The Female Reproductive System, Schemes and Mind Maps of Physiology

Download The Female Reproductive System and more Schemes and Mind Maps Physiology in PDF only on Docsity! The Female Reproductive System Paul F. Terranova, Ph.D.38 C H A P T E R The fertility of the mature human female is cyclic. The release from the ovary of a mature female germ cell or ovum occurs at a distinct phase of the menstrual cycle. The secretion of ovarian steroid hormones, estradiol and prog- esterone, and the subsequent release of an ovum during the menstrual cycle are controlled by cyclic changes in LH and FSH from the pituitary gland, and estradiol and proges- terone from the ovaries. The cyclic changes in steroid hor- mone secretion cause significant changes in the structure and function of the uterus in preparing it for the reception of a fertilized ovum. At different stages of the menstrual cy- cle, progesterone and estradiol exert negative- and posi- tive-feedback effects on the hypothalamus and on pituitary gonadotrophs, generating the cyclic pattern of LH and FSH release characteristic of the female reproductive sys- tem. Since the hormonal events during the menstrual cycle are delicately synchronized, the menstrual cycle can be readily affected by stress and by environmental, psycho- logical, and social factors. The female cycle is characterized by monthly bleeding, resulting from the withdrawal of ovarian steroid hormone support of the uterus, which causes shedding of the super- ficial layers of the uterine lining at the end of each cycle. The first menstrual cycle occurs during puberty. Menstrual ■ AN OVERVIEW OF THE FEMALE REPRODUCTIVE SYSTEM ■ THE HYPOTHALAMIC-PITUITARY AXIS ■ THE FEMALE REPRODUCTIVE ORGANS ■ FOLLICULOGENESIS, STEROIDOGENESIS, ATRESIA, AND MEIOSIS ■ FOLLICLE SELECTION AND OVULATION ■ FORMATION OF THE CORPUS LUTEUM FROM THE POSTOVULATORY FOLLICLE ■ THE MENSTRUAL CYCLE ■ ESTROGEN, PROGESTIN, AND ANDROGEN: TRANSPORT AND METABOLISM ■ PUBERTY ■ MENOPAUSE ■ INFERTILITY C H A P T E R O U T L I N E 1. Pulses of hypothalamic GnRH regulate the secretion of LH and FSH, which enhance follicular development, steroido- genesis, ovulation, and formation of the corpus luteum. 2. LH and FSH, in coordination with ovarian theca and granu- losa cells, regulate the secretion of follicular estradiol. 3. Ovulation occurs as the result of a positive feedback of fol- licular estradiol on the hypothalamic-pituitary axis that in- duces LH and FSH surges. 4. Follicular development occurs in distinct steps: primordial, primary, secondary, tertiary, and graafian follicle stages. 5. Follicular rupture (ovulation) requires the coordination of appropriately timed LH and FSH surges that induce in- flammatory reactions in the graafian follicle, leading to dissolution at midcycle of the follicular wall by several ovarian enzymes. 6. Follicular atresia results from the withdrawal of go- nadotropin support. 7. The formation of a functional corpus luteum requires the presence of an LH surge, adequate numbers of LH recep- tors, sufficient granulosa cells, and significant proges- terone secretion. 8. The uterine cycle is regulated by estradiol and proges- terone, such that estradiol induces proliferation of the uter- ine endometrium, whereas progesterone induces differen- tiation of the uterine endometrium and the secretion of distinct products. 9. During puberty, the hypothalamus begins to secrete in- creasing quantities of GnRH, which increases LH and FSH secretion, enhances ovarian function, and leads to the first ovulation. 10. Menopause ensues from the loss of numerous oocytes in the ovary and the subsequent failure of follicular develop- ment and estradiol secretion. LH and FSH levels rise from the lack of negative feedback by estradiol. K E Y C O N C E P T S 667 668 PART X REPRODUCTIVE PHYSIOLOGY cycles are interrupted during pregnancy and lactation and cease at menopause. Menstruation signifies a failure to con- ceive and results from regression of the corpus luteum and subsequent withdrawal of luteal steroid support of the su- perficial endometrial layer of the uterus. AN OVERVIEW OF THE FEMALE REPRODUCTIVE SYSTEM An overview of the interactions of hormonal factors in fe- male reproduction is shown in Figure 38.1. The female hormonal system consists of the brain, pituitary, ovaries, and reproductive tract (oviduct, uterus, cervix, and vagina). In the brain, the hypothalamus produces gonadotropin-re- leasing hormone (GnRH), which controls the secretion of luteinizing hormone (LH) and follicle-stimulating hor- mone (FSH). The mature ovary has two major functions: the matura- tion of germ cells and steroidogenesis. Each germ cell is ul- timately enclosed within a follicle, a major source of steroid hormones during the menstrual cycle. At ovulation, the ovum or egg is released and the ruptured follicle is trans- formed into a corpus luteum, which secretes progesterone as its main product. FSH is primarily involved in stimulat- ing the growth of ovarian follicles, while LH induces ovu- lation. Both LH and FSH regulate follicular steroidogenesis and androgen and estradiol secretion, and LH regulates the secretion of progesterone from the corpus luteum. Ovarian steroids inhibit the secretion of LH and FSH with one ex- ception: Just prior to ovulation (at midcycle), estradiol has a positive-feedback effect on the hypothalamic-pituitary axis and induces significant increases in the secretion of GnRH, LH, and FSH. The ovary also produces three polypeptide hormones. Inhibin suppresses the secretion of FSH. Activin (an inhibin-binding protein) increases the se- cretion of FSH, and follistatin (an activin-binding protein) reduces the secretion of FSH. Shortly after fertilization, the embryo begins to develop placenta cells, which attach to the uterine lining and unite with the maternal placental cells. The placenta produces several pituitary-like and ovarian steroid-like hormones. These hormones support placental and fetal development throughout pregnancy and have a role in parturition. The mammary glands are also under the control of pituitary hormones and ovarian steroids, and provide the baby with immunological protection and nutritional support through lactation. Lactation is hormonally controlled by prolactin (PRL) from the anterior pituitary, which regulates milk production, and oxytocin from the posterior pituitary, which induces milk ejection from the breasts. THE HYPOTHALAMIC-PITUITARY AXIS The hypothalamic-pituitary axis has an important role in regulating the menstrual cycle. GnRH, a decapeptide pro- duced in the hypothalamus and released in a pulsatile man- ner, controls the secretion of LH and FSH through a portal vascular system (see Chapter 32). Blockade of the portal system reduces the secretion of LH and FSH and leads to ovarian atrophy and a reduction in ovarian hormone secre- tion. The secretion of GnRH by the hypothalamus is regu- lated by neurons from other brain regions. Neurotransmit- ters, such as epinephrine and norepinephrine, stimulate the secretion of GnRH, whereas dopamine and serotonin in- hibit secretion of GnRH. In addition, ovarian steroids and peptides and hypothalamic neuropeptides can regulate the secretion of GnRH. GnRH stimulates the pituitary go- nadotrophs to secrete LH and FSH. GnRH binds to high- affinity receptors on the gonadotrophs and stimulates the secretion of LH and FSH through a phosphoinositide-pro- tein kinase C-mediated pathway (see Chapter 1). A graph of LH release throughout the female life span is shown in Figure 38.2. During the neonatal period, LH is re- leased at low and steady rates without pulsatility; this pe- riod coincides with lack of development of mature ovarian follicles and very low to no ovarian estradiol secretion. Pul- satile release begins with the onset of puberty and for sev- eral years is expressed only during sleep; this period coin- cides with increased but asynchronous follicular development and with increased secretion of ovarian estra- diol. Upon the establishment of regular functional men- strual cycles associated with regular ovulation, LH pulsatil- ity prevails throughout the 24-hour period, changing in a monthly cyclic manner. In postmenopausal women whose ovaries lack sustained follicular development and exhibit



Age Environment Drugs Hypothalamus GnRH Anterior pituitary PRL Ovary Reproductive tract Secondary sex characteristics Brain Centers Inhibin activin follistatin     Dopamine FSH/LH

Estradiol, progesterone, androgen , , Regulation of the reproductive tract in the female. The main reproductive hormones are shown in boxes. Positive and negative regulations are depicted by plus and minus signs. FIGURE 38.1 Progression from primordial to the next stage of follicu- lar development, the primary stage, occurs at a relatively constant rate throughout fetal, juvenile, prepubertal, and adult life. Once primary follicles leave the resting pool, they are committed to further development or atresia. Most become atretic, and typically only one fully developed fol- licle will ovulate. The conversion from primordial to pri- mary follicles is believed to be independent of pituitary go- nadotropins. The exact signal that recruits a follicle from a resting to a growing pool is unknown; it could be pro- grammed by the cell genome or influenced by local ovarian growth regulators. The first sign that a primordial follicle is entering the growth phase is a morphological change of the flattened pregranulosa cells into cuboidal granulosa cells. The cuboidal granulosa cells proliferate to form a single contin- uous layer of cells surrounding the oocyte, which has en- larged from 20 m in the primordial stage to 140 m in di- ameter. At this stage, a glassy membrane, the zona pellucida, surrounds the oocyte and serves as means of at- tachment through which the granulosa cells communicate with the oocyte. This is the primary follicular stage of de- velopment, consisting of one layer of cuboidal granulosa cells and a basement membrane. The follicle continues to grow, mainly through prolifer- ation of its granulosa cells, so that several layers of granu- losa cells exist in the secondary follicular stage of develop- ment (see Fig. 38.4). As the secondary follicle grows deeper into the cortex, stromal cells, near the basement membrane, begin to differentiate into cell layers called theca interna and theca externa, and a blood supply with lymphatics and nerves forms within the thecal component. The granulosa layer remains avascular. The theca interna cells become flattened, epithelioid, and steroidogenic. The granulosa cells of secondary follicles acquire receptors for FSH and start producing small amounts of estrogen. The theca externa remains fibroblastic and provides structural support to the developing follicle. Development beyond the primary follicle is go- nadotropin-dependent, begins at puberty, and continues in a cyclic manner throughout the reproductive years. As the follicle continues to grow, theca layers expand, and fluid- filled spaces or antra begin to develop around the granulosa cells. This early antral stage of follicle development is re- ferred to as the tertiary follicular stage (see Fig. 38.4). The critical hormone responsible for progression from the pre- antral to the antral stage is FSH. Mitosis of the granulosa cells is stimulated by FSH. As the number of granulosa cells increases, the production of estrogens, the binding capac- ity for FSH, the size of the follicle, and the volume of the follicular fluid all increase significantly. As the antra increase in size, a single, large, coalesced antrum develops, pushing the oocyte to the periphery of the follicle and forming a large 2- to 2.5-cm-diameter graafian follicle (preovulatory follicle; see Fig. 38.4). Three distinct granulosa cell compartments are evident in the graafian follicle. Granulosa cells surrounding the oocyte are cumulus granulosa cells (collectively called cumulus oophorus). Those cells lining the antral cavity are called antral granulosa cells and those attached to the basement membrane are called mural granulosa cells. Mural and antral granulosa cells are more steroidogenically active than cumulus cells. In addition to bloodborne hormones, antral follicles have a unique microenvironment in which the follicular fluid con- tains different concentrations of pituitary hormones, steroids, peptides, and growth factors. Some are present in the follicular fluid at a concentration 100 to 1,000 times higher than in the circulation. Table 38.2 lists some parame- ters of human follicles at successive stages of development in CHAPTER 38 The Female Reproductive System 671 TABLE 38.1 Different Stages in the Development of an Ovum and Follicle Stage Process Ovum Follicle Fetal life Migration Primordial germ cells Mitosis Oogonia Primordial follicle First meiotic division begins Primary oocyte Primary follicle Birth Arrest in prophase Growth of oocyte and follicle Puberty Follicular maturation Secondary follicle Cycle Antral follicle Ovulation Resumption of meiosis Secondary oocyte Graafian follicle Emission of first polar body Arrest in metaphase Corpus luteum Fertilization Second meiotic division complete Zygote Emission of second polar body Implantation Mitotic divisions Embryo Blastocyst Parturition Body Patterning Fetus Corpus albicans 672 PART X REPRODUCTIVE PHYSIOLOGY the follicular phase. There is a 5-fold increase in follicular di- ameter and a 25-fold rise in the number of granulosa cells. As the follicle matures, the intrafollicular concentration of FSH does not change much, whereas that of LH increases and that of PRL declines. Of the steroids, the concentrations of estradiol and progesterone increase 20-fold, while androgen levels remain unchanged. The follicular fluid contains other substances, including inhibin, activin, GnRH-like peptide, growth factors, opioid peptides, oxytocin, and plasminogen activator. Inhibin and activin inhibit and stimulate, respectively, the release of FSH from the anterior pituitary. Inhibin is secreted by granulosa cells. In addition to its effect on FSH secretion, inhibin also has a local effect on ovarian cells. Primordial follicle Primary follicle Early tertiary follicle Secondary follicle Graafian follicle Basement membrane Oocyte Granulosa cells Basement membrane Granulosa cells Zona pellucida Fully grown oocyte Presumptive theca Basement membrane Granulosa cells Zona pellucida Fully grown oocyte Theca externa Basement membrane Fully grown oocyte Multiple layers of granulosa cells Zona pellucida Antrum Theca interna Theca interna Cumulus oophorus Zona pellucida Antrum (follicular fluid) Corona radiata Basement membrane Granulosa cells Theca externa The developing follicle, from primordial through graafian. (Modified from Erickson GF. In: Sciarra JJ, Speroff L, eds. Reproductive En- docrinology, Infertility, and Genetics. New York: Harper & Row, 1981.) FIGURE 38.4 TABLE 38.2 Different Parameters of Follicles During the First Half of the Menstrual Cycle Granulosa Cycle Diameter Volume Cells FSH (day) (mm) (mL) (106) ng/mL LH PRL A E2 P4 1 4 0.05 2 2.5 — 60 800 100 — 4 7 0.15 5 2.5 — 40 800 500 100 7 12 0.50 15 3.6 2.8 20 800 1,000 300 12 20 0.50 50 3.6 2.8 5 800 2,000 2,000 FSH, follicle-stimulating hormone; LH, luteinizing hormone; PRL, prolactin; A, androstenedione; E2, estradiol; P4, progesterone. (Modi- fied from Erickson GF. An analysis of follicle development and ovum maturation. Semin Reprod Endocrinol 1986;4:233–254.) Granulosa and Theca Cells Both Participate in Steroidogenesis The main physiologically active steroid produced by the follicle is estradiol, a steroid with 18 carbons. Steroidoge- nesis, the process of steroid hormone production, depends on the availability of cholesterol, which originates from several sources and serves as the main precursor for all of steroidogenesis. Ovarian cholesterol can come from plasma lipoproteins, de novo synthesis in ovarian cells, and choles- terol esters within lipid droplets in ovarian cells. For ovar- ian steroidogenesis, the primary source of cholesterol is low-density lipoprotein (LDL). The conversion of cholesterol to pregnenolone by cho- lesterol side-chain cleavage enzyme is a rate-limiting step regulated by LH using the second messenger cAMP (Fig. 38.5). LH binds to specific membrane receptors on theca cells, activates adenylyl cyclase through a G protein, and increases the production of cAMP. cAMP increases LDL receptor mRNA, the uptake of LDL cholesterol, and cholesterol ester synthesis. cAMP also increases the trans- port of cholesterol from the outer to the inner mitochondr- ial membrane, the site of pregnenolone synthesis, using a unique protein called steroidogenic acute regulatory pro- tein (StAR). Pregnenolone, a 21-carbon steroid of the progestin family, diffuses out of the mitochondria and en- ters the ER, the site of subsequent steroidogenesis. Two steroidogenic pathways may be used for subse- quent steroidogenesis (see Fig. 37.9). In theca cells, the delta 5 pathway is predominant; in granulosa cells and the corpus luteum, the delta 4 pathway is predominant. Preg- nenolone gets converted to either progesterone by 3-hy- droxysteroid dehydrogenase in the delta 4 pathway or to 17-hydroxypregnenolone by 17-hydroxylase in the delta 5 pathway. In the delta 4 pathway, progesterone gets converted to 17-hydroxyprogesterone (by 17-hydroxy- lase), which is subsequently converted to androstenedione and testosterone by 17,20-lyase and 17-hydroxysteroid dehydrogenase (17-ketosteroid reductase), respectively. In the delta 5 pathway, 17-hydroxypregnenolone gets con- verted to dehydroepiandrosterone (by 17,20-lyase), which is subsequently converted to androstenedione by 3-hy- droxysteroid dehydrogenase. The androgens contain 19 carbons. Testosterone and androstenedione diffuse from the thecal compartment, cross the basement membrane, and enter the granulosa cells. In the granulosa cell, under the influence of FSH, with cAMP as a second messenger, testosterone and androstene- dione are then converted to estradiol and estrone, respec- tively, by the enzyme aromatase, which aromatizes the A ring of the steroid and removes one carbon (see Fig. 38.5; see Fig. 37.9). Estrogens typically have 18 carbons. Estrone can then be converted to estradiol by 17-hydroxysteroid dehydrogenase in granulosa cells. In summary, estradiol secretion by the follicle requires cooperation between granulosa and theca cells and coordi- nation between FSH and LH. An understanding of this two-cell, two-gonadotropin hypothesis requires recogni- tion that the actions of FSH are restricted to granulosa cells because all other ovarian cell types lack FSH receptors. LH actions, on the other hand, are exerted on theca, granulosa, and stromal (interstitial) cells and the corpus luteum. The expression of LH receptors is time-dependent because theca cells acquire LH receptors at a relatively early stage, whereas LH receptors on granulosa cells are induced by FSH in the later stages of the maturing follicle. The biosynthetic enzymes are differentially expressed in the two cells. Aromatase is expressed only in granulosa cells, and its activation and induction are regulated by FSH. Granulosa cells are deficient in 17-hydroxylase and cannot proceed beyond the C-21 progestins to gen- erate C-19 androgenic compounds (see Fig. 38.5). Conse- quently, estrogen production by granulosa cells depends on an adequate supply of exogenous aromatizable andro- gens, provided by theca cells. Under LH regulation, theca cells produce androgenic substrates, primarily an- drostenedione and testosterone, which reach the granu- losa cells by diffusion. The androgens are then converted to estrogens by aromatization. In follicles, theca and granulosa cells are exposed to dif- ferent microenvironments. Vascularization is restricted to the theca layer because blood vessels do not penetrate the CHAPTER 38 The Female Reproductive System 673 C apillary Granulosa cellTheca cell FSH B asem ent m em brane LH R eceptor ATP cAMP R eceptor Androstenedione Testosterone Cholesterol Pregnenolone 17OH pregnenolone Dehydroepiandrosterone LH ATP cAMP Cholesterol Pregnenolone Progesterone Androstenedione Testosterone cAMP Estradiol Estrone ATP cAMP R eceptor     The two- cell, two- gonadotropin hypothesis. The follicular theca cells, un- der control of LH, produce androgens that diffuse to the follicular granulosa cells, where they are converted to estrogens via an FSH-sup- ported aromatization reac- tion. The dashed line indi- cates that granulosa cells cannot convert progesterone to androstenedione because of the lack of the enzyme 17-hydroxylase. FIGURE 38.5 676 PART X REPRODUCTIVE PHYSIOLOGY corpus luteum regresses, a process called luteolysis or luteal regression. Luteolysis occurs as a result of apoptosis and necrosis of the luteal cells. After degeneration, the luteinized cells are replaced by fibrous tissue, creating a nonfunctional structure, the corpus albicans. Therefore, the corpus luteum is a transient endocrine structure formed from the postovulatory follicle. It serves as the main source of cir- culating steroids during the luteal (postovulatory) phase of the cycle and is essential for maintaining pregnancy during the first trimester (see Case Study) as well as maintaining menstrual cycles of normal length. The process of luteinization begins before ovulation. Af- ter acquiring a high concentration of LH receptors, granu- losa cells respond to the LH surge by undergoing morpho- logical and biochemical transformation. This change involves cell enlargement (hypertrophy) and the develop- ment of smooth ER and lipid inclusions, typical of steroid- secreting cells. Unlike the nonvascular granulosa cells in the follicle, luteal cells have a rich blood supply. Invasion by capillaries starts immediately after the LH surge and is facil- itated by the dissolution of the basement membrane be- tween theca and granulosa cells. Peak vascularization is reached 7 to 8 days after ovulation. Differentiated theca and stroma cells, as well as granulosa cells, are incorporated into the corpus luteum, and all three classes of steroids—androgens, estrogens, and progestins— are synthesized. Although some progesterone is secreted before ovulation, peak progesterone production is reached 6 to 8 days after the LH surge. The life span of the corpus lu- teum is limited. Unless pregnancy occurs, it degenerates within about 13 days after ovulation. During the menstrual cycle, the function of the corpus luteum is maintained by LH; therefore, LH is referred to as a luteotropic hormone. Lack of LH can lead to luteal insufficiency (see Clinical Fo- cus Box 38.1). Regression of the corpus luteum at the end of the cycle is not understood. Luteal regression is thought to be induced by locally produced luteolytic agents that inhibit LH action. Several ovarian hormones, such as estrogen, oxytocin, prostaglandins, and GnRH, have been proposed, but their role as luteolysins is controversial. The corpus luteum is res- cued from degeneration in the late luteal phase by the action of human chorionic gonadotropin (hCG), an LH-like hor- mone that is produced by the embryonic trophoblast during the implantation phase (see Chapter 39). This hormone binds the LH receptor and increases cAMP and proges- terone secretion. THE MENSTRUAL CYCLE Under normal conditions, ovulation occurs at timed inter- vals. Sexual intercourse may occur at any time during the cy- cle, but fertilization occurs only during the postovulatory period. Once pregnancy occurs, ovulation ceases, and after parturition, lactation also inhibits ovulation. The first men- strual cycle occurs in adolescence, usually around age 12. The initial period of bleeding is called the menarche. The first few cycles are usually irregular and anovulatory, as the result of delayed maturation of the positive feedback by estradiol on a hypothalamus that fails to secrete significant GnRH. During puberty, LH secretion occurs more during periods of sleep than during periods of being awake, result- ing in a diurnal cycle. CLINICAL FOCUS BOX 38.1 Luteal Insufficiency Occasionally, the corpus luteum will not produce sufficient progesterone to maintain pregnancy during its very early stages. Initial signs of early spontaneous pregnancy termi- nation include pelvic cramping and the detection of blood, similar to indications of menstruation. If the corpus luteum is truly deficient, then fertilization may occur around the ide- alized day 14 (ovulation), pregnancy will terminate during the deficient luteal phase, and menses will start on sched- ule. Without measuring levels of hCG, the pregnancy detec- tion hormone, the woman would not know that she is preg- nant because of the continuation of regular menstrual cycles. Luteal insufficiency is a common cause of infertil- ity. Women are advised to see their physician if pregnancy does not result after 6 months of unprotected intercourse. Analysis of the regulation of progesterone secretion by the corpus luteum provides insights into this clinical prob- lem. There are several reasons for luteal insufficiency. First, the number of luteinized granulosa cells in the corpus luteum may be insufficient because of the ovulation of a small follicle or the premature ovulation of a follicle that was not fully developed. Second, the number of LH recep- tors on the luteinized granulosa cells in the graafian follicle and developing corpus luteum may be insufficient. LH re- ceptors mediate the action of LH, which stimulates prog- esterone secretion. An insufficient number of LH receptors could be due to insufficient priming of the developing fol- licle with FSH. It is well known that FSH increases the num- ber of LH receptors in the follicle. Third, the LH surge could have been inadequate in inducing full luteinization of the corpus luteum, yet there was sufficient LH to induce ovu- lation. It has been estimated that only 10% of the LH surge is required for ovulation, but the amount required for full luteinization and adequate progesterone secretion to maintain pregnancy is not known. If progesterone values are low in consecutive cycles at the midluteal phase and do not match endometrial biop- sies, exogenous progesterone may be administered in order to prevent early pregnancy termination during a fertile cycle. Other options include the induction of follic- ular development and ovulation with clomiphene and hCG. This treatment would likely produce a large, healthy, estrogen-secreting graafian follicle with suffi- cient LH receptors for luteinization. The exogenous hCG is given to supplement the endogenous LH surge and to ensure full stimulation of the graafian follicle, ovulation, adequate progesterone, and luteinization of the develop- ing corpus luteum. The average menstrual cycle length in adult women is 28 days, with a range of 25 to 35 days. The interval from ovu- lation to the onset of menstruation is relatively constant, av- eraging 14 days in most women and is dictated by the fixed life span of the corpus luteum. In contrast, the interval from the onset of menses to ovulation (the follicular phase) is more variable and accounts for differences in cycle lengths among ovulating women. The menstrual cycle is divided into four phases (Fig. 38.6). The menstrual phase, also called menses or menstruation, is the bleeding phase and lasts about 5 days. The ovarian follicular phase lasts about 10 to 16 days; folli- cle development occurs, estradiol secretion increases, and the uterine endometrium undergoes proliferation in re- sponse to rising estrogen levels. The ovulatory phase lasts 24 to 48 hours, and the luteal phase lasts 14 days. In the luteal phase, progesterone is produced, and the en- dometrium secretes numerous proteins in preparation for implantation of an embryo. The cycles become irregular as menopause approaches around age 50, and cycles cease thereafter. During the re- productive years, menstrual cycling is interrupted by con- ception and lactation and is subjected to modulation by physiological, psychological, and social factors. The Menstrual Cycle Requires Synchrony Among the Ovary, Brain, and Pituitary The menstrual cycle requires several coordinated elements: hypothalamic control of pituitary function, ovarian follicu- lar and luteal changes, and positive and negative feedback of ovarian hormones at the hypothalamic-pituitary axis. We have discussed separately the mechanisms that regulate the synthesis and release of the reproductive hormones; now we put them together in terms of sequence and inter- action. For this purpose, we use a hypothetical cycle of 28 days (see Fig. 38.6), divided into four phases as follows: menstrual (days 0 to 5), follicular (days 0 to 13), ovulatory (days 13 to 14), and luteal (days 14 to 28). During menstruation, estrogen, progesterone, and in- hibin levels are very low as a result of the luteal regression that has just occurred and the low estrogen synthesis by im- mature follicles. The plasma FSH levels are high while LH CHAPTER 38 The Female Reproductive System 677 Menses FSH LH 50 40 30 20 10 0 (m IU /m L) LH peak 20 10 1 0 P ro ge st er on e (n g/ m L) E st ra di ol ( pg /m L) P E2β 17-OH P 300 200 100 0 2 4 F ol lic le d ia m et er (m m ) 20 10 Day: Phase: Menstrual 50 40 30 20 10 0 (m IU /m L) 2 1 17-H ydroxyprogesterone (ng/m L) 6 8 10 12 14 20 22 24 26 28 20 Follicular Ovulation Day of menstrual cycle Luteal C orpus luteum diam eter (m m ) Ovulatory Luteal regression 16 18 10 Hormonal and ovarian events during the menstrual cycle. P, progesterone; E2, estra- diol; 17-OH P, 17-hydroxyprogesterone. FIGURE 38.6 678 PART X REPRODUCTIVE PHYSIOLOGY levels are low in response to the removal of negative feed- back by estrogen, progesterone, and inhibin. A few days later, however, LH levels slowly begin to rise. FSH acts on a cohort of follicles recruited 20 to 25 days earlier from a resting pool of smaller follicles. The follicles on days 3 to 5 average 4 to 6 mm in diameter, and they are stimulated by FSH to grow into the preantral stages. In response to FSH, the granulosa cells proliferate, aromatase activity increases, and plasma estradiol levels rise slightly between days 3 and 7. The designated dominant follicle is selected between days 5 and 7, and increases in size and steroidogenic activ- ity. Between days 8 and 10, plasma estradiol levels rise sharply, reaching peak levels above 200 pg/mL on day 12, the day before the LH surge. During the early follicular phase, LH pulsatility is of low amplitude and high frequency (about every hour). Coin- ciding pulses of GnRH are released about every hour. As estradiol levels rise, the pulse frequency in GnRH further increases, without a change in amplitude. The mean plasma LH level increases and further supports follicular steroido- genesis, especially since FSH has increased the number of LH receptors on growing follicles. During the midfollicular to late follicular phase, rising estradiol and inhibin from the dominant follicle suppress FSH release. The decline in FSH, together with an accumulation of nonaromatizable androgens, induces atresia in the nonselected follicles. The dominant follicle is saved by virtue of its high density of FSH receptors, the accumulation of FSH in its follicular fluid (see Table 38.2), and the acquisition of LH receptors by the granulosa cells. The midcycle surge of LH is rather short (24 to 36 hours) and is an example of positive feedback. For the LH surge to occur, estradiol must be maintained at a critical concentration (about 200 pg/mL) for a sufficient duration (36 to 48 hours) prior to the surge. Any reduction of the 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 do not induce an LH surge. Paradoxically, although it ex- erts negative feedback on LH release most of the time, pos- itive feedback by estradiol is required to generate the mid- cycle surge. Estrogen exerts its effects directly on the anterior pitu- itary, with GnRH playing a permissive, albeit mandatory, role. This concept is derived from experiments in monkeys whose medial basal hypothalamus, including the GnRH- producing neurons, was destroyed by lesioning, resulting in a marked decrease in plasma LH levels. The administration of exogenous GnRH at a fixed frequency restored LH re- lease. When estradiol was given at an optimal concentration for an appropriate time, an LH surge was generated, in spite of maintaining steady and unchanging pulses of GnRH. The mechanism that transforms estradiol from a nega- tive to a positive regulator of LH release is unknown. One factor involves an increase in the number of GnRH recep- tors on the gonadotrophs, increasing pituitary responsive- ness to GnRH. Another factor is the conversion of a stor- age pool of LH (perhaps within a subpopulation of gonadotrophs) to a readily releasable pool. Estrogen may also increase GnRH release, serving as a fine-tuning or fail- safe mechanism. A small but distinct rise in progesterone occurs before the LH surge. This rise is important for aug- menting the LH surge and, together with estradiol, pro- motes a concomitant surge in FSH. There are indications that the midcycle FSH surge is important for inducing enough LH receptors on granulosa cells for luteinization, stimulating plasminogen activator for follicular rupture, and activating a cohort of follicles destined to develop in the next cycle. The LH surge reduces the concentration of 17-hy- droxylase and subsequently decreases androstenedione production by the dominant follicle. Estradiol levels de- cline, 17-hydroxyprogesterone increases, and progesterone levels plateau. The prolonged exposure to high LH levels during the surge down-regulates the ovarian LH receptors, accounting for the immediate postovulatory suppression of estradiol. As the corpus luteum matures, it increases prog- esterone production and reinitiates estradiol secretion. Both reach high plasma concentrations on days 20 to 23, about 1 week after ovulation. During the luteal phase, circulating FSH levels are sup- pressed by the elevated steroids. The LH pulse frequency is reduced during the early luteal phase, but the amplitude is higher than that during the follicular phase. LH is impor- tant at this time for maintaining the function of the corpus luteum and sustaining steroid production. In the late luteal phase, both LH pulse frequency and amplitude are reduced by a progesterone-dependent, opioid-mediated suppres- sion of the GnRH pulse generator. After the demise of the corpus luteum on days 24 to 26, estradiol and progesterone levels plunge, causing the withdrawal of support of the uterine endometrium, culmi- nating within 2 to 3 days in menstruation. The reduction in ovarian steroids acts centrally to remove feedback inhi- bition. The FSH level begins to rise and a new cycle is ini- tiated. Estradiol and Progesterone Influence Cyclic Changes in the Reproductive Tract The female reproductive tract undergoes cyclic alterations in response to the changing levels of ovarian steroids. The most notable changes occur in the function and histology of the oviduct and uterine endometrium, the composition of cervical mucus, and the cytology of the vagina (Fig. 38.7). At the time of ovulation, there is also a small but detectable rise in basal body temperature, caused by prog- esterone. All of the above parameters are clinically useful for diagnosing menstrual dysfunction and infertility. The oviduct is a muscular tube lined internally with a cil- iated, secretory, columnar epithelium with a deeper stromal tissue. Fertilization occurs in the oviduct, after which the zygote enters the uterus; therefore, the oviduct is involved in transport of the gametes and provides a site for fertiliza- tion and early embryonic development. Estrogens maintain the ciliated nature of the epithelium, and ovariectomy causes a loss of the cilia. Estrogens also increase the motil- ity of the oviducts. Exogenous estrogen given around the time of fertilization can cause premature expulsion of the fertilized egg, whereas extremely high doses of estrogen can cause “tube locking,” the entrapment of the fertilized drogens. The adrenals begin to produce significant amounts of androgens (dehydroepiandrosterone and an- drostenedione) 4 to 5 years prior to menarche, and this event is called adrenarche. The adrenal androgens are re- sponsible in part for pubarche. Adrenarche is independ- ent of gonadarche. MENOPAUSE Menopause is the time after which the final menses occurs. It is associated with the cessation of ovarian function and reproductive cycles. Generally, menstrual cycles and bleed- ing become irregular, and the cycles become shorter from the lack of follicular development (shortened follicular phases). The ovaries atrophy and are characterized by the presence of few, if any, healthy follicles. The decline in ovarian function is associated with a de- crease in estrogen secretion and a concomitant increase in LH and FSH, which is characteristic of menopausal women (Table 38.3). It is used as a diagnostic tool. The elevated LH stimulates ovarian stroma cells to continue producing androstenedione. Estrone, derived almost entirely from the peripheral conversion of adrenal and ovarian androstene- dione, becomes the dominant estrogen (see Fig. 37.9). Be- cause the ratio of estrogens to androgens decreases, some women exhibit hirsutism, which results from androgen ex- cess. The lack of estrogen causes atrophic changes in the breasts and reproductive tract, accompanied by vaginal dryness, which often causes pain and irritation. Similar changes in the urinary tract may give rise to urinary distur- bances. The epidermal layer of the skin becomes thinner and less elastic. Hot flashes, as a result of the loss of vasomotor tone, os- teoporosis, and an increased risk of cardiovascular disease are not uncommon. Hot flashes are associated with episodic in- creases in upper body and skin temperature, peripheral va- sodilation, and sweating. They occur concurrently with LH pulses but are not caused by the gonadotropins because they are evident in hypophysectomized women. Hot flashes, con- sisting of episodes of sudden warmth and sweating, reflect temporary disturbances in the hypothalamic thermoregula- tory centers, which are somehow linked to the GnRH pulse generator. Osteoporosis increases the risk of hip fractures and es- trogen replacement therapy reduces the risk. Estrogen an- tagonizes the effects of PTH on bone but enhances its ef- fect on kidney, i.e., it stimulates retention of calcium. Estrogen also promotes the intestinal absorption of calcium through 1,25-dihydroxyvitamin D3. Menopausal symptoms are often treated with hormone replacement therapy (HRT), which includes estrogens and progestins. HRT is not an uncommon treatment to improve the quality of life. In some patients, treatment with estro- 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 opinion is that the benefit of treating postmenopausal women with estrogens for limited periods outweighs any risk of developing breast or endometrial carcinomas. INFERTILITY One of five women in the United States will be affected by infertility. A thorough understanding of female endocrinol- ogy, anatomy, and physiology are critical to gaining in- sights into solving this major health problem. Infertility can be caused by several factors. Environmental factors, disor- ders of the central nervous system, hypothalamic disease, pituitary disorders, and ovarian abnormalities can interfere with follicular development and/or ovulation. If a normal ovulation occurs, structural, pathological, and/or endocrine problems associated with the oviduct and/or uterus can pre- vent fertilization, impede the transport or implantation of the embryo, and, ultimately, interfere with the establish- ment or maintenance of pregnancy. Amenorrhea Is Caused by Endocrine Disruption Menstrual cycle disorders can be divided into two cate- gories: amenorrhea, the absence of menstruation, and oligomenorrhea, infrequent or irregular menstruation. Pri- mary amenorrhea is a condition in which menstruation has never occurred. An example is Turner’s syndrome, also called gonadal dysgenesis, a congenital abnormality caused by a nondisjunction of one of the X chromosomes, resulting in a 45 X0 chromosomal karyotype. Because the two X chro- mosomes are necessary for normal ovarian development, women with this condition have rudimentary gonads and do not have a normal puberty. Because of ovarian steroid defi- ciency (lack of estrogen), secondary sex characteristics re- main prepubertal, and plasma LH and FSH are elevated. Other abnormalities include short stature, a webbed neck, a coarctation of the aorta, and renal disorders. Another congenital form of primary amenorrhea is hy- pogonadotropism with anosmia, similar to Kallmann’s syn- CHAPTER 38 The Female Reproductive System 681 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 through normal puberty and have low and nonpulsatile LH and FSH levels. However, they can have normal stature, female karyotype, and anosmia. The disorder is caused by a failure of olfactory lobe development and GnRH defi- ciency. Primary amenorrhea can also be caused by a con- genital malformation of reproductive tract structures origi- nating from the müllerian duct, including the absence or obstruction of the uterus, cervix, or upper vagina. Secondary amenorrhea is the cessation of menstrua- tion for longer than 6 months. Pregnancy, lactation, and menopause are common physiological causes of second- ary amenorrhea. Other causes are premature ovarian fail- ure, polycystic ovarian syndrome, hyperprolactinemia, and hypopituitarism. Premature ovarian failure is characterized by amenor- rhea, low estrogen levels, and high gonadotropin (LH and FSH) levels before age 40. The symptoms are similar to those of menopause, including hot flashes and an in- creased risk of osteoporosis. The etiology is variable, in- cluding chromosomal abnormalities; lesions resulting from irradiation, chemotherapy, or viral infections; and autoimmune conditions. Polycystic ovarian syndrome, also called Stein-Leven- thal syndrome, is a heterogeneous group of disorders char- acterized by amenorrhea or anovulatory bleeding, an ele- vated LH/FSH ratio, high androgen levels, hirsutism, and obesity. Although the etiology is unknown, the syndrome may be initiated by excessive adrenal androgen production, during puberty or following stress, that deranges the hypo- thalamic-pituitary axis secretion of LH. Androgens are con- verted peripherally to estrogens and stimulate LH release. Excess LH, in turn, increases ovarian stromal and thecal an- drogen production, resulting in impaired follicular matura- tion. The LH-stimulated ovaries are enlarged and contain many small follicles and hyperplastic and luteinized theca cells (the site of LH receptors). The elevated plasma an- drogen levels cause hirsutism, increased activity of seba- ceous glands, and clitoral hypertrophy, which are signs of virilization in females. Hyperprolactinemia is also a cause of secondary amen- orrhea. Galactorrhea, a persistent milk-like discharge from the nipple in nonlactating individuals, is a frequent symp- tom and is due to the excess prolactin (PRL). The etiology of hyperprolactinemia is variable. Pituitary prolactinomas account for about 50% of cases. Other causes are hypo- thalamic disorders, trauma to the pituitary stalk, and psy- chotropic medications, all of which are associated with a reduction in dopamine release, resulting in an increased PRL secretion. Hypothyroidism, chronic renal failure, and hepatic cirrhosis are additional causes of hyperprolactine- mia. In some forms of hypothyroidism, increased hypo- thalamic thyrotropin-releasing hormone (TRH) is thought to contribute to excess PRL secretion, as experimental stud- ies reveal that exogenous TRH increases the secretion of PRL. The mechanism by which elevated PRL levels sup- press ovulation is not entirely clear. It has been postulated that PRL may inhibit GnRH release, reduce LH secretion in response to GnRH stimulation, and act directly at the level of the ovary by inhibiting the action of LH and FSH on fol- licle development. Oligomenorrhea can be caused by excessive exercise and by nutritional, psychological, and social factors. Anorexia nervosa, a severe behavioral disorder associated with the lack of food intake, is characterized by extreme malnutrition and endocrine changes secondary to psycho- logical and nutritional disturbances. About 30% of patients develop amenorrhea that is not alleviated by weight gain. Strenuous exercise, especially by competitive athletes and dancers, frequently causes menstrual irregularities. Two main factors are thought to be responsible: a low level of body fat, and the effect of stress itself through endorphins that are known to inhibit the secretion of LH. Other types of stress, such as relocation, college examinations, general illness, and job-related pressures, have been known to in- duce some forms of oligomenorrhea. Female Infertility Is Caused by Endocrine Malfunction and Abnormalities in the Reproductive Tract The diagnosis and treatment of amenorrhea present a chal- lenging problem. The amenorrhea must first be classified as primary or secondary, and menopause, pregnancy, and lac- tation must be excluded. The next step is to determine whether the disorder originates in one of the following ar- eas: the hypothalamus and central nervous system, the an- terior pituitary, the ovary, and/or the reproductive tract. Several treatments can alleviate infertility problems; for example, some success has been achieved in hypothalamic disease with pulsatile administration of GnRH. When hy- pogonadotropism is the cause of infertility, sequential ad- ministration of FSH and hCG is a common treatment for inducing ovulation, although the risk of ovarian hyperstim- ulation and multiple ovulations is increased. Hyperpro- lactinemia can be treated surgically by removing the pitu- itary adenoma containing numerous lactotrophs (prolactin-secreting cells). It can also be treated pharmaco- logically with bromocriptine, a dopaminergic agonist that reduces the size and number of the lactotrophs and PRL se- cretion. Treatment with clomiphene, an antiestrogen that binds to and blocks estrogen receptors, can induce ovula- tion in women with endogenous estrogens in the normal range. Clomiphene reduces the negative feedback effects of estrogen and thus increases endogenous FSH and LH se- cretion. When reproductive tract lesions are the cause of infertility, corrective surgery or in vitro fertilization is the treatment of choice. CHAPTER 38 The Female Reproductive System 683 DIRECTIONS: Each of the numbered items or incomplete statements in this section is followed by answers or by completions of the statement. Select the ONE lettered answer or completion that is BEST in each case. 1. Estradiol synthesis in the graafian follicle involves (A) Activation of LH-stimulated granulosa production of androgen (B) Stimulation of aromatase in the granulosa cell by FSH (C) Decreased secretion of progesterone from the corpus luteum, resulting in increased LH (D) Inhibition of the LH surge during the preovulatory period (E) Synergy between FSH and progesterone 2. Granulosa cells do not produce estradiol from cholesterol because they do not have an active (A) 17-Hydroxylase (B) Aromatase (C) 5-Reductase (D) Sulfatase (E) Steroidogenic acute regulatory protein 3. A clinical sign indicating the onset of the menopause is (A) The onset of menses near age 50 (B) An increase in plasma FSH levels (C) An excessive presence of corpora lutea (D) An increased number of cornified cells in the vagina (E) Regular menstrual cycles 4. Increased progesterone during the postovulatory period is associated with (A) Proliferation of the uterine endometrium (B) Enhanced development of graafian follicles (C) Luteal regression (D) An increase in basal body temperature by 0.5 to 1.0 C (E) Increased secretion of FSH 5. The theca interna cells of the graafian follicle are distinguished by (A) Their capacity to produce androgens from cholesterol (B) The lack of cholesterol side-chain cleavage enzyme (C) Aromatization of testosterone to estradiol (D) The lack of a blood supply (E) The production of inhibin 6. Disruption of the hypothalamic- pituitary portal system will lead to (A) High circulating levels of PRL, low levels of LH and FSH, and ovarian atrophy (B) Enhanced follicular development as a result of increased circulating levels of PRL (C) Ovulation, followed by increased circulating levels of progesterone (D) A reduction of ovarian inhibin levels, followed by increased circulating FSH (E) Excessive androgen production by the ovaries 7. Inhibin is an ovarian hormone that (A) Inhibits the secretion of LH and PRL (B) Is produced by granulosa cells and inhibits the secretion of FSH (C) Only has local ovarian effects and no effect on the secretion of FSH (D) Has two forms, A and B, with the same  subunits but distinct  subunits (E) Binds activin and increases FSH secretion 8. Spinnbarkeit formation is induced by (A) Secretory endometrium (B) Progesterone action on the uterus (C) Androgen production from the ovaries (D) Estrogen action on the vaginal secretions (E) Prolactin secretion 9. Successful fertilization is most likely to occur when the oocyte is in (A) The oviduct and has entered the second meiotic division (B) The uterus and has completed the first meiotic division (C) Metaphase of mitosis (D) The graafian follicle, which then enters the oviduct (E) The uterus, extruding the second polar body and implanting 10.The enzyme, 5-reductase is responsible for (A) Conversion of cholesterol to pregnenolone and enhancing steroidogenesis (B) Conversion of testosterone to dihydrotestosterone (C) Aromatization of testosterone to estradiol (D) Increasing the synthesis of LH (E) Female secondary sex characteristics SUGGESTED READING Carr BR, Blackwell RE. Textbook of Re- productive Medicine. Norwalk, CT: Appleton & Lange, 1998. Griffin JE, Ojeda, SR. Textbook of En- docrine Physiology. 4th Ed. New York: Oxford University Press, 2000. Johnson MH, Everitt BJ. Essential Repro- duction. Oxford: Blackwell Science, 2000. Kettyle WM, Arky RA. Endocrine Patho- physiology. Philadelphia: Lippincott- Raven, 1998. Van Voorhis BJ. Follicular development. In: Knobil E, Neill JD, eds. The En- cyclopedia of Reproduction. New York: Academic Press, 1999;376–389. Van Voorhis BJ. Follicular steroidogenesis. In: Knobil E, Neill JD, eds. The Ency- clopedia of Reproduction. New York: Academic Press, 1999;389–395. Yen SSC, Jaffe RB, Barbieri RL. Reproduc- tive Endocrinology. 4th Ed. Philadel- phia: WB Saunders, 1999. R E V I E W Q U E S T I O N S