosis in disorders such as schizophre- tween actin and myosin provides the forces that result nia. While the etiology of schizophrenia is far from un- in shortening. Skeletal and cardiac muscle have repeat- derstood and many transmitter systems may be in- ing sarcomeres, but smooth muscle does not. Smooth volved, all neuroleptics block dopamine receptors. and cardiac muscles have small cells, whereas skeletal 10. The answer is A. The intralaminar nuclei of the thala- muscle has large cells. mus receive input from the brainstem reticular activat- 2. The answer is B. The width of the I band changes be- ing system and convey information to the cortex. cause the thin filaments enter farther into the A band. These nuclei are critical for the maintenance of arousal The Z lines move closer together. The decrease in I and consciousness. Without the intralaminar nuclei, band width and the moving of the Z lines together are beta rhythms and attention would be severely compro- proportional, but there is no change in A band dimen- mised. Both slow-wave and REM sleep would be af- sions. fected because the regulation of sleep is also driven by 3. The answer is B. ATP must bind to the myosin heads the reticular activating system and its input. to allow the crossbridges to detach and the cycle to 11. The answer is D. Somatic sensory information from continue. the left hand would be perceived in the right cortex, 4. The answer is A. Relaxed skeletal muscle is in a state of which does not generate language. To verbally explain inhibited contraction. The enzymatic activity of myosin what the object is, the information must cross to the is greatly enhanced by its interaction with actin. The left hemisphere. This crossing occurs through the cor- role of calcium is as an activator, not an inhibitor; at rest, pus callosum. The fornix and hippocampus would be the concentration of free calcium is low. involved in storing memories about particular items, 5. The answer is C. Removal of calcium from the myofil- not in retrieving the memory. Neither the primary so- ament space into the sarcoplasmic reticulum (not the matic sensory cortex on the left side nor the visual cor- extracellular space) is an absolute requirement for nor- tex on either side plays a role in identifying an object mal relaxation. A reduction of ATP would promote placed in the left hand by tactile cues. rigor, not relaxation. 12. The answer is D. The hippocampus is crucial for the 6. The answer is B. When the myofilament overlap is de- formation of long-term (declarative) memory. With- creased above the optimal length, fewer crossbridges
APPENDIX A Answers to Review Questions 713 (borne on the myosin filaments) are able to interact events and will not be affected by the blocked postsy- with actin, and there is a proportionate decrease in the naptic membrane. force produced. The filaments actually come closer to- 4. The answer is B. The contraction will be twitch-like, gether as the muscle becomes thinner. but it will have increased amplitude, reflecting the ad- 7. The answer is C. The sarcoplasmic reticulum releases ditional calcium released from the SR in response to calcium rapidly and in close proximity to the myofila- the second stimulus. Its duration will also be increased ments. Calcium is not stored in the T tubules and is not for the same reason. involved in action potential events at the sarcolemma 5. The answer is A. This is the definition of isometric. in skeletal muscle. The three other responses address factors that might 8. The answer is A. Calcium diffuses away from the tro- change the size of the contraction but have nothing to ponin complex because the intracellular concentration do with whether it is isometric. has become low and the gradient favors dissociation. 6. The answer is B. As long as the muscle is actually lift- Calcium does not bind to active sites on myosin mole- ing the afterload, this is the only factor that determines cules, and individual actin molecules do not have en- the force. The other factors may make the muscle zymatic activity. shorten faster or slower, but they do not affect the 9. The answer is C. ATP is the immediate source of en- force produced. ergy. The other substances are in metabolic pathways 7. The answer is A. This is a statement of relationship that that provide energy, via several routes, into the ATP is graphically represented in the force-velocity curve. pool. They are not used directly in the crossbridge cy- Regarding choice D, note that it is force that deter- cle. mines velocity and not the other way around. 10. The answer is B. The condition called rigor mortis de- 8. The answer is C. This is a point at the maximum of the velops after death because the processes that generate power output curve. F max and V max represent points of ATP stop. ADP does not contain energy usable to sup- zero power. A velocity of two-thirds V max corresponds port contraction. to a force too small to produce maximal power. 11. The answer is B. By shifting its metabolism to anaero- 9. The answer is C. The forearm/biceps combination, be- bic pathways (glycolysis), the muscle keeps function- cause of the proportions involved, operates at a me- ing at the expense of generating end products that will chanical disadvantage with regard to force, trading de- eventually require oxygen consumption for their fur- creased hand force for increased hand velocity. ther processing. This condition is called oxygen 10. The answer is D. This mixture of fiber types is ideal for deficit. 12. The answer is C. A reduction in the calcium-pumping the stated exercise because it can mobilize energy ability of the sarcoplasmic reticulum would leave a quickly. Choice A is a possibility, but almost all mus- higher concentration of calcium ions in the myofila- cles have some mixture of fiber types. ment space for a longer time. The diffusion of calcium 11. The answer is B. Isometric contraction is possible away from the regulatory proteins would be slower, when the volume of the organ is prevented from and crossbridges would detach less rapidly; conse- changing, as by a closed sphincter. Any shortening of quently, the muscle would relax more slowly. Activa- smooth muscle in a hollow organ would be against tion processes would not be as affected because they some sort of load. do not directly depend on the effectiveness of the cal- 12. The answer is C. The level of phosphorylation would cium pump. decline because the myosin light chains dephosphory- lated by the phosphatase could not be rephosphory- lated by MLCK because it would no longer be calmod- ulin-activated, as a result of the lowered cellular Chapter 9 calcium. Choice A represents the skeletal muscle con- 1. The answer is B. This is a chemically gated channel dition. without a highly selective filter and voltage sensor 13. The answer is B. This emphasizes the primary role of mechanism. Both sodium and potassium pass through myosin-based regulation in smooth muscle. Choice A it simultaneously down their respective electro- represents the skeletal muscle condition, while choices chemical gradients. C and D do not reflect the actual physiological effects; 2. The answer is B. The endplate potential and the action in particular, choice D is the reverse of the truth. potential are based on changed ionic permeabilities, 14. The answer is C. While smooth and skeletal muscle but the postsynaptic channels in the endplate region can exert about the same amount of force per cross- are not voltage-sensitive. This means that the endplate sectional area, smooth muscle does it much more eco- potential cannot regenerate and be propagated. Be- nomically. It is capable of extreme shortening when cause the channels do not select between sodium and conditions external to the muscle allow. potassium, the endplate potential is close to zero. As 15. The answer is B. The crossbridge cycle of smooth such, it can never assume a large inside-positive value. muscle is similar to that of skeletal muscle, with the 3. The answer is A. The postsynaptic membrane channels added complexity (in some smooth muscles) of the are blocked by the bound curare molecules and will not latch state of crossbridges. allow ions to pass; therefore, this membrane will not 16. The answer is C. Smooth muscle membrane receptors depolarize. The other choices are all presynaptic perform a wide variety of functions and are involved in
714 APPENDICES both chemical and electrical activities at the mem- responding to bacteria. The hexose monophosphate brane. shunt is an enzyme cascade (not a reactant) that func- tions to provide high levels of reduced NADPH to drive this reaction. G proteins are not reactants, but Chapter 10 play an essential role in the activation of this cellular 1. The answer is C. Cardiac muscle has small cells that cascade. Similarly, the enzyme myeloperoxidase is not must be coupled electrically for communication to oc- a reactant; it enhances the ability of reactants, such as cur. Because it receives no motor innervation, it must hydrogen peroxide, to exert a lethal effect on invading be spontaneously active. bacteria. 2. The answer is B. The intercalated disk is the site of 3. The answer is A. T cells are infected by HIV in indi- electrical coupling and mechanical linkage, both of viduals who have AIDS. B cells, like T cells, are lym- which are necessary for the tissue to behave as a syn- phocytes, but they are not targets for HIV. Neu- cytium. trophils are not lymphocytes and are not infected by 3. The answer is B. Cardiac muscle is similar to skeletal the AIDS virus. Monocytes and basophils similarly are muscle in both the structure of its contractile apparatus not targets for the virus that causes AIDS. and the means by which it is regulated. It is similar to 4. The answer is B. Umbilical cord blood, derived from smooth muscle in its small cell size and syncytial be- the circulating blood of newborn infants, possesses havior. high levels of hematopoietic progenitors. Levels of cir- 4. The answer is C. Until the relative refractory period is culating progenitors rapidly decrease after birth, de- over, the muscle cannot be restimulated. By this time, pleting the progenitor content within the circulating it has begun to relax, so a smooth (fused) tetanus can blood of adults. The spleen of adult humans functions not occur. as a hematopoietic organ in certain disease states, such 5. The answer is B. Because the afterload is removed at as leukemia. However, in other animals and in devel- the end of the isotonic portion of the contraction, it is oping human fetuses, the spleen plays an important not available to reextend the muscle and relaxation oc- role in the hematopoietic response. While the liver and curs isometrically at the shortened length. the thymus are important in hematopoiesis and im- 6. The answer is C. Although the relationship is not lin- mune reconstitution prior to birth, these organs are not ear, the muscle is extended in proportion to the pre- involved in hematopoiesis in adult humans. load. In the intact heart, when the heart is filled more 5. The answer is E. When specifically programmed T at rest, the muscle will shorten a greater distance when cells or B cells of the adaptive immune system first rec- it contracts. ognize specific antigens, they begin to divide rapidly, 7. The answer is D. Because the force is high, the muscle generating several copies of cells similarly pro- is nearer the limit set by the length-tension curve. grammed against the inciting stimulus. Hematopoiesis 8. The answer is C. As is the case for skeletal muscle, involves the nonspecific generation of all cells in when the muscle is shortening isotonically, the only blood, including leukocytes, erythrocytes, and factor that controls the force is the afterload. The platelets. Hematotherapy is a therapeutic process in other factors mentioned will affect the velocity or ex- which specifically amplified cells are infused in pa- tent of the shortening, not the force. tients to increase resistance to infection or to restore 9. The answer is C. Inotropic interventions of many hematopoiesis. Inflammation is not a specific response types, including heart rate changes, epinephrine, and against individual antigenic determinants and does not digitalis-like drugs, all affect the availability of calcium require T cell or B cell amplification. Similarly, innate to the contractile proteins. immunity does not require amplification of T cells or B 10. The answer is C. The force-velocity curve states the cells as a result of interaction with an invading stimulus basic relationship between the speed of shortening and but is affected by cells present and programmed to re- the afterload at a given level of contractility. This rela- spond to specific stimuli. tionship can be modified (up or down) by changes in 6. The answer is B. Delayed-type hypersensitivity reac- contractility. tions to PPD and other specific antigens develop slowly over 24 to 48 hours as T cells become activated and secrete factors that effect the skin response. B cells Chapter 11 play no role in this type of reaction; instead, they pro- 1. The answer is C. Adult erythrocytes normally do not duce antibodies involved in more immediate re- contain any carboxyhemoglobin, which is formed sponses. Neutrophils do not arrive at sites of delayed- when hemoglobin binds carbon monoxide. Adult ery- type hypersensitivity in large numbers. Eosinophils throcytes possess two distinct types of hemoglobin, play a role in immediate hypersensitivity to many anti- HbA and HbA 2 . These hemoglobin molecules may be gens that cause symptoms of allergy, such as sneezing saturated with oxygen (HbO 2 ) or reduced to Hb when and stuffy nose, but do not participate in the delayed oxygen is released to cells within tissues. response. Finally, the response to PPD is driven by 2. The answer is D. Superoxide anion is generated when cells programmed to respond specifically to this anti- oxygen is reduced by cytoplasmic NADPH. The re- gen derived from the bacteria that cause tuberculosis, duction is carried out by the enzyme NADPH oxidase, and not by a metabolite of this protein. which is not a reactant but a catalyst activated in cells 7. The answer is C. Antibody specificity is dictated by the
APPENDIX A Answers to Review Questions 715 sequence of amino acids within the variable regions of R P/Q the light and heavy chains. The Fc region is a site for an- tibody docking to effector cells and does not play a role where Q 95 5 100 mL/min in antigen binding. The constant region has a similar and P 75 25 50 mm Hg. structure in antibodies of widely divergent specificity R 50/100 0.5 mm Hg/(mL/min) 0.5 PRU and, therefore, does not dictate specificity. Fc receptors are sites on immune effector cells that interact with the Fc region of the antibody molecule and do not define an Chapter 13 antibody’s specificity. The J chain is a unique portion of secreted IgA molecules that allows the molecule to 1. The answer is B. Voltage-gated Na channels are re- move from the circulation through mucous membranes. sponsible for phase 0 in ventricular muscle. Voltage- 2 8. The answer is D. The extrinsic coagulation pathway is gated Ca channels are responsible for phase 0 in activated when tissue thromboplastin (tissue factor) is nodal cells. The potassium channels mentioned do not play a role in mediating depolarization. released from injured tissues. Activation of factor X oc- 2. The answer is D. The form of the QRS will be normal curs later and is a step involved in the activation of because electrical excitation of the ventricles occurs both the intrinsic and the extrinsic pathways. Activa- over essentially the normal pathway (i.e., AV node to tion of factor XII is the first step in activation of the in- bundle branches to Purkinje system to myocardium). trinsic coagulation pathway. Conversion of prothrom- The T wave will be normal as well. With complete bin to thrombin and conversion of fibrinogen to fibrin heart block, P waves and QRS complexes are com- are the final steps that lead to clot formation by either pletely independent of each other. Some PR intervals the intrinsic or the extrinsic pathway. could be shortened by chance, others will be very long; that is, there is no predictable PR interval. There will not be a consistent ratio of P waves to QRS complexes Chapter 12 because the two are disassociated, but the average ra- tio would be 80/40 or 2:1. 1. The answer is C. See equation 3 in the text. 3. The answer is B. The shape of the QRS complex will 2. The answer is C. See equation 6 in the text. Changes be significantly different from normal because depolar- in transmural pressure can be caused by changes inside ization now originates in the right ventricle and prop- or outside of a vessel (see equation 5). The viscosity of agates in a retrograde fashion. Because the right side of blood does not directly affect transmural pressure. Re- the heart depolarizes before the left, the configuration sistance, not transmural pressure, is proportional to the of the QRS may resemble that seen with left bundle length of a tube. branch block, another situation in which the right side 3. The answer is D. When the heart stops, blood contin- of the heart depolarizes before the left. The duration of ues to flow from the arteries to the veins until the pres- the QRS complex will be increased because the spe- sures in the two sides of the circulation are equal. That cialized conducting system of the ventricles is not fully pressure is mean circulatory filling pressure. Hemody- employed: Depolarization moves through more slowly namic pressure is the potential energy that causes conducting muscle instead of the rapidly conducting blood to flow. Mean arterial pressure is the average Purkinje system. Retrograde conduction through the pressure in the aorta or a large artery over the cardiac AV node is extremely unlikely, so P waves will not fol- cycle. Transmural pressure is the difference between low each QRS complex. Because excitation of the atria the pressure inside and outside a blood vessel. Hydro- and ventricles is still independent, there will be no pre- static pressure is the pressure caused by the force of dictable PR interval. gravity acting on a fluid. 4. The answer is D. Voltage-gated Ca 2 channels are pri- 4. The answer is D. Although flow velocity, viscosity, marily responsible for the upswing of the action poten- and tube diameter all influence turbulence, it is the tial (phase 0) of nodal cells. Voltage-gated Na chan- combination of these variables (plus the density of nels are inactivated because the resting membrane blood), expressed as the Reynolds number (equation 4 potential in these cells never becomes sufficiently nega- in the text), that determines whether flow is turbulent tive to allow reactivation. Acetylcholine-activated K or laminar. channels are important only in mediating the effect of 5. The answer is E. ACh on the pacemaker potential of nodal cells. Inward rectifying K channels are responsible for maintaining Compliance V/P the resting membrane potential in nonnodal cells but 30 mL/40 mm Hg have a less important role in cells with a pacemaker po- 0.75 mL/mm Hg tential. 5. The answer is B. Atrial repolarization normally occurs 6. The answer is B. See equation 1 in text. The tube is during the QRS complex. A dipole is created by atrial analogous to the systemic circulation in which there repolarization but it is not observed on the ECG be- are many branches. The overall resistance can be cal- cause the dipole created by ventricular depolarization culated from the sum of the flows through the individ- is much larger. ual branches and P, provided it is the same for all 6. The answer is D. Depolarization of the ventricles pro- branches. ceeds from subendocardium to subepicardium, but this
716 APPENDICES does not result in the P wave. In lead I, when the ECG is smallest when the mean axis is directed perpendicu- electrode attached to the right arm is positive relative lar to a line drawn between the two shoulders because to the electrode attached to the left arm, a downward de- both electrodes are equally influenced by the negative flection is recorded. AV nodal conduction is slower and positive sides of the dipole. than atrial conduction, but this does not cause the P 13. The answer is C. The ST segment of the normal ECG wave. When cardiac cells are depolarized, the inside of occurs during a period when both ventricles are com- the cells is positive or neutral relative to the outside of pletely depolarized. It is present in all leads. the cells. 7. The answer is C. Stimulation of the sympathetic nerves Chapter 14 to the normal heart decreases the duration of the ven- tricular action potential and, therefore, decreases the 1. The answer is C. Loop B shows increased contractility QT interval. As heart rate increases, the duration of di- because stroke volume is increased at a constant pre- astole and, therefore, the TP interval decreases. In- load and afterload. When loop B is compared to loop creased conduction velocity in the AV node decreases A, preload is not increased or decreased because there the duration of the PR interval. Fewer P waves than is no change in the pressure or volume at which the mi- QRS complexes are indicative of AV block. On the tral valve closes and isovolumetric contraction begins. contrary, sympathetic stimulation may reverse AV Afterload is not changed because there is no change in block. The frequency of QRS complexes increases the pressure or volume at which the aortic valve opens with the heart rate. and ejection begins. The evidence that stroke volume 8. The answer is D. The drug could act on 1 -adrenergic is increased is the larger volume difference between the receptors to increase the rate of depolarization of point at which the aortic valve opens and closes—that sinoatrial nodal cells. An adrenergic receptor antago- is, between isovolumetric contraction and relaxation. nist would have the opposite effect, as would a cholin- 2. The answer is A. The aortic and mitral valves are never ergic receptor agonist and the closing of voltage-gated open at the same time. This is the basic principle of the Ca 2 channels. Opening of acetylcholine-activated cardiac pump. The first heart sound is caused by clo- K channels would slow pacemaker depolarization by sure of the mitral and tricuspid valves. The mitral valve keeping the membrane potential closer to the K equi- is open throughout diastole except isovolumetric relax- librium potential. ation. Left ventricular pressure is less than aortic pres- 9. The answer is C. Excitation of the ventricles does not sure during diastole and isovolumetric contraction but ordinarily lead to excitation of the atria because retro- is greater than aortic pressure during a substantial pe- grade conduction in the AV node is unusual. Norepi- riod of ventricular ejection. Ventricular filling occurs nephrine modulates the ventricular force of contrac- during diastole. tion and conduction velocity and lowers the threshold 3. The answer is C. Aortic pressure reaches its lowest for excitation, but it does not, by itself, initiate excita- value during the isovolumetric contraction phase of tion. Excitation of the ventricles is initiated by phase 0 ventricular systole. The second heart sound is associ- of the action potential. Normal ventricular cells do not ated with closure of the aortic valve. Left atrial pressure exhibit pacemaker potentials. is less than left ventricular pressure during ventricular 10. The answer is C. AV nodal cells exhibit action poten- systole and isovolumetric relaxation. The ventricles tials characterized by slow depolarization (phase 0) eject blood during all of systole except isovolumetric because fast voltage-gated Na channels do not par- contraction. Ventricular end-diastolic volume is ticipate. This is because the diastolic potential of these greater than end-systolic volume. cells does not become sufficiently negative to allow re- 4. The answer is D. Increased ventricular filling means activation of Na channels. Acetylcholine slows and a larger end-diastolic volume. Of the three points norepinephrine speeds conduction velocity. AV nodal representing increased end-diastolic volume, only cells are capable of pacemaker activity but at a rate of choice D is on a higher ventricular function curve, approximately 25 to 40 beats/min. signaling increased contractility. If you chose choice 11. The answer is C. When stimulation of the parasympa- A, you recognized that the upper curve represented thetic nerves to the normal heart leads to complete in- increased contractility, but missed the fact that end- hibition of the SA node for several seconds, nodal es- diastolic volume would be increased as well. If you cape usually occurs. In this situation, pacemaker selected choices C or D, you recognized increased activity usually is taken over by cells in the AV node or end-diastolic volume, but did not understand that in- bundle of His. QRS complexes are normal because the creased contractility means that the ventricular func- pacemaker activity is high enough in the conducting tion curve would be higher. Point B is the graphical system to lead to a normal pattern of ventricular exci- definition of decreased contractility at an unchanged tation. T waves would be normal for the same reason. end-diastolic volume. Because at least one beat begins without atrial excita- 5. The answer is B. Drug B increases the internal work of tion, there would be fewer P waves than either QRS the left ventricle more than drug A because it increases complexes or T waves. external work by increasing pressure. Drug A increases 12. The answer is B. The R wave in lead I of the ECG re- the external work of the left ventricle the same as drug flects a net dipole associated with ventricular depolar- B. External work is stroke volume multiplied by mean ization. Repolarization causes the T wave. The R wave arterial pressure, so equivalent increases in stroke vol-
APPENDIX A Answers to Review Questions 717 ume and pressure yield equivalent increases in stroke heart rate with no change in stroke volume gives a dou- work. Because drug B increases internal work more bling of cardiac output; if SVR is halved at the same than drug A, total work is more increased. For this rea- time, then mean arterial pressure will not change. Ar- son, drug B increases the oxygen consumption of the terial compliance influences pulse pressure but not heart more than drug A. The “double product” (aortic mean arterial pressure. pressure times heart rate) is greater for drug B than for 3. The answer is C. If the cuff is too small, it takes a falsely drug A. Cardiac efficiency is higher with drug A than high pressure in the cuff to transmit sufficient pressure with drug B because efficiency is a measure of the oxy- to the vessel wall for total occlusion of the artery. gen cost of external work. Because of the greater inter- Blood pressure may be falsely high in patients with nal work, drug B increases oxygen consumption more badly stiffened arteries because of the extra pressure than drug A. The ratio of external work to oxygen con- needed to compress the arteries. The measurement sumption would be higher for drug A than drug B. gives an indirect reading of systolic and diastolic pres- 6. The answer is D. sure; mean arterial pressure must be calculated. The measurement depends on the appearance of sound to sig- CO HR SV HR (EDV ESV) nal systolic pressure 70 beats/min (130 60) mL 4. The answer is C. Vessel radius is the most important 4,900 mL/min variable influencing vascular resistance. Resistance changes occur primarily in small arteries and arterioles. SW SV MAP Blood viscosity and length are important determinants 70 mL 90 mm Hg of underlying vascular resistance, but ordinarily do not 6,300 mL mm Hg change enough to be influential in altering vascular re- 7. The answer is B. sistance. ˙ 5. The answer is E. Standing up causes a shift in blood CO VO 2 /(aO 2 vO 2 ) from the chest to the periphery, lowering central blood 4,000 mL O 2 /min/(190 30 mL O 2 /L) volume. The diameter of the leg veins increases be- 25 L/min cause of increased transmural pressure caused by the column of blood in the vessels above them. Right atrial SV CO/HR pressure decreases and, therefore, decreases filling of 25 (L/min)/(180 beats/min) the ventricles and stroke volume. 139 mL/beat 6. The answer is B. By convention, the first of the two 8. The answer is D. Electrical pacing to a heart rate of numbers is the systolic pressure and the second is the 200 beats/min would decrease time for filling and re- diastolic pressure. duce end-diastolic volume. A reduction in afterload would make it easier for the ventricle to eject blood Pulse pressure 125 75 mm Hg and would raise stroke volume. An increase in end- 50 mm Hg diastolic pressure will increase end-diastolic fiber length and increase the force of contraction and Mean arterial pressure 75 mm Hg 50 mm Hg/3 stroke volume. Stimulation of the vagus nerves slows 92 mm Hg the heart, increases the time for ventricular filling, 7. The answer is B. Mean arterial pressure both before and increases stroke volume. Stimulation of sympa- and after the tricuspid valve becomes incompetent is thetic nerves to the heart increases heart rate and 110 mm Hg. The pressure gradient before tricuspid in- contractility. Despite the decreased filling accompa- sufficiency is P a P ra 107 mm Hg. The pressure nying an increase in heart rate, stroke volume will gradient after the valve becomes incompetent is 110 stay the same or increase because of the increased 13 97 mm Hg. If all other hemodynamic factors re- contractility. main unchanged (which would be unlikely in this situ- ation), systemic blood flow will fall in proportion to Chapter 15 the decrease in pressure gradient. 8. The answer is A. Pulse pressure is determined by stroke 1. The answer is C. Strictly speaking, mean arterial pres- volume and arterial compliance. Stroke volume is un- sure minus right atrial pressure equals cardiac output changed, and if arterial compliance were to remain times systemic vascular resistance. Right atrial pressure constant, the pulse pressure would not change. How- is often ignored because it is so much smaller than ever, an increase in mean arterial pressure will tend to mean arterial pressure that it does not have much effect stretch the aorta and decrease its compliance. Ejecting on the calculation. the same stroke volume into a less compliant aorta will 2. The answer is B. A stroke volume change with no result in an increased pulse pressure. change in heart rate means that cardiac output is 9. The answer is A. The increase in transmural pressure changed. If we assume that mean arterial pressure is de- exerted by the column of blood above the veins would termined by CO and SVR and SVR is constant, then have little effect on their volume if they were as stiff as mean arterial pressure must have changed. Heart rate the arteries. In this situation, relatively little blood changes with no changes in cardiac output or SVR will would accumulate in the veins and little would be dis- have no effect on mean arterial pressure. A doubling of placed from the central blood volume.
718 APPENDICES Chapter 16 tion coefficient (plasma colloid osmotic pressure tissue colloid osmotic pressure)]. 1. The answer is B. Although small arteries do have a sig- nificant resistance, arterioles dominate the total resist- ance. Chapter 17 2. The answer is B. Molecular-sized openings within the tight junctions are the most influential sites sieving the 1. The answer is A. Increased arterial blood pressure or molecules that diffuse through the capillary wall. Large the increased cardiac output of exercise imposes an in- defects are highly permeable areas, but their occur- creased workload on the heart, and the coronary ves- rence is too infrequent to affect the total amount of sels dilate to improve oxygen delivery. When the material moved. blood pressure falls or the blood lacks oxygen, the au- 3. The answer is A. All the other possibilities include one toregulatory mechanisms of the heart vasculature di- minor force for filtration or absorption. late the microvessels to maintain the blood flow. 4. The answer is C. Myogenic mechanisms seem to in- 2. The answer is C. Resting after a meal is associated with volve only the physical loading of vascular muscle cells reduced sympathetic nervous system activity and re- in the form of stretch and increased tension or in just duced arterial pressure, but the expected increase in increased tension. blood flow would not meet the substantially increased 5. The answer is A. Each of the choices is a function of metabolic needs of the intestine during nutrient pro- the microcirculation, but its most important function cessing. Much more potent mechanisms are needed to by far is to provide tissue with nutrients and remove increase blood flow, such as increased NO production. the wastes. Although parasympathetic nervous system activity in- 6. The answer is A. Lipids are not particularly water-sol- creases during food absorption, the effect on blood uble and must primarily diffuse through the lipid layers flow is minor. of cell membranes. A small amount of lipid does move 3. The answer is C. The hepatic arterial and portal venous through water-filled channels. blood mix in the capillaries of the hepatic acinus. 7. The answer is B. The cardiovascular system is designed 4. The answer is C. Brain blood flow is constant despite to support a much higher metabolic rate than exists at large changes in the arterial blood pressure because rest. Only a fraction of the available blood flow is nec- vascular resistance usually changes in the same direc- essary for functioning at rest, and the remainder moves tion as the arterial pressure and by almost the same per- slowly through the venules and smallest veins. centage. 8. The answer is C. The interstitial space consists of al- 5. The answer is D. The skeletal muscle vasculature has a ternating gel and liquid areas with a low plasma protein 20-fold or greater range of blood flows, from minimal concentration. It is permeable compared to the capil- perfusion at rest tovery high blood flows during in- lary wall. tense exercise. No other organ system has appreciably 9. The answer is D. Both adenosine diphosphate (ADP) more than a 4- to 5-fold change in blood flow from rest and acetylcholine cause the release of NO from en- to maximum flow. dothelial cells. The other choices involve mechanisms 6. The answer is D. See Figure 17.6. that function without endothelial cells. 7. The answer is D. The autoregulatory range is shifted to 10. The answer is A. Although all of the choices are events higher pressures because the arteries and arterioles in- that happen in lymph vessels, the first key event is crease their resistance. The functional and structural lowering the lymphatic hydrostatic pressure to enable changes increase the arterial pressure at which au- tissue fluid to enter the lymphatic vessel. toregulation of blood flow occurs, but increase the 11. The answer is C. Nerve fibers, not vascular smooth lowest pressure at which blood flow can be main- muscle, release norepinephrine. The norepinephrine tained. from the sympathetic nerves simply diffuses from the 8. The answer is B. Oxygenated blood from the placenta axons and binds to specific receptors on smooth mus- does not become fully mixed with blood returning for cle cells. the superior vena cava and is diverted through the fora- 12. The answer is A. More capillaries in use at a constant men ovale into the left atrium. Consequently, the oxy- blood flow actually slows the flow velocity in individ- gen content of blood in the ascending aorta is signifi- ual capillaries. The distances between capillaries are cantly greater than that in the ductus arteriosus. The decreased. The perfusion of additional capillaries does upper body, brain, and coronary arteries are supplied not influence the permeability of the individual capil- by vessels that branch from the aorta before the ductus laries. arteriosus. The ductus carries blood with lower oxygen 13. The answer is B. The amount of oxygen exchanged is content into the aorta, to perfuse the lower body and equal to the product of the blood flow and the arterial- fetal placenta. venous oxygen content difference: 200 mL/min (20 mL/100 mL 15 mL/100 mL) 10 mL/min. Chapter 18 14. The answer is D. Fluid will be filtered at a net pressure of 4 mm Hg. The balance of hydrostatic pressures is 1. The answer is B. Norepinephrine, the sympathetic 22 mm Hg (capillary hydrostatic pressure tissue hy- postganglionic neurotransmitter, causes constriction drostatic pressure) and is greater than the balance of of blood vessels in the skin. Increased sensitivity to NE colloid osmotic pressures, which is 18 mm Hg [reflec- would greatly reduce skin blood flow, which would
APPENDIX A Answers to Review Questions 719 cause the skin to be cold and painful. Epinephrine con- would be decreased. The heart rate would be elevated stricts skin blood vessels; abnormally low epinephrine by the increased sympathetic activity and decreased in the blood would allow skin vessels to dilate. An in- parasympathetic activity caused by the baroreceptor sensitivity of blood vessels to epinephrine would have reflex. the same effect. As there are no parasympathetic 9. The answer is B. Standing up increases the transmural nerves to skin blood vessels, parasympathetic activity pressure in the veins of the legs. Because the veins are does not affect blood flow in the skin. Although acetyl- highly compliant, their volume increases at the ex- choline causes nitric oxide release from skin blood ves- pense of central blood volume. A lower central blood sels, this would cause vasodilation. volume means reduced cardiac filling pressure (pre- 2. The answer is B. Activation of parasympathetic nerves load). Within seconds, the decrease in preload de- to the heart would lower the heart rate below its in- creases stroke volume, cardiac output, and arterial trinsic rate. However, with all effects of norepineph- pressure. However, within the first minute, the arterial rine and epinephrine blocked, the sympathetic nervous baroreflex and the cardiopulmonary reflex work to- system cannot raise the heart rate above its intrinsic gether to increase sympathetic activity and decrease rate. The withdrawal of parasympathetic nerve tone parasympathetic activity. As a result, cardiac contrac- could only raise the heart rate to the intrinsic rate. (See tility and heart rate increase, and cardiac output de- Chapter 13 for a discussion of intrinsic heart rate.) creases less than it would have without compensation. 3. The answer is D. The cold pressor response is initiated “Noncritical” vascular regions, such as the splanchnic by the stimulation of pain receptors by exposing the area and skin, constrict in response to increased sym- surface of the skin to ice water. pathetic nervous system activity. Brain blood flow 4. The answer is A. The release of acetylcholine from changes little because sympathetic nerve activation parasympathetic nerves to the sinoatrial node results in causes little vasoconstriction in the brain and autoreg- a slowing of diastolic depolarization of pacemaker cells ulation of blood flow prevents a fall in brain blood and a slowing of the heart rate. ACh slows conduction flow, even if mean arterial pressure decreases. velocity, inhibits NE release from sympathetic termi- 10. The answer is C. Pressure diuresis lowers arterial pres- nals, enhances NO release from endothelial cells, and di- sure by lowering blood volume and, thereby, lowering lates blood vessels of the external genitalia (via NO)— cardiac output. All of the other choices do lower arte- all by binding to muscarinic receptors. rial pressure, but are not caused by pressure diuresis. 5. The answer is A. The function of these baroreceptors 11. The answer is C. By increasing the excretion of salt is the rapid short-term regulation of arterial blood and water, blood volume is decreased. Central blood pressure. The receptors start firing at a pressure of ap- volume participates in this decrease, reducing ventric- proximately 40 mm Hg. They completely adapt over 1 ular filling, cardiac output, and venous return as well to 2 days, not weeks. In general, changes in barorecep- (remember that cardiac output equals venous return in tor activity have little effect on cerebral blood flow. the steady state). Both the muscle pump and the respi- The sympathetic activity following a fall in blood pres- ratory pump increase the pressure gradient toward the sure results in increased heart rate and contractility, heart and increase venous return and central blood vol- which raises myocardial metabolism and coronary ume. Lying down increases venous return and central blood flow. blood volume by reducing venous volume of the lower 6. The answer is D. Peripheral chemoreceptor activation extremities. Going into space is similar to lying down, plays a significant role in enhancing the diving response in that the force of gravity on blood is removed and by enhancing peripheral vasoconstriction and brady- blood is not held in the leg veins when a person is up- cardia. Activation is increased by a decrease in pH and right. Therefore, central blood volume is increased. by a lowering of arterial PO 2 , not oxygen content. Pe- ripheral chemoreceptors are located in the aortic and Chapter 19 carotid bodies. 7. The answer is B. The fight-or-flight response and ex- 1. The answer is D. Pleural pressure is the most negative ercise are characterized by increased sympathetic tone at total lung capacity because of the elastic recoil of the and decreased parasympathetic tone. The diving re- lungs pulling inward. At residual volume, pleural pres- sponse is associated with increased parasympathetic sure would be the least negative. Choice E is not an op- and sympathetic tone. The cold pressor response is tion because pleural pressure is positive during a forced characterized by increased sympathetic activity to the vital capacity maneuver. heart and blood vessels. 2. The answer is A. Transpulmonary pressure is equal to 8. The answer is D. The hemorrhage has decreased arte- alveolar pressure minus pleural pressure. rial pressure below normal. The fall in blood volume 3. The answer is B. The outward recoil of the chest wall would result in a fall in central blood volume, right and the inward recoil of the lungs reach equilibrium at ventricular end-diastolic volume, and cardiopulmonary FRC. At residual volume, the outward recoil of the receptor activity. Carotid baroreceptor activity would chest is the greatest and the inward recoil of the lung be lowered in the presence of a low mean arterial pres- is the smallest. At total lung capacity, the inward recoil sure. The resulting sympathetic activity would cause of the lung is the greatest. vasoconstriction in the splanchnic bed, and especially 4. The answer is B. Transairway pressure is pressure with a lowered arterial pressure, splanchnic blood flow across the airways and is measured by subtracting pleu-
720 APPENDICES ral pressure from airway pressure (Pta Paw Ppl). the base. Vascular resistance is high at the apex be- Transairway pressure is most negative in the condi- cause alveolar pressure exceeds capillary pressure. tions described in choice B. Transairway pressure is the 5. The answer is C. In the supine position, the heart is in most positive in the conditions described in choice D. the middle of the chest. Pulmonary arterial pressure at 5. The answer is D. The ratio for FEV 1/FVC is 0.80 (80%) the top of the chest is 15 cm H 2 O minus 7.5 cm H 2 O for healthy adults, including trained athletes. This 7.5 cm H 2 O. Therefore, arterial pressure exceeds value tends to decrease with age. venous pressure (7 cm H 2 O). Since alveolar pressure is 6. The answer is C. Emphysema is an obstructive disor- less than venous pressure in a healthy individual, we der that leads to highly compliant lungs, while pul- have the situation that Pa Pv PA, or a zone 3. monary edema, fibrosis, congestion, and respiratory There is no zone 4. distress syndrome are restrictive disorders that lead to 6. The answer is C. A drop in venous pressure has the stiff lungs with decreased compliance. greatest effect in zone 3 because the pressure gradient 7. The answer is D. An increase in airway diameter low- for flow is determined by the arterial-venous pressure ers airway resistance, which has the greatest effect on difference. In zone 1 there is no flow, and the pressure forced expiration. Total lung capacity, inspiratory ca- gradient for flow in zone 2 is the arterial-alveolar pres- pacity, and tidal volume would not appreciably sure difference. change. FRC is high with asthma and would decrease 7. The answer is A. At the base, both airflow and blood with a bronchodilator. flow are higher; however, blood flow exceeds airflow ˙ ˙ 8. The answer is C. A restrictive lung disease causes a de- at the base, which results in a low VA/Q ratio. At the crease in FEV 1, FVC, FRC, and RV. However, the ra- apex, blood flow and airflow are lower than at the base, tio of FEV 1/FVC is likely to be increased. but airflow is greater than blood flow, which leads to a ˙ ˙ 9. The answer is A. Minute ventilation is equal to expired high VA/Q. air per minute, tidal volume times frequency of breath- 8. The answer is C. The regional differences in blood ing, or alveolar ventilation plus dead space ventilation. flow and airflow are the result of gravity. 10. The answer is D. Tidal volume minute ventilation 9. The answer is C. The ventilation-perfusion ratio is (8 L/min) frequency (10 breaths/min) 0.8 highest at the apex and lowest at the base of the lung. L/breath. As a result, the lungs are overventilated at the apex rel- 11. The answer is E. Fibrosis leads to stiff lungs, resulting ative to blood flow; PO 2 is high and PCO 2 is low at the in reduced compliance and the need for more work to apex. ˙ inflate the lungs. Stiffer lungs also have greater elastic 10. The answer is B. R P/Q (20 5 mm Hg)/5 L recoil, so the lungs will deflate easier. per min 3 mm Hg/L per min. 12. The answer is D. There is no airflow during breath 11. The answer is C. 20 cm H 2 O 1.36 cm H 2 O per mm holding with an open glottis. Under these conditions, Hg 15 mm Hg. ˙ alveolar pressure equals atmospheric pressure. 12. The answer is C. P R Q 4 mm Hg/L/min 13. The answer is E. C L V/P 0.5 L/5 cm H 2O 5 L/min 20 mm Hg. 0.1 L/cm H 2O 14. The answer is C. PTP PA Ppl 1 (7) cm Chapter 21 H 2O 6 cm H 2O 15. The answer is D. TLC VC RV 5.0 L 1.2 L 1. The answer is D. The A-aO 2 gradient in a healthy per- ˙ ˙ 6.2 L son is due to both a low VA/Q ratio at the base of the ˙ ˙ 16. The answer is B. VD VE VA 7.0 L/min 5.0 lungs and a small shunt from the bronchial circulation. L/min 2.0 L/min 2. The answer is A. A decrease in the diffusion distance will lead to an increase in DL. A decrease in capillary blood volume, surface area, cardiac output, and blood Chapter 20 hemoglobin concentration will decrease DL. 3. The answer is D. The equilibrium curves are not simi- 1. The answer is E. The pulmonary circulation is a high- lar; that for CO 2 is steeper and more linear. The blood flow, low-pressure, low-resistance, and high-compli- carries more CO 2 than O 2 . The presence of CO 2 will ance system. increase the P 50 . Although red cells carry most of the O 2 , 2. The answer is D. Pulmonary vascular resistance de- the plasma carries the majority of the CO 2 (mainly as creases with an increase in pulmonary arterial pressure. bicarbonate). The primary reason is capillary recruitment, but it is 4. The answer is A. A decrease in hemoglobin concentra- also due to capillary distension. Pulmonary vascular re- tion will decrease the O 2 content, but will not affect sistance is increased at low and high lung volumes (see the oxygen saturation or PO 2 . Fig. 20.6) and by hypoxia. 5. The answer is B. All will favor the unloading of oxygen 3. The answer is D. The pulmonary and the systemic cir- from hemoglobin except a rise in pH. ˙ ˙ culations both receive all of the cardiac output and 6. The answer is D. A low VA/Q ratio will cause hypox- have the same flow. Pressure, resistance, and compli- emia, but it will have little effect on arterial PCO 2 be- ance are different. cause of the linearity of the CO 2 equilibrium curve. 4. The answer is B. The gravitational effect on the pul- Also, a low PaO 2 stimulates ventilation, which pro- monary circulation causes blood flow to be greatest at motes CO 2 loss.
APPENDIX A Answers to Review Questions 721 7. The answer is E. In a normal resting condition, the Chapter 23 blood leaving the lungs is 98% saturated with oxygen, and the blood returning to the lungs is 75% saturated 1. The answer is C. Renal clearance is measured in vol- ume of plasma per unit time. with oxygen. With vigorous exercise, blood leaving 2. The answer is D. Na reabsorption by collecting duct the lungs is still 98% saturated, but blood returning is principal cells occurs via a Na channel called ENaC usually less than 75% saturated because more oxygen (epithelial sodium channel). Na reabsorption in prox- is unloaded from hemoglobin in exercising muscles. imal tubule cells is coupled to transport of solutes via 8. The answer is B. Carbon monoxide will lower oxygen cotransport (e.g., Na-glucose) and antiport (e.g., content and saturation, but the arterial PO 2 is un- Na /H exchanger) mechanisms. Na reabsorption in changed. Airway obstruction or pulmonary edema will the thick ascending limb involves a Na-K-2Cl cotrans- lower O 2 saturation and arterial PO 2 . porter and, in the distal convoluted tubule, a Na-Cl co- ˙ ˙ 9. The answer is D. A shunt, low VA/Q ratio, and diffu- transporter. Collecting duct intercalated cells are pri- sion impairment all cause an increase in the A-aO 2 gra- marily concerned with acid-base, not Na , transport. dient. The reason the A-aO 2 gradient is normal with 3. The answer is B. Amount concentration volume generalized hypoventilation is that both alveolar oxy- or volume amount/concentration. Volume 570 gen and arterial oxygen tension decrease together. mosm/day 1,140 mosm/kg H 2 O 0.5 kg H 2 O/day 10. The answer is C. The alveolar gas equation is required (or, 0.5 L/day because urine is mostly water and a liter to obtain the A-aO 2 gradient. The alveolar gas equation of urine weighs about 1 kg). is PAO 2 150 mm Hg 1.2 PaCO 2 . 4. The answer is D. Long loops of Henle are associated ˙ 11. The answer is D. DL VCO/PACO 10 mL/0.5 mm with a steep gradient in the medulla because there is Hg 20 mL/min per mm Hg. more opportunity for countercurrent multiplication. A drug that inhibits Na reabsorption by the thick as- cending limb will reduce the single effect, resulting in a loss of the medullary gradient. A very low GFR results Chapter 22 in inadequate input of solute into the medulla and a di- 1. The answer is D. The basic rhythm exists in the ab- minished ability to concentrate the urine. Excess water sence of the pontine respiratory group, afferent vagal intake causes the medullary gradient to fall because too input to the pons and medulla, or an intact spinal cord. much water is added to the medulla. A protein-defi- These can modify the rhythm of breathing but are not cient diet results in less urea production by the liver required. and less urea accumulation in the kidney medulla. 2. The answer is A. A brief early burst by the inspiratory 5. The answer is A. The decrease in vascular resistance neurons occurs with expiration. leads to an increase in glomerular blood flow. 3. The answer is D. An inverse relationship exists be- Glomerular capillary pressure will fall, however, and tween hypoxia-induced hyperventilation and oxygen consequently, GFR will fall. The filtration fraction content. Hypoxia-induced hyperventilation is depend- (GFR/RPF) will fall because GFR falls and RPF rises. ent on PaCO 2 and more on carotid than aortic Less fluid is filtered into the space of Bowman’s cap- chemoreceptors. sule, so the hydrostatic pressure there should fall. 4. The answer is D. Stimulation of lung C fibers will cause 6. The answer is B. Active reabsorption of Na , powered bronchoconstriction, apnea, rapid shallow breathing, by the Na /K -ATPase, is the main driving force for and skeletal muscle relaxation. water reabsorption. Reabsorption of amino acids and 5. The answer is E. CSF and plasma differ in protein con- water is secondary to active Na reabsorption. There centration, PCO 2 , and electrolyte composition (includ- is no active water reabsorption, and pinocytosis is too ing the [H ]). small to account for appreciable water reabsorption. The high colloid osmotic pressure in peritubular capil- 6. The answer is B. Slow-wave sleep is characterized by laries favors uptake of reabsorbed fluid from the renal periodic breathing, hypercapnia, and a decreased sen- interstitial fluid, but does not cause the removal of fluid sitivity to hypoxia. The cough reflex is suppressed, and from the proximal tubule lumen. skeletal muscle relaxation is less than in REM sleep. 7. The answer is B. The percentage excretion is equal to 7. The answer is B. During sleep, airway irritation will not 100 excreted Na /filtered Na 100 (U Na V) ˙ evoke a cough, but will evoke apnea and arousal. Air- (P Na GFR) 100 (U Na V) P Na (U IN ˙ ˙ way occlusion or hypercapnia will evoke arousal. V/P IN) 100 U Na/P Na U IN/P IN 7,000/140 8. The answer is E. Negative-feedback systems are not 10/1 5. necessarily the most stable. 8. The answer is D. In the autoregulatory range, vascular 9. The answer is C. The control of ventilation by PaCO 2 resistance falls when arterial blood pressure falls. works primarily through the central chemoreceptors. Changes in vessel caliber primarily occur in vessels up- However, the central effects are mediated indirectly stream to the glomeruli (cortical radial arteries and af- through a change in CSF [H ], and the sensitivity is ferent arterioles). Because autoregulatory range ex- inversely related to PaO 2 . tends from an arterial blood pressure of about 80 to 10. The answer is B. Minute ventilation is inversely related 180 mm Hg, renal blood flow is not maintained when to SaO 2 and increases in linear fashion as SaO 2 de- blood pressure is low; in fact, the sympathetic nervous creases. system will be activated and cause intense vasocon-
722 APPENDICES striction in the kidneys. Renal autoregulation does not 18. The answer is C. There is an inverse hyperbolic rela- depend on nerves. tionship between plasma [creatinine] and GFR and, 9. The answer is B. When the kidney is producing maxi- therefore, a rise in plasma [creatinine] is associated mally concentrated urine, fluid in the cortical collecting with a fall in GFR (see Fig. 23.7). The greatest absolute duct becomes isosmotic with the surrounding cortical in- change in GFR occurs when plasma [creatinine] dou- terstitial fluid. Therefore, the osmolality will be about bles starting from a normal GFR and plasma [creati- 300 mosm/kg H 2 O; it cannot go above this value because nine]. hyperosmotic values (compared to systemic blood 19. A is the answer. Granular cells (also known as juxta- plasma) can be produced only in the kidney medulla. glomerular cells) are located primarily in the wall of af- 10. The answer is B. The patient is older and severely dehy- ferent arterioles and are the major site of renin synthe- drated; the GFR can be expected to be low. Conse- sis and release. quently, the proximal tubules may be able to reabsorb all 20. The answer is E. GFR K f (P GC P BS COP). of the filtered glucose (because the filtered load is re- Therefore, K f 42 nL/min (50 12 24) mm Hg duced), even though the plasma [glucose] is elevated. If 3.0 nL/min per mm Hg. splay is increased, glucose Tm is low, or threshold is low, glucose should be present (not absent) from the urine. An abnormally high glucose Tm would reduce Chapter 24 glucose excretion; however, in the scenario presented, this is not a likely cause of the absence of glucose in the 1. The answer is B. ICF volume is calculated by subtract- urine. ing ECF volume from the total body water. The other 11. The answer is D. Excretion of phenobarbital is pro- fluid volumes can be determined from the volume of moted by increasing urine output and making the urine distribution of a single indicator, such as radioactive more alkaline. The latter would keep phenobarbital in sulfate for ECF volume, radioiodinated serum albumin its anionic form, which is not reabsorbed by the kidney for plasma volume, and deuterium oxide for total body tubules. water. 12. The answer is C. Inulin clearance is the standard for 2. The answer is A. Cardiac failure results in a decrease in measuring GFR. PAH clearance is used to measure re- effective arterial blood volume, which stimulates thirst. nal plasma flow, not GFR. Because angiotensin stimulates thirst, a low plasma 13. The answer is C. Liddle’s syndrome is due to excessive level would have the opposite effect. Distension of the activity of the Na channel in collecting duct principal atria (increased blood volume) or stomach inhibits cells, leading to salt retention and hypertension. Bart- thirst. Volume expansion and a low plasma osmolality ter and Gitelman syndromes are salt-wasting disorders; both inhibit thirst. blood pressure would tend to be low, not high. Dia- 3. The answer is B. AVP is synthesized in the cell bodies betes insipidus and renal glucosuria produce excessive of nerve cells located in the supraoptic and paraven- fluid loss and would not be likely causes of the patient’s tricular nuclei of the anterior hypothalamus. hypertension. 4. The answer is D. From the indicator dilution method, 14. The answer is A. In the absence of arginine vaso- the plasma volume 10 Ci 4 Ci/L 2.5 L. If the pressin, the kidneys produce a large volume of osmot- hematocrit ratio is 0.4, then the blood volume 2.5 L ically dilute urine. plasma 0.6 L plasma per L blood 4.17 L. 15. The answer is C. The renal clearance of PAH is the 5. The answer is A. An increase in central blood volume highest (it is nearly equal to the renal plasma flow) be- will stretch the atria, cause the release of atrial natri- cause PAH is not only filtered by the glomeruli but is uretic peptide, and result in diminished Na reabsorp- also secreted vigorously by proximal tubules. Creati- tion. All other choices produce increased tubular Na nine is filtered and secreted, to a small extent only, in reabsorption. the human kidney. Inulin is only filtered. Urea is fil- 6. The answer is B. The loop of Henle (mostly the thick tered and variably reabsorbed; its clearance is always ascending limb) reabsorbs about 65% of the filtered 2 below the inulin clearance in people. Na has the low- Mg . est clearance of all because filtered Na is extensively 7. The answer is C. Infusion of isotonic saline tends to reabsorbed. raise blood pressure, decrease renal sympathetic nerve 16. The answer is A. The filtered load of the substance is activity, and increase fluid delivery to the macula P x GFR 2 mg/mL 100 mL/min 200 mg/min. densa; all of these changes suppress renin release. All The rate of excretion is U x 10 mg/mL 5 mL/min other choices result in increased renin release. 50 mg/min. Hence, more substance X was filtered 8. The answer is E. Skeletal muscle cells contain large than was excreted, and the difference, 200 mg/min amounts of K ; injury of these cells can result in addi- 50 mg/min 150 mg/min, gives the rate of tubular re- tion of large amounts of K to the ECF. Insulin, epi- absorption of substance X. nephrine, and HCO 3 promote the uptake of K by 17. The answer is C. The true renal plasma flow (RPF) cells. Hyperaldosteronism causes increased renal ex- ˙ a rv C PAH /E PAH U PAH V/P PAH (P PAH P PAH )/P a- cretion of K and a tendency to develop hypokalemia. PAH 0.60 5.0/0.02 (0.02 0.01)/0.02 300 9. The answer is B. PTH inhibits tubular reabsorption of 2 mL/min. The renal blood flow RPF/(1 hematocrit) phosphate, stimulates tubular reabsorption of Ca , 300/(1 0.40) 500 mL/min. and increases bone resorption. PTH secretion is in-
APPENDIX A Answers to Review Questions 723 creased in patients with chronic renal failure. Its secre- plasma osmolality but inappropriately concentrated 2 tion is stimulated by a fall in plasma ionized Ca . urine. The subject in choice A may have diabetes in- 10. The answer is D. Aldosterone increases K secretion sipidus. The subject in choice B has a low plasma os- and Na reabsorption by cortical collecting ducts. It molality, but the urine osmolality is appropriately low. does not affect water permeability. The subjects in choices C and E are normal, although 11. The answer is B. Autoregulation refers to the relative the subject in choice E is producing concentrated urine constancy of renal blood flow and GFR despite and may be water-deprived. changes in arterial blood pressure. Mineralocorticoid 18. The answer is A. The low blood pH and hyper- escape refers to the fact that the salt-retaining action of glycemia (or hyperosmolality) would tend to raise mineralocorticoids does not persist but is overpowered plasma [K ], yet the plasma [K ] is normal. These by factors that promote renal Na excretion. Satura- findings suggest that the total body store of K is re- tion of transport occurs when the maximal rate of tu- duced. Remember that most of the body’s K is within bular transport is reached. Tubuloglomerular feedback cells. In uncontrolled diabetes mellitus, the osmotic di- results in afferent arteriolar constriction when fluid de- uresis (increased Na and water delivery to the corti- livery to the macula densa is increased; it contributes to cal collecting ducts), increased renal excretion of renal autoregulation. poorly reabsorbed anions (ketone body acids), and el- 12. The answer is C. Nephrogenic diabetes insipidus is evated plasma aldosterone level (secondary to volume characterized by increased output of dilute urine. depletion) would all favor enhanced excretion of K Plasma AVP is elevated because of the volume deple- by the kidneys. The subject has normokalemia, not hy- tion. Plasma osmolality is on the high side of the nor- pokalemia or hyperkalemia. mal range because of the loss of dilute fluid in the 19. The answer is D. Isotonic saline does not change cell urine. The increased urine output is not due to diabetes volume. The plasma AVP level will fall because of vol- mellitus because there is no glucose in the urine and ume expansion and cardiovascular stretch receptor in- the urine is very dilute. Diuretic drug abuse should not hibition of its release. The plasma aldosterone level produce very dilute urine because Na reabsorption is will be low because of inhibited release of renin and inhibited. Neurogenic diabetes insipidus is unlikely be- less angiotensin II formation. The plasma ANP level cause the plasma AVP level is reduced in this case. Pri- will be increased from stretch of the cardiac atria. A mary polydipsia produces output of a large volume of large part of the infused isotonic saline will be filtered dilute urine, but plasma osmolality and AVP levels are through capillary walls into the interstitial fluid. decreased. 20. The answer is A. ECF volume and blood volume are in- 13. The answer is E. Na is the major osmotically active creased, but these should promote Na excretion, not solute in the ECF and is the major determinant of the lead to Na retention by the kidneys. A decrease in ef- amount of water in and, hence, volume of this com- fective arterial blood volume is the best explanation for partment. renal Na retention. 14. The answer is A. Although the plasma osmolality is ex- traordinarily high, the plasma Na , glucose, and BUN Chapter 25 are normal. This indicates the presence of another solute (it could be ethanol) in the plasma. The calcu- 1. The answer is D. Using the Henderson-Hasselbalch lated osmolality 2 [Na ] [glucose]/18 equation, 6.0 9.0 log ([NH 3 ]/[NH 4 ]), [BUN]/2.8 280 5.6 5.4 291 mosm/kg H 2 O, [NH 3 ]/[NH 4 ] 10 3.0 1:1,000. a lot less than the measured osmolality (370 mosm/kg 2. The answer is B. The plasma [HCO 3 ] is easily calcu- H 2 O). Simple dehydration would cause a rise in lated from the formula: [H ] 24 PCO 2 /[HCO 3 ], plasma [Na ]. Diabetes insipidus or diabetes mellitus so [HCO 3 ] 24 24/48 12 mEq/L. Alternatively, cannot explain the high osmolality. The normal BUN the Henderson-Hasselbalch equation could be used, does not support the existence of renal failure. but it requires the use of logarithms. 15. The answer is B. The inhibitor will block the conver- 3. The answer is E. The collecting duct is lined by a tight sion of angiotensin I to angiotensin II, and therefore, epithelium and can lower the urine pH to 4.5 (a tubule 2.9 the plasma angiotensin I level will rise and the plasma fluid/plasma [H ] ratio of 10 /1 or about 800/1 if angiotensin II and aldosterone levels will fall. The plasma pH is 7.4). The proximal convoluted tubule is plasma bradykinin level will rise because the convert- lined by a leaky epithelium and can lower tubule fluid ing enzyme catalyzes the breakdown of this hormone. pH to about 6.7 (a tubule fluid/plasma [H ] ratio of 0.7 The plasma renin level will rise because (1) the fall in 10 /1 or 5/1 when plasma pH is 7.4). Other nephron blood pressure stimulates renin release, and (2) an- segments beyond the proximal convoluted tubule do giotensin II directly inhibits renin release by acting on not lower tubular fluid pH as much as the collecting the granular cells of afferent arterioles, so that this in- ducts. hibition is removed when less angiotensin II is present. 4. The answer is A. The kidneys filter about 4,320 16. The answer is D. In response to an increase in dietary mEq/day of HCO 3 and usually reabsorb all but a few K intake, the cortical collecting duct principal cells mEq/day; reabsorption of HCO 3 occurs via H se- increase the rate of K secretion, accounting for most cretion and consumes the bulk of secreted H . A typ- of the K excreted in the urine. ical excretion rate for NH 4 is about 50 mEq/day; for 17. The answer is D. The subject in choice D has a low titratable acid about 25 mEq/day. The quantity of free
724 APPENDICES H in a typical urine sample (e.g., 2 L/day, pH 6.0) is capillary blood flow; note the abnormally low PO 2 . negligible (e.g., 0.002 mEq/day). Choice C represents the normal condition for arterial 5. The answer is C. Net acid excretion is calculated from: blood. Choice E represents simple acute respiratory al- urinary titratable acid urinary NH 4 urinary kalosis. HCO 3 excretion 30 60 2 88 mEq/day, in this case. Chapter 26 6. The answer is E. In the process of excreting titratable acid and ammonia, the kidneys generate and add to the 1. The answer is B. Successive small intestinal structures blood an equivalent amount of new HCO 3 . There- between the serosa and mucosa are longitudinal mus- fore, the answer is 200 500 700 mEq. cle, myenteric plexus, a network of interstitial cells of 7. The answer is E. When Na reabsorption is stimu- Cajal network, circular muscle, submucous plexus, and lated, Na /H exchange is increased, resulting in muscularis mucosae. greater H secretion in the proximal tubule and loop 2. The answer is D. Interstitial cells of Cajal are pace- of Henle. Additionally, increased Na reabsorption in maker cells that generate electrical slow waves. The the collecting ducts renders the duct lumen more neg- other cell types do not generate electrical slow waves. ative, which favors H secretion. All of the other fac- 3. The answer is C. Inhibitory motor neurons determine tors result in decreased H secretion. when electrical slow waves trigger contractions. Dam- 8. The answer is C. The subject has a severe metabolic age to the enteric nervous system, including the in- acidosis. The anion gap (140 105 6 19 mEq/L) hibitory motor neurons, frees the musculature from in- is high. Methanol intoxication (see Table 25.5) pro- hibition. In the absence of inhibition, the muscle duces this type of acid-base disturbance, resulting contracts continuously in a disorganized manner. Ef- mainly from formic acid production. Acute renal fail- fective propulsion is impossible in the absence of the ure would also produce a high anion gap metabolic aci- ENS. dosis, but because the BUN is normal, this is unlikely. 4. The answer is C. Of the possible choices, only cell Uncontrolled diabetes mellitus also produces a high bodies in the dorsal vagal nucleus have axons ending in anion gap metabolic acidosis, but because the plasma the wall of the stomach. glucose is normal, this is unlikely. Diarrhea produces a 5. The answer is A. Fast EPSPs in the ENS are mediated metabolic alkalosis. A drug that depresses breathing mainly by nicotinic receptors for ACh. Hyperpolariz- produces retention of CO 2 and respiratory acidosis. ing after-potentials reduce excitability. Metabotropic 9. The answer is C. Because of the low ambient baromet- receptors stimulate adenylyl cyclase. Fast EPSPs are ric pressure and oxygen tension at high altitude, hy- not hyperpolarizing potentials. poxia develops. Therefore, we can immediately rule 6. The answer is C. Suppression of EPSPs by NE could be out choices A and D. Choice B is a subject with hy- through an action at the presynaptic site of ACh re- poxia that resulted from inadequate ventilation; this lease or an action at the postsynaptic membrane. The subject has CO 2 retention and a respiratory acidosis. finding that NE does not affect the action of exoge- Hypoxia stimulates ventilation and results in a low nously applied ACh, blocking the fast EPSP indicates PCO 2 and respiratory alkalosis. Choice E shows values that the mechanism of suppression of the EPSPs is sup- for an acute respiratory alkalosis; the plasma [HCO 3 ] pression of ACh release at the synapse. has been lowered by 4 mEq/L, corresponding to the 20 7. The answer is D. Once triggered by the stimulus, the mm Hg decrease below normal in PCO 2 (see Table action potential travels from muscle fiber to muscle 25.4). Choice C shows typical values for a chronic fiber as the ionic current travels across gap junctions. (one week) respiratory alkalosis; the kidneys have fur- Gap junctions account for the functional electrical ther lowered the plasma [HCO 3 ] and reduced the syncytial properties of smooth muscle. Nerve fibers severity of the alkalemia. and the release of neurotransmitter cannot account for 10. The answer is D. Aspirin (salicylate) intoxication pro- the spread of the action potential and associated con- duces a mixed acid-base disturbance—respiratory alka- traction because tetrodotoxin blocked all neural func- losis (as a result of stimulation of the respiratory cen- tion. Interstitial cells of Cajal is not correct because the ter) and metabolic acidosis (as a result of inhibition of action potential traveled from cell to cell in the bulk of oxidative metabolism and accumulation of lactic and the smooth muscle. Electrical slow waves are not cor- ketone body acids). The respiratory alkalosis predom- rect because the action potential was triggered by a inates during the first several hours in adults; metabolic stimulus applied at one point, not slow waves originat- acidosis occurs at the same time and becomes over- ing along the segment of intestine. whelming late in the course of the intoxication. Choice 8. The answer is E. Rapid transit is not likely because the D shows the predominant respiratory alkalosis; the re- loss of inhibitory motor neurons results in delayed duction in plasma [HCO 3 ] is accounted for by the ac- transit (i.e., pseudoobstruction). Accelerated gastric cumulation of organic acids in the blood and is too emptying does not occur mainly because pseudoob- early to reflect significant renal compensation. Choice struction in the duodenum presents a high resistance to A represents metabolic acidosis with normal respira- inflow from the stomach. Gastroesophageal reflux is tory compensation. Choice B represents respiratory not correct because in the absence of inhibition, the acidosis as a result of alveolar hypoventilation or a mis- lower esophageal sphincter remains contracted and is a match between alveolar ventilation and pulmonary barrier to reflux. Diarrhea is unlikely because diarrhea
APPENDIX A Answers to Review Questions 725 requires intestinal propulsion and this is compromised meal, mechanoreceptors signal the CNS. When the by the loss of inhibitory motor neurons. Inhibitory mo- limits of adaptive relaxation in the reservoir are tor neurons are necessary for the relaxation of sphinc- reached, signals from the stretch receptors in the reser- ters. voir’s walls account for the sensations of fullness and 9. The answer is D. Longitudinal muscle is relaxed and satiety. Overdistension is perceived as discomfort. circular muscle is contracted in the propulsive seg- Adaptive relaxation appears to malfunction in the ment. Longitudinal muscle contracts and circular mus- forms of functional dyspepsia characterized by the cle is inhibited in the receiving segment. symptoms described in this question. If adaptive relax- 10. The answer is A. Choice A is correct because sphinc- ation is compromised (e.g., by an enteric neuropathy), ters function to prevent reflux; therefore, flow across a mechanoreceptors are activated at lower distending sphincter is generally unidirectional. Choice B is not volumes and the CNS wrongly interprets the signals as correct because tone in the lower esophageal sphincter if the gastric reservoir were full. None of the other is increased during the MMC in the stomach. Choice choices would be expected to activate mechanosen- C is incorrect because the sphincter cannot be relaxed sory signaling of the state of fullness of the gastric after blockade of the inhibitory innervation by a local reservoir. anesthetic. Choice D is incorrect because pressure in 16. The answer is E. Power propulsion is the pattern of the sphincter is higher than in the two compartments motility for defense of the intestinal tract. It occurs in it separates. Choice E is incorrect because inhibitory the retrograde direction during emetic responses that neurons fire to relax the sphincter during a swallow. empty the lumen of threatening material in the upper 11. The answer is D. Physiological ileus is defined as the small intestine. It occurs in the orthograde direction in absence of contractile activity. It is a significant behav- the lower small intestine and in the large intestine ior pattern, requiring a functional ENS. Each of the where it also functions to quickly eliminate threatening other neurally programmed patterns involves contrac- substances or organisms from the intestine. In the large tile behavior and motility. intestine, secretion flushes the material from the mu- 12. The answer is D. Gastric emptying of particles greater cosa and holds it in suspension in the lumen. This is than about 7 mm does not occur during the digestive followed by power propulsion, which rapidly clears state. The lag phase is the time required for the stom- the lumen of the material. This form of behavior is de- ach to grind large particles into smaller particles in this fensive but has the adverse effects of diarrhea and ab- size range. Choice A is not correct because conversion dominal pain. None of the other choices evokes con- from interdigestive to digestive states occurs immedi- scious sensations during daily occurrence. ately upon the first few swallows of a meal. Choice B is 17. The answer is D. Observations on the transit of mark- incorrect because cephalic and gastric phases of acid ers after instillation in the human cecum show that the secretion reach maximum near the onset of the lag markers remain for the longest time in the transverse phase. Choice C is incorrect because the lag phase is at colon. Transit is significantly faster in the other parts the beginning of the emptying curve, not at the end. of the large intestine. Choice E is incorrect because the lag phase does not 18. The answer is D. Examination of older patients often apply for a liquid meal. reveals weakness in the pelvic floor musculature. 13. The answer is A. The plateau phase of the gastric ac- Weakness in the puborectalis muscle allows the tion potential and the associated trailing contraction anorectal angle to straighten and lose its barrier func- increase in direct relation to the amount of ACh re- tion to the passage of feces into the anorectum. Choice leased by excitatory motor neurons to the antral mus- A is incorrect because the rectoanal reflex (i.e., relax- culature. The higher the firing frequency of the excita- ation of the internal anal sphincter in response to dis- tory motor neurons, the more ACh is released. Choice tension of the rectum) does not weaken significantly in B is not correct because the release of NE from sympa- older persons. Choice B is incorrect because a deficit in thetic postganglionic neurons decreases the amplitude sensory detection, not elevated sensitivity, can be a of the plateau phase of the gastric action potential. factor in fecal incontinence. Choice C is incorrect be- Choice C is incorrect because the firing frequency of cause adult Hirschsprung’s disease results in constipa- the pacemaker does not affect the amplitude of the tion, not incontinence. The myopathic form of plateau phase. Opening of the pylorus cannot affect pseudoobstruction is not associated with fecal inconti- the trailing contraction; nevertheless, the pylorus is nence because propulsive motility is absent as a result closed as the trailing contraction approaches. Choice E of weakening of the intestinal smooth muscle. is incorrect because firing of the motor neurons to the gastric reservoir does not directly influence the inner- Chapter 27 vation of the antral pump. 14. The answer is D. Lipids (fats) have the greatest effect 1. The answer is D. Salivary secretion is exclusively un- in slowing gastric emptying because they have the der neural control. The others need both neural and highest caloric content. Decreased pH in the duode- hormonal stimulation and are, therefore, only partially num is also a powerful suppressant of gastric emptying. stimulated by the sight, smell, and chewing of food However, the question asks about an ingested meal, (cephalic phase). The sight, smell, and chewing of not conditions in the duodenum. food stimulate the parasympathetic nervous system, 15. The answer is A. As the gastric reservoir fills during a which stimulates salivary secretion.
726 APPENDICES 2. The answer is C. The uptake of bile acid by hepato- atic secretion rich in bicarbonate. CCK stimulates the cytes is sodium-dependent and is not dependent on gallbladder to contract and the pancreas to secrete a calcium, iron, potassium, or chloride. juice rich in enzymes. 3. The answer is A. Intrinsic factor is critical for the ab- 13. The answer is B. Secretin stimulates secretion of a bi- sorption of vitamin B 12 by the ileum. None of the other carbonate-rich pancreatic juice. Somatostatin, gastrin, substances is secreted by parietal cells. Gastrin, so- and insulin do not. CCK stimulates a pancreatic secre- matostatin, and CCK are secreted by specialized GI tion rich in enzymes and potentiates the action of se- endocrine cells, whereas chylomicrons are produced cretin. by enterocytes. 14. The answer is C. Excessive production of gastrin re- 4. The answer is C. Although the cephalic and intestinal sults in acid hypersecretion and peptic ulcer disease. phases stimulate gastric secretion, the gastric phase is, Patients with Zollinger-Ellison syndrome do not suffer by far, the most important. from excessive acid reflux, excessive secretion of CCK, 5. The answer is B. Carbonic anhydrase catalyzes the for- failure of the liver to secrete VLDLs, or failure to se- mation of carbonic acid from carbon dioxide and wa- crete a bicarbonate-rich pancreatic juice. ter. It is not involved in the formation of carbon diox- 15. The answer is B. Lactase hydrolyzes lactose to form ide from carbon and oxygen, bicarbonate ion from both glucose and galactose. None of the other combi- carbonic acid, hydrochloric acid, or hypochlorous nations is correct. acid. 16. The answer is A. Maltase hydrolyzes maltose to form 6. The answer is B. Parasympathetic stimulation induces glucose. Because maltose does not contain galactose or the release of kallikrein by the salivary acinar cells, fructose, none of the other choices is correct. which converts kininogen to form lysyl-bradykinin (a 17. The answer is C. Fructose is taken up by enterocytes potent vasodilator). Bradykinin is a vasoactive peptide. by facilitated diffusion. Both glucose and galactose are Kininogen is the precursor for kinins. Kinins include taken up by enterocytes through a sodium-dependent bradykinin and lysyl-bradykinin. Aminopeptidase re- transporter. Xylose and sucrose are not taken up by en- leases amino acids from the amino end of peptides and terocytes. is found in the brush border membrane and cytoplasm 18. The answer is D. Pancreatic lipase hydrolyzes triglyc- of enterocytes. eride to form 2-monoglyceride and two fatty acids. 7. The answer is D. Intrinsic factor is secreted by the The hydrolysis of phosphatidylcholine, not triglyc- parietal cells of the stomach and is not secreted by the eride, results in the formation of lysophosphatidyl- salivary glands. Lactoferrin, amylase, mucin, and mu- choline. Although diglyceride is an intermediate in the ramidase are found in saliva. hydrolysis of triglyceride by pancreatic lipase, the hy- 8. The answer is B. In the fasting state, the pH of the drolysis continues until 2-monoglyceride and fatty stomach is low, between 1 and 2. acids are formed. Pancreatic lipase does not hydrolyze 9. The answer is A. Salivary secretion is inhibited by at- triglyceride totally to form glycerol and fatty acids. ropine. Atropine is an anticholinergic drug that com- 19. The answer is C. The small intestine transports dietary petitively inhibits ACh at postganglionic sites, inhibit- triglyceride as chylomicrons in lymph. VLDLs are se- ing parasympathetic activity. Pilocarpine actually creted by the small intestine during fasting. Although stimulates salivation because of its muscarinic action. some dietary fatty acids are transported in the portal Cimetidine is an antagonist for the histamine H 2 re- blood bound to albumin, it is not the predominant ceptor. Aspirin is the most widely used analgesic (pain pathway for the transport of dietary lipids to the circu- reducer), antipyretic (fever reducer), and anti-inflam- lation by the small intestine. The intestine does not se- matory drug. Omeprazole inhibits the H /K -ATPase crete LDLs, and although it does secrete HDLs, they and, thus, inhibits acid secretion. are not used as a vehicle for transporting dietary lipids 10. The answer is C. The chief cells of the stomach secrete to the blood by the small intestine. pepsinogen, and the parietal cells of the stomach se- 20. The answer is C. Amino acids, as well as dipeptides crete hydrochloric acid and intrinsic factor. Gastrin and tripeptides, use different brush border transporters and CCK are secreted by specialized endocrine cells. for their uptake. Dipeptides and tripeptides are not 11. The answer is B. Histamine interacts with its receptor taken up passively by any part of the GI tract. in parietal cells to increase the intracellular cAMP. His- 21. The answer is A. Dietary protein is transported in the tamine does not cause an increase in intracellular portal blood as free amino acids. Although dipeptides sodium or cGMP or a decrease in intracellular calcium. and tripeptides are taken up by enterocytes, they are 12. The answer is D. When the pH of the stomach falls hydrolyzed by the brush border membrane, as well as below 3, the antrum secretes somatostatin, which acts by cytoplasmic peptidase to form free amino acids. locally to inhibit gastrin release; therefore, somato- 22. The answer is D. Vitamin B 1 is a water-soluble vitamin. statin inhibits gastric secretion. Enterogastrones are Vitamins A, D, E, and K are all fat-soluble vitamins. hormones produced by the duodenum that inhibit gas- 23. The answer is B. Vitamin D plays an important indi- tric secretion and motility. Intrinsic factor is involved rect role in the absorption of calcium by the GI tract. in the absorption of vitamin B 12 and is not involved in The other vitamins listed are not involved in the ab- the release of gastrin. Secretin is a hormone secreted sorption of calcium. by the duodenal and jejunal mucosa when exposed to 24. The answer is C. Vitamin A is transported in chylomi- acidic chyme and is responsible for stimulating pancre- crons as ester. Vitamins D, E, and K are transported in
APPENDIX A Answers to Review Questions 727 the free form associated with chylomicrons. Vitamin correct because the pancreas does not produce more B 12, a water-soluble vitamin, is transported in the blood glucagon in portacaval shunt patients. Choice B is in- bound to transcobalamin. correct because the kidneys are capable of removing 25. The answer is C. Potassium is passively absorbed by glucagon in these patients. However, the kidneys are the jejunum. The other choices do not apply to the ab- not nearly as important as the liver in removing sorption of potassium by the small intestine. glucagon in healthy individuals. Choice D is incorrect 26. The answer is C. Ascorbic acid enhances iron absorp- because the small intestine does not produce glucagon. tion mostly by its reducing capacity, keeping iron in Choice E is incorrect because blood flow to the small the ferrous state. Ascorbic acid does not enhance heme intestine is not compromised in portacaval shunt pa- iron absorption, nor does it affect heme oxygenase ac- tients. tivity or the production of ferritin or transferrin. 8. The answer is C. The liver makes transferrin to carry iron in the blood. Hemosiderin is an intracellular com- plex of ferric hydroxide, polysaccharides, and proteins. Chapter 28 Haptoglobin binds free hemoglobin in the blood. 1. The answer is D. Alcohol dehydrogenase catalyzes the Ceruloplasmin is a circulating plasma protein involved conversion of alcohol to acetaldehyde, which is then in the transport of copper. Lactoferrin is an iron-bind- converted to acetate. Acetate is then metabolized by ing glycoprotein found in secretions (e.g., milk, saliva) hepatocytes. Cytochrome P450 is a primary compo- and in neutrophil granules; it appears to contribute to nent of the oxidative enzyme system involved in the antimicrobial host defenses. metabolism of drugs. NADPH-cytochrome P450 re- 9. The answer is A. Smokers inhale polycyclic aromatic ductase is an enzyme involved in phase I reactions of hydrocarbons, which stimulate drug-metabolizing en- drug metabolism. There is no such enzyme as alcohol zymes. Therefore, smokers have higher levels of he- oxygenase. Glycogen phosphorylase is an enzyme in- patic drug-metabolizing enzymes than nonsmokers. volved in glycogen breakdown, not alcohol metabo- The level of drug-metabolizing enzymes in the liver is lism. lowered by malnutrition and is lower in the newborn. 2. The answer is C. Unlike patients who have diabetes, 10. The answer is C. Phase I reactions of drug metabolism healthy humans are capable of keeping their blood glu- refer to the addition of one or more polar groups to the cose within a relatively narrow range after a meal, 120 drug molecule. Hydrophilic, not hydrophobic, groups to 150 mg/dL. Blood levels of 30 to 50 mg/dL and 50 are introduced into the drug molecule in a phase I re- to 70 mg/dL indicate hypoglycemia, and blood levels action. The conjugation of drugs with glucuronic acid, of 220 to 250 mg/dL and 300 to 350 mg/dL indicate glycine, taurine, or sulfate is a phase II reaction. hyperglycemia. 11. The answer is C. A healthy liver converts vitamin D 3. The answer is A. The liver has the enzyme glucose-6- (cholecalciferol) to form 25-hydroxycholecalciferol, phosphatase, but muscle does not. Consequently, mus- but a diseased liver has a reduced capacity to do so. cle is incapable of releasing glucose from glucose 6- The kidney, not the liver, is responsible for the con- phosphate. Glucose undergoes reactions other than version of 25-hydroxycholecalciferol to 1,25-dihy- glycolysis. Both liver and muscle have glucose-1-phos- droxycholecalciferol. Vitamin D, not 1,25-hydroxyc- phatase and glycogen phosphorylase enzymes. The holecalciferol, is absorbed by the small intestine. synthesis of glucose, called gluconeogenesis, is carried 12. The answer is A. LDLs are removed from the blood by out mostly in the liver and, to some extent, in the kid- the liver by binding to LDL receptors, followed by en- neys. docytosis of the LDL-receptor complex. LDLs do not 4. The answer is A. Fatty acid synthesis occurs only in the bind to HDL receptors, albumin, transferrin, or cerulo- cytoplasm. Mitochondria are involved in fatty acid ox- plasmin. idation rather than synthesis. Fatty acid synthesis does not occur in the nucleus. Endosomes and the Golgi ap- Chapter 29 paratus are not involved in fatty acid synthesis. 5. The answer is B. Although both chylomicrons and 1. The answer is C. Antipyretics, such as aspirin, inhibit VLDLs are triglyceride-rich lipoproteins, the liver, un- the synthesis of prostaglandin E 2 , which mediates the like the small intestine, produces only VLDLs. LDLs elevation of the thermoregulatory set point during and HDLs are not triglyceride-rich lipoproteins. Chy- fever. Antipyretics cannot prevent the increase in core lomicron remnants are generated in the circulation by temperature during exercise because that increase is the metabolism of chylomicrons. not produced by an elevated thermoregulatory set 6. The answer is C. Both urea and glutamine play an im- point (see Fig. 29.11). Therefore, considerations of the portant role in the storage and transport of ammonia in possible harm or benefits as a result of the increase, as the blood. Histidine, phenylalanine, methionine, and in choices A and B, are irrelevant. As antipyretics do lysine are not involved in ammonia transport. not directly stimulate heat loss responses, choices D 7. The answer is C. The liver is one of the major sites for and E are not applicable. the removal of hormones, including glucagon. Conse- 2. The answer is D. Blood vessels in the skin have a dual quently, patients with a portacaval shunt have high nervous control, but both vasoconstriction and active levels of circulating glucagon and other hormones be- vasodilation are mediated by sympathetic fibers. The cause portal blood bypasses the liver. Choice A is in- nerve endings that control sweating are also part of the
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