The “typical” menstrual cycle is 28 ± 7 days with menstrual flow lasting 4 ± 2 days and blood loss averaging 20 to 60 mL. By convention, the first day of vaginal bleeding is considered day 1 of the menstrual cycle. Menstrual cycle intervals vary among women and often for an individual woman at different times during her reproductive life. In a study of more than 2700 women, menstrual cycle intervals were found to be most irregular in the 2 years following menarche and the 3 years preceding menopause (Treloar, 1967). Specifically, a trend toward shorter intervals followed by interval lengthening is common during the menopausal transition. The menstrual cycle is least variable between the ages of 20 and 40 years.
When viewed from a perspective of ovarian function, the menstrual cycle can be defined as a preovulatory follicular phase and postovulatory luteal phase (Fig. 15-12). Corresponding phases in the endometrium are termed the proliferative and secretory phases (Table 15-4). For most women, the luteal phase of the menstrual cycle is stable, lasting 13 to 14 days. Thus, variations in normal cycle length generally result from variable duration of the follicular phase (Ferin, 1974).
Gonadotropin control of the ovarian and endometrial cycles. The ovarian-endometrial cycle has been structured as a 28-day cycle. The follicular phase (days 6 to 14) is characterized by rising levels of estrogen, thickening of the endometrium, and selection of the dominant “ovulatory” follicle. During the luteal phase (days 15 to 28), the corpus luteum produces estrogen and progesterone, which prepare the endometrium for implantation. If implantation occurs, the developing blastocysts will begin to produce human chorionic gonadotropin (hCG) and rescue the corpus luteum, thus maintaining progesterone production. FSH = follicle-stimulating hormone; LH = luteinizing hormone. (Reproduced with permission from Cunningham FG, Leveno KJ, Bloom SL, et al: Williams Obstetrics, 24th ed. New York: McGraw-Hill Education; 2014.)
TABLE 15-4Menstrual Cycle Characteristics ||Download (.pdf) TABLE 15-4 Menstrual Cycle Characteristics
|Cycle day ||1–5 ||6–14 ||15–28 |
|Ovarian phase ||Early follicular ||Follicular ||Luteal |
|Endometrial phase ||Menstrual ||Proliferative ||Secretory |
|Estrogen/progesterone ||Low levels ||Estrogen ||Progesterone |
The adult human ovary is oval with a length of 2 to 5 cm, a width of 1.5 to 3 cm, and a thickness of 0.5 to 1.5 cm. During the reproductive years, the ovary weighs between 5 and 10 g. It is composed of three parts: an outer cortical region, which contains both the germinal epithelium and the follicles; a medullary region, which consists of connective tissue, myoid-like contractile cells, and interstitial cells; and a hilum, which contains blood vessels, lymphatics, and nerves that enter the ovary (Fig. 15-13).
Ovarian anatomy and various sequential steps of follicular development.
Ovaries have two interrelated functions: the generation of mature oocytes and the production of steroid and peptide hormones that create an environment in which fertilization and subsequent implantation in the endometrium can occur. Within each cycle, endocrine functions of the ovary correlate closely to the morphologic appearance and disappearance of follicles and corpus luteum.
The ovary develops from three major cellular sources: (1) primordial germ cells, which arise from the endoderm of the yolk sac and differentiate into the primary oogonia; (2) coelomic epithelial cells, which develop into granulosa cells; and (3) mesenchymal cells from the gonadal ridge, which become the ovarian stroma. Additional information regarding gonadal differentiation is found in Chapter 18.
Primordial germ cells can be seen in the yolk sac as early as the third week of gestation (Gosden, 2013). These cells begin their migration into the gonadal ridge during the sixth week of gestation and generate primary sex cords. The ovary and testes are indistinguishable by histologic criteria until approximately 10 to 11 weeks of fetal life.
After the primordial cells reach the gonad, they continue to multiply through successive mitotic divisions. Starting at 12 weeks’ gestation, a subset of oogonia will enter meiosis to become primary oocytes. Primary oocytes are surrounded by a single layer of flattened granulosa cells, creating a primordial follicle.
All oogonia either develop into primary oocytes or become atretic. Classical teaching states that additional oocytes cannot be generated postnatally. This differs markedly from the male, in whom sperm are produced continuously throughout adulthood. Exciting recent studies suggest that ovarian stem cells may be able to generate mature oocytes, providing hope for significant advances in female fertility preservation. Currently, these results remain preliminary and somewhat controversial (Notarianni, 2011; Virant-Klun, 2015).
The maximal number of oogonia is achieved at the 20th week of gestation, at which time 6 to 7 million oogonia are present in the ovary (Baker, 1963). Approximately 1 to 2 million oogonia are present at birth. Fewer than 400,000 are present at the initiation of puberty, of which fewer than 500 are destined to ovulate. Therefore, most germ cells are lost through atresia (Hsueh, 1996). Follicular atresia is thought not to be a passive, necrotic process, but rather a precisely controlled active process, namely apoptosis, which is under hormonal control. Apoptosis begins in utero and continues throughout reproductive life.
As previously mentioned, primary oogonia enter meiosis in utero to become primary oocytes. These oocytes are arrested in development at prophase during the first meiotic division. Meiotic progression resumes each month in a cohort of follicles. Meiosis I is completed in the oocyte destined for ovulation in response to the LH surge. Meiosis II begins, and the process is arrested, this time in the second meiotic metaphase. Meiosis II is completed only if the ovum is fertilized (Fig. 15-14).
The steps of oocyte development and corresponding follicular maturation. In the fetal period, once the primordial germ cells arrive in the gonad, they differentiate into oogonia. Mitotic division of oogonia increases the population. Many oogonia further differentiate into primary oocytes, which begin meiosis. However, the process arrests after only prophase is completed. A primary oocyte with its surrounding epithelial cells is called a primordial follicle. In childhood, primary oocytes remain suspended in prophase. Beginning in puberty and extending through the reproductive years, several primordial follicles mature each month into primary follicles. A few of these continue development to secondary follicles. One or two secondary follicles progress to a tertiary or graafian follicle stage. At this stage, the first meiotic division completes to produce a haploid secondary oocyte and a polar body. During this process, cytoplasm is conserved by the secondary oocyte. Consequently, the polar body is disproportionately small. The secondary oocyte enters meiosis II, which then arrests in metaphase. One of the secondary oocytes is released at ovulation. If the oocyte is fertilized, completion of the second meiotic division follows. If fertilization fails to occur, then the oocyte degenerates before completion of the second meiotic division.
Normal oocyte development requires cytoplasmic modifications in addition to meiotic maturation. Changes in microtubules and actin filaments enable rearrangement of cellular organelles to allow for successful polar body extrusion and fertilization (Coticchio, 2015). The cumulus cells modulate maturation both by cell-to-cell contact via gap junctions and by secretion of paracrine factors. Our growing understanding of these factors and processes is improving in vitro maturation protocols to aid fertility preservation and infertility treatments.
Ovarian stroma contains interstitial cells, contractile cells, and connective tissue cells. These last cells provide structural support to the ovary. The group of interstitial cells that surround a developing follicle differentiates into theca cells. Under gonadotropin stimulation, these cells increase in size and develop lipid stores, characteristic of steroid-producing cells (Saxena, 1972).
Another group of interstitial cells in the ovarian hilum are known as hilus cells. These closely resemble testicular Leydig cells, and hyperplasia or neoplastic changes in hilar cells may result in excess testosterone secretion and virilization. The normal role of these cells is unknown, but their intimate association with blood vessels and neurons suggest that they may convey systemic signals to the remainder of the ovary.
Ovarian Hormone Production
The normal functioning ovary synthesizes and secretes estrogens, androgens, and progesterone in a precisely controlled pattern determined, in part, by the pituitary gonadotropins, FSH and LH. The most important secretory products of ovarian steroid biosynthesis are progesterone and estradiol. However, the ovary also secretes quantities of estrone, androstenedione, testosterone, and 17α-hydroxyprogesterone. Sex steroid hormones play an important role in the menstrual cycle by preparing the uterus for implantation of a fertilized ovum. If implantation does not occur, ovarian steroidogenesis declines, the endometrium degenerates, and menstruation ensues.
Ovarian estrogen biosynthesis requires the combined action of two gonadotropins (LH and FSH) on two cell types (theca and granulosa cells). This concept is known as the two-cell theory of ovarian steroidogenesis (Fig. 15-15) (Peters, 1980). Until the late antral stage of follicular development, LH-receptor expression is limited to the thecal compartment, and FSH-receptor expression is limited to the granulosa cells.
Diagram illustrates the two-cell theory of ovarian follicular steroidogenesis. Theca cells contain large numbers of luteinizing hormone (LH) receptors. Binding of LH to these receptors leads to cyclic AMP activation and synthesis of androstenedione from cholesterol. Androstenedione diffuses across the basement membrane of theca cells to enter granulosa cells of the ovary. Here, under the activation of follicle-stimulating hormone (FSH), androstenedione is converted by the enzyme aromatase to estrone and estradiol. cAMP = cyclic adenosine monophosphate; DHEA = dehydroepiandrosterone; 3β-HSD = 3β-hydroxysteroid dehydrogenase; 17β-HSD1 = 17β-hydroxysteroid dehydrogenase; R = receptor. (Adapted with permission from Larsen PR, Kronenberg HM, Melmed S: William’s Textbook of Endocrinology, 10th edition. Philadelphia: Elsevier/Saunders; 2003.)
Theca cells express all of the enzymes needed to produce androstenedione. This includes high levels of CYP17 gene expression, whose enzyme product catalyzes 17-hydroxylation. This is the rate-limiting step in the conversion of progesterones to androgens (Sasano, 1989). This enzyme is absent in the granulosa cells, so they are incapable of producing the androgenic precursors needed to produce estrogens. Granulosa cells therefore rely on the theca cells. Namely, in response to LH stimulation, theca cells synthesize the androgens androstenedione and testosterone. These androgens are secreted into the extracellular fluid and diffuse across the basement membrane to the granulosa cells to provide precursors for estrogen production. In contrast to theca cells, granulosa cells have high levels of aromatase activity in response to FSH stimulation. Thus, these cells efficiently convert androgens to estrogens, primarily the potent estrogen estradiol. In sum, ovarian steroidogenesis is dependent on the effects of LH and FSH acting independently on the theca cells and granulosa cells, respectively.
Steroidogenesis across the Life Span
Circulating levels of the gonadotropins LH and FSH vary markedly at different ages of a woman’s life. In utero, the fetal human ovary has the capacity to produce estrogens by 8 weeks’ gestation. However, a minimal amount of steroid is actually synthesized during fetal development (Miller, 1988). During the second trimester, the plasma levels of gonadotropins rise to levels similar to those observed in menopause (Temeli, 1985). The fetal hypothalamic-pituitary axis continues to mature during this time, becoming more sensitive to the high circulating levels of estrogen and progesterone secreted by the placenta (Kaplan, 1976). Prior to birth and in response to these high steroid levels, fetal gonadotropins fall to low levels.
After delivery, gonadotropin levels in the neonate rise abruptly due to separation from the placenta and subsequent freedom from placental steroid inhibition (Winter, 1976). The elevated gonadotropin levels persist for the first few months of life and then decline to low levels in early childhood (Schmidt, 2000). There may be multiple etiologies for the low gonadotropin levels during this period of life. The hypothalamic-pituitary axis has increased sensitivity to negative feedback, even by the low circulating levels of gonadal steroids at this stage. There may be a direct CNS role in maintaining low gonadotropin levels. In support of this mechanism, low levels of LH and FSH are found even in children with gonadal dysgenesis who lack negative feedback by gonadal steroids.
With puberty, one early sign is a sleep-associated increase in LH secretion (Fig. 15-16). Over time, increased gonadotropin secretion is noted throughout the day. An increased FSH to LH ratio is typical in the premenarchal girl and postmenopausal woman. During the reproductive years, LH exceeds FSH levels, inverting this ratio. Increased gonadotropin levels stimulate ovarian estradiol production. The rise in estrogen levels prompts the growth spurt, maturation of the female internal and external genitalia, and development of a female habitus including pubertal breast enlargement, which is termed thelarche. Activation of the pituitary-adrenal axis results in an increase in adrenal androgen production and the associated pubertal development of axillary and pubic hair, termed adrenarche or pubarche. Increased gonadotropin levels ultimately lead to ovulation and subsequent menses. The first menstrual period defines menarche. This developmental process takes approximately 3 to 4 years and is discussed further in Chapter 14.
Variations in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during different life stages in the female. (Modified with permission from Faiman C, Winter JS, Reyes FI: Patterns of gonadotrophins and gonadal steroids throughout life, Clin Obstet Gynaecol. 1976 Dec;3(3):467–483.)
Following menopause, the postmenopausal ovary contains only a few follicles. As a result, plasma estrogen and inhibin levels decrease markedly after cessation of ovulatory cycles. Through loss of this negative feedback, LH and FSH levels are strikingly elevated. Elevated LH levels can stimulate production of C-19 steroids (mainly androstenedione) in ovarian stromal cells. This ovarian-derived androstenedione and adrenal androgens can be converted by peripheral tissues to estrone, the principal serum estrogen in the postmenopausal women. The major site for the conversion of androstenedione to estrone is adipose tissue. Peripheral conversion of circulating androstenedione to estrone is directly correlated to body weight. For a given body weight, conversion is higher in postmenopausal women than in premenopausal women. These low circulating estrogen levels are usually not adequate to protect against bone loss.
Gonadal Peptides and the Menstrual Cycle
Of the multiple gonadal peptides, three—inhibin, activin, and follistatin—modulate gonadotrope activity in addition to effects within the ovary (de Kretser, 2002). As suggested by their names, inhibin decreases and activin stimulates gonadotrope function. Follistatin suppresses FSHβ gene expression, most likely by binding to and thereby preventing the interaction of activin with its receptor (Xia, 2009).
Inhibin and activin are closely related peptides. Inhibin consists of an α-subunit (unrelated to the LH and FSH glycoprotein α-subunit) linked by a disulfide bridge to one of two highly homologous β-subunits to form inhibin A (αβA) or inhibin B (αβB). Activin is composed of homodimers (βAβA, βBβB) or heterodimers (βAβB) of the same β-subunits as inhibin (Bilezikjian, 2012). In contrast, follistatin is structurally unrelated to either inhibin or activin.
Although originally isolated from follicular fluid, these “gonadal” peptides are expressed in the pituitary, ovary, testes, and placenta and in the brain, adrenal, liver, kidney, and bone marrow to provide diverse tissue-specific functions (Muttukrishna, 2004). Activin and follistatin most likely act as autocrine/paracrine factors in the tissues in which they are expressed, including the ovary.
In contrast, ovarian-derived inhibins circulate in significant concentrations and are believed to be critical for negative feedback of gonadotropin gene expression. Specifically, during the early follicular phase, FSH stimulates the secretion of inhibin B by the granulosa cells (Fig. 15-17) (Buckler, 1989). However, increasing levels of circulating inhibin B blunt later FSH secretion in the follicular phase. During the luteal phase, regulation of inhibin production comes under the control of LH and switches from inhibin B to inhibin A (McLachlan, 1989). Inhibin B levels peak with the LH surge, whereas inhibin A levels peak a few days later, in the midluteal phase. All inhibin levels decline with the loss of luteal function and remain low during the luteal-follicular transition and early follicular phase. The inverse relationship between circulating inhibin levels and FSH secretion is consistent with a negative-feedback role for inhibin in regulating FSH secretion.
Graphs of gonadotropin, inhibin, and sex-steroid level changes during a normal menstrual cycle. The top graph displays peaking of luteinizing hormone (LH) (purple line) and follicle-stimulating hormone (FSH) (pink line) levels. The middle graph shows changing levels of inhibin A and inhibin B. Note that inhibin B levels (green line) peak temporally near the midcycle surge in the LH level, whereas maximal elevation of inhibin A (orange line) occurs several days following this peak. In the bottom graph, elevations in estradiol levels (red line) are noted prior to the surge in LH levels and in the midluteal phase. Progesterone levels (blue line) peak in the midluteal phase. E2 = estradiol; P4 = progesterone.
Distinct from these three peptides, insulin-like growth factors also mediate ovarian function. Only IGF-II is involved in primordial follicle development, but both IGF-I and IGF-II stimulate growth of secondary follicles. Gonadotropins stimulate IGF-II production in theca cells, granulosa cells, and luteinized granulosa cells. Receptors for IGF are expressed on the theca and granulosa cells, supporting an autocrine/paracrine action in the follicle. FSH also mediates expression of IGF-binding proteins. This system, although complex, allows additional fine-tuning of intrafollicular activity (Silva, 2009).
Development begins with primordial follicles that were generated during fetal life (see Fig. 15-14). These follicles consist of an oocyte arrested in the first meiotic division surrounded by a single layer of flattened granulosa cells. The follicles are separated from the stroma by a thin basement membrane. Preovulatory follicles are avascular. As such, they are critically dependent on diffusion and on the later development of gap junctions for obtaining nutrients and clearing metabolic waste. Diffusion also allows passage of steroid precursors from the theca to the granulosa cell layer.
In the primary follicle stage, the granulosa cells of developing follicles become cuboidal and increase in number to form a pseudostratified layer. Intercellular gap junctions develop between adjacent granulosa cells and between granulosa cells and the developing oocyte (Albertini, 1974). These connections allow the passage of nutrients, ions, and regulatory factors between cells. Gap junctions also allow cells without gonadotropin receptors to receive signals from cells with receptor expression. As a result, hormone-mediated effects can be transmitted throughout the follicle.
During this stage, the oocyte begins to secrete products to form an acellular coat known as the zona pellucida. The human zona pellucida contains at least three proteins, named ZP1, ZP2, and ZP3. In current physiologic models, receptors on the acrosome head of the sperm recognize ZP3. This interaction releases acrosomal contents that permit penetration of the zona pellucida and ovum fertilization. Enzymes released from the acrosome induce alterations in ZP2 that result in hardening of the coat. This prevents fertilization of the oocyte by more than one sperm (Gupta, 2015).
Development of a secondary, or preantral, follicle includes final growth of the oocyte and a further increase in granulosa cell number. The stroma around the granulosa cell layer differentiates into the theca interna and the theca externa (Eppig, 1979).
Tertiary follicles, also called antral follicles, form from ongoing development in selected oocytes. In these, follicular fluid collects between the granulosa cells, ultimately producing a fluid-filled space known as the antrum. Granulosa cells in the antral follicle are histologically and functionally divided into two groups. The granulosa cells surrounding the oocyte form the cumulus oophorus, whereas the granulosa cells surrounding the antrum are known as mural granulosa cells. Antral fluid consists of a plasma filtrate and factors secreted by the granulosa cells. These locally produced factors, which include estrogen and growth factors, are present in substantially higher concentrations in follicular fluid than in the circulation and are likely critical for successful follicular maturation (Asimakopoulos, 2006; Silva, 2009). Further accumulation of antral fluid results in a rapid increase in follicular size and development of a preovulatory, or graafian, follicle (Hennet, 2012).
During this process, early stages of development (up to the secondary follicle) do not require gonadotropin stimulation and thus are said to be “gonadotropin-independent.” Final follicular maturation requires adequate amounts of circulating LH and FSH and is therefore said to be “gonadotropin-dependent” (Butt, 1970). Of note, data suggest that progression from gonadotropin-independent to dependent stages is not as discrete as previously believed.
Concept of a Selection Window
Follicular development is a multistep process, which proceeds over at least 3 months and culminates in ovulation from a single follicle. Each month, a group of follicles known as a cohort begins a phase of semisynchronous growth. The size of this cohort appears to be proportional to the number of inactive primordial follicles within the ovaries and has been estimated at 3 to 11 follicles per ovary in young women (Hodgen, 1982; Pache, 1990). Importantly, the ovulatory follicle is recruited from a cohort that began development two to three cycles prior to the ovulatory cycle. During this time, most follicles will die as they will not be at an appropriate stage of development during the selection window.
During the luteal-follicular transition, a small increase in FSH levels is responsible for selection of the single dominant follicle that will ultimately ovulate (Schipper, 1998). As previously described, theca cells produce androgens, which are converted to estrogens by the granulosa cells. Estrogen levels increase with increased follicular size, enhance the effects of FSH on granulosa cells, and create a feed-forward action on follicles that produce estrogens.
Intrafollicular levels of the insulin-like growth factors are believed to synergize with FSH to help select the dominant follicle (Son, 2011). Additional studies have also demonstrated elevated levels of vascular endothelial growth factor (VEGF) around the follicle that will be selected. This follicle would presumably be exposed to higher levels of circulating factors such as FSH (Ravindranath, 1992).
Granulosa cells also produce inhibin B, which passes from the follicle into the plasma and specifically inhibits the release of FSH, but not of LH, by the anterior pituitary. The combined production of estradiol and inhibin B by the dominant follicle results in the decline of follicular-phase FSH levels and may be responsible at least in part for the failure of the other follicles to reach preovulatory status during any one cycle.
Ongoing follicular maturation requires the successful conversion from an “androgen-dominant” microenvironment to an “estrogen-dominant” one. At low concentrations, androgens stimulate aromatization and contribute to estrogen production. However, intrafollicular androgen levels will rise if aromatization in the granulosa cells lags behind androgen production by the thecal layer. At higher concentrations, androgens are converted to the more potent 5α-androgens, such as dihydrotestosterone. These androgens inhibit aromatase activity, cannot be aromatized to estrogens, and inhibit FSH induction of LH-receptor expression on the granulosa cells (Gervásio, 2014).
This model predicts that follicles that lack adequate FSH receptor and granulosa cell number will remain primarily androgenic and will therefore become atretic. An increased androgen-to-estrogen ratio is found in the follicular fluid of atretic follicles, and several studies have demonstrated that high estrogen levels prevent apoptosis.
IGF-I also has apoptosis-suppressing activity and is produced by granulosa cells. This action of IGF-I is suppressed by certain IGF-binding proteins that are present in the follicular fluid of atretic follicles. The action of FSH to prevent atresia may therefore result, in part, from its ability to stimulate IGF-I synthesis and suppress the synthesis of the IGF-binding proteins.
During the end of a previous cycle, estrogen, progesterone, and inhibin levels decrease abruptly with a corresponding increase in circulating FSH levels (Hodgen, 1982). As just described, this increase in FSH level is responsible for recruitment of the cohort of follicles that contains the follicle destined for ovulation. Despite general belief, sonographic studies in women have demonstrated that ovulation does not alternate sides, but occurs randomly from either ovary (Baird, 1987).
In women with waning ovarian function, the FSH level at this time of the cycle is elevated relative to that of younger women, presumably due to a loss of ovarian inhibin production in the previous luteal phase. As a result, measurement of early follicular or cycle day 3 FSH and estradiol levels is frequently performed in infertility clinics. The accelerated increase in serum FSH levels results in more robust recruitment of follicles and may explain both the shortened follicular phase observed in these older reproductive-aged women and the increased incidence of spontaneous twinning.
During the midfollicular phase, follicles produce increased amounts of estrogen and inhibin, resulting in a decline in FSH levels through negative feedback. This drop in FSH levels is believed to contribute to selection of the follicle destined to ovulate, termed the dominant follicle. Based on this theory, nondominant follicles express decreased numbers of FSH receptors and therefore are unable to respond adequately to declining FSH levels.
During most of follicular development, granulosa cell responses to FSH stimulation include an increase in granulosa cell number, an increase in aromatase expression, and, in the presence of estradiol, expression of LH receptors on the granulosa cells. With the development of LH-receptor expression during the late follicular phase, granulosa cells begin to produce small amounts of progesterone. This progesterone decreases granulosa cell proliferation, thereby slowing follicular growth (Chaffkin, 1992).
Toward the end of the follicular phase, estradiol levels increase dramatically. For reasons that are not completely understood but perhaps relate to changes at the kisspeptin neurons, the rapid estradiol level increase triggers a change from negative to positive feedback at both the hypothalamus and anterior pituitary gland to generate a surge in LH levels. Estradiol concentrations of 200 pg/mL for 50 hours are necessary to initiate this surge (Young, 1976). A small preovulatory increase in progesterone concentrations generates an FSH level surge, which occurs in tandem with the LH surge (McNatty, 1979). Progesterone may also augment the ability of estradiol to trigger the LH surge. These effects may explain the occasional induction of ovulation in anovulatory amenorrheic women when given progesterone to induce menses.
The LH surge acts rapidly on both the granulosa and theca cells of the preovulatory follicle to terminate the genes involved in follicular expression and turn on the genes necessary for ovulation and luteinization. In addition, the LH surge initiates the reentry of the oocyte into meiosis, expansion of the cumulus oophorus, synthesis of prostaglandins, and luteinization of granulosa cells. The mean duration of the LH surge is 48 hours, and ovulation occurs approximately 36 to 40 hours after the onset of the LH surge (Hoff, 1983; Lemarchand-Beraud, 1982). Abrupt termination of the surge is postulated to follow acutely increased steroid and inhibin secretion by the corpus luteum. Alternatively, the secretion of a gonadotropin surge-inhibiting/attenuating factor (GnSIF/AF) by either the ovary or hypothalamus is also postulated. However, the identity of this factor remains unknown (Vega, 2015).
The granulosa cells surrounding the oocyte, unlike mural granulosa cells, do not express LH receptors or synthesize progesterone. These cumulus oophorus granulosa cells develop tight gap junctions between themselves and with the oocyte. The cumulus mass that accompanies the ovulating oocyte is believed to provide a rough surface and increased size to improve oocyte “pick-up” by the tubal fimbria.
It has recently been found that amphiregulin, epiregulin, and beta-cellulin, which are epidermal growth factor-like factors, can be substituted to elicit the morphologic and biochemical events triggered by LH (Hsieh, 2009). Thus, these growth factors are part of the downstream cascade that begins with LH binding to its receptor and ends with ovulation.
Based on sonographic surveillance, extrusion of the oocyte lasts only a few minutes (Fig. 15-18) (Knobil, 1994). The exact mechanism of this expulsion is poorly defined but is not due to an increase in follicular pressure (Espey, 1974). The presence of proteolytic enzymes in the follicle, including plasmin and collagenase, suggests that these enzymes are responsible for follicular wall thinning (Beers, 1975). The preovulatory gonadotropin surge stimulates expression of tissue plasminogen activator by the granulosa and theca cells. The surge also decreases expression of plasminogen inhibitor, resulting in a marked increase in plasminogen activity (Piquette, 1993).
During laparoscopy, a stigma on the ovarian surface (arrow) prior to ovulation is seen. (Used with permission from Dr. David Rogers.)
Prostaglandins also reach a peak concentration in follicular fluid during the preovulatory gonadotropin surge (Lumsden, 1986). Prostaglandins may stimulate smooth muscle contraction in the ovary, thereby contributing to ovulation (Yoshimura, 1987). Women undergoing infertility treatment are advised to avoid prostaglandin synthetase inhibitors in the preovulatory period to avoid luteinized unruptured follicle syndrome (LUFS) (Smith, 1996). Controversy exists as to whether LUFS should be considered pathologic or simply a sporadic event (Kerin, 1983).
Following ovulation, the remaining follicular cells differentiate into the corpus luteum, literally yellow body (Corner, 1956). This process, which requires LH stimulation, includes both morphologic and functional changes known as luteinization. The granulosa and theca cells proliferate and undergo hypertrophy to form granulosa-lutein cells and smaller theca-lutein cells, respectively (Patton, 1991).
During corpus luteum formation, the basement membrane that separates granulosa cells from theca cells degenerates and allows vascularization of previously avascular granulosa cells. Capillary invasion begins 2 days after ovulation and reaches the center of the corpus luteum by the fourth day. This increase in perfusion provides these luteal cells with access to circulating low-density lipoprotein (LDL), which is used to provide precursor cholesterol for steroid biosynthesis. This marked increase in blood supply can have clinical implications, as pain from a hemorrhagic corpus luteum cyst is a relatively frequent presentation to emergency rooms.
Adequate steroidogenesis in the corpus luteum depends on serum LH levels, LH receptors on luteal cells, and a sufficient number of luteal cells. Thus, it is critical that LH receptor expression on granulosa cells was appropriately induced during the prior follicular phase. Furthermore, blunted serum LH concentrations have been correlated with a shortened luteal phase. Luteal function is also influenced by gonadotropin levels from the preceding follicular phase. A reduction in LH or FSH secretion is correlated with poor luteal function. Presumably, a lack of FSH leads to a decrease in the total number of granulosa cells. Furthermore, luteal cells in these suboptimal cycles will have a decreased number of FSH-induced LH receptors and thus will be less responsive to LH stimulation.
Based on the corpus luteum’s steroidogenic products, the luteal phase is considered progesterone dominant, which contrasts with the estrogen dominance of the follicular phase. Increased vascularization, cellular hypertrophy, and an increased number of intracellular organelles transform the corpus luteum into the most active steroidogenic tissue in the body. Maximal levels of progesterone production are observed in the midluteal phase and have been estimated at an impressive 40 mg of progesterone per day. Ovulation can be safely assumed to have occurred if the progesterone level exceeds 3 ng/mL on cycle day 21.
Although progesterone is the most abundant ovarian steroid during the luteal phase, estradiol is also produced in significant quantities. Estradiol levels drop transiently immediately after the LH surge. This decline may explain the midcycle spotting noticed by some women. The reason for this decrease is not known, but it may result from a direct inhibition of granulosa cell growth by increasing progesterone levels (Hoff, 1983). The decline in estradiol levels is followed by a steady increase to reach a maximum during the midluteal phase.
The corpus luteum produces large quantities of inhibin A. This coincides with a decrease in circulating FSH levels in the luteal phase. If inhibin A levels decline at the end of the luteal phase, FSH levels rise once more to begin selection of a oocyte cohort for the next menstrual cycle.
If pregnancy does not occur, the corpus luteum regresses through a process called luteolysis. The mechanism for luteolysis is poorly understood, but luteal regression is presumed to be tightly regulated as luteal cycle length varies minimally among women. Following luteolysis, the blood supply to the corpus luteum diminishes, progesterone and estrogen secretion drop precipitously, and the luteal cells undergo apoptosis and become fibrotic. This creates the corpus albicans (white body).
If pregnancy occurs, hCG produced by the early gestation “rescues” the corpus luteum from atresia by binding to and activating the LH receptor on luteal cells. hCG stimulation of corpus luteum steroidogenesis maintains endometrial stability until placental steroid production is adequate to assume this function late in the first trimester. For this reason, surgical removal of the corpus luteum during pregnancy should be followed by progesterone replacement as outlined in Chapter 9 until approximately 10 weeks’ gestation.