Physiology_Levy

Physiology_Levy. Cumulus cells are the inner cells that surround the oocyte (they are also referred to as the cumulus oophorus and corona radiata). The innermost layer of cumulus cells maintains gap and adhesion junctions with the oocyte. Cumulus cells are released with the oocyte (collectively referred to as the cumulus-oocyte complex) during the process of ovulation. Cumulus cells are crucial for the ability of the fimbriated end of the oviduct to “capture” and move the oocyte by a ciliary transport mechanism along the length of the oviduct to the site of fertilization (see Early antral follicles are dependent on pituitary FSH for normal growth. Large antral follicles become highly dependent on pituitary FSH for their growth and sustained viability. As discussed later, 2to 5-mm follicles are recruited to enter a rapid growth phase via the transient increase in FSH that occurs toward the end of the previous menstrual cycle. The Gamete


Physiology_Levy

Physiology_Levy. The Gamete The oocyte grows rapidly in the early stages of antral follicles; growth then slows in larger follicles. During the antral stage the oocyte synthesizes sufficient amounts of cell cycle components so it becomes competent to complete meiosis I at ovulation. (Note that the human egg arrests after ovulation at a second point, metaphase II, until it is fertilized by sperm.) Thus in early primary and secondary follicles, the oocyte fails to complete meiosis I because of a dearth of specific meiosis-associated proteins. However, larger antral follicles gain meiotic competence but still maintain meiotic arrest until the midcycle LH surge. Meiotic arrest is achieved by maintenance of elevated cyclic adenosine monophosphate (cAMP) levels in the mature oocyte ( Figs.


Physiology_Levy

Physiology_Levy. Figs. •Fig. 44.19 ModelofhowLHsurgeleadstoresumptionofmeiosis.PDE,phosphodiesterase.Granulosa & cumulus cells ZP GPR3 AMP cAMP PKA PDE 3A MEIOTIC ARREST (–) (–) LH SURGE LHSURGEcGMPcAMPMEIOTICRESUMPTIONGsACPDE3AcGMP cGMP cGMP 44.18 44.19 ). The constitutively active (i.e., not requiring a ligand) Gs protein-coupled receptor GPR3 maintains high cAMP. The oocyte-specific phosphodiesterase PDE3A degrades cAMP to inactive AMP. Before the LH surge, PDE3A is inhibited by cGMP, which is produced within cumulus and granulosa cells and enters the oocyte via gap junctions.


Physiology_Levy

Physiology_Levy. •Fig. 44.20 Two-cellmodelforsteroidogenesisinthedominantfollicle.Top panel: MG,muralgranulosa;T,theca.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.)LHreceptor LH LDLR and HDLR-mediated uptake FSH receptor Expression of LH receptor Expression of CYP19 (aromatase) LH receptor FSH Expression and activation of StAR protein Expression of steroidogenic enzymes Acetate Cholesterol Pregnenolone Progesterone 17 (OH) Progesterone Androstenedione Testosterone Thecal cell Granulosa cell StAR protein CYP11A1 CYP17 CYP17 CYP19 CYP19 EstroneAndrostenedione Testosterone Estradiol-17˜3˜-HSD 17˜-HSD 17˜-HSD 17˜-HSD Blood vessel Basal lamina MG A a C C T The thecal cells of large antral follicles produce significant amounts of androstenedione and less testosterone. Androgens are converted to estradiol-17β by the granulosa cells (


Physiology_Levy

Physiology_Levy. The thecal cells of large antral follicles produce significant amounts of androstenedione and less testosterone. Androgens are converted to estradiol-17β by the granulosa cells ( Fig. 44.20 ). At this stage, FSH stimulates proliferation of granulosa cells and induces the expression of CYP19 (aromatase) required for estrogen synthesis. Additionally the mural granulosa cells of the large antral follicles produce increasing amounts of inhibin during the early follicular phase. Low levels of estrogen and inhibin negatively feed back on FSH secretion, thereby contributing to selection of the follicle with the most FSH-responsive cells. As already discussed, at the end of a previous menstrual cycle, a crop of large (2–5 mm) antral follicles (see Fig.


Physiology_Levy

Physiology_Levy. As already discussed, at the end of a previous menstrual cycle, a crop of large (2–5 mm) antral follicles (see Fig. 44.17 ) are recruited by a rise in FSH to begin rapid gonadotropin-dependent development. The total number of recruited follicles in both ovaries can be as high as 20 in a younger woman (<33 years old) but rapidly declines at older ages. The number of recruited follicles is reduced to the ovulation quota (one in humans) by the process of selection. As FSH levels decline the rapidly growing follicles progressively undergo atresia until one follicle is left. Generally the largest follicle with the most FSH receptors of the recruited crop becomes the dominant follicle. Selection occurs during the early follicular phase. By midcycle the dominant follicle becomes a large preovulatory follicle that is 20 mm in diameter and contains about 50 million granulosa cells by the midcycle gonadotropin surge. The Gamete


Physiology_Levy

Physiology_Levy. The Gamete The oocyte is competent to complete meiosis I but remains arrested in the dominant follicle until the LH surge. Growth of the oocyte continues but at a slower rate until the oocyte reaches a diameter of about 140 µm by ovulation (i.e., ≈20 times the diameter of an erythrocyte). The newly selected follicle emerges as a significant steroidogenic “gland.” Ovarian steroidogenesis requires both theca and granulosa cells. As discussed earlier, thecal cells (see


Physiology_Levy

Physiology_Levy. The newly selected follicle emerges as a significant steroidogenic “gland.” Ovarian steroidogenesis requires both theca and granulosa cells. As discussed earlier, thecal cells (see Fig. 44.20, T ) express LH receptors and produce primarily androstenedione. Basal levels of LH stimulate expression of steroidogenic enzymes in thecal cells. The thecal cells are richly vascularized and thus have access to cholesterol within the lipoprotein articles LDL and HDL. LH promotes expression of the LDL receptor and HDL receptor (SR-B1), which import cholesterol. LH also promotes robust expression of CYP11A1 (side chain cleavage enzyme), 3β-HSD, and CYP17 with both 17-hydroxylase activity and 17,20-lyase activity. Androgens (primarily androstenedione but also some testosterone) released from the theca diffuse into the mural granulosa cells or enter the vasculature surrounding the follicle. The mural granulosa cells (see


Physiology_Levy

Physiology_Levy. The mural granulosa cells (see Fig. 44.20, MG) of the selected follicle have a high number of FSH receptors and are very sensitive to FSH, which upregulates CYP19 (aromatase) gene expression and activity. CYP19 converts androstenedione to the weak estrogen estrone and converts testosterone to the potent estrogen estradiol-17β. Granulosa cells express activating isoforms of 17β-HSD, which converts the less active estrone to highly active estradiol17β. In addition, FSH induces expression of inhibin B during the follicular phase. Importantly, FSH also induces expression of LH receptors in mural granulosa cells during the second half of the follicular phase (see Fig. 44.20). Thus mural granulosa cells acquire the ability to respond to LH, which allows these cells to maintain high levels of CYP19 in the face of declining FSH levels. Acquisition of LH receptors also ensures that mural granulosa cells respond to the LH surge. The Dominant Follicle During the Periovulatory Period


Physiology_Levy

Physiology_Levy. The Dominant Follicle During the Periovulatory Period The periovulatory period is defined as the time from the onset of the LH surge to expulsion of the cumulus-oocyte complex out of the ovary (i.e., ovulation). This process lasts for 32 to 36 hours in women. Starting at the same time and superimposed on the process of ovulation is a change in the steroidogenic function of theca and mural granulosa cells. This process is called luteinization and culminates in formation of a corpus luteum that is capable of producing high amounts of progesterone, along with estrogen, within a few days after ovulation. Thus the LH surge induces the onset of complex processes during the periovulatory period that complete the gametogenic function of the ovary for a given month and switches the endocrine function to prepare the female reproductive tract for implantation and gestation.


Physiology_Levy

Physiology_Levy. The LH surge induces dramatic structural changes in the dominant follicle that involves its rupture, ovulation of the cumulus-oocyte complex, and biogenesis of a new structure called the corpus luteum from the remaining thecal and mural granulosa cells. Major structural changes occur during this transition: 1. Before ovulation the large preovulatory follicle presses against the ovarian surface and generates a poorly vascularized bulge of the ovarian wall called the stigma. The LH surge induces release of inflammatory cytokines and hydrolytic enzymes from the theca and granulosa cells. These secreted components lead to breakdown of the follicle wall, tunica albuginea, and surface epithelium in the vicinity of the stigma ( Fig. 44.21 ). At the end of this process the antral cavity becomes continuous with the peritoneal cavity.


Physiology_Levy

Physiology_Levy. Fig. 44.21 ). At the end of this process the antral cavity becomes continuous with the peritoneal cavity. •Fig. 44.21 Ovulation.GVBD,germinalvesiclebreakdown.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadel-phia:Mosby;2013.)Surface epithelium Tunica albugineaLuteinizing theca Blood vessels invading granulosa Luteinizing mural granulosa without basal lamina Peritoneal cavity Ruptured antrum Expanded cumulus Zona pellucida First polar body 2° oocyte after GVDB 2. The attachment of the cumulus cells to the mural granulosa cells degenerates, and the cumulus-oocyte complex becomes free-floating within the antral cavity (see Fig. 44.21 ). Cumulus cells also respond to the LH surge by secreting hyaluronic acid and other extracellular matrix components. These substances enlarge the entire cumulus-oocyte complex, a process called cumulus expansion (see


Physiology_Levy

Physiology_Levy. Fig. 44.21 ). This enlarged cumulusoocyte complex is more easily captured and transported by the oviduct. The expanded cumulus also makes the cumulus-oocyte complex easier for spermatozoa to find. Sperm express a membrane hyaluronidase that allows them to penetrate the expanded cumulus. The cumulusoocyte complex is released through the ruptured stigma through a relatively slow process. 3. The basal lamina of mural granulosa cells is broken down so that blood vessels and outer-lying theca cells can push into the granulosa cells. Granulosa cells secrete angiogenic factors such as vascular endothelial growth factor (VEGF), angiopoietin 2, and basic fibroblast growth factor (bFGF), which significantly increase the blood supply to the new corpus luteum. The Gamete Before ovulation the primary oocyte is competent to complete meiosis, but it is arrested in prophase I (see Fig.


Physiology_Levy

Physiology_Levy. The Gamete Before ovulation the primary oocyte is competent to complete meiosis, but it is arrested in prophase I (see Fig. 44.18 ). The LH surge inhibits production of cGMP by granulosa and cumulus cells, thereby removing inhibition of the oocyte-specific PDE3A. PDE3A proceeds to degrade cAMP to inactive AMP, thereby removing the brake on meiotic progression. The oocyte then progresses to meta-phase II and subsequently arrests at metaphase II until fertilization. Both theca and mural granulosa cells express LH receptors at the time of the LH surge. The LH surge induces differentiation of the granulosa cells—a process that continues for several days after ovulation. During the periovulatory period, the LH surge induces the following shifts in steroidogenic activity of the mural granulosa cells (now turning into granulosa lutein cells). 1.


Physiology_Levy

Physiology_Levy. 1. Transient inhibition of CYP19 expression and consequently estrogen production. The rapid decline in estrogen helps turn off the positive feedback on LH secretion. 2. Breakdown of the basal lamina and vascularization of the granulosa cells. This makes LDL and HDL cholesterol accessible to these cells for steroidogenesis. The LH surge also increases expression of the LDL receptor and HDL receptor (SR-BI) in granulosa cells. 3. Onset of expression of StAR protein, CYP11A1 (side chain cleavage enzyme), and 3β-HSD ( Fig. 44.22 ). Expression of these enzymes are key to the onset of production of high levels of progesterone by these cells. As discussed later, high progesterone synthesis is absolutely necessary for maintenance of pregnancy. Because CYP17 activity, especially its 17,20-lyase function, is largely absent in granulosa lutein cells, progesterone is not further metabolized to another steroid but instead exits the cells and enters the circulation.


Physiology_Levy

Physiology_Levy. •Fig. 44.22 Steroidogenicpathwaysinthecorpusluteum(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.)LH LH receptor LDLR and HDLR-mediated uptake Acetate Cholesterol Stimulation of steroidogenesis LH LH receptor LDLR and HDLR-mediated uptake Cholesterol Pregnenolone Stimulation of steroidogenesis StAR protein CYP11A1 Androstenedione Androstenedione Progesterone Estradiol-17˜3˜-HSD The Corpus Luteum


Physiology_Levy

Physiology_Levy. The Corpus Luteum After ovulation the remnant of the antral cavity fills with blood from damaged blood vessels in the vicinity of the stigma. This gives rise to a corpus hemorrhagicum. Within a few days, red blood cells and debris are removed by macrophages, and fibroblasts fill in the antral cavity with a hyaline-like extracellular matrix. In the mature corpus luteum the granulosa cells, now called granulosa lutein cells, enlarge and become filled with lipid (cholesterol esters). The enlarged granulosa lutein cells collapse into and partially fill in the old antral cavity. The theca along with blood vessels, mast cells, macrophages, leukocytes, and other resident connective tissue cells infiltrate the granulosa layer at multiple sites.


Physiology_Levy

Physiology_Levy. The human corpus luteum is programmed to live for 14 days, plus or minus 2 days (corpus luteum of menstruation), unless “rescued” by the LH-like hormone human chorionic gonadotropin (hCG), which originates from an implanting embryo. If rescued, the corpus luteum of pregnancy will remain viable during the pregnancy (usually ≈ 9 months). The mechanism by which the corpus luteum of menstruation regresses in 14 days is not fully understood. The corpus luteum appears to become progressively less sensitive to basal levels of LH, so that hCG binding to the LH receptor is needed for continued health and function of the corpus luteum. Regression appears to involve release of the prostaglandin PGF2α from both granulosa lutein cells and the uterus in response to declining levels of progesterone during the second week of the luteal phase. Several paracrine factors (endothelin, monocyte chemotactic protein-1) from immune and vascular cells are likely to play a role in the demise and removal of


Physiology_Levy

Physiology_Levy. the second week of the luteal phase. Several paracrine factors (endothelin, monocyte chemotactic protein-1) from immune and vascular cells are likely to play a role in the demise and removal of granulosa lutein cells. The corpus luteum is ultimately turned into a scarlike body called the corpus albicans, which sinks into the medulla of the ovary and is slowly absorbed.


Physiology_Levy

Physiology_Levy. The Gamete The LH surge induces two parallel events, ovulation and luteinization. If ovulation occurs normally, the corpus luteum is devoid of a gamete. Before the LH surge, the granulosa cells have very low capacity to convert cholesterol into a steroid hormone. The LH surge induces the onset of expression of CYP11A1, 3β-HSD and StAR protein, allowing granulosa lutein cells to convert cholesterol into progesterone. Because CYP17 expression is extremely low, progesterone accumulates and moves out of the granulosa lutein cells and enters the vasculature. Progesterone production by the corpus luteum (see


Physiology_Levy

Physiology_Levy. Fig. 44.22 ) increases steadily from the onset of the LH surge and peaks during the midluteal phase. The main purpose of this timing is to transform the uterine lining into an adhesive and supportive structure for implantation and early pregnancy. As discussed later the midluteal phase is synchronized with early embryogenesis so the uterus is optimally primed when a blastocyst tumbles into the uterus around day 22 of the menstrual cycle. Estradiol continues to be produced by theca lutein cells and granulosa lutein cells. Estrogen production transiently decreases in response to the LH surge but then rebounds and peaks at the midluteal phase. Estradiol induces the progesterone receptor in progesterone target cells, such as the uterine endometrium, and ensures a full response to progesterone. Luteal hormonal output is absolutely dependent on basal LH levels (see


Physiology_Levy

Physiology_Levy. Luteal hormonal output is absolutely dependent on basal LH levels (see Fig. 44.22 ). In fact, progesterone output is closely correlated with the pulsatile pattern of LH release in women. Both FSH and LH are reduced to basal levels during the luteal phase by negative feedback from progesterone and estrogen. In addition, granulosa lutein cells secrete inhibin, which selectively represses FSH secretion.


Physiology_Levy

Physiology_Levy. The corpus luteum must generate large amounts of progesterone to support implantation and early pregnancy. Accordingly the life of the corpus luteum is very regular, and a shortened luteal phase typically leads to infertility. The quality of the corpus luteum is largely dependent on the size and health of the dominant follicle from which it developed, which in turn is dependent on normal hypothalamic and pituitary stimulation during the follicular phase. Numerous factors that perturb hypothalamic and pituitary output during the follicular phase, including heavy exercise, starvation, high prolactin levels, and abnormal thyroid function, can lead to luteal phase deficiency and infertility.


Physiology_Levy

Physiology_Levy. Follicular atresia refers to the demise of an ovarian follicle. During atresia the granulosa cells and oocytes undergo apoptosis. The thecal cells typically persist and repopulate the cellular stroma of the ovary. The thecal cells retain LH receptors and the ability to produce androgens and are collectively referred to as the “interstitial gland” of the ovary. Follicles can undergo atresia at any time during development. Follicular Development With Respect to the Monthly Menstrual Cycle


Physiology_Levy

Physiology_Levy. The human menstrual cycle strictly refers to the monthly discharge of discarded uterine lining as menstrual blood or menstrual flow (a period referred to as menses) through the process of menstruation (see later). In fact it is the onset or lack thereof of menses, as detected by the woman herself, that is the primary evidence for the cessation of menstruation (e.g., due to pregnancy or menopause) or a change in the duration and/or frequency of the menstrual cycle. However, it is useful from an endocrinological perspective to consider the human menstrual cycle as having an ovarian cycle and a uterine cycle, with the latter being driven by the former. As discussed later, there are also hypothalamic, pituitary, oviductal, and vaginal components of the human menstrual cycle. The reproductive function of the menstrual cycle is the collective orchestration by ovarian hormones of the functions of the hypothalamus, pituitary, uterus, oviduct, cervix, and vagina—and even the ovary itself—to:


Physiology_Levy

Physiology_Levy. function of the menstrual cycle is the collective orchestration by ovarian hormones of the functions of the hypothalamus, pituitary, uterus, oviduct, cervix, and vagina—and even the ovary itself—to: (1) produce a fertilizable gamete (egg), (2) provide a supportive environment for intercourse, reception of sperm, fertilization of egg and early embryogenesis, (3) prepare the uterine lining for implantation, placentation and pregnancy, and (4) minimize the possibility of a superimplantation (i.e., a second implantation) from occurring, and/or prevent an ascending infection from moving up to the uterus from the vagina.


Physiology_Levy

Physiology_Levy. The first half of the monthly menstrual cycle is referred to as the follicular phase of the ovary and is characterized by recruitment and growth of a large antral follicle, selection of the dominant follicle, and growth of the dominant follicle until ovulation. The dominant follicle must contain a fully developed oocyte and somatic follicle cells that secrete high levels of estrogen. The second half of the monthly menstrual cycle is referred to as the luteal phase of the ovary and is dominated by hormonal secretions of the corpus luteum. The corpus luteum must secrete both progesterone and estradiol for progression of the normal cycle. Regulation of Late Stages of Follicular Development, Ovulation, and Luteinization: The Human Menstrual Cycle


Physiology_Levy

Physiology_Levy. Regulation of Late Stages of Follicular Development, Ovulation, and Luteinization: The Human Menstrual Cycle As stated earlier, late stages of follicular development and luteal function are absolutely dependent on normal hypothalamic and pituitary function. As in the male, hypothalamic neurons secrete GnRH in a pulsatile manner. GnRH in turn stimulates LH and FSH production by pituitary gonadotropes. A high frequency of GnRH pulses (1 pulse per 60–90 minutes) selectively promotes LH production, whereas a slow frequency promotes FSH production. A major difference between the male and female reproductive axes is the midcycle gonadotropin surge, which is dependent on a constant high level of estrogen coming from the dominant follicle. A highly dynamic “conversation” occurs among the ovary, pituitary, and hypothalamus in which the events of the menstrual cycle are orchestrated, beginning with the ovary at the end of the luteal phase of a previous nonfertile cycle (


Physiology_Levy

Physiology_Levy. Fig. 44.23 ). Events that follow are numbered according to Fig. 44.24 : Event 1: In the absence of fertilization and implantation, the corpus luteum regresses and dies (called luteolysis). This leads to a dramatic decline in levels of progesterone, estrogen, and inhibin by day 24 of the menstrual cycle. Event 2: The pituitary gonadotrope perceives the end of luteal function as a release from negative feedback (see Fig. 44.23B , Late Luteal Phase). This leads to an increase in FSH about 2 days before the onset of menstruation. The basis for the selective increase in FSH is incompletely understood, but it may be due to the slow frequency of GnRH pulses during the luteal phase, which in turn is due to high progesterone levels. CHAPTER 44 The Male and Female Reproductive Systems


Physiology_Levy

Physiology_Levy. CHAPTER 44 The Male and Female Reproductive Systems Event 3: The rise in FSH levels recruits a crop of large (2–5 mm in diameter) antral follicles to begin rapid, highly gonadotropin-dependent growth. These follicles produce low levels of estrogen and inhibin B. Event 4: The gonadotrope responds to the slowly rising levels of estrogen and inhibin B by decreasing FSH secretion (see Fig. 44.23A , Early Follicular Phase). The absence of progesterone promotes an increase in the frequency of GnRH pulses, thereby selectively increasing LH synthesis and secretion by the gonadotrope. Thus the LH:FSH ratio slowly increases throughout the follicular phase. Event 5: The ovary’s response to declining FSH levels is follicular atresia of all of the recruited follicles except for one dominant follicle (see


Physiology_Levy

Physiology_Levy. Event 5: The ovary’s response to declining FSH levels is follicular atresia of all of the recruited follicles except for one dominant follicle (see Fig. 44.23A , Early Follicular Phase). Thus the process of selection is driven by an extreme dependency of follicles on FSH in the face of declining FSH secretion. Usually only the largest follicle with the most FSH receptors and best blood supply can survive. This follicle produces increasing amounts of estradiol-17β and inhibin B. A critical action of FSH at this time is induction of the expression of LH receptors in the mural granulosa cells of the dominant follicle (see Fig. 44.23A , Late Follicular Phase).


Physiology_Levy

Physiology_Levy. Fig. 44.23A , Late Follicular Phase). Event 6: Once the dominant follicle causes circulating estrogen levels to exceed 200 pg/mL for about 50 hours in women, estrogen exerts a positive feedback on the gonadotrope to produce the midcycle LH surge. This is enhanced by the small amount of progesterone secreted at midcycle. The exact mechanism of the positive feedback is unknown, but it occurs largely at the level of the pituitary. GnRH receptors and the sensitivity to GnRH signaling increase dramatically in the gonadotropes. The hypothalamus contributes to the gonadotropin surge by increasing the frequency of GnRH pulses. Event 7: The LH surge drives meiotic maturation, ovulation, and differentiation of granulosa cells into progesterone-producing cells (see Fig. 44.23A , Late Follicular Phase).


Physiology_Levy

Physiology_Levy. Event 7: The LH surge drives meiotic maturation, ovulation, and differentiation of granulosa cells into progesterone-producing cells (see Fig. 44.23A , Late Follicular Phase). Event 8: Rising levels of progesterone, estrogen, and inhibin A by the mature corpus luteum negatively feed back on pituitary gonadotropes. Even though estradiol levels exceed the 200-pg/mL threshold for positive feedback, the high progesterone levels now produced by the corpus luteum block any positive feedback of estradiol. Consequently both FSH and LH levels decline to basal levels (see Fig. 44.23B , Mid-Luteal Phase).


Physiology_Levy

Physiology_Levy. Fig. 44.23B , Mid-Luteal Phase). Event 9: Basal levels of LH (but not FSH) are absolutely required for normal corpus luteum function. However, the corpus luteum becomes progressively insensitive to LH signaling and will die unless LH-like activity (i.e., hCG from an implanted embryo) increases. In a nonfertile cycle the corpus luteum of menstruation will regress in 14 days, and progesterone and estrogen levels will start to decline by about 10 days, thereby cycling back to event 1 (see Fig. 44.23B , Late Luteal Phase).


Physiology_Levy

Physiology_Levy. 808 SECTION8Berne & Levy Physiology •Fig. 44.23 A,Endocrinesignalingleadingtotheovulationofadominantfollicleattheendofthefollicularphaseofthemenstrualcycle.B,Endocrinesignalingduringthelutealphaseofanon-pregnantmenstrualcycleleadingtothedeathofthecorpusluteumandrecruitmentoffolliclestobeginnextcycle.LATE FOLLICULAR d8-14 EARLY FOLLICULAR d3-7 Dominant follicle COC Ruptured follicle Growing large antral follicles recruited by FSH Decreasing FSH basal LH (–)(–)(+)(+)High E2 no P4 Gonado-tropes GnRH neurons GnRH neurons Kisspeptin neurons Kisspeptin neurons Moderate E2 & inhibin no P4 LH surge @ midcycle GnRH rapid pulses Gonado-tropes GnRH slow pulses • Increasing (–) feedback causing lower FSH • Follicular atresia • Selection of dominant follicle Switch to (+) feedback-especially at level of pituitary sensitivity to rapid GnRH pulses • Meiotic maturation • Luteinization • Ovulation of cumulus-oocyte complex (COC) A. Follicular Phase LATE LUTEAL (d25-28) MID-LUTEAL (d17-24) Corpus


Physiology_Levy

Physiology_Levy. of pituitary sensitivity to rapid GnRH pulses • Meiotic maturation • Luteinization • Ovulation of cumulus-oocyte complex (COC) A. Follicular Phase LATE LUTEAL (d25-28) MID-LUTEAL (d17-24) Corpus luteum from ovulated dominant follicle Large antral recruitable follicles Dying corpus luteum (corpus albicans) If no implantation no rescue by hCG Maintains active corpus luteum FSH recruits large antral follicles new cycle starts Loss of negative feedack from ovary after corpus luteum dies Gonado-tropes GnRH neurons Kisspeptin neurons GnRH rapid pulses Gonado-tropes GnRH neurons Kisspeptin neurons GnRH slow pulses (–)(–)High P4 moderate & inhibition FSH Peak Basal LH & FSH No E2 inhibin or P4 B. Luteal Phase


Physiology_Levy

Physiology_Levy. CHAPTER 44 The Male and Female Reproductive Systems 809 1. Corpus luteum dies, E and P levels fall. 5. Declining FSH levels progressively cause atresia of all but 1 follicle – leading to selection of dominant follicle, which produces high levels of E. 9. The corpus luteum progressively becomes less sensitive to basal LH – dies if levels of LH-like activity (i.e., hCG) do not increase. 3. FSH recruits a cohort of large antral follicles to enter rapid growth phase. Follicles secrete low amounts of E and inhibin. 7. LH surge induces meiotic maturation, ovulation and luteinization. The corpus luteum produces high P, along with E and inhibin. 4. E and inhibin negatively feed back on FSH. FSH LH Pituitary Progesterone OvaryEstradiol-17˜2. Pituitary responds to falling E and P by increasing FSH secretion. 6. High E has positive feedback on gonadotropes— LH (and some FSH) surges. 8. High P, E and inhibin negatively feed back on LH and FSH, returning them to basal levels.


Physiology_Levy

Physiology_Levy. •Fig. 44.24 Thehumanmenstrualcycle,withemphasisonthe“dialogue”betweenovaryandpituitarygonadotropes.NotethattherelativechangesinthelevelsofE2andinhibinareshownbythesameline. From this sequence of events it is evident that the ovary is the primary clock for the menstrual cycle. The timing of the two main pituitary-based events—the transient rise in FSH that recruits large antral follicles and the LH surge that induces ovulation—is determined by two ovarian events. These are respectively the highly regular life span of the corpus luteum and its demise after 14 days, and growth of the dominant follicle to the point at which it can maintain a sustained high production of estrogen that induces a switch to positive feedback at the pituitary. In essence the dominant follicle tells the pituitary it is ready to undergo ovulation and luteinization. The Oviduct


Physiology_Levy

Physiology_Levy. The Oviduct The oviducts (also called the uterine tubes and the fallopian tubes) are muscular tubes with the distal ends close to the surface of each ovary and the proximal ends traversing the wall of the uterus. The oviducts are divided into four sections (going from distal to proximal): the infundibulum, or open end of the oviduct, which has fingerlike projections called fimbriae that sweep over the surface of the ovary; the ampulla, which has a relatively wide lumen and extensive folding of the mucosa; the isthmus, which has a relatively narrow lumen and less mucosal folding; and the intramural or uterine segment, which extends through the uterine wall at the superior corners of the uterus ( Fig. 44.25 The main functions of the oviducts are to: 1.


Physiology_Levy

Physiology_Levy. Fig. 44.25 The main functions of the oviducts are to: 1. Capture the cumulus-oocyte complex at ovulation and transfer the complex to a midway point (the ampullary-isthmus junction), where fertilization takes place. Oviductal secretions coat and infuse the cumulusoocyte complex and are likely required for viability and fertilizability. 2. Provide a site for sperm storage. Women who ovulate up to 5 days after sexual intercourse can get pregnant. Sperm remain viable by adhering to the epithelial cells lining the isthmus. The secretions of the oviduct also induce capacitation and hyperactivity of sperm. 3. Secrete fluids that provide nutritional support to the preimplantation embryo. The timing of movement of the embryo into the uterus is critical because the uterus has an implantation window of about 3 days. The oviduct needs to hold the early embryo until it reaches the blastocyst stage (5 days after fertilization) and then allow it to pass into the uterine cavity.


Physiology_Levy

Physiology_Levy. 810 SECTION8Berne & Levy Physiology •Fig. 44.25 Schematicofthefemalereproductivesystem.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.)Fundus of uterusIsthmusAmpulla Infundibulum with fimbriae Uterine (fallopian) tube Ovary Body (corpus) of uterus Internal genitalia External genitalia Cervix of uterus Vagina Clitoris Vaginal introitus Opening of female urethra Mons pubis Labia majora Labia minora


Physiology_Levy

Physiology_Levy. The wall of the oviduct is composed of a mucosa (called the endosalpinx), a two-layered muscularis (called the myosalpinx), and an outer-lying connective tissue (the perisalpinx). The endosalpinx is thrown into many folds, almost to the extent that the lumen is obliterated, and is lined by a simple epithelium made up of two cell types: ciliated cells and secretory cells. The cilia are most numerous at the infundibular end and propel the cumulus-oocyte complex toward the uterus. The cilia on the fimbriae are the sole mechanism for transport of the ovulated cumulus-oocyte complex. Once the complex passes through the ostium of the oviduct and enters the ampulla, it is moved by both cilia and peristaltic contractions of the muscularis.


Physiology_Levy

Physiology_Levy. The secretory cells produce a protein-rich mucus that is conveyed along the oviduct to the uterus by the cilia. This ciliary-mucus escalator maintains a healthy epithelium, moves the cumulus-oocyte complex toward the uterus, and may provide directional cues for swimming sperm. Movement of the cumulus-oocyte complex slows at the ampullary-isthmus junction, where fertilization normally takes place. This appears to be due in part to thick mucus produced by the isthmus and increased tone of the muscularis of the isthmus. The composition of oviductal secretions is complex and includes growth factors, enzymes, and oviduct-specific glycoproteins. Note that the clinical process of in vitro fertilization has shown that secretions of the oviduct are not absolutely necessary for fertility. However, normal oviductal function is absolutely required for both fertilization and implantation after in vivo insemination (i.e., natural sexual intercourse). Normal oviductal function also minimizes the


Physiology_Levy

Physiology_Levy. normal oviductal function is absolutely required for both fertilization and implantation after in vivo insemination (i.e., natural sexual intercourse). Normal oviductal function also minimizes the risk of ectopic implantation and ectopic pregnancy, which occurs most often within the oviduct.


Physiology_Levy

Physiology_Levy. Hormonal Regulation During the Menstrual Cycle


Physiology_Levy

Physiology_Levy. In general, estrogen secreted during the follicular phase increases epithelial cell size and height in the endosalpinx. Estrogen increases blood flow to the lamina propria of the oviducts, promotes production of oviduct-specific glycoproteins (whose functions are poorly understood), and increases ciliogenesis throughout the oviduct. Estrogen promotes secretion of thick mucus in the isthmus and increases the tone of the muscularis of the isthmus, thereby keeping the cumulus-oocyte complex at the ampullary-isthmus junction for fertilization. High progesterone, along with estrogen, during the early luteal to midluteal phase decreases epithelial cell size and function. Progesterone promotes deciliation. It also decreases the secretion of thick mucus and relaxes the tone in the isthmus. In addition it should be noted that oviductal epithelial cells express the LH receptor, which may synergize with estrogen to optimize oviductal function during the periovulatory period. The Uterus


Physiology_Levy

Physiology_Levy. The Uterus The uterus is a single organ that sits in the midline of the pelvic cavity between the bladder and the rectum. The mucosa of the uterus is called the endometrium, the three-layered thick muscularis is called the myometrium, and the outer connective tissue and serosa are called the perimetrium. The parts of the uterus are (1) the fundus, which is the portion that rises superiorly from the entrance of the oviducts, (2) the body of the uterus, which makes up most of the uterus, (3) the isthmus, a short narrowed part of the body at its inferior end, and (4) the cervix, which extends into the vagina (see Figs. 44.13 and 43.25). Because the cervical mucosa is distinct from the rest of the uterus and does not undergo the process of menstruation, it will be discussed separately later. The established functions of the uterus are all related to fertilization and pregnancy (discussed later). The main functions of the uterus are to: 1.


Physiology_Levy

Physiology_Levy. The established functions of the uterus are all related to fertilization and pregnancy (discussed later). The main functions of the uterus are to: 1. assist movement of sperm from the vagina to the oviducts 2. provide a suitable site for attachment and implantation of the blastocyst, including a thick nutrient-rich stroma 3. limit the invasiveness of the implanting embryo so it stays in the endometrium and does not reach the myometrium 811 •Fig. 44.26 Diagramoftheorganizationofglandsandbloodflowwithintheuterineendometrium.(FromStrausIII.In:YenSSCetal[eds].Reproductive Endocrinology. 4thed.Philadelphia:Saunders;1999.)Radial branch Spiral artery Uterine gland ENDOMETRIUM MYOMETRIUM Uterine artery Functional Zone Basal Zone Venous lakes Arcuate CHAPTER 44 The Male and Female Reproductive Systems 4.


Physiology_Levy

Physiology_Levy. CHAPTER 44 The Male and Female Reproductive Systems 4. provide a maternal side of the mature placental architecture, including the basal plate to which the fetal side attaches, and large intervillous spaces that become filled with maternal blood after the first trimester 5. grow and expand with the growing fetus so it develops within an aqueous nonadhesive environment 6.


Physiology_Levy

Physiology_Levy. provide strong muscular contractions to expel the fetus and placenta at term To understand the function of the uterus and uterine changes during nonfertile menstrual cycles, the fine structure of the endometrium and the relationship of uterine blood supply to the endometrium will be reviewed (Fig. 44.26). The luminal surface of the endometrium is covered with a simple cuboidal/columnar epithelium. The epithelium is •Fig. 44.27 Themenstrualcycleoftheuterineendometrium.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.) continuous with mucosal glands (called uterine glands) that extend deep into the endometrium. The mucosa is vascularized by spiral arteries, which are branches of the uterine artery that run through the myometrium. The terminal arterioles of the spiral arteries project just beneath the surface epithelium. These arterioles give rise to a subepithelial plexus of capillaries and venules that have ballooned thin-walled segments called


Physiology_Levy

Physiology_Levy. of the spiral arteries project just beneath the surface epithelium. These arterioles give rise to a subepithelial plexus of capillaries and venules that have ballooned thin-walled segments called venous lakes or lacunae. The lamina propria itself is densely cellular. The stromal cells of the lamina propria play important roles during both pregnancy and menstruation.


Physiology_Levy

Physiology_Levy. About two-thirds of the luminal side of the endometrium is lost during menstruation and is called the functional zone (also called the stratum functionalis) (see Fig. 44.26 ). The basal third of the endometrium that remains after menstruation is called the basal zone (also called the stratum basale). The basal zone is fed by straight arteries that are separate from the spiral arteries, and it contains all the cell types of the endometrium (i.e., epithelial cells from the remaining tips of glands, stromal cells, and endothelial cells). Hormonal Regulation of the Uterine Endometrium During the Menstrual Cycle Monthly oscillations in ovarian steroids induce the uterine endometrium to enter different stages. At the time of selection of the dominant follicle and its elevating production of estradiol, the uterine endometrium is just ending menstruation. The stratum functionalis has been shed and only the stratum basale remains ( Fig. 44.27).


Physiology_Levy

Physiology_Levy. Fig. 44.27). The rising levels of estrogen during the mid to late follicular phase of the ovary induce the proliferative phase of the uterine endometrium. Estrogen induces all cell types in the stratum basale to grow and divide. In fact the definition of an “estrogenic” compound has historically been one that is “uterotropic.” Estrogen increases cell proliferation directly through its cognate receptors (ER-α and ER-β), which regulate gene expression ( Fig. 44.28 ). Estrogen also controls uterine growth indirectly through local production of growth factors. In addition, estrogen induces expression of progesterone receptors, thereby “priming” the uterine endometrium so it can respond to progesterone during the luteal phase of the ovary. By ovulation, the thickness of the stratum functionalis has been reestablished under the proliferative actions of estradiol-17β (see


Physiology_Levy

Physiology_Levy. By ovulation, the thickness of the stratum functionalis has been reestablished under the proliferative actions of estradiol-17β (see Fig. 44.27 ). After ovulation the corpus luteum produces high levels of progesterone along with estradiol-17β. The luteal phase of the ovary switches the proliferative phase of the uterine endometrium to the secretory phase. In general, progesterone inhibits further endometrial growth and induces differentiation of epithelial and stromal cells. Progesterone induces the uterine glands to secrete a nutrient-rich product that supports blastocyst viability. As the secretory phase proceeds the mucosal uterine glands become corkscrewed and sacculated (see Fig.


Physiology_Levy

Physiology_Levy. Fig. 44.27 ). Progesterone also induces changes in adhesivity of the surface epithelium, thereby generating the “window of receptivity” for implantation of an embryo (see nancy). Additionally, progesterone promotes differentiation of stromal cells into “predecidual cells,” which must be prepared to form the decidua of pregnancy or to orchestrate menstruation in the absence of pregnancy.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Progesteroneopposestheproliferativeactionsofestradiol-17β anddownregulatestheestrogenreceptor(ER).Progesteronealsoinducesinactivating isoforms of 17β-HSD, therebyconvertingtheactiveestradiol-17β intotheinactiveestrone.Thisoppositionofthemitogenicactionsofestradiol-17β byprogesteroneisimportanttoprotecttheuterineendometriumfromestrogen-induceduterinecancer.Incontrast,administrationof“unopposed estrogen” towomensignificantlyincreasestheriskforuterinecancer. Fig.44.28 ).Forexample,theSERMtamoxifen isusedasanERantagonistforthetreatmentofbreastcancer(whoseearlyprogressionispromotedbyestrogen).BindingofSERMtotheERinducesconformationalchangesthatallowco-repressorstobindtotheERorpromotedegradationoftheER(orboth;see Fig.


Physiology_Levy

Physiology_Levy. Fig. 44.28 ).Becausetamoxifenhassomeuterotropicactivity(i.e.,makesuterineendometrialtissuegrow),newerSERMssuchasraloxifene havebeendevelopedtohaveERantagonistactivityonthebreast,beneficialERagonistactivityonbone(seelater),andnoactivityorERantagonisticactivityontheuterineendometrium. In a nonfertile cycle, death of the corpus luteum results in sudden withdrawal of progesterone, which leads to changes in the uterine endometrium that result in loss of the lamina functionalis (see Fig. 43.27). Menstruation normally lasts for 4 to 5 days (called a period), and the volume of blood loss ranges from 25 to 35 mL. Menstruation coincides with the early follicular phase of the ovary. Hormonal Regulation of the Myometrium


Physiology_Levy

Physiology_Levy. Hormonal Regulation of the Myometrium The smooth muscle cells of the myometrium are also responsive to changes in steroid hormones. Peristaltic contractions of the myometrium favor movement of the luminal contents from the cervix to the fundus at ovulation, and these contractions probably play a role in rapid bulk transport of ejaculated sperm from the cervix to the oviducts. During menstruation, contractions propagate from the fundus to the cervix, thereby promoting expulsion of sloughed stratum functionalis. The size and number of smooth muscle cells are determined by estrogen and progesterone. Healthy cycling women maintain a robust myometrium, whereas the myometrium progressively thins in postmenopausal women. The most drastic changes are seen during pregnancy, when the smooth muscle cells increase from 50 to 500 µm in length. The pregnant myometrium also has a greater number of smooth muscle cells and more extracellular matrix.


Physiology_Levy

Physiology_Levy. Disordersofmenstruationarerelativelycommonandincludemenorrhagia (heavymenstrualflowleadingtolossofmorethan80mLofblood),metrorrhagia irregularandsometimesprolongedmenstrualflowbetweennormalperiods),anddysmenorrhea (painfulperiods).Theexistenceofafewirregularperiods,calledoligomenorrhea, andtheabsenceofperiods,calledamenorrhea, areoftenduetodysfunctionofthehypothalamic-pituitary-ovarianaxisasopposedtolocalpelvicpathophysiology. Because endometrial tissue is naturally sloughed in fragments that contain viable cells, endometrial tissue occasionally gains access to other parts of the female tract (e.g., oviducts, ovary), as well as the lower part of the abdomen and associated structures (e.g., rectouterine pouch of Douglas, as shown in


Physiology_Levy

Physiology_Levy. Fig. 44.13 ). These implants give rise to endometriosis—a foci of hormonally responsive endometrial tissue outside the uterus. The spread of endometriosis may be due to reflux of menstrual tissue into the oviducts or movement of tissue through lymphatics, or both. Endometriosis frequently exhibits cyclic bleeding and is associated with infertility, pain on defecation, pain on urination, pain with sexual intercourse, or generalized pelvic pain. The Cervix The cervix is the inferior extension of the uterus that projects into the vagina (see


Physiology_Levy

Physiology_Levy. Figs. 44.13 44.25 ). It has a mucosa that lines the endocervical canal, which has a highly elastic lamina propria and a muscularis that is continuous with the myometrium. The part of the cervix that extends into the vaginal vault is called the ectocervix, whereas the part surrounding the endocervical canal is called the endocervix. The openings of the endocervical canal at the uterus and vagina are called the internal cervical os and the external cervical os, respectively. The cervix acts as a gateway to the upper female tract—at midcycle the endocervical canal facilitates sperm viability and entry. During the luteal phase the endocervical canal impedes passage of sperm and microbes, thereby inhibiting superimplantation of a second embryo or ascending infection into the placenta, fetal membranes, and fetus. The cervix physically supports the weight of the growing fetus. At term, cervical softening and dilation allow passage of the newborn and placenta from the uterus into the vagina.


Physiology_Levy

Physiology_Levy. Hormonal Regulation of Cervical Mucus During the Menstrual Cycle The endocervical canal is lined by simple columnar epithelium that secretes cervical mucus in a hormonally responsive manner. Estrogen stimulates production of a copious quantity of thin, watery, slightly alkaline mucus that is an ideal environment for sperm. Progesterone stimulates production of a scant, viscous, slightly acidic mucus that is hostile to sperm. During the normal menstrual cycle the conditions of the cervical mucus are ideal for sperm penetration and viability at the time of ovulation. The Vagina The vagina is one of the copulatory structures in women and acts as the birth canal (see


Physiology_Levy

Physiology_Levy. The Vagina The vagina is one of the copulatory structures in women and acts as the birth canal (see Figs. 44.13 44.25 ). Its mucosa is lined by a nonkeratinized stratified squamous epithelium. The mucosa has a thick lamina propria enriched with elastic fibers and is well vascularized. There are no glands in the vagina, so lubrication during intercourse comes from (1) cervical mucus (especially with intercourse that occurs midcycle), (2) a transudate (i.e., ultrafiltrate) from the blood vessels of the lamina propria, and (3) the vestibular glands. The mucosa is surrounded by a relatively thin (i.e., relative to the uterus and cervix) two-layered muscularis and an outer connective tissue. The vaginal wall is innervated by branches of the pudendal nerve, which contribute to sexual pleasure and orgasm during intercourse. Hormonal Regulation During the Menstrual Cycle


Physiology_Levy

Physiology_Levy. Hormonal Regulation During the Menstrual Cycle The superficial cells of the vaginal epithelium are continually desquamating, and the nature of these cells is influenced by the hormonal environment. Estrogen stimulates proliferation of the vaginal epithelium and increases its glycogen content (referred to as “cornification”—but in humans, true cornification or keratinization does not occur). The glycogen is metabolized to lactic acid by commensal lactobacilli, thereby maintaining an acidic environment. This inhibits infection by noncommensal bacteria and fungi. Progesterone increases the desquamation of epithelial cells. The External Genitalia The female external genitalia are surrounded by the labia majora (homologues of the scrotum) laterally and the mons pubis anteriorly (see


Physiology_Levy

Physiology_Levy. The External Genitalia The female external genitalia are surrounded by the labia majora (homologues of the scrotum) laterally and the mons pubis anteriorly (see Fig. 44.25 ). The vulva collectively refers to an area that includes the labia majora and mons pubis plus the labia minora, the clitoris, the vestibule of the vagina, the vestibular bulbs (glands), and the external urethral orifice. The vulva is also referred to as the pudendum by clinicians. The structures of the vulva serve the functions of sexual arousal and climax, directing the flow of urine, and partially covering the opening of the vagina, thereby inhibiting entry of pathogens.


Physiology_Levy

Physiology_Levy. The clitoris is the embryological homologue of the penis and is composed of two corpora cavernosa, which attach the clitoris to the ischiopubic rami, and a glans. These structures are composed of erectile tissue and undergo the process of erection in essentially the same manner as the penis. Unlike the penis, clitoral tissue is completely separate from the urethra. Thus the clitoris is involved in sexual arousal and climax at orgasm. The vagina is likewise involved in sexual satisfaction but also serves as the copulatory organ and birth canal. Hormonal Regulation During the Menstrual Cycle The structures of the vulva do not show marked changes during the menstrual cycle. However, the health and function of these structures are dependent on hormonal support. The external genitalia and vagina are responsive to androgens (testosterone and dihydrotestosterone) and estrogen. Androgens also act on the central nervous system (CNS) to increase libido in women.


Physiology_Levy

Physiology_Levy. Biology of Estradiol-17β and Progesterone Biological Effects of Estrogen and Progesterone


Physiology_Levy

Physiology_Levy. Biological Effects of Estrogen and Progesterone Estradiol-17β and progesterone fluctuate during the menstrual cycle, and they have multiple effects that can be categorized according to whether they are directly related to the reproductive system or not. Both hormones have profound effects on the ovary, oviduct, uterus, cervix, vagina, and external genitalia and on the hypothalamus and pituitary. Estrogen and progesterone also have important effects on nonreproductive tissues: Bone: Estrogen is required for closure of the epiphyseal plates of long bones in both sexes. Estradiol-17β has a bone anabolic and calciotropic effect (see ). It stimulates intestinal Ca++ absorption. Estradiol-17β is also one of the most potent regulators of osteoblast and osteoclast function. Estrogen promotes survival of osteoblasts and apoptosis of osteoclasts, thereby favoring bone formation over resorption. Low estrogen levels associated with menopause leads to bone loss and osteoporosis.


Physiology_Levy

Physiology_Levy. Liver: The overall effect of estradiol-17β on the liver is to improve circulating lipoprotein profiles. Estrogen increases expression of the LDL receptor, thereby increasing clearance of cholesterol-rich LDL particles by the liver. Estrogen also increases circulating levels of HDL. Estrogen regulates hepatic production of several transport proteins, including cortisol-binding protein, thyroid hormone–binding protein, and SHBG. CHAPTER 44 The Male and Female Reproductive Systems Cardiovascular organs: Premenopausal women have significantly less cardiovascular disease than men or post-menopausal women do. Estrogen promotes vasodilation through increased production of nitric oxide, which relaxes vascular smooth muscle and inhibits platelet activation. Single-nucleotide polymorphisms in the estrogen receptor have been associated with increased cardiovascular disease.


Physiology_Levy

Physiology_Levy. Integument: Estrogen and progesterone maintain healthy smooth skin with normal epidermal and dermal thickness. Estrogen stimulates proliferation and inhibits apoptosis of keratinocytes. In the dermis, estrogen and progesterone increase collagen synthesis and inhibit breakdown of collagen by suppressing matrix metalloproteinases. Estrogen also increases glycosaminoglycan production and deposition in the dermis and promotes wound healing.


Physiology_Levy

Physiology_Levy. CNS: Estrogen is neuroprotective—that is, it inhibits neuronal cell death in response to hypoxia or other insults. Estrogen’s positive effects on angiogenesis may account for some of the beneficial and stimulant-like actions of estrogen on the CNS. Progesterone acts on the hypothalamus to increase the set point for thermoregulation, thereby elevating body temperature approximately 0.5°F. This is the basis for using body temperature measurements to determine whether ovulation has occurred. Progesterone is a CNS depressant. Loss of progesterone on demise of the corpus luteum of menstruation is the basis for premenstrual dysphoria (premenstrual syndrome [PMS]). Progesterone also acts on the brainstem to sensitize the ventilatory response to PCO2 so that ventilation increases and PCO2 decreases.


Physiology_Levy

Physiology_Levy. Adipose tissue: Estrogen decreases adipose tissue by decreasing lipoprotein lipase activity and increasing hormone-sensitive lipase (i.e., it has a lipolytic effect). Loss of estrogen results in accumulation of adipose tissue, especially in the abdomen. Transport and Metabolism of Ovarian Steroids Steroid hormones are slightly soluble in blood and are bound to plasma proteins. Approximately 60% of the estrogen is transported bound to SHBG, 20% is bound to albumin, and 20% is in the free form. Progesterone binds primarily to cortisol-binding globulin (transcortin) and albumin. Because it has relatively low binding affinity for these proteins, its circulating half-life is about 5 minutes.


Physiology_Levy

Physiology_Levy. Although the ovary is the primary site of estrogen production, peripheral aromatization of androgens to estrogens can generate locally high levels of estradiol-17β in some tissues. Peripheral conversion of adrenal and ovarian androgens serves as an important source of estrogen after menopause (discussed later). The fact that CYP19 (aromatase) is expressed in the breast is the basis for the use of aromatase inhibitors in the treatment of estrogen-dependent breast cancer in postmenopausal women. •Fig. 44.29 Patternofgonadotropinsecretionthroughoutlife.Notethetransientpeaksduringgestationandearlyinfancyandthelowlevelsthereafterinchildhood.Womensubsequentlyhavemonthlycyclicbursts,withluteinizinghormone(LH)exceedingfollicle-stimulatinghormone(FSH);mendonot.Bothgendersshowincreasedgonadotropinproductionafterage50,withFSHexceedingLH.


Physiology_Levy

Physiology_Levy. Estrogens and progestins are degraded in the liver to inactive metabolites, conjugated with sulfate or glucuronide, and excreted in urine. Major metabolites of estradiol include estrone, estriol, and catecholestrogens (2-hydroxyestrone and 2-methoxyestrone). The major metabolite of progesterone is pregnanediol, which is conjugated with glucuronide and excreted in urine. Ontogeny of the Reproductive Systems Unlike most other organ systems, the reproductive systems undergo significant changes in their activity during the life span of a man or woman (


Physiology_Levy

Physiology_Levy. Unlike most other organ systems, the reproductive systems undergo significant changes in their activity during the life span of a man or woman ( Fig. 44.29 ). Development of the reproductive systems occurs in utero and results in female or male fetuses. After birth and during infancy, the reproductive systems are largely quiescent. At puberty the hypothalamic-pituitary-gonadal axes “wake up” and the gonads begin producing sex steroids, which in turn induce the sexually dimorphic changes in appearance and behavior associated with men and women. The reproductive life span of women is set by their ovarian reserve and degree of follicular development (see earlier) and ends at menopause, usually in the fifth decade of life. Loss of estrogen production by the ovaries has a clear clinical impact on many postmenopausal women. Men continue to produce sperm throughout life but can experience a decline in androgen production (andropause), which is associated with its own clinical sequelae.


Physiology_Levy

Physiology_Levy. The reproductive system of women undergoes dramatic changes during pregnancy. Production of gonadotropin and gonadal steroids is switched from the maternal hypothalamic-pituitary-ovarian axis, which is strongly repressed during pregnancy, to the fetal placenta. Indeed, it is the endocrine function of fetal placental tissue that maintains a quiescent gravid uterus, (2) alters maternal physiology to ensure fetal nutrition in utero, (3) alters maternal pituitary function and mammary gland development to ensure ongoing fetal nutrition after birth, and determines the time of labor and delivery (also called parturition). The placenta also plays an important role in fetal testosterone production and male differentiation of the reproductive system before the fetal hypothalamus and pituitary develop into a functional axis. Fertilization, Early Embryogenesis, Implantation, and Placentation


Physiology_Levy

Physiology_Levy. Fertilization, Early Embryogenesis, Implantation, and Placentation Fertilization, early embryogenesis, implantation, and early gestation are all synchronized with the human menstrual cycle ( Fig. 44.30 ). Just before ovulation the ovary is in the late follicular stage and produces high levels of estrogen. Estrogen promotes growth of the uterine endometrium and induces expression of the progesterone receptor. Estrogen ultimately induces the LH surge, which in turn induces meiotic maturation of the oocyte and ovulation of the cumulus-oocyte complex. The events between fertilization and implantation take about 6 days to complete, so implantation occurs at about day 22 of the menstrual cycle. At this time the ovary is in the midluteal phase and secreting large amounts of progesterone. Progesterone stimulates secretion from the uterine glands, which provide nutrients to the embryo. This is referred to as histiotropic nutrition and is an important


Physiology_Levy

Physiology_Levy. CHAPTER 44 The Male and Female Reproductive Systems 817 •Fig. 44.30 Synchronizationofeventsofthemenstrualcycle(ovaryandendometrium)withfertiliza-tion,earlyembryonicdevelopmentwithintheoviduct,andimplantationofembryo(blastocyst)intotheuterineendometrium.E2,estradiol;P4,progesterone.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.)d13 Peak E2 levels Onset of LH surge Dominant follicle-high E2 output d7 Ovary and pituitary Late follicular phase d13 Resumption of meiosis d20 Blastocyst in uterus d14 d15 Early luteal phase d15 First polar body and arrest at metaphase II 35 hours after onset of LH surge d21 Late luteal phase Growth of functional zone Induction of P4 receptors P4 induces secretion from E2-primed glands, and opposition of E2 mitogenic effects Receptive period Decreased antiadhesion protein expression Increased adhesion protein expression Uterine endometrium Arrested primary oocyte Egg and embryo Late proliferative phase Early secretory


Physiology_Levy

Physiology_Levy. Receptive period Decreased antiadhesion protein expression Increased adhesion protein expression Uterine endometrium Arrested primary oocyte Egg and embryo Late proliferative phase Early secretory phase Late secretory phase d28 Rescue of CL by hCG d20 d24 d16 Fertilization pronuclear stage d23 Blastocyst hatches from zona pellucida and implantation begins on day 22–23 (6–7 days after fertilization) d22d17 2-cell embryo d26 Completion of interstitial implantation mode of maternal-to-fetal transfer of nutrients for about the first trimester of pregnancy, after which it is replaced by hemotropic nutrition (see later). Progesterone inhibits myometrial contraction and prevents release of paracrine factors (e.g., cytokines, prostaglandins, chemokines, and vasoconstrictors) that lead to menstruation. Progesterone induces the “window of receptivity” in the uterine endometrium, which exists from about day 20 to day 24 of the menstrual cycle. This receptive phase is associated with increased


Physiology_Levy

Physiology_Levy. Progesterone induces the “window of receptivity” in the uterine endometrium, which exists from about day 20 to day 24 of the menstrual cycle. This receptive phase is associated with increased adhesivity of the endometrial epithelium and involves formation of cellular extensions called pinopodes on the apical surface of endometrial epithelia, along with increased expression of adhesive proteins (e.g., integrins, cadherins) and decreased expression of antiadhesive proteins (e.g., mucins) in the apical cell membrane.


Physiology_Levy

Physiology_Levy. When a fertilized egg implants in the uterus, the uterine endometrium is at its full thickness, is actively secreting, and is capable of tightly adhering to the implanting embryo. Fertilization accomplishes both recombination of genetic material to form a new genetically distinct organism and initiation of events that begin embryonic development. Several steps must occur to achieve successful (unassisted) fertilization (Fig. 44.31 3,4 ˜Ca++ Zona Egg plasma pellucida ZP2 membrane 3 • Fig. 44.31 Events involved in fertilization (see text for details). (Modified from White BA, Porterfield SP. Endocrine Physiology. 4th ed. Philadelphia: Mosby; 2013.) Step 1: Penetration of the expanded cumulus by the sperm. This involves digestion of the extracellular matrix of the cumulus by a membrane hyaluronidase, PH-20.


Physiology_Levy

Physiology_Levy. Step 1: Penetration of the expanded cumulus by the sperm. This involves digestion of the extracellular matrix of the cumulus by a membrane hyaluronidase, PH-20. Step 2: Penetration of the zona pellucida by the sperm. This involves binding of the sperm to the zona protein ZP3 (step 2a), which induces release of acrosomal enzymes (called the acrosomal reaction (step 2b). The sperm secondarily bind to another zona protein, ZP2 (step 2c), as the zona pellucida is digested and the sperm swims through to the egg (step 2d). Step 3: Fusion of the sperm and egg membrane takes place. Step 4: A Ca++ signaling cascade (see occurs.


Physiology_Levy

Physiology_Levy. Step 3: Fusion of the sperm and egg membrane takes place. Step 4: A Ca++ signaling cascade (see occurs. Step 5: The signaling cascade activates the exocytosis of enzyme-filled vesicles called cortical granules that reside in the outermost, or cortical, region of the unfertilized egg. The enzymes contained in the cortical granules are released to the outside of the egg upon exocytosis. These enzymes modify both ZP2 and ZP3 of the zona pellucida such that ZP2 can no longer bind acrosomereacted sperm, and ZP3 can no longer bind capacitated acrosome-intact sperm. Thus only one sperm usually enters the egg. Occasionally, more than one sperm does enter the egg. This results in a triploid cell that is unable to develop further. Therefore prevention of polyspermy is critical for normal development of the fertilized egg.


Physiology_Levy

Physiology_Levy. Step 6: The entire sperm enters the egg during fusion. The flagellum and mitochondria disintegrate, so most of the mitochondrial DNA in cells is maternally derived. Once inside the egg, decondensation of the sperm DNA occurs. A membrane called the pronucleus forms around the sperm DNA as the newly activated egg completes the second meiotic division. In mammalian eggs a large initial release of Ca++ is fol lowed by a series of subsequent smaller Ca++ oscillations that can last for hours. A major consequence of this signaling pathway is that it “wakes up” the metabolically quiescent •Fig. 44.32 Overviewofgeneticeventsafterfertilizationuptothefirstembryoniccleavage.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.) egg so it can resume meiosis and begin embryonic development. This process is called egg activation. The activated egg completes the second meiotic division as the sperm DNA decondenses and a pronucleus forms around it (


Physiology_Levy

Physiology_Levy. The activated egg completes the second meiotic division as the sperm DNA decondenses and a pronucleus forms around it ( Fig. 44.32). Once the egg has completed meiosis, CHAPTER 44 The Male and Female Reproductive Systems a pronucleus forms around the female chromosomes as well. A centrosome contributed by the sperm becomes a microtubule organizing center from which microtubules extend until they contact the female pronucleus. The male and female DNA replicate as the two pronuclei are pulled together. Once the pronuclei contact each other, the nuclear membranes break down, the chromosomes align on a common metaphase plate, and the first cleavage occurs. Fertilization typically occurs on day 16 to 17 of the men strual cycle, and implantation occurs about 6 days later. Thus the first week of embryogenesis takes place within the lumens of the oviduct and uterus. For most of this time the embryo remains encapsulated by the zona pellucida.


Physiology_Levy

Physiology_Levy. Thus the first week of embryogenesis takes place within the lumens of the oviduct and uterus. For most of this time the embryo remains encapsulated by the zona pellucida. The first two cleavages take about 2 days, and the embryo reaches a 16-cell morula by 3 days. The outer cells of the morula become tightly adhesive with each other and begin transporting fluid into the embryonic mass. During days 4 and 5 the transport of fluid generates a cavity called the blastocyst cavity, and the embryo is now called a blas Fig. 44.33 ). The blastocyst is composed of two subpopulations of cells: an eccentric inner cell mass and an outer epithelial-like layer of trophoblasts. The region of the trophoblast layer immediately adjacent to the inner cell mass is referred to as the embryonic pole, and it is this region that attaches to the uterine endometrium at Fig. 44.33


Physiology_Levy

Physiology_Levy. Fig. 44.33 The embryo resides within the oviduct during the first 3 days and then enters the uterus. By 5 to 6 days of develop ment the trophoblasts of the blastocyst secrete proteases that digest the outer-lying zona pellucida. At this point, corresponding to about day 22 of the menstrual cycle, the “hatched” blastocyst is able to adhere to and implant into the receptive uterine endometrium (see Fig. 44.33 At the time of attachment and implantation the tro phoblasts differentiate into two cell types: an inner layer of cytotrophoblasts and an outer layer of multinuclear/ Fig. 44.33).


Physiology_Levy

Physiology_Levy. Fig. 44.33 At the time of attachment and implantation the tro phoblasts differentiate into two cell types: an inner layer of cytotrophoblasts and an outer layer of multinuclear/ Fig. 44.33). The cytotrophoblasts initially provide a feeder layer of continu ously dividing cells. Syncytiotrophoblasts initially perform three general types of function: adhesive, invasive, and endocrine. Syncytiotrophoblasts express adhesive surface proteins (i.e., cadherins and integrins) that bind to uterine surface epithelia and, as the embryo implants, to compo nents of the uterine extracellular matrix. In humans the embryo completely burrows into the superficial layer of the endometrium (see


Physiology_Levy

Physiology_Levy. Fig. 44.33). This mode of implanta tion, called interstitial implantation, is the most invasive among placental mammals. Invasive implantation involves adhesion-supported migration of syncytiotrophoblasts into the endometrium, along with the breakdown of extracel lular matrix by secretion of matrix metalloproteinases and other hydrolytic enzymes. The endocrine function begins with the onset of implantation, when syncytiotrophoblasts start secreting the LH-like protein hCG, which maintains the viability of


Physiology_Levy

Physiology_Levy. Extraembryonic Primary Secondary Extraembryonic Remains of primary mesoderm yolk sac yolk sac forming coelom yolk sac •Fig. 44.33 A,Beginningofimplantation.Thetrophoblasthasdifferentiatedintocytotrophoblastand syncytiotrophoblast layers. B, As the syncytiotrophoblast layer increases in size and invades deeper, this layer begins to surround and erode maternal vessels, forming lacunae filled with maternal blood. C, Interstitial implantation is almost complete. Extensions of cytotrophoblasts have formed that will becomecoveredbyalayerofsyncytiotrophoblast.Atthispoint,theyarecalled“primaryvilli”.D,Interstitial implantationiscomplete.Extraembryonicmesodermalhasdevelopedfromtheepitheliallayers(amnion, primaryyolksac),andwillformaninnerlayerofthevilli,forming“secondaryvilli”.Ultimately,themesoderm willgiverise toumbilicalbloodvesselswithinthecoreofthe villus,therebyformingtertiaryvilli.(From CarlsonBM.Human Embryology and Developmental Biology.Philadelphia:Mosby;2004.) the corpus luteum and


Physiology_Levy

Physiology_Levy. Embryology and Developmental Biology.Philadelphia:Mosby;2004.) the corpus luteum and thus progesterone secretion. Syn-As implantation and placentation progress, syncytiotrocytiotrophoblasts also become highly steroidogenic. By 10 phoblasts take on the important functions of phagocytosis weeks the syncytiotrophoblasts acquire the ability to make (during histiotropic nutrition) and bidirectional placental progesterone at sufficient levels to maintain pregnancy transfer of gases, nutrients, and wastes. Exchange across independently of a corpus luteum. Syncytiotrophoblasts the syncytiotrophoblasts involves diffusion (e.g., gases), produce several other hormones as well as enzymes that facilitated transport (e.g., GLUT1-mediated transfer of modify hormones. glucose), active transport (e.g., amino acids by specific transporters), and pinocytosis/transcytosis (e.g., of irontransferrin complexes).


Physiology_Levy

Physiology_Levy. There is also a maternal response to implantation that involves transformation of the endometrial stroma. This response, called decidualization, involves an enlargement of stromal cells as they become lipid-and glycogen-filled decidual cells (at this time the endometrium is referred to as the decidua). The decidua forms an epithelial-like sheet with adhesive junctions that inhibit migration of the implanting embryo. The decidua also secretes factors such as tissue inhibitors of metalloproteinases (TIMPs) that moderate the activity of syncytiotrophoblast-derived hydrolytic enzymes in the endometrial matrix. Consequently, decidualization allows regulated invasion during implantation. Normally the implanting embryo and placenta do not extend to and involve the myometrium.


Physiology_Levy

Physiology_Levy. Placenta accreta istheburrowingoftheembryocompletelythroughtheendometriumandadhesionoftheplacentatothemyometrium,aconditionassociatedwithpotentiallylife-threateningpostpartum hemorrhage. Thedecidualresponseoccursonlyintheuterus.Thusthehighlyinvasivenatureofthehumanembryoposesconsiderablerisktothemotherinthecaseofectopic implantation. Ectopic implantation referstoimplantationofanembryoatasiteotherthantheuterus,andectopic pregnancy referstoadevelopingembryoatasiteofectopicimplantation.Mostectopicpregnancies(>90%)occurwithintheoviducts(calledtubal pregnancies),buttheycanalsooccurintheovaryandabdominalcavity.Implantationintheoviductsisoftenassociatedwithlong-terminfectionandinflammation(calledpelvic inflammatory


Physiology_Levy


Physiology_Levy

Physiology_Levy. The first hormone produced by syncytiotrophoblasts is hCG, which is structurally related to the pituitary glycoprotein hormones (see ). As such, hCG is composed of a common α-glycoprotein subunit (α-GSU) and a hormone-specific β subunit (β-hCG). Antibodies used to detect hCG (i.e., in laboratory assays and over-the-counter pregnancy tests) are designed to specifically detect the β subunit. hCG is most similar to LH and binds with high affinity to the LH receptor. The β subunit of hCG is longer than that of LH and contains more sites for glycosylation, which greatly increases the half-life of hCG to 24 to 30 hours. The stability of hCG allows it to rapidly accumulate in the maternal circulation such that hCG is detectable within maternal serum within 24 hours of implantation. Serum hCG levels double every 2 days for the first 6 weeks and peak at about 10 weeks. Serum hCG then declines to a constant level at about 50% of the peak value (Fig. 44.34A •Fig. 44.34


Physiology_Levy

Physiology_Levy. Serum hCG levels double every 2 days for the first 6 weeks and peak at about 10 weeks. Serum hCG then declines to a constant level at about 50% of the peak value (Fig. 44.34A •Fig. 44.34 CirculatinglevelsofhCGandhPLinmaternalbloodduringpregnancy.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.)100 80 60Human chorionic gonadotropin(mIU/mL)40 20 10 0 10 20 30 40 Weeks of gestationA B 10 8Human placental lactogen(µg/mL)6 4 2 0 10 20 30 40 Weeks of gestation


Physiology_Levy

Physiology_Levy. The primary action of hCG is to stimulate LH receptors on the corpus luteum. This prevents luteolysis and maintains a high level of luteal-derived progesterone production during the first 10 weeks. The rapid increase in hCG is responsible for the nausea of “morning sickness” associated with early pregnancy. A small amount (i.e., 1%–10%) of hCG enters the fetal circulation. hCG stimulates fetal Leydig cells to produce testosterone before the fetal gonadotropic axis is fully mature. hCG also stimulates the fetal adrenal cortex (see later) during the first trimester. The placenta produces a high amount of progesterone, which is absolutely required to maintain a quiescent myometrium and a pregnant uterus. Progesterone production by the placenta is largely unregulated—the placenta produces as much progesterone as the supply of cholesterol and the levels of CYP11A1 and 3β-HSD allow (


Physiology_Levy

Physiology_Levy. Fig. 44.35 ). Notably, placental steroidogenesis differs from that in the adrenal cortex, ovaries, and testis in that cholesterol is transported into the placental mitochondria by a mechanism that is independent of StAR protein. Thus this first step in steroidogenesis is not a regulated rate-limiting step in the placenta as it is in other steroidogenic glands. This means that fetuses with an inactivating mutation in StAR protein will develop lipoid congenital adrenal hyperplasia (see ) and hypogonadism but will have normal progesterone levels produced by their placenta. Progesterone production by the placenta does not require fetal tissue. Consequently, progesterone levels are largely independent of fetal health and cannot be used as a measure of fetal health. Maternal progesterone levels continue to increase throughout pregnancy.


Physiology_Levy

Physiology_Levy. •Fig. 44.35 Productionofprogesteronebysyncytiotrophoblastandestrogensbyfetoplacentalunit.Intervillous space (Maternal) Sycytiotrophoblast Cholesterol pregnenolone Fetal zone adrenal cortex Pregnenolone Pregnenolone-s 17OH-Pregnenolone-s Sulfo-Transferase CYP11A1 Star-related protein CYP11A1 Star protein CYP17 (Hydroxylase) CYP17 (17/20 lyase) ACTH Cholesterol Fetal pituitary CYP19 Aromatase E3 E2 E1 CYP19 Aromatase Sulfatase 16OH DHEA 16OH A'DIONE 16OH T Progesterone 16OH DHEAS DHEAS DHEAS DHEAS DHEAS16OH DHEAS Fetal liver DHEA A'DIONE T 3˜HSD 3˜HSD 17˜HSD Actions in maternal compartment Actions in maternal compartment Peripheral conversion to E2 MC2R


Physiology_Levy

Physiology_Levy. Progesterone is released primarily into the maternal circulation and is required for implantation and maintenance of pregnancy. Progesterone also has several effects on maternal physiology and induces breast growth and differentiation. The switch from corpus luteum–derived progesterone to placental-derived progesterone (referred to as the luteal-placental shift) is complete at about the eighth week of pregnancy. Progesterone (and pregnenolone) are used by the transitional zone of the fetal cortex to make cortisol late in pregnancy. Estrogens are also produced by syncytiotrophoblasts. Syncytiotrophoblasts are similar to ovarian granulosa cells in that they lack CYP17 and are dependent on another cell type to provide 19-carbon androgens for aromatization (see Fig. 44.35 ). The ancillary androgen-producing cells reside in the fetal adrenal cortex.


Physiology_Levy

Physiology_Levy. Fig. 44.35 ). The ancillary androgen-producing cells reside in the fetal adrenal cortex. The fetal adrenal cortex contains an outer definitive zone, a middle transitional zone, and an inner fetal zone. The definitive and transitional zones give rise to the zona glomerulosa and zona fasciculata, respectively. Aldosterone synthesis is initiated close to parturition. Synthesis of cortisol begins at about 6 months and increases during late gestation. The fetal zone is the predominant portion of the adrenal cortex in the fetus; it constitutes as much as 80% of the bulk of the large fetal adrenal and is the site of most fetal adrenal steroidogenesis. The fetal zone strongly resembles the zona reticularis in that it expresses little or no 3β-HSD (see


Physiology_Levy

Physiology_Levy. Fig. 44.35 ). The fetal zone primarily releases the sulfated form of the inactive androgen dehydroepiandrosterone sulfate (DHEAS) throughout most of gestation. Production of DHEAS from the fetal adrenal is absolutely dependent on fetal ACTH from the fetal pituitary by the end of the first trimester. The DHEAS released from the fetal zone has two fates. First, DHEAS can go directly to the syncytiotrophoblast, where it is desulfated by a placental steroid sulfatase and used as a 19-carbon substrate for the synthesis of estradiol-17β and estrone (see Fig. 44.35 ). The second fate of DHEAS is 16-hydroxylation in the fetal liver by the enzyme CYP3A7. 16-Hydroxyl-DHEAS is then converted by syncytiotrophoblasts to the major estrogen of pregnancy, estriol (see


Physiology_Levy

Physiology_Levy. Fig. 44.35 ). In X-linked ichthyosis, the steroid sulfatase is low or missing, resulting in loss of active (i.e., desulfated) estrogen production by the fetoplacental unit. Pregnancy is normal, but because estrogens promote parturition, the pregnancy is prolonged and usually ends with physician-induced labor. The baby boy has a skin disorder of varying degrees of severity that is called ichthyosis (scaly skin), owing to buildup of layers of shed cells within the stratum corneum. This form of ichthyosis is readily treatable by topical creams.


Physiology_Levy

Physiology_Levy. Maternal estrogen levels increase throughout pregnancy. Because estrogen production is dependent on a healthy fetus, estriol levels can be used as one measure of fetal health. The collective term used for the placental syncytiotrophoblasts and fetal organs in the context of estrogen production is the fetoplacental unit. Estrogens increase uteroplacental blood flow, enhance LDL receptor expression in syncytiotrophoblasts, and induce several components (e.g., prostaglandins, oxytocin receptors) involved in parturition. Estrogens increase breast growth directly and indirectly through stimulation of maternal pituitary prolactin production. Estrogens also increase lactotrope size and number, thereby increasing overall pituitary mass by more than twofold by term. Estrogens also affect several other aspects of maternal physiology.


Physiology_Levy

Physiology_Levy. Human placental lactogen (hPL), also called human chorionic somatomammotropin (hCS), is a 191–amino acid protein hormone produced in the syncytiotrophoblast that is structurally similar to growth hormone (GH) and prolactin (PRL). Its function overlaps those of both GH and PRL. It can be detected within the syncytiotrophoblast by 10 days after conception and in maternal serum by 3 weeks’ gestation (see Fig. 44.34 ). Maternal serum levels rise progressively throughout the remainder of the pregnancy. The quantity of hormone produced is directly related to the size of the placenta, such that as the placenta grows during gestation, hPL secretion increases. As much as 1 g/day of hPL can be secreted late in gestation.


Physiology_Levy

Physiology_Levy. Like GH, hPL is protein anabolic and lipolytic. Its antagonistic action to insulin is the major basis for the diabetogenicity of pregnancy. Like PRL, it stimulates mammary gland growth and development. Mammary gland development in pregnancy results from the actions of hPL, PRL, estrogens, and progestins. hPL inhibits maternal glucose uptake and use, thereby increasing serum glucose levels. Glucose is a major energy substrate for the fetus, and hPL increases fetal glucose availability. CHAPTER 44 The Male and Female Reproductive Systems As with hCG, far less hPL is found in the fetal circulation than in the maternal circulation. This suggests that the hormones may play a more important role in the mother than in the fetus. hPL is not essential for the pregnancy. Both hPL and PRL act as fetal growth hormones and stimulate production of the fetal growth-promoting hormones insulinlike growth factor (IGF)-I and IGF-II.


Physiology_Levy

Physiology_Levy. Both hPL and PRL act as fetal growth hormones and stimulate production of the fetal growth-promoting hormones insulinlike growth factor (IGF)-I and IGF-II. Ironically, fetal GH does not appear to regulate growth, and have normal birth weight. Diabetogenicity of Pregnancy Fig.


Physiology_Levy

Physiology_Levy. 44.36 ). During the last half of pregnancy when hPL levels are highest, maternal energy metabolism shifts from an anabolic state in which nutrients are stored to a catabolic state sometimes described as accelerated starvation, in which maternal energy metabolism shifts toward fat utilization with sparing of glucose. As maternal use of glucose for energy decreases, lipolysis increases and fatty acids become major energy sources. Peripheral responsiveness to insulin decreases and pancreatic insulin secretion increases. Beta cell hyperplasia occurs in pregnancy. Although this does not usually lead to a clinical condition, pregnancy aggravates existing diabetes mellitus, and diabetes can develop for the first time in pregnancy. If the diabetes resolves spontaneously with delivery, the condition is referred to as gestational diabetes. Other hormones contributing to the diabetogenicity of pregnancy are estrogens and progestins, because both these hormones decrease insulin sensitivity.


Physiology_Levy

Physiology_Levy. Human pregnancy lasts an average of 40 weeks from the beginning of the last menstrual period (gestational age). This corresponds to an average fetal age of 38 weeks. Par turition is the process whereby uterine contractions lead to childbirth. Labor consists of three stages: strong uterine contractions that force the fetus against the cervix, with dilation and thinning of the cervix (several hours); delivery of the fetus (<1 hour); and delivery of the placenta, along with contractions of the myometrium to halt bleeding (<10 minutes). Control of parturition in humans is complex, and the exact mechanisms underlying its control are not well understood. Placental CRH and the Fetal Adrenal Axis


Physiology_Levy

Physiology_Levy. The placenta produces corticotropin-releasing hormone (CRH), which is identical to the 41–amino acid peptide produced by the hypothalamus. Placental CRH production and maternal serum CRH levels increase rapidly during late pregnancy and labor. Moreover, circulating CRH is either in the form of free CRH, which is bioactive, or complexed to a CRH-binding protein. Maternal levels of CRH-binding protein plummet during late pregnancy and labor, so free CRH levels increase. Placental CRH also accumulates in the fetal circulation and stimulates fetal ACTH secretion. ACTH stimulates both fetal adrenal cortisol production and fetoplacental estrogen production. In contrast to the inhibitory effect of cortisol on hypothalamic CRH production, cortisol stimulates placental CRH production. This establishes a self-amplifying positive feedback. CRH itself promotes myometrial contractions by sensitizing the uterus to oxytocin and prostaglandins (see ). Estrogens also directly and indirectly stimulate


Physiology_Levy

Physiology_Levy. a self-amplifying positive feedback. CRH itself promotes myometrial contractions by sensitizing the uterus to oxytocin and prostaglandins (see ). Estrogens also directly and indirectly stimulate myometrial contractility. Moreover, this model correlates the onset of parturition with cortisol-induced maturation of fetal systems, including the lungs and gastrointestinal tract.


Physiology_Levy

Physiology_Levy. 824 SECTION8Berne & Levy Physiology •Fig. 44.36 Overviewofenergyusebythematernalandfetalcompartments.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.)Decreased maternal glucose use Antiinsulin action hPL Placenta Glucose Amino acids Fetus Lipolysis Proteolysis Amino acidsFatty acids for maternal use Although a rise in maternal serum estrogen and a drop in progesterone levels occur late in gestation in some species, no change in the ratio of the two hormones is seen in human serum. However, “functional” progesterone withdrawal involving changes in uterine progesterone receptor and progesterone metabolism has been proposed.


Physiology_Levy

Physiology_Levy. Oxytocin is secreted from the pars nervosa (posterior pituitary) (see ). Oxytocin, which stimulates powerful uterine contractions, plays a major role in progression and completion of parturition. Oxytocin is released in response to stretch of the cervix through a neuroendocrine reflex; it stimulates uterine contractions and thereby facilitates delivery. Oxytocin can be used to induce parturition, and uterine sensitivity to oxytocin increases before parturition. Because maternal serum oxytocin levels do not increase until after parturition has begun, oxytocin is not thought to initiate parturition. However, progesterone inhibits and estrogen stimulates synthesis of oxytocin receptors, and although maternal serum progesterone levels do not decrease immediately before human parturition, estrogen levels rise and oxytocin receptor synthesis increases.


Physiology_Levy

Physiology_Levy. Prostaglandins and other cytokines increase uterine motility, and levels of these compounds increase during parturition, thereby facilitating delivery. Their exact role in initiating parturition is not known. Prostaglandin levels in amniotic fluid, fetal membranes, and uterine decidua increase before the onset of labor. Prostaglandin F2α and prostaglandin E2 increase uterine motility. Large doses of these compounds have been used to induce labor. Because estrogens stimulate prostaglandin synthesis in the uterus, amnion, and chorion, the rising estrogen levels late in gestation can increase uterine prostaglandin formation before parturition.


Physiology_Levy

Physiology_Levy. Uterine size is thought to be a factor regulating parturition because stretch of smooth muscle, including the uterus, increases muscle contraction. In addition, uterine stretch stimulates uterine prostaglandin production. Multiple births generally occur prematurely. The tendency for early delivery can be a result of increased uterine size, increased fetal production of chemicals stimulating delivery, or both. CHAPTER 44 The Male and Female Reproductive Systems 825 • Fig. 44.37 Diagram of the structure of the breast, along with some pathological conditions of the breast and where they occur. (From Crum CP et al. In: Kumar V et al [eds]. Robbins Basic Pathology. 7th ed. Philadelphia: Saunders; 2003.) Structure of the Mammary Gland The mammary gland is composed of 15 to 20 lobes, each with an excretory lactiferous duct that opens at the nipple (


Physiology_Levy

Physiology_Levy. Fig. 44.37 ). The lobes in turn are composed of several lobules that contain secretory structures called alveoli and the terminal portions of the ducts. The epithelium of the alveoli and ducts is composed of two cell layers: apical luminal epithelial cells and basal myoepithelial cells. There is strong evidence for the presence of adult mammary stem cells within this epithelium. The luminal epithelial cells of the alveoli are the producers of milk, and the luminal cells of the ducts convey and modify the secreted milk. Myoepithelial cells are stellate smooth muscle–like cells, and contraction of these cells in response to a stimulus (i.e., milk let-down) expels milk from the lumens of the alveoli and ducts. Lobes and lobules are supported within a connective tissue matrix. The other major tissue component of the breast is adipose tissue. The lactiferous ducts empty at the nipple, a highly innervated hairless protrusion of the breast designed for suckling by an infant. The nipple is


Physiology_Levy

Physiology_Levy. tissue component of the breast is adipose tissue. The lactiferous ducts empty at the nipple, a highly innervated hairless protrusion of the breast designed for suckling by an infant. The nipple is surrounded by a pigmented hairless areola that is lubricated by sebaceous glands. Protrusion of the nipple, called erection, is mediated by sympathetic stimulation of smooth muscle fibers in response to suckling and other mechanical stimulation, erotic stimulation, and cold.


Physiology_Levy

Physiology_Levy. Hormonal Regulation of Mammary Gland Development At puberty, estrogen increases ductal growth and branching. With onset of the luteal phases of the ovary, progesterone and estrogen induce ductal growth and formation of rudimentary alveoli. During nonpregnant cycles the breasts develop somewhat and then regress. Estrogen also increases deposition of adipose tissue, which makes a major contribution to breast size and overall form. Adipose tissue expresses CYP19/aromatase, so accumulation of this tissue in the breast increases local production of estrogens from circulating androgens.


Physiology_Levy

Physiology_Levy. Breast development is facilitated by pregnancy, during which extensive ductal growth and branching and lobuloalveolar development occur. The parenchymal growth of the breast during development occurs at the expense of stroma, which is degraded to make room for enlarging lobuloalveolar structures. Several placental hormones stimulate breast development, including estrogen, progesterone, placental lactogen, and a growth hormone variant (GH-V). Estrogen acts on the breast both directly and indirectly through increasing maternal pituitary PRL. Estrogen increases PRL secretion from pituitary lactotropes. Estrogen also stimulates lactotrope hypertrophy and proliferation, which accounts for the twofold increase in pituitary volume during pregnancy in humans. Although epithelial cells express genes encoding milk protein and enzymes involved in milk production, progesterone inhibits the onset of milk production and secretion 826 SECTION8Berne & Levy Physiology •Fig. 44.38


Physiology_Levy

Physiology_Levy. cells express genes encoding milk protein and enzymes involved in milk production, progesterone inhibits the onset of milk production and secretion 826 SECTION8Berne & Levy Physiology •Fig. 44.38 Neuroendocrinereflexcausedbysucklingatthenippleandleadingtosecretionofoxytocinandprolactin.Inturnthesehormonesinducecontinuedmilkproduction(galactopoiesis)andmilklet-down.Prolactinalsoinduceslactationalamenorrhea.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.)Magnocellular neurons Parvicellular neurons Lactotropes Gonadotropes Lactational amenorrhea Parvicellular neurons Hypothalamus Breast Ovary Pars distalis Pars nervosa ˜ GnRH˜ Dopamine ˜ LH and FSH ° PRF?? ° Prolactin GalactopoiesisConcentration of myoepithelial cells Milk let-down Sucking at nipple ° Oxytocin (lactogenesis).


Physiology_Levy

Physiology_Levy. After parturition, the human breast produces colostrum, which is enriched with antimicrobial and antiinflammatory proteins. In the absence of placental progesterone, normal breast milk production occurs within a few days. The lobuloalveolar structures produce milk, which is subsequently modified by the ductal epithelium. Lactogenesis and maintenance of milk production (galactopoiesis) require stimulation by pituitary PRL in the presence of normal levels of other hormones, including insulin, cortisol, and thyroid hormone. Although placental estrogen stimulates PRL secretion during pregnancy, the stimulus for PRL secretion during the nursing period is suckling by the infant (


Physiology_Levy

Physiology_Levy. Fig. 44.38 ). Levels of PRL are directly correlated with frequency and duration of suckling at the nipple. The link between suckling at the nipple and PRL secretion involves a neuroendocrine reflex in which dopamine secretion at the median eminence is inhibited (the PRL release inhibitory factor; see ). It is also possible suckling increases secretion of unidentified PRL-releasing hormones. PRL also inhibits release of GnRH, and consequently, nursing can be associated with lactational amenorrhea (see


Physiology_Levy

Physiology_Levy. PRL also inhibits release of GnRH, and consequently, nursing can be associated with lactational amenorrhea (see Fig. 44.38 ). This effect of prolactin has been called “nature’s contraceptive,” and it may play a role in spacing out pregnancies. However, only regular nursing over a 24-hour period is sufficient to induce a PRL-induced anovulatory state in the mother. Thus lactational amenorrhea is not an effective or reliable form of birth control for most women. Inhibition of GnRH by high levels of PRL is important clinically. A prolactinoma is the most common form of hormone-secreting pituitary tumor, and hyperprolactinemia is a significant cause of infertility in both sexes. Hyperprolactinemia can likewise be associated with galactorrhea (inappropriate flow of breast milk) in men and women. Suckling at the nipple also stimulates release of oxytocin from the pars nervosa (see Fig. 44.38). Contraction of myoepithelial cells induces milk let-down, or expulsion of milk from the


Physiology_Levy

Physiology_Levy. Suckling at the nipple also stimulates release of oxytocin from the pars nervosa (see Fig. 44.38). Contraction of myoepithelial cells induces milk let-down, or expulsion of milk from the Invasive breast cancer (IBC) isamajorcancerinwomenandcanbeclassifiedintoseveralcategories.MostnewlydiagnosedIBCisclassifiedasluminal A, whichisusuallyderivedfromluminalcellsofterminalductsoralveoli.LuminalAIBCdisplayssomeepithelialorganization,includingEcadherin–mediatedcell-cellcontacts,andispoorlymotileandpoorlyaggressive.Thisformalsoexpressestheestrogen receptor α (ERα) andisdependentonestrogenicstimulationforgrowth.EarlydiagnosisofluminalAIBCconfersagoodprognosis.Treatmentforearlysmalltumorsthatare“node-negative”(i.e.,havenotspreadtonearbylymphnodes)typicallyinvolvessurgicalremoval(“lumpectomy”),followedbyradiationtreatment,followedby5yearsofdailytamoxifentreatment.TamoxifenisaSERMthatopposesestrogeninthebreast.


Physiology_Levy


Physiology_Levy

Physiology_Levy. alveolar and ductal lumens. Thus the nursing infant does not gain milk by applying negative pressure to the breast from suckling. Rather, milk is actively ejected through a neuroendocrine reflex. Oxytocin release and milk let-down can be induced by psychogenic stimuli such as the mother hearing a baby crying on television or thinking about her baby. Such psychogenic stimuli do not affect PRL release. Though related to depletion of ovarian follicles, the causes and process of menopause are poorly understood. Age-related changes in the CNS, including critical patterns of GnRH secretion, precede follicular depletion and may play an important role in menopause. Because follicles do not develop in response to LH and FSH secretion, estrogen and progesterone levels drop. Loss of the negative-feedback inhibition of estrogen on GnRH and LH/FSH results in a marked rise in serum LH and FSH. FSH levels rise more than LH levels. This could result from loss of ovarian inhibin.


Physiology_Levy

Physiology_Levy. Menopause typically occurs between 45 and 55 years of age. It extends over a period of several years. Initially the cycles become irregular and are periodically anovulatory. The cycles tend to shorten, primarily in the follicular phase. Eventually the woman ceases to cycle altogether. Serum estradiol levels drop to about a sixth the mean levels for younger cycling women, and progesterone levels drop to about a third those in the follicular phase of younger women. Production of these hormones does not cease entirely, but the primary source of these hormones in postmenopausal women becomes the adrenal, although interstitial cells of the ovarian stroma continue to produce some steroids. Most circulating estrogens are now produced peripherally from androgens. Because estrone is the primary estrogen produced in adipose tissue, it becomes the predominant estrogen in postmenopausal women.