Physiology: Female Reproductive System Lecture Notes PDF 2024-25

Physiology: Female Reproductive System Page 1 of 21 Dr. Jeyasuria Pancharatnam Session Learning Objectives: 1. Summarize the ovarian & endometrial cycles, hormones that influence secondary sex characteristics, influence of the brain on...

Physiology: Female Reproductive System Page 1 of 21 Dr. Jeyasuria Pancharatnam Session Learning Objectives: 1. Summarize the ovarian & endometrial cycles, hormones that influence secondary sex characteristics, influence of the brain on the reproductive cycle, and hormones involved. 2. Describe the regulatory control of the female menstrual rhythm including both ovarian and endometrial cycles, influence of the hypothalamic-pituitary-ovarian axis, patterns of gonadotropin levels & response to GnRH, clinical problems related to GnRH, GnRH mediated signaling in the gonadotrophs, effects of inhibins & activins, feedback by ovarian steroids to produce normal menstrual rhythm. 3. Describe the hormonal regulation of ovarian steroids including steroid synthesis, 2-cell/2- gonadotropin model, ovarian cycle, ovulation, and the formation of the corpus luteum. 4. Describe the physiological changes of the endometrial (uterine, menstrual) cycle that occur during the menstrual, proliferative, and secretory phases. Session Outline: I. Overview and Basic Concepts A. Ovarian & Endometrial Cycles B. Hormonal Influence on Female Secondary Sex Characteristics C. Influence of the Brain on the Reproductive Cycle D. Summary of Hormones Involved in the Reproductive Cycle II. Control of the Female Menstrual Rhythm A. Menstrual Cycle Includes Both Ovarian & Endometrial Cycles B. Control of the Hypothalamic-Pituitary-Ovarian Axis C. Patterns of Gonatropin Levels Throughout Life & Response to GnRH D. Clinical Problems Related to GnRH E. GnRH Signal Transduction in the Gonadotrophs F. Inhibins & Activins G. Feedback by Ovarian Steroids III. Ovarian Steroids A. Synthesis of Ovarian Steroids B. Two Cell, Two Gonadotropin Model C. Ovarian Cycle D. Ovulation E. Formation of the Corpus Luteum IV. Endometrial (Uterine, Menstrual) Cycle A. Menstrual Phase B. Proliferative Phase C. Secretory Phase Supplemental Reading Costanzo, L.S. Physiology, 6th ed., Elsevier: Philadelphia 2018 https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780323478816000107?scrollTo=%23hl0000515 Physiology: Female Reproductive System Page 2 of 21 Dr. Jeyasuria Pancharatnam I. Overview & Basic Concepts Reproductive function in female humans is controlled by hormones that emanate from the hypothalamic - pituitary - gonadal axis. Ovulation - The release of a mature ovum from the ovary concludes the menstrual cycle. Ovulation is regulated by cyclic functional interactions among signals cascades from hypothalamus, the anterior pituitary, and the ovaries. Reproductive capability is cyclic and reduces over the reproductive life ending with menopause. The ovaries and the uterine lining (endometrium) undergo rhythmic changes. Ovarian hormones; estrogens and progestins control cervical and uterine function. Menstruation reflects the periodic shedding of the endometrium. The female reproductive tract is designed to function in sperm and ovum transport, fertilization, implantation, and pregnancy. A. Ovarian & Endometrial Cycles Figure 1. The ovarian and endometrial cycles. The menstrual cycle comprises parallel ovarian and endometrial cycles. The follicular phase of the ovarian cycle and the menses start on day 0. In this idealized example, ovulation occurs on day 14, and the entire cycle lasts 28 days. Cycle of changes in ovary and endometrium (uterus) averages 28 days (Figure 1) and is controlled by the anterior pituitary, hypothalamus & ovary. 1. Ovarian cycle Follicular and Luteal phases Changes in ovary during & after maturation of oocyte at day 14 2. Endometrial (Uterine) Cycle menstrual, proliferative, and secretory phases prepares uterus to receive fertilized ovum if implantation does not occur, the stratum functionalis is shed during menstruation Pituitary hormones act on the ovaries Ovaries produce eggs Ovaries produce hormones that act on the uterus and brain Uterus prepares for pregnancy, and then is stripped of its lining if implantation did not occur Physiology: Female Reproductive System Page 3 of 21 Dr. Jeyasuria Pancharatnam B. Hormonal Influence on Female Secondary Sex Characteristics Estrogens control / act on Breast development Fat distribution Bone formation Uterus (these lectures) Liver and heart Androgens produced in the adrenal cortex control Pubic and axillary hair growth Libido C. Influences of the Brain on the Reproductive Cycle From the brain Gonadotrophs and Gonadotroph releasing hormones regulate ovarian function Sex steroids are closely related to one another (see hormone biosynthesis) Both sexes produce androgens and estrogen Androgens predominate in males Most testosterone comes from testes Estrogens are dominant in females Ovary produces estrogens (estradiol and estrone, progestins and androgens) Adrenal gland secretes small amounts of sex steroids D. Summary of Hormones Involved in the Reproductive Cycle GnRH (Gonadotropin Releasing Hormone) secreted by the hypothalamus controls reproductive cycle. GnRH stimulates the anterior pituitary to secrete FSH & LH. FSH (follicle stimulating hormone) initiates growth of follicles that secrete estrogen. LH (luteinizing hormone) stimulates ovulation & promotes formation of the corpus luteum which secretes mostly progesterone, estrogens, relaxin & inhibin. Ø Estrogen maintains reproductive organs Ø Progesterone prepares uterus for implantation and the mammary glands for milk secretion Ø Relaxin facilitates implantation in the relaxed uterus Ø Inhibin inhibits the secretion of FSH Physiology: Female Reproductive System Page 4 of 21 Dr. Jeyasuria Pancharatnam II. Control of the Female Menstrual Rhythm A. The menstrual cycle includes both the ovarian and endometrial cycles Involves cyclic changes in two organs orchestrated by timed hormone production (Fig 2) Ovarian cycle includes the follicular phase and luteal phase, separated by ovulation. The endometrial cycle includes the menstrual, proliferative, and secretory phases. Figure 2. General Overview of events in the ovaries and cervix during the reproductive cycle. The endometrial cycle. The ovarian cycle includes the follicular phase—in which the follicle develops—and the luteal phase—in which the remaining follicular cells develop into the corpus luteum. The endometrial cycle has three parts: the menstrual, the proliferative, and the secretory phases. Progesterone release increases basic body temperature. Physiology: Female Reproductive System Page 5 of 21 Dr. Jeyasuria Pancharatnam B. The menstrual cycle is controlled by the hypothalamic-pituitary-ovarian axis Neurons in the hypothalamus synthesize, store, and release gonadotropin releasing hormone (GnRH) in a pulsatile fashion. Figure 3. Hypothalamic-pituitary- ovarian axis. The hypothalamus secretes GnRH that causes gonadotrophs of the anterior pituitary to synthesize and release FSH and LH. LH binds to receptors on theca cells and increases biosynthesis of progestins and androgens. The androgens enter granulosa cells, which convert the androgens to estrogens. The dashed arrow indicates that the granulosa cells also have LH receptors. FSH binds to receptors on granulosa cells and synthesis of relevant enzymes (e.g., aromatase), activins, and inhibins. Negative feedback on the hypothalamic- pituitary-ovarian axis occurs by several routes. The activins and inhibins act only on the anterior pituitary. The estrogens and progestins act on both the anterior pituitary and hypothalamus, by exerting both positive and negative feedback controls. Estrogens and progestins primarily control endometrial maturation and menstruation reflects changes in hormone secretion. After puberty GnRH neurons change rhythmic pulses. Early in the follicular phase of the cycle, when the gonadotrophs are not very GnRH sensitive, GnRH elicits only a small rise in LH. Later in the follicular phase pituitary become much more sensitive and each burst of GnRH triggers a much larger release of LH. Pulse-generating mechanism of the hypothalamus controls cyclic reproductive function and the menstrual cycle. The frequency of GnRH release, and thus LH release, determines the specific response of the gonad. Estradiol released by the late stage follicle enhances the sensitivity of the gonadotrophs to GnRH. In contrast continuous administration of GnRH (or an analogue) causes downregulation of the gonadotroph GnRH receptor and thus suppresses gonadotropin release and gonadal function. Physiology: Female Reproductive System Page 6 of 21 Dr. Jeyasuria Pancharatnam C. Patterns of Gonadotropin Levels Throughout Life & Response to GnRH Figure 4. The levels of both LH and FSH peak during fetal life and again during early infancy, before falling to low levels throughout the rest of childhood. At the onset of puberty, LH and FSH levels slowly rise and then begin to oscillate at regular monthly intervals. At menopause, gonadotropin levels rise to very high levels. The four insets show daily changes in gonadotropin levels. Continuous administration of GnRH leads to downregulation (suppression) of gonadotropin secretion whereas pulsatile release of GnRH stimulates LH secretion (Figure 5). Figure 5. Pulsatile release of GnRH and pulsatile secretion of LH. (Data from Wang CF, Lasley BL, Lein A, Yen SS: J Clin Endocrinol Metab 1976; 42:718-728.) Physiology: Female Reproductive System Page 7 of 21 Dr. Jeyasuria Pancharatnam D. Clinical Problems Related to GnRH Kallmann syndrome. Disordered migration of GnRH hypothalamic cells during embryologic development causes disease - hypogonadotropic hypogonadism and anosmia (loss of sense of smell). Consequence: amenorrhea (no menstrual cycles). The pituitary and gonads of these individuals can function properly when appropriately stimulated. Women treated with exogenous gonadotropins or GnRH analogues —pulsatile administration with a programmed infusion pump — can have normal folliculogenesis, ovulation, and pregnancy. Endometriosis. Common condition caused by the aberrant presence of endometrial tissue outside the uterine cavity. The tissue responds to estrogens during the menstrual cycle and is source of pain and other problems (infertility). Continuous administration of GnRH analogue inhibits replenishment of the receptor for GnRH in the gonadotrophs in the anterior pituitary. Low GnRH receptors are available for optimum GnRH action, thereby diminishing gonadotropin secretion and producing relative hypoestrogenism. Because estrogen stimulates the endometrium, GnRH or GnRH analogues causes involution and diminution of endometriotic tissue. Physiology: Female Reproductive System Page 8 of 21 Dr. Jeyasuria Pancharatnam E. GnRH Signal Transduction in the Gonadotrophs GnRH stimulates gonadotrophs in anterior pituitary to secrete FSH and LH, which stimulate ovarian cells to secrete estrogens and progestins. 1. GnRH enters binds to GnRH receptors on the surface of the gonadotrophs (Figure 6). 2. GnRH binds to a G protein-linked receptor coupled to Gnq. Activation of phospholipase C (PLC), which, in turn, hydrolyzes phosphatidyl-inositol 4,5-biphosphonate (PIP2) to inositol 1,4,5-triphosphate (IP3, and diacylglycerol (DAG). IP3 and DAG are second messengers. Release of Ca2+ from the endoplasmic reticulum by IP causes an increase in [Ca2+]I (internally stored). influx of extracellular Ca2+ (over channels) à elevated [Ca2+]. high [Ca2+]i triggers gonadotropin release. In addition to the IP3 pathway, GnRH also acts through the DAG pathway. The DAG formed by PLC stimulates protein kinase C, which indirectly leads to increases in gene transcription. Figure 6. Gonadotropin secretion. PKC, protein kinase C.1. Binding of GnRH to G-protein–linked receptor activates the PLC pathway and the release of Ca2+ from internal stores. 2. The activated PLC also leads to the formation of DAG3 which stimulates PKC.4. PKC phosphorylates targets that indirectly stimulate gene transcription.5. LH and FSH are αβ dimers. The α subunits are identical. The β subunit determines specificity. 6. Gonadotropins are synthesized, dimerized, and glycosylated in the secretory pathway, regulated by the rhythm of GnRH.7. Ca2+ released from internal stores activates Ca2+ channels leading to sustained ↑[Ca2+] i. 8. The ↑[Ca2+] i triggers exocytosis and release of gonadotropin. Physiology: Female Reproductive System Page 9 of 21 Dr. Jeyasuria Pancharatnam F. Inhibins & Activins Ovaries produce peptide hormones: Inhibins, which inhibit FSH secretion, and Activins, which activate its expression in the gonadotrophic cells Belong to transforming growth factor (TGF-) supergene family Inhibin and activin dimers are constructed from a related set of building blocks: a glycosylated 20-kDa α subunit and two non-glycosylated 12-kDa beta subunits, one called β A and the other called β b (Figure 7). Simplified, the inhibins repress FSH production by gonadotrophs. The activins are produced in the same tissues as the inhibins, but they stimulate-rather than inhibit-FSH release from pituitary cells. Figure 7. The inhibins and activins. The inhibins and activins are peptide hormones that are made up of a common set of building blocks. For both the inhibins and the activins, disulfide bonds link the two subunits. Physiology: Female Reproductive System Page 10 of 21 Dr. Jeyasuria Pancharatnam G. Feedback by Ovarian Steroids, estrogens and progestins Ovarian estrogens and progestins feedback negatively on both the hypothalamus and the gonadotrophs of the anterior pituitary to reduce both LH and FSH. Estrogens exert negative feedback at both low and high concentrations, progestins are effective only at high concentrations. Figure 8 Hormonal changes during the menstrual cycle. The menstrual cycle is a cycle of the hypothalamic-pituitary- ovarian axis, as well as a cycle of the targets of the ovarian hormones: the endometrium of the uterus. Therefore, the menstrual cycle includes both an ovarian cycle—which includes the follicular phase, ovulation, and the luteal phase—and an endometrial cycle—which includes the menstrual, the proliferative, and the secretory phases. Positive Feedback by Ovarian Steroids - Mainly estradiol rises in the early follicular phase then steeply drops the second half - Estradiol levels reach threshold for a minimum of 2 days-and perhaps because of the accelerated rate of estradiol secretion-the hypothalamic-pituitary axis reverses its sensitivity to estrogens-that is, estrogens now feed-back positively on the axis. - One effect of positive feedback is that estrogens now increase the sensitivity of anterior pituitary gonadotrophs to GnRH inducing a LH surge critical for ovulation. Negative Feedback by Inhibins - Feedback repression of FSH by inhibins. Inhibins have intra-ovarian effect of decreasing androgen production, (intra-follicular estrogen production). Positive Feedback by the Activins - Activins promote FSH release GnRH independent, (not LH). intra-ovarian action à stimulating estrogen synthesis. Summary- Activins and inhibins regulate the activity of the follicular cells during the menstrual cycle. Physiology: Female Reproductive System Page 11 of 21 Dr. Jeyasuria Pancharatnam Modulation of gonadotropin secretion by positive and negative ovarian feedback produces the normal menstrual rhythm - Processes summarized and shown in Figure 9: The pulsatile release of GnRH from the hypothalamus, causes pulsatile release of LH and FSH from the gonadotrophs. - Gonadotropins (LH/FSH) cause release of ovarian steroids, which act on the hypothalamic- pituitary axis, - the interaction between the ovarian steroids and gonadotropin release is an example of feedback. - bidirectional ‘negative feedback throughout most of the menstrual cycle but positive feedback immediately before ovulation. - follicular phase is characterized by a relatively high frequency of GnRH-and thus LR-pulses. - Early follicular phase, estradiol is low but rising, LH pulses amplitude gradually increases with time. Figure 9: Hormonal control of the menstrual cycle (Silverthorn, 2nd Edition) Physiology: Female Reproductive System Page 12 of 21 Dr. Jeyasuria Pancharatnam - Late follicular phase, estrogen level increase causes both the frequency and the amplitude of the LH pulses to increase. Ovarian estradiol levels, feed-back positively on the hypothalamic-pituitary axis. Late in the follicular phase, the net effect of this increased frequency and amplitude of LH and FSH pulses is an increase levels. - The LH surge occurs around the 13th to 14th day of the follicular phase. - Positive feedback of estrogens, progestins, and activins on the hypothalamic-pituitary axis induce LH surge 3-fold increase superimposed on the smaller FSH surge. - Primary trigger of the gonadotropin (FSH/LH)) surge is a rise in estradiol to very high threshold levels just before the LH surge. - First, the accelerated rate of increase in estradiol levels in the preovulatory phase sensitizes the gonadotrophs in the anterior pituitary to GnRH pulses. - Second, the increasing estrogen levels also modulate hypothalamic neuronal activity and induce a GnRH surge, presumably through GnRH neurons in the preoptic area of the hypothalamus. Estradiol induces the mid-cycle surge of LH and, to a lesser extent, FSH. - Rising levels of the activins-secreted by granulosa cells-also act in a positive feedback manner to contribute to the FSH surge. In addition, gradually increasing levels of LH trigger the preovulatory follicle to increase its secretion of progesterone. These increasing-but still "low"-levels of progesterone also have a positive feedback effect on the hypothalamic- pituitary axis together with the positive feedback effect of the estrogens. Progesterone is not the primary trigger for the LH surge; it enhances the effects of estradiol. - Gonadotropin surge causes ovulation and luteinization. The ovarian follicle ruptures and releases the oocyte and with it the surrounding cumulus and corona cells. - A physiological change luteinization-in the granulosa cells of the follicle causes these cells to secrete progesterone rather than estradiol - The granulosa and theca cells undergo structural changes that transform them into luteal cells. - Early luteal phase of the menstrual cycle, circulating levels of LH and FSH rapidly decrease. Caused by negative feedback by three ovarian hormones-estradiol, progesterone, and inhibin. Levels of ovarian steroids decrease. Late luteal phase, the luteal cells of the corpus luteum increase estradiol, progesterone, and inhibin. This causes-in typical negative feedback fashion-the continued decrease of gonadotropin. - By approx. 48 hours before onset of the menses, the pulsatile rhythm of LH secretion has decreased to one pulse every 3 to 4 hours. As a result, circulating levels of LH slowly fall. - The gradual demise of the corpus luteum decreases progesterone, estradiol, and inhibin. After the onset of menstruation, the hypothalamic-pituitary axis returns to a follicular-phase pattern of LH secretion (i.e., a gradual increase in the frequency of GnRH pulses). Physiology: Female Reproductive System Page 13 of 21 Dr. Jeyasuria Pancharatnam III. OVARIAN STEROIDS A. Synthesis of Ovarian Steroids From cholesterol, the ovary synthesizes estradiol, the major estrogen, and progesterone, the major progestin. Cholesterol available through diet and synthesized in the liver from acetate. Ovarian cells can synthesize cholesterol de novo. Alternatively, cholesterol can enter cells in the form of LDL cholesterol. The rate limiting step is the mitochondrial cytochrome P-450 enzyme catalyzes the conversion of cholesterol to pregnenolone. Ovarian cells then convert pregnenolone to progestins and estrogens. Cells in the ovaries are different from Leydig cells in the testis, they have an aromatase that converts androstenedione to estrone and testosterone to estradiol. Once formed estrone can be converted into the more powerful estrogen estradiol and vice versa (Figure 10). The two major progestins, progesterone and 17a- hydroxyprogesterone, are formed even earlier in the biosynthetic pathway than the adrenal androgens. Functionally, progesterone is the more important progestin, and it has higher circulating levels and causes increase in basal body temperature. Figure 10. Biosynthesis of the ovarian steroids. This scheme summarizes the synthesis of the progestins and estrogens from cholesterol. The individual enzymes are shown in the horizontal and vertical boxes; these enzymes are located in either the smooth endoplasmic reticulum (SER) or the mitochondria. The side-chain– cleavage enzyme that produces pregnenolone is also known as 20,22- desmolase. The chemical groups modified by each enzyme are highlighted in the reaction product. The ovary differs from the testis in having aromatase, which converts androgens to estrogens. Physiology: Female Reproductive System Page 14 of 21 Dr. Jeyasuria Pancharatnam B. Two-cell, two-gonadotropin model Summary: Estrogen biosynthesis requires two ovarian cells (theca and granulosa) and two gonadotropins, whereas progestin synthesis requires only a single cell. Theca cells take up cholesterol and produce the adrenal androgens, but they do not have the aromatase necessary for estrogen production. Granulosa cells have the aromatase, but they lack the 17a-hydroxylase necessary for producing adrenal androgens (two cells). The superficial theca cell is near blood vessels and LDL cholesterol. In the follicular stage, the granulosa cells produce most cholesterol de novo. At corpus luteum stage the accompanying vascularization allows granulosa-lutein cell to take up LDL cholesterol and to thus synthesize large amounts of progesterone. - theca cells have LH receptors, and granulosa cells have both LH and FSH receptors! - At low concentrations, the weak androgens produced by the theca cells are substrates for estrogen synthesis by the granulosa cells, in addition to enhancing the aromatase activity of granulosa cells. - At high concentrations, conversion of androgens to estrogens is diminished. Instead, the weak androgens are preferentially converted by 5a-reductase to more potent androgens, such as dihydrotestosterone, a substance that cannot be converted to estrogen. Furthermore, these 5a- reduced androgens inhibit aromatase activity. Thus, the net effect of a high-androgen environment in the follicle is to decrease estrogen production. These androgens also inhibit LH receptor formation on follicular cells. - In the luteal phase of the cycle, luteinization of the follicle substantially changes the biochemistry of the theca and granulosa cells. - Blood vessels invade deep toward the granulosa- lutein cells. The increased vascularity facilitates the delivery of LDL cholesterol to the granulosa-lutein and process cholesterol-as it does in theca cells causing high progesterone synthesis midluteal phase. Indeed, the major products of the corpus luteum are progesterone and 17a-Hydroxyl progesterone, (some estradiol). See Fig 11 on next page. Physiology: Female Reproductive System Page 15 of 21 Dr. Jeyasuria Pancharatnam Figure 11. Two-cell, two-gonadotropin model. During the follicular phase, the major product of the follicle is estradiol, whereas during the luteal phase, the major products of the corpus luteum are the progestins, although estradiol synthesis is still substantial. In the follicular phase, LH primes the theca cell to convert cholesterol to androstenedione. Because the theca cell lacks aromatase, it cannot generate estradiol from this androstenedione. Instead, the androstenedione diffuses to the granulosa cell, whose aromatase activity has been stimulated by FSH. The aromatase converts the androstenedione to estradiol. In the luteal phase, the vascularization of the corpus luteum makes low LDL available to the granulosa-lutein cells. Thus, both the theca-lutein and the granulosa-lutein cells can produce progesterone, the major product of the corpus luteum. For production of 17α-hydroxyprogesterone (17α-OH progesterone), some of the progesterone diffuses into the theca-lutein cell, which has the 17α- hydroxylase activity needed for converting the progesterone to 17α-hydroxyprogesterone. The theca-lutein cell can also generate the androstenedione, which diffuses into the granulosa- lutein cell for estradiol synthesis. AC, adenylyl cyclase. Physiology: Female Reproductive System Page 16 of 21 Dr. Jeyasuria Pancharatnam A summary of hormones and their actions can be found in Figure 12. Figure 12: C. The Ovarian Cycle: Folliculogenesis, Ovulation, and formation of the Corpus Luteum Summary: Follicles mature in stages from primordial to graafian (or preovulatory) follicles. Oocyte maturation- the production of a Figure 13 haploid female gamete capable of fertilization by a sperm-begins in the fetal ovary Figure 13. Follicular development, as well as the subsequent division and ovulation, is central to control of the menstrual cycle. Meiosis is completed and the first polar body is extruded. Oocyte maturation is complete when the resulting haploid oocyte is capable of fertilization by a sperm. Consult the Histology notes on Female Reproductive System for more details. Physiology: Female Reproductive System Page 17 of 21 Dr. Jeyasuria Pancharatnam Types of granulosa cells: (1) mural granulosa cells, which are the farthest from the center of the follicle, are the most metabolically active, and contain large quantities of LH receptors and enzymes that are necessary for the synthesis of steroids; (2) cumulus granulosa cells are shed with the oocyte at the time of ovulation; cannot generate estrogens respond less to LH and have a low overall LH receptor content. (3) antral granulosa cells, facing the antrum, and left behind within the follicle to become the large luteal cells of the corpus luteum. Each month, a cohort of follicles is recruited, one of which achieves dominance One follicle is recruited during the early days of the current menstrual cycle and achieves dominance. FSH and LH maturate the follicles but only one dominant will appear Anti Mullerian hormone (AMH)* reduces FSH sensitivity in other follicles and acts as break Less dominant follicles undergo atresia- (death) The mechanism is not fully understood Estrogen induces FSH receptor expression, more effective use of FSH quicker growth the production of estrogens and inhibins allows the dominant follicle to become prominent and to gain an even greater edge over its competitors. D. Ovulation - Estradiol secretion by the dominant follicle triggers the LH surge, which, in turn, signals ovulation Summary: Ovulation occurs at the midpoint of every normal menstrual cycle and is triggered by the LH surge, which, in turn, is stimulated by rapidly rising levels of estradiol (Figure 14). -High estradiol secretion, signals the hypothalamic- pituitary system that follicular maturation is complete and that the hypothalamic- pituitary axis can now release a bolus of gonadotropin to induce ovulation. -LH surge terminates as a result of rising levels of progesterone, through negative feedback, and as a result of loss of the positive feedback by estradiol. Figure 14 - secondary oocyte starts second meiotic division, and arrests in metaphase until fertilization. It is surrounded by the zona pellucida and follicular cells, the corona radiata. -Before ovulation, the cumulus oophorus expands under the influence of LH, and eventually a complex consisting of the cumulus, the oocyte, and its surrounding cells breaks free with its "stalk" and floats inside the antrum, surrounded by follicular fluid stimulated by FSH. Physiology: Female Reproductive System Page 18 of 21 Dr. Jeyasuria Pancharatnam -Release of the oocyte: LH and progesterone enhance the activity of proteolytic enzymes (e.g., collagenase) within the follicle and thus lead to the digestion of connective tissue in the follicular wall. - oocyte, picked up by the fimbriae of the fallopian tube moves over the surface of the ovary. -through the infundibulum into the ampulla by means of ciliary movement of the tubal epithelium, as well as by muscular contractions of the tube. -Fertilization, takes place in the ampullary portion of the fallopian tube (see pregnancy). E. Formation of the Corpus Luteum After ovulation, the theca and granulosa cells of the follicle differentiate into the theca-lutein and granulosa-lutein cells of the highly vascularized corpus luteum (Fig 15). The granulosa and theca cells Figure 15 form the highly vascularized corpus luteum, a temporary endocrine organ (major product is progesterone). Cells differentiate LH dependent into theca-lutein cells and granulosa- lutein respectively. During the luteal phase of the menstrual cycle, estrogens and progestins inhibit folliculogenesis. Luteal function begins to decrease ~11days after ovulation by an unknown mechanism Growth and involution of the corpus luteum produce the rise and fall in progestins and estrogens during the luteal phase of the menstrual cycle The luteal phase is primarily dominated by progesterone secretion. Estrogen production by the corpus luteum is largely a function of the theca-lutein or the small cells, which also produce androgens. Progesterone production rises before follicular rupture. After ovulation, progesterone levels rise sharply and peak in ~7 days. Progesterone acts locally to inhibit follicular growth during the luteal phase. In addition, progesterone may act centrally by inhibiting gonadotropin secretion. Estradiol levels also rise during the luteal phase and reflect production by the corpus luteum. The estradiol produced during the luteal phase is necessary for the occurrence of progesterone-induced changes in the endometrium. Unless rescued by hCG (see pregnancy)-produced by the placenta (syncytial trophoblasts) of the blastocyst-luteal production of progesterone ceases toward the end of the menstrual cycle. hCG produced by the developing conceptus maintains steroidogenic function of the corpus luteum until approximately the ninth week of gestation, at which time placental function is Physiology: Female Reproductive System Page 19 of 21 Dr. Jeyasuria Pancharatnam well established. If not rescued by pregnancy, the hormone-producing cells of the corpus luteum degenerate and leave behind a fibrotic corpus albicans. Mifepristone (formerly known as RU-486), is a medication that causes early medical/chemical abortion in pregnant women by blocking receptors of progesterone, needed to maintain pregnancy. IV. THE ENDOMETRIAL (UTERINE, MENSTRUAL) CYCLE The ovarian hormones drive the morphological and functional changes of the endometrium during the monthly cycle Summary: The ovarian steroids-estrogens and progestins-control the cyclic monthly growth and breakdown of the endometrium. - The three major phases in the endometrial cycle are the menstrual, proliferative, and secretory phases. A. The Menstrual Phase If the oocyte was not fertilized and pregnancy did not occur in the previous cycle, a sudden diminution in estrogen and progesterone secretion will cause corpus luteum to demise. As hormonal support of the endometrium is withdrawn, the tissue breaks down and menstrual bleeding ensues. This moment is defined as day-1 of the menstrual cycle. After menstruation, all that remains on the inner surface of most of the uterus is a thin layer of non- epithelial stromal cells and some remnant glands. In ovary 20 follicles that began to develop 6 days before are now beginning to secrete estrogen fluid is filling the antrum from granulosa cells In uterus declining levels of progesterone caused spiral arteries to constrict -- glandular tissue dies stratum functionalis layer is sloughed off along with 50 to 150 ml of blood Menstrual Abnormalities Amenorrhea refers to the absence of menstrual periods; it may be either primary (meaning a woman never developed menstrual periods) or secondary (absence of menstrual periods in a woman who was previously menstruating). Hormone imbalance contributing to menstrual abnormalities can be caused by: Pregnancy, Breast-feeding, Menopause Contraceptives, Medications Life style factors - Low body weight. Excessive exercise. Stress (HPA/HPG) Pathological Factors - Polycystic ovary syndrome, Thyroid Malfunction, Pituitary tumor, Premature menopause Structural reasons – uterine scarring, lack of reproductive organs, structural abnormalities of the vagina Dysmenorrhea = pain associated with menstruation Abnormal uterine bleeding = excessive amount or duration or inter-menstrual Progesterone Withdrawal Test - Progesterone Challenge, A Diagnostic Test for Secondary Amenorrhea Physiology: Female Reproductive System Page 20 of 21 Dr. Jeyasuria Pancharatnam B. The Proliferative – Preovulatory Phase Endometiral proliferation and differentiation stimulated by estrogen that is secreted by the developing follicles. Levels of estrogen rise early in the follicular phase and peak just before ovulation. Estrogen receptor levels in the endometrium also increase during the follicular phase of the menstrual cycle. Lasts from day 6 to 14 (most variable timeline) In the ovary (follicular phase) Follicular secretion of estrogen & inhibin has slowed the secretion of FSH Dominant follicles survive to day 6 By day 14, graafian follicle has enlarged & bulges at surface Increasing estrogen levels trigger secretion of LH In the uterus (proliferative phase) Increasing estrogen levels have repaired & thickened the stratum functionalis to 4-10 mm C. The Secretory - Postovulatory Phase During the early luteal phase of the ovarian cycle, progesterone further stimulates the 17p- HSD and sulfation reactions. These anti-estrogenic effects halt the proliferative phase of the endometrial cycle. (Figure 16) -Progesterone also stimulates the glandular components of the endometrium and thus induces secretory changes in the endometrium. Figure 16 (yellow arrow=endometrium) Endometrial changes Phases of the uterine cycle Estrogen Progesterone Early menses Late menses Proliferative Secretory Physiology: Female Reproductive System Page 21 of 21 Dr. Jeyasuria Pancharatnam During the middle to late secretory phase, the secretory capacity of the endometrial glands is increased (Figure 17). Endometrial vascularization increases, glycogen content increases, and the thickness of the endometrium increases to 5 to 6 mm. The endometrial glands become engorged with secretions. At 9-10 days after ovulation, stromal cells between the Figure 17. Uterine cycle phases glands surrounding the spiral arteries enlarge. Spindle- shaped stromal cells differentiate into rounded decidual cells under the influence of progesterone and they form secretory products typical of decidual cells. The functional layer (stratum functionale) of endometrium is the layer that proliferates early in the monthly endometrial cycle, later interacts with the embryo during pregnancy, is shed after pregnancy, and is also shed each month during menstruation. The deepest layer of the endometrium (stratum basale) is the layer left behind after parturition or menstruation. The cells of the zona basalis give rise to the proliferation at the beginning of the next endometrial cycle. - During the late luteal phase of the menstrual cycle just before the next menstruation, levels of both estrogens and progestins diminish leading to eventual demise of the upper two thirds of the endometrium. During this period, the spiral arteries rhythmically spasm to cause ischemic tissue damage and hemorrhage. The average loss of blood, tissues, and serous fluid amounts to ~30 mL. - Menstrual blood does not clot because of the presence of fibrolysins released from necrotic endometrial tissue. Premenstrual Syndrome Physical & emotional distress during the postovulatory (luteal) phase that disappears at onset of menstruation. Signs & symptoms are variable; mood swings, depression, headache, fatigue, backache, constipation, breast tenderness, edema. Oral contraceptives are an effective treatment; careful diet & exercise may help.