Goal 7: Physiology of Female Reproduction

What is a polycystic ovary and its effects?

Polycystic Ovarian Syndrome (PCOS) androgen excess due to hypertrophy of theca interna Common cause of infertility; hirsutism, insulin resistance, obesity, prevalence ca. 10%

Uterine changes occur in what 3 phases during the menstrual cycle?

During each menstrual cycle, along with ovarian changes, uterine changes also occur simultaneously. Uterine changes occur in three phases: - Menstrual phase - Proliferative phase - Secretory phase.

What will you see at each segment of the hypothalamus-anterior pituitary-ovary axis? Benefit of pulsatile release?

• Hypothalamus: Gonadotropin releasing hormone: (GnRH) • Anterior pituitary: secreted in response to GnRH - Follicle stimulating hormone (FSH) - Luteinizing hormone (LH or LHcg) • Ovary: hormones are secreted in response to the stimulus coming from the anterior pituitary. - Estrogens (Estrone, Estradiol. Estriol) - Androgens (Androstenedione, Dehydroepiandrostenedione (DHEA), Testosterone) - Progestogens - Inhibins - Activins - Anti-Mullerian Hormone (AMH) Note: Estrogens evolved from androgens as a reproductive strategy in early vertebrates that are able to be hermaphroditic (sexes intermingled), gonochastic (separate sexes) depending or parthenogenic (female cloning without sperm, "virgin births") depending on environmental conditions (based on environment-gene interactions). This explains finding both masculinizing hormones (androgens) and feminizing hormones (estrogens) in both sexes in all vertebrate animals, including humans. -Pulsatile release prevents downregulation

What occurs during the luteal phase (timeline)? Which 2 cells are formed, what is their secretion? What occurs after fertilization, cell responsible? What is luteogenic and what is luteolytic? What is the function of the luteolytic agent?

- extends between 15th and 28th day of menstrual cycle; compared to the follicular phase, relatively non-variable in duration, usually 11-14 days (most consistent phase, follicular is the more variable phase) - LH stimulates development of corpus luteum from ruptured follicle cells, theca interna and granulosa "lutein" cells express LH receptors (LH receptors also known as LHCG receptors)- because responsive to HCg >The follicular theca cells luteinize into small luteal cells (thecal-lutein cells) and follicular granulosa cells luteinize into large luteal cells (granulosal-lutein cells) forming the corpus luteum - Corpus luteum granulosa lutein cells secrete mostly progesterone & some estrogen, also inhibin A; theca lutein cells secrete androgens and progesterone - Progesterone prepares endometrium for possible pregnancy - Fate of corpus luteum depends upon whether ovum is fertilized or not. After fertilization syncytiotrophoblast cells (precursor to placenta) produce hCG. LHCG receptors stimulate steroidogenesis for maintaining pregnancy. hCG is luteogenic; PGF2alpha is luteolytic (can degenerate corpus albicans into corpus lutea).

What are the 9 main targets estrogen acts on?

-Effect on ovarian follicles -Effect on uterus -Effect on fallopian tubes -Effect on vagina -Secondary sexual characteristics -Effect on breast -Effect on bones -Effect on metabolism -Effect on electrolytes and blood vessels?

What occurs during the menstrual phase? Initiated by what (2x)? Causes what? Timeline?

A. Menstrual Phase (Menses) • It lasts for about 4 to 5 days, initiated by absence of fertilization & lack of hCG from embryo to maintain corpus luteum secretion of estrogen and progesterone. • After ovulation, if pregnancy does not occur, the thickened endometrium is shed or desquamated. This desquamated endometrium is expelled out through vagina along with blood and tissue fluid. • Sudden reduction in the release of estrogen and progesterone causes sudden involution of endometrium.

What are the 3 major measures of granulosa cell function?

Activins, Inhibins & AMH: Measures of Granulosa Cell Function

Effects of activin, inhibin and AMH? Which are a measure of ovarian reserve? When do the inhibins peak? Associated disease? When does AMH peak?

Activins, Inhibins & AMH: Measures of Granulosa Cell Function • Activins increases FSH-induced aromatization of androgens • Inhibins decreases FSH secretion - Inhibin A peaks at the middle of the luteal phase > Increased inhibin A with increased beta-hCG, decreased alpha-fetoprotein and estriol is suggestive of Down Syndrome (Quad Screen at 16-18 weeks gestation can diagnose). (after ovulation) - Inhibin B peaks at the middle of the follicular phase, measure of ovarian reserve (before ovulation) • Anti-Mullerian Hormone (AMH) - AMH inhibits recruitment of follicles with insufficient numbers of FSH receptors for maturation, permits selection of dominant follicle (largest number of FSH receptors and blood vessels) for maturation and ovulation - AMH peaks at age 27.5 years, measure of fertility and ovarian reserve

What occurs during the proliferative phase of the menstrual cycle? Timeline?

B. Proliferative Phase • Usually extends usually from 5th to 14th day of menstrual cycle • It corresponds to the follicular phase of ovarian cycle. • Endometrial cells proliferate rapidly, epithelium reappears on the surface of endometrium. • Uterine glands start developing within the endometrial stroma • Blood vessels appear in the stroma All these uterine changes during proliferative phase occur because of the influence of estrogen released from ovary.

What occurs during the secretory phase of the menstrual cycle? Timeline? Main function of this phase?

C. Secretory Phase • Usually extends between 15th to 28th day of menstrual cycle. • After ovulation, corpus luteum is developed in the ovary. It secretes a large quantity of progesterone along with a small amount of estrogen. Estrogen causes further proliferation of cells in uterus, so that the endometrium becomes more thick. • Progesterone causes further enlargement of endometrial stroma and further growth of glands (enhancing their secretory function). Secretory phase is the preparatory period, during which the uterus is prepared for implantation of ovum.

What phases are the changes in the ovary divided into? Describe the first phase and what happens in between the phases? What is the timeline of the first phase?

Changes in the ovary during each menstrual cycle occur in two phases: - Follicular phase - Luteal phase. • Ovulation occurs in between these two phases. • A. Follicular Phase Follicular phase extends from the 5th day of the cycle until the time of ovulation, which takes place on 14th day. Can be 11-27 days in duration, main determinant of the total cycle. Compared to luteal, highly variable in duration; e.g., prolongation delays ovulation during periods of stress. - FSH from anterior pituitary stimulates follicle growth - Follicles grow into Graafian (mature) follicle - Granulosa cells of follicle secrete estrogens and inhibin - Increasing levels of estrogens and inhibin inhibit FSH - Increasing estrogens also stimulates secretion of LH

Describe the path of oogenesis? What is a degenerate corpus lutean, usefulness?

Diploid (Oogonium) (mitotic divisions)> Primary Oocyte (first polar body after meiosis 1) > (completion of meiosis 1 & 2) Secondary Oocyte (arrested at metaphase of meiosis 2)* > ovulation (released from ovary)* > second polar body and fertilized egg (diploid zygote) Primary oocyte before birth; each month after puberty (ovulation); after fertilization (fertilized egg) Corpus albican is a degenerate corpus lutean; you can count it to see how many menstrual cycles she has had; scab forms

What are the main targets of progesterone (8x)?

Effect on ovaries, fallopian tubes, uterus, cervix, respiration, mammary glands, thermogenic effect, electrolyte balance and blood vessels

4 phases of the ovarian cycle? What causes mensuration cycle to begin, which days does it occur? Describe the 2 surges seen at ovulation, which dominates, why? When are ova released, when does the release stop?

In previous lessons, we learned: That primordial germ cells develop into primary diploid oocytes halted at the prophase meiosis I stage of development for up to 50 years. • That at menarche, the menstrual cycle hormones induce further development to the metaphase meiosis II in 1-2 dominant haploid ovarian follicles which is halted at the time of release of one polar body. • That ova are released (ovulated) each month until menopause, and oogenesis is completed at fertilization at the time of release of a second polar body. In this lesson, we will learn: • That the first part of the menstrual cycle consists of the beginning of menses counted as day 1 (when we see the blood) until about day 5 due to a sharp decrease in estrogen and progesterone. • That the second part consists of an ovarian follicular phase and a uterine proliferative phase dominated by a wave of estrogen which peaks just 1-2 days before ovulation. • That the third part occurs in the middle of the menstrual cycle which is the ovulatory phase induced by positive feedback of estrogen dominated by a large LH spike (surge) with suppression of an FSH spike by inhibin B. • That the fourth part consists of an ovarian luteal phase and a uterine secretory phase dominated by a wave of progesterone. -Ovulation is an inflammatory process

What are the 3 main estrogens, what synthesizes it, regulation? What is E2 mainly responsible for? What is the main progesterone, what synthesizes it, regulation? Responsible for what?

In previous lessons, we learned: • That estrogens are a category of feminizing gonadal (sex) steroid hormones that are responsible for the development and regulation of the female reproductive system. • That progestogens are a category of gonadal and placental steroid hormones that are responsible for maintaining pregnancy and embryogenesis. In this lesson, we will learn: • That there the three estrogens estrone (E1), estradiol (E2) and estriol (E3); made by the ovarian granulosa cells regulated largely by FSH; E2 is mainly responsible for growth of ovarian follicles and endometrium and secondary sex characteristics of women. • That progesterone (P4) is the main progestogen made by the corpus luteum and placenta regulated by LH, mainly responsible for vascularization, secretion and decidualization of the endometrium in preparation for embryo implantation and pregnancy.

What is the main hormone responsible for regulation of GnRH? Synthesized where? What type of secretion is LH, FSH? Describe GnRH pulses during each ovarian cycle change?

In previous lessons, we learned: • That the classical 28-day menstrual cycle consists of a menstrual phase followed by follicular and proliferative phases, followed by a midpoint ovulatory phase, followed by luteal and secretory phases. In this lesson, we will learn: • That kisspeptin in arcuate and paraventricular nuclei of the hypothalamus regulates the pulsatile release of GnRH and, in turn, pulsatile secretion of FSH and LH. • That GnRH pulses begin to increase during the menstrual phase to about q2h (1 ever 2 hours) during the follicular phase, to continuous during the ovulatory phase, then decreasing to about q4h during the luteal phase. Slower pulsations favor FSH

Summary- what is the main estrogen, made by what, regulated by what and its function? After menopause what is the main source of estrogen and aromatase? What is the main progesterone, made from what, main effects (3x)?

In this lesson, we learned: • That estrogens are made from androstenedione and testosterone via aromatase (estrogen synthase) in ovarian granulosa cells is regulated by FSH and FSH receptors; estrogen is mainly responsible for growth of ovarian follicles and endometrium. After menopause, visceral fat is a woman's main source of aromatase and estrogen. • That main estrogen (estradiol, E2) is needed for full expression of progesterone receptors. • That E2 is a vasodilator, causes renal retention of sodium, closes the epiphyseal growth plate, produces triangular deposition of pubic hair, smooth skin, pelvic widening, breast growth, stratification of vaginal epithelium and production of thin stringy cervical mucus at ovulation and other effects. • That progesterone (P4) made by the corpus luteum and placenta is regulated by LH and LHCG receptors, mainly responsible for vascularization, secretion and decidualization of the endometrium in preparation for embryo implantation and pregnancy, secretory alveoli of breast tissue, thick cervical mucus after ovulation, vasodilation, raises basal body temperature at ovulation, renal retention of sodium and stimulation of the medullary respiratory centers.

What is the major function of estrogen? Requirement for progesterone to have an effect? Effects on ovarian follices, fallopian tubes, uterus, and vagina?

Major function of estrogen is to promote cellular proliferation and tissue growth in the sexual organs and in other tissues, related to reproduction and to induce expression of progesterone receptors (estrogen priming). -In order for progesterone to have an effect, needs to be secreted with estrogen • Effect on ovarian follicles: Estrogen promotes the growth of ovarian follicles by increasing the proliferation of the follicular cells. • Effect on uterus: Enlargement of uterus to about double of its childhood size due to the proliferation of endometrial cells (good for fertilization) and change in cervical mucus from dry thick to thin, watery & stringy consistency just before ovulation (ferning). -Proliferation and dilatation of blood vessels of endometrium (preparing for progesterone) • Effect on fallopian tubes: Acts on the mucosal lining of the fallopian tubes and increases the number and size of the epithelial cells. It increase ciliary activity (sweeping motion for ovulating ovum, prevents ectopic pregnancy). • Effect on Vagina: Changes the vaginal epithelium from cuboidal into stratified type (more resistant to trauma and infection). -Lack causes thin vaginal wall and painful intercourse

What occurs during ovulation phase? Regulation? What factors contribute to the main process in ovulation? What 2 clinical factors can inhibit this phase?

Ovulation is the process by which the dominant follicle, the largest possessing the most FSH and LH receptors, ruptures with consequent discharge of ovum into the abdominal cavity. Regulated by LH surge (in middle of menstrual cycle). Fallopian tube fimbriae lined with cilia picks up the ovulated oocyte from the ovarian stigma. A local inflammatory process is mediated by pro-inflammatory cytokines, PGE2 & collagenase. Fallopian tube cilia promote movement of ovum to uterus after Fertilization. Ciliary dysfunction (ciliary dyskinesia) is a cause of infertility in cystic fibrosis (thick mucus) and Kartgener's syndrome. Note: NSAIDS are anti-inflammatory agents which inhibit ovulation. - Ovulation occurs on 14th day of menstrual cycle in a normal cycle of 28 days, usually at midpoint of cycle

What is the pathophysiology of the menstrual cycle? Cause (3x)?

Pathophysiology: During the next 24 hours, the tortuous blood vessels in the endometrium undergo severe constriction. • Endometrial vasoconstriction is because of three reasons: - Involution of endometrium - Actions of vasoconstrictor substances like prostaglandin (also luteolytic), released from tissues of involuted endometrium - Sudden lack of estrogen and progesterone (which are vasodilators) • Vasoconstriction leads to hypoxia, which results in necrosis of the endometrium • Necrosis causes rupture of blood vessels and oozing of blood

What are symptoms of menopause?

SYMPTOMS • Symptoms do not appear in all women. Some women develop mild symptoms and some women develop severe symptoms. • Hot flashes characterized by extreme flushing of the skin associated with uncontrolled fluctuations in plasma estrogen. • Vasomotor instability: Wide fluctuation in blood pressure may be present. (estrogen relaxes blood vessels) • Others are; osteoporosis, atherosclerosis, Fatigue, Nervousness, Emotional outburst like crying and anger, Mental depression, Insomnia, Palpitation, Vertigo, Headache, Numbness or tingling sensation.

What is the source of secretion for estrogen? When does secretion peak? Describe its synthesis?

Source of Secretion • In a normal non-pregnant woman, estrogen is secreted in large quantity by granulosa cells of ovarian follicles and in small quantity by corpus luteum of the ovaries. • Estrogen secretion peaks at the later stage of the follicular phase before ovulation. Synthesis • Estrogen is derived from androgens, particularly androstenedione, which is secreted by theca interna cells. Androstenedione migrates from theca cells to granulosa cells, where it is converted into estrogens by the activity of the enzyme aromatase (also known as estrogen synthase). Androstenecione and testosterone are the main ovarian androgens

Describe the source of progesterone (P4) secretion, its synthesis and circulation and metabolism?

Source of Secretion • In non-pregnant women, a small quantity of progesterone is secreted by theca interna cells of ovaries during the first half of menstrual cycle (follicular/proliferative phase). But, a large quantity of progesterone is secreted during the latter half of each menstrual cycle (secretory phase) by the corpus luteum Synthesis: Progesterone is synthesized from acetate or cholesterol in the ovaries, along with estrogen • Circulation and metabolism: Like estrogen, progesterone is also transported in the blood by the plasma proteins - albumin and globulin. Metabolized by the liver as well

Summary- what hormone controls pulsatile firing of GnRH? What can inhibit this firing? When does GnRH, FSH and LH have a continuous secretion? Cause of amenorrhea? Menopause results from what? What causes PCOS?

Summary In this lesson, we learned: • That kisspeptin regulates pulsatile firing of hypothalamic GnRH neurons. • That pulsatile release of GnRH is inhibited by CRH and cortisol (stress) marijuana (THC) and cocaine; thereby, accounting for some cases of amenorrhea and infertility. • That pulsatile secretion of GnRH, FSH and LH becomes continuous during ovulation when there is a temporary decline in estrogen and at menopause when there also is a decline in estrogen. • That amenorrhea results from a number of causes associated with disruption of the hypothalamo-pituitary-ovarian axis; e.g., extremely low body weight and adiposity. • That menopause results from ovarian failure; thereby increasing FSH and LH. • That PCOS results from excessive ovarian production of androgens, associated with masculinization, infertility, obesity, metabolic syndrome and diabetes.

What is the product and substrate of the thecal and granulosa cell secretions?

Thecal cell: Cholesterol and Testosterone (aromatase activity absent) Granulosa cell: Cholesterol and Estradiol (aromatase aka estragon synthase activity present) Androstenedione diffuses through the teca cells through the blood capillaries to granulosa cells Granulosa cell: Cholesterol > Pregnenolone > Progesterone (also goes to thecal cell) > Androstenedione > Estrone & Testosterone > Estradiol (goes to blood) Leydig cell: Cholesterol > Pregnenolone > Progesterone > 17 alpha-OH progesterone > Androstenedione > Testosterone

What are the 3 main types of estrogen? Quantity and potency is higher in which? Describe the circulation and metabolism of estrogen (conjugation with 2x)? What can cause estrogen build up?

Types • Estrogen is present in three forms in plasma: -Estrone (E1) -β-estradiol (E2) -Estriol (E3) The quantity and potency of β-estradiol (E2) is more than the others. >Circulation and Metabolism • These steroid hormones are lipid soluble, hence they can easily diffuse down their concentration gradients into the capillary blood. • Estrogen is degraded mainly in the liver. Here, it is conjugated with glucuronides and sulfates. About one fifth of the conjugated product is excreted in the bile while most of the remainder into the urine. • Diminished liver function can cause excess estrogen build up. -Causing infertility because too much endometrium

Main function of androgen in women? Describe the migration of androgens? 2 main ovarian androgens? When do its levels peak? Androgens synthesized where? Androgen functions (4x)? Effect on female libido?

• Androstenedione migrates from theca cells to granulosa cells, where it is converted into estrogens by the activity of the enzyme aromatase (also known as estrogen synthase). Androstenedione dehydroepiandrostenedione (DHEA) and testosterone are the main ovarian androgens. • Androgen plasma levels peak just before ovulation, associated with peak estrogen levels and sex drive (libido). -Important •Dehydroepiandrostenedione (DHEA) is made in the ovaries and is the main androgen made in the zona reticualris of the adrenal cortex (adrenal androgen). Largely responsible for the female sex drive (libido). • The main functions of androgens in females in negative feedback control of FSH and LH protecting against hyperestrogenism. • Androgens work with estrogens to increase follicle maturation and trigger ovulation. Androgens relax uterus and increase cervical collagen. -Lack can cause infections

Describe hormonal regulation: Late luteal phase?

• Corpus luteum degenerates after 11-12 days because of inadequate FSH & LH. • It stops producing estrogen & progesterone; endometrium breaks down. • Negative feedback on axis stops, so GnRH, FSH, LH secretion resumes and follicles begin developing. -Morning after pill is synthetic progesterone to inhibit ovulation

Estrogen effects on breasts, bones, metabolism, electrolytes & blood vessels?

• Effect on Breast: Development of stromal tissues of breasts, Growth of an extensive ductile system. • Effect on Bones: Estrogen increases osteoblastic activity (androgens have same effect), at the same time, estrogen causes early fusion of the epiphysis with the diaphysis. In old age, the lack of estrogen makes women susceptible to low bone mineral density, osteopenia and osteoporosis. • Effect on Metabolism: Estrogen induces anabolism of proteins and increases fat deposition in subcutaneous tissues. • Effect on Electrolytes & Blood Vessels: Estrogen causes sodium and water retention from the renal tubules mostly significant in pregnancy, acts as a vasodilator via NO (cGMP).

Progesterone effects on the ovaries, mammary glands, thermogenic effect, effects on respiration, effects on electrolyte balance (what is the excessive progesterone effect) and vessel?

• Effect on Ovaries: Progesterone inhibits ovulation, synthetic progesterone known as levonorgestrel used as the "morning-after" or "Plan B" pill (inhibiting effects on ovulation). • Effect on Mammary glands: Progesterone promotes the development of lobules and alveoli of mammary glands by proliferating and enlarging the alveolar cells. It also makes the breasts secretory in nature. • Thermogenic Effect: Progesterone increases the body temperature after ovulation by acting on hypothalamic centers. • Effect on Respiration: During luteal phase of menstrual cycle and during pregnancy, progesterone increases the ventilation via respiratory center. -COPD patients you give progesterone • Effect on Electrolyte Balance & Blood Vessels (same as estrogen): Progesterone increases the reabsorption of sodium and water from the renal tubules. However, in large doses, it is believed to cause excretion of sodium and water. Progesterone acts as a vasodilator, mainly via endothelial NO.

Describe the hormonal regulation: Late follicular phase and ovulation?

• Estrogen rises, switches to positive feedback on axis: anterior pituitary cells may be now sensitized to GnRH & progesterone • Positive feedback → LH/FSH surges (lower FSH surge due to inhibin). • LH induces ovulation; highest frequency of GnRH pulsations. • LH luteinizes follicle cells: thecal cells migrate, mix with granulosa, blood vessels invade. • Now LH stimulates granulosa cells to begin synthesizing progesterone (luteal phase). • Ovulation is accomplished at the ovarian stigma by a local inflammatory response involving PGE2, collagenase and a number of other pro-inflammatory cytokines. NSAIDS can inhibit or delay ovulation.

Describe the regulation of estrogen secretion? What inhibits FSH/GnRH and what increases/decreases FSH activity? What are measures of ovarian reserve?

• Estrogen secretion is regulated by follicle-stimulating hormone (FSH) released from anterior pituitary. • Granulosa cells have many FSH receptors. After binding with the receptors, FSH acts via cAMP and stimulates the secretory activities of the granulosa cells. • Estrogen inhibits secretion of FSH and GnRH by negative feedback. • Activins increase FSH activity, aromatization of androgens. • Inhibin secreted by granulosa cells also decreases estrogen secretion, by inhibiting the secretion of FSH and GnRH. • AMH & Inhibin secreted by granulosa are measures of ovarian reserve (measure of fertility).

Describe hormonal regulation: early to mid-luteal phase?

• Estrogen, progesterone & inhibin from corpus luteum exert negative feedback on axis; GnRH pulsing slows to q4h. • Progesterone stimulates development of secretory endometrium and raises body temperature set point.

Describe the hormonal regulation: Early to mid-follicular phase?

• GnRH pulses q2h. • Negative & positive (autocrine) feedback by estrogens (at ovulation). • Theca cells have good blood & LDL supply; LH stimulates androgen production; diffuses to granulosa cells. • Granulosa cells: poor blood & LDL supply; not expressing LH receptors (only some for progesterone but mostly for thecal cells); no progesterone synthesis. • FSH stimulates granulosa cells' conversion of androgens to estrogens by aromatase (estrogen synthase).

What undergoes regulation of progesterone secretion? Excessive secretion can inhibit what? LH receptors expressed mainly by which cells?

• LH from anterior pituitary activates the corpus luteum to secrete progesterone. • Secretion of LH is influenced by the gonadotropin-releasing hormone secreted in hypothalamus. • LH receptors are expressed mainly by theca interna cells. • Excess Progesterone inhibits the release of LH from anterior pituitary by negative feedback.

What causes luteal phase defect, amenorrhea, dysmenorrhea, abnormal uterine bleeding?

• Luteal Phase Defect = Short luteal phase (<11 days) • Insufficient progesterone to support pregnancy -Most consistent time (follicular more variable, stress can delay) • Amenorrhea = absence of menstruation • Caused by hormone imbalance, extreme weight loss or low body fat as with rigorous athletic training • Dysmenorrhea = pain associated with menstruation • Severe enough to prevent normal functioning • Caused by uterine tumors, ovarian cysts, endometriosis or intrauterine devices • "Mittelschmerz" is pain at the cycle midpoint, associated with ovulation • Abnormal uterine bleeding = excessive amount or duration of menstrual bleeding • Caused by fibroid tumors or hormonal imbalance -Estrogen= contraction of uterus, dilation of vessels

What is menopause? Effect? When does it usually occur? Cause (3x)? What happens to FSH and LH during menopause and ovulation in premenopausal women?

• Menopause is defined as the period when permanent cessation of menstruation takes place. Normally, it occurs at the age of 45 to 55 years. • Early menopause may occur because of surgical removal of ovaries (ovariectomy) or uterus (hysterectomy). CAUSE FOR MENOPAUSE • Due to advancement of age, the atrophy of ovaries occurs. • Throughout a woman's sexual life, about 450 of the primordial follicles grow into Graafian follicles and ovulate, while thousands of the follicles degenerate. • At the age of 45 years, only few primordial follicles remain in the ovary to be stimulated by FSH and LH. • When estrogen secretion becomes almost zero, FSH and LH are continuously secreted, similar to what occurs at ovulation in a premenopausal woman, When all the primordial follicles are atrophied, estrogen secretion stops completely. -Adrenal glands and fat are other sources of estrogen

What is the menstrual cycle, begins a what age ends at what age? What is the duration of the menstrual cycle? Menstrual cycle changes divided into what 4 physical groups?

• Menstrual cycle is defined as cyclic events that take place in a rhythmic fashion during the reproductive period of a woman's life. Menstrual cycle starts at the age of 12 to 15 years, which marks the onset of puberty (Menarche). Menstrual cycle ceases at the age of 45 to 50 years (menopause). DURATION OF MENSTRUAL CYCLE • Duration of menstrual cycle is usually 28 days. But, under physiological conditions, it may vary between 20 and 40 days. CHANGES DURING MENSTRUAL CYCLE • During each menstrual cycle, series of changes occur in ovary and accessory sex organs. • These changes are divided into 4 groups: 1. Ovarian changes 2. Uterine changes 3. Vaginal changes 4. Cervical changes

Describe when estrogen vs progesterone reach peak secretion? What cells secrete the 2?

• Ovarian follicle secretes large quantity of estrogen and corpus luteum secretes large quantity of progesterone. • Estrogen secretion reaches the peak twice in each cycle; once during follicular phase just before ovulation and another one during luteal phase. • On the other hand, progesterone is virtually absent during follicular phase till prior to ovulation. But it plays a critical role during luteal phase.

What is the main function of progesterone and requires what? What are its effects on the uterus, fallopian tubes, cervix?

• Progesterone is concerned mainly with the final preparation of the uterus for pregnancy and the breasts for lactation, requires estrogen for full expression of progesterone receptors (estrogen priming). • Effect on uterus: promotes the secretory activities of uterine endometrium during the secretory phase of the menstrual cycle. - Increases the size of uterine glands and these glands become more tortuous - Increases the blood supply to endometrium (so that placenta can eventually develop) • Effect on fallopian tubes: it promotes the secretory activities of mucosal lining of the fallopian tubes. Secretions of fallopian tubes are necessary for nutrition of the fertilized ovum. • Effect on cervix: closes the cervix (estrogen does opposite), increases the thickness of cervical mucosa and thereby inhibits the transport of sperm into uterus (contraceptive function). Progesterone from corpus luteum changes cervical mucus from thin, watery, stringy (estrogen effect) to thick creamy consistency (progesterone effect) immediately after ovulation. -After ovulation more progesterone and less estrogen

Estrogen effect on secondary sexual characteristics?

• Secondary Sexual Characteristics: -Hair distribution in the pubic region and axilla (triangle -Skin becomes soft and smooth. Vascularity of skin also increases. -Body shape: Shoulders become narrow, hip broadens. Fat deposition increases in breasts and buttocks. -Broadening of pelvis with increased transverse diameter.

Summary of the 4 divisions of the menstrual cycle? Which is most consistent?

• That days 1-5 of the classic 28-day menstrual cycle is the menses or menstrual phase initiated by luteolysis with decrements in plasma progesterone and estrogen which increases pulsatile release of GnRH, FSH and LH (because of negative feedback). • That days 6-13 is the relatively variable ovarian follicular phase and uterine proliferative phase; increased pulses of GnRH, FSH and LH increase androgen production by theca and waves of estrogen and inhibin B by granulosa cells, peaking on day 13. A woman's libido, therefore, usually peaks around day 13. • That day 14 is the ovulatory phase at the midpoint of the cycle induced by positive feedback of estrogen dominated by a large LH spike (surge) with suppression of an FSH spike by inhibin B from granulosa cells, local inflammation at the site of the ovarian stigma, PGE2 and collagenase activity. • That days 15-28 consists of a relatively invariable ovarian luteal phase and a uterine secretory phase initiated by luteogenesis mediated by theca and granulosa cells remaining at the ovarian stigma, producing a smaller wave of estrogen and a larger wave of progesterone. -Most consistent phase

What peptide important for hormonal regulation, synthesized where? What decreases pulsations of GnRH? What describes FSH pulsation? FSH stimulates what? LH triggers what?

• The regulatory system is a highly integrated system, which includes hypothalamus, anterior pituitary and ovary with its growing follicle. • Regulation starts with hypothalamic arcuate & paraventricular nuclei production fo kisspeptin (named after the "Hershey Kiss" candy because of Hershey (Pennsylvania) Medical Center discovery of kisspeptin. • Kisspeptin regulates pulsatile firing of GnRH neurons; q2h during follicular phase, continuous during ovulatory phase, q4h during luteal phases. Continuous after menopause. • Pulsatile release of GnRH produces pulsatile secretion of LH & FSH. CRH & cortisol (stress), marijuana (THC), cocaine inhibit pulsatile secretion of GnRH, LH and FSH • FSH stimulates the recruitment and growth of immature ovarian follicles. LH triggers ovulation and sustains corpus luteum. -Inhibin explains why FSH levels remain during slow