Female Hormonal Cycle PDF

Female Hormonal System Introduction The primary sex organs are a pair of ovaries. 1. Produce eggs or ova 2. Secrete: a)Female sex hormones; estrogen & progesterone. b)Small quantities of androgens & other hormones. They contain primary ovarian follicles Their number ↓ wit...

Female Hormonal System Introduction The primary sex organs are a pair of ovaries. 1. Produce eggs or ova 2. Secrete: a)Female sex hormones; estrogen & progesterone. b)Small quantities of androgens & other hormones. They contain primary ovarian follicles Their number ↓ with age; At birth → 2 millions At puberty → 300,00 Surrounded by two types of cells Granulosa cells → secretes estrogen & progesterone Theca cells: form mainly the androgens Introduction Reproductive function in the female is regulated by interactions of hormones from the 1) hypothalamus, 2) anterior pituitary, and 3) ovaries. 1. Hypothalamus Gonadotropin-releasing hormone (GnRH), stimulates the anterior pituitary. 2. Anterior pituitary: a) Follicle-stimulating hormone (FSH) Stimulates development of the follicles in the ovaries. b) Luteinizing hormone (LH) Stimulates development of the corpus luteum in the ovaries. 3. Ovaries (follicle and corpus luteum) → Estrogen and progesterone. Estrogen in particular and progesterone to a lesser extent, inhibit the release of LH and FSH through either a direct pituitary, or indirect hypothalamic effect.  Hypothalamus GnRH - Ant. Pituitary FSH LH - Estrogen Progesterone Monthly Hormonal Cycle The Menstrual Cycle The cyclic events that take place during the reproductive period of a woman’s life, during which one mature ovum is released from the ovary, and the uterine endometrium is prepared for implantation of the fertilized ovum. Starts at the age of 12 to 15 years, which marks the onset of puberty; called menarche. The first several cycles usually do not include ovulation. Duration 28 days, may vary between 20 – 40 days. Ceases at the age of 45 to 50 years. Called menopause. Is controlled by the hypothalamus-pituitary axis Gonadotropin releasing hormone (GnRH) from hypothalamus FSH & LH from the anterior pituitary. Phases of Menstrual Cycle A. The ovarian cycle The events that take place in the ovaries Divided into 3 phases: a) Follicular phase (or preovulatory phase) b) Ovulation phase c) Luteal phase (or postovulatory phase) B. Uterine cycle; the events that take place in the uterus. Characterized by three phases: (1) Proliferation. (2) Secretory changes. (3) Menstruation. Ovarian Cycle ↑↑↑GnRH - FSH ↓↓↓Estrogen Progesterone ↑↑↑Estrogen Progesterone 1- Follicular Phase When a female child is born, each ovum is surrounded by a single layer of granulosa cells collectively (ovum+ granulosa cell) called a primordial follicle. Throughout childhood, the granulosa cells are believed to: a) Provide nourishment for the ovum b) Secrete an oocyte maturation inhibiting factor that keeps the ovum suspended in its primordial state in the prophase stage of meiotic division. Then, after puberty, and under the effect of FSH and LH (especially FSH) the ovaries together with some of the follicles within them begin to grow. Follicles enlarged, followed by growth of additional layers of granulosa cells to form the primary follicles; secretes fluid rich in estrogen, accumulated causes an antrum to appear. A second mass of cells called the theca collect outside the granulosa cells; secretes androgens and progesterone. 1- Follicular Phase At the beginning of the monthly cycle (day 1; first day of uterine bleeding or menses), ↓estrogen & progesterone concentrations ➔ hypothalamus receives no inhibitory signals ➔ ↑ GnRH ➔ ↑↑↑ FSH and LH. FSH stimulates development of 12 to 14 primary ovarian follicles. Follicles are surrounded by granulosa cells, begin to secrete estrogen. Estrogen promotes development of additional FSH & LH receptors on the granulosa cells accompanied by growth of surrounding layers of thecal cells. After 1 week of, one follicle begins to outgrow the others, the remaining follicles, undergo atresia and degenerate. ↑↑ blood concentration of estrogen → inhibitory signal to hypothalamus → ↓↓ GnRH -→ ↓↓FSH and LH ➔ prevents the development of additional follicles. The dominant follicle continues to develop because of its positive feedback cycle, whereas the other vesicular follicles involute.  Interaction of follicular theca and granulosa cells The theca cells respond to LH and produce androgens as well as progesterone in the preovulatory large follicles. Androgen then used by the granulosa cells to produce estrogen under the control of FSH. Granulosa cells in the large preovulatory follicles also respond to LH and produce progesterone. Ovulation Ovulation occurs 14 days before the onset of menstruation. Initiated by LH surge (6- to 10-fold above normal), occurs 2 days (48 hours; peaking about 16 hours) before ovulation. LH surge is preceded by estrogen peak secreted from granulosa cells which exert +ve feedback resulting in mid-cyclic peak of LH > FSH. Estrogen secretion begins to fall 1 day before ovulation Thecal cells secrete progesterone as well as a proteolytic enzyme causes dissolution of the follicular capsule. The wall of the follicle ruptures, the oocyte & surrounding layers of granulosa cells enter the abdominal cavity at the opening to the fallopian tube. Blood fills the ruptured follicle forming the corpus hemorrhagicum, may escape into the abdominal cavity causing irritation of the peritoneum and lower abdominal pain.  Ovulation Ovulation occurs in an environment of: (1)Rapid growth of the follicle. (2)Diminishing estrogen secretion after a prolonged phase of excessive secretion. (3)Initiation of secretion of progesterone. The LH also has a specific effect on the granulosa and theca cells, converting them into lutein cells which secret mainly progesterone.  Corpus Luteum—“Luteal” Phase of the Ovarian Cycle The high concentration of LH converts the structure remaining after ovulation which contains layers granulosa and thecal cells, to the yellowish; corpus luteum A. Granulosa cells secrete ↑↑↑progesterone & smaller amounts of estrogen B. Thecal cells produce androgenic hormones, testosterone, and androstenedione, most of which converted to the female hormones in the adjacent granulosa cells. Formation and continuity of corpus luteum depends on LH: A. If there is no pregnancy: After 12 days, → ↑↑ estrogen (in particular) & -to a lesser extent- progesterone→ feedback inhibition on LH level ➔ corpus luteum degenerates. Within 2 days → ↑ FSH and LH secretion ➔ development of new group of primary follicles, initiating another cycle. B. If there pregnancy: The hCG secreted by the embryo acts as LH to maintain the corpus luteum & estrogen & progesterone secretion (no new ovarian cycle until after delivery). Monthly Endometrial Cycle The changes that take place in the endometrium driven by the cyclic production of ovarian hormones Characterized by three phases: (1) Proliferation. (2) Secretory changes. (3) Menstruation. Proliferative & Secretory Phases 1- Proliferative Phase Starts after menstruation & continues to time of ovulation (i.e. from day 5 to day 14) during the next 10 days. Initiated by the action of estrogen which stimulates proliferation of endometrium to reach a thickness of up to 4 millimeters (x10 times). 2- Secretory Phase Stars from ovulation, peak at 1 week after, ends –if no pregnancy– with menstruation (from day 14 to the end of the cycle ‘day 28’), continues with pregnancy Brought about by progesterone secreted from corpus luteum after ovulation. It prepares the endometrium for implantation of fertilized ovum. It cause: a) The glands to secrete fluid b) Endometrial cells to accumulate lipids and glycogen in their cytoplasm c) Development of endometrium vascularity  3- Menstruation 1. Degeneration of the corpus luteum due to feedback inhibition of Est & Prog on LH. 2. Involution of the endometrium to about 65% of its previous thickness. 3. Endometrial arteries become more tortuous and vasospastic → tissue ischemia & necrosis. 4. Hemorrhagic areas develop in the necrotic tissue. 5. The outer layers separate from the uterine wall. 6. Loss of all the superficial layers of the endometrium are lost, only a thin layer of basal endometrial stroma remains ➔ Shedding out of the endometrium with bleeding. 7. Development of uterine contractions – to expel the shed tissue and blood – stimulated by: 1) Distention of the uterine cavity, 2) ↑prostaglandin E2 released from the ischemic and necrotic tissue, and 3) ↓progesterone. The menstrual fluid is about 30 – 80 ml, mostly arterial & nonclotting because of the presence of fibrinolysin, released from the endometrial tissue. Summary Summary Ovulation occurs 14 days prior to the last day of the cycle: The 1st phase; (follicular phase) is variable while the 2nd phase (luteal phase) is constant. Follicular growth & development depends on FSH. LH is the hormone of ovulation preceded by estrogen peak Progesterone is responsible for raised body temperature associated with ovulation. Effect of Estrogen & progesterone on FSH & LH: +ve feedback effect mainly Estrogen; (before ovulation; follicular phase) –ve feedback effect (after ovulation; luteal phase) Uterine cycle: Proliferative phase depends on the action of estrogen Secretary phase depends on the action of progesterone Diagnosis of pregnancy depends on detection of hCG in the blood or the urine Functions of the Ovarian Hormones Ovarian Hormones The ovaries secrete two classes of hormones: A. Estrogens → Estradiol is the most important of the estrogens. B. Progestins → Progesterone is the dominant progestin. Steroid hormones synthesized from cholesterol and to a slight extent from acetyl coenzyme A. Secreted from: 1) Ovaries; in the nonpregnant female: 2) Placenta: during pregnancy 3) Adrenal cortex: synthesize only minute amounts.  Ovarian Hormones Estrogen are secreted from developing follicles (1st half of the cycle) and corpus luteum (2nd half of the cycle). Nearly all of the progesterone is produced in the corpus luteum; only small amounts formed in the mature follicle the day immediately before ovulation. Androgens from theca cells are converted into estrogens by the enzyme aromatase (stimulated by FSH) in the granulosa cells. Theca cells lack aromatase, they cannot convert androgens to estrogens. Both estrogens and progesterone are transported in the blood bound loosely with plasma albumin and with specific estrogen and progesterone-binding globulins. The liver inactivates estrogens by two ways: Conjugation with glucuronides and sulfates, excreted in the bile and in the urine. Converts the potent estrogens estradiol and estrone into the impotent estrogen estriol. ➔ diminished liver function → ↑ the activity of estrogens in the body → hyperestrinism. Progesterone is degraded by the liver to non-active pregnanediol Functions of Estrogen 1. Plays a critical role in the menstrual cycle. 2. Growth and proliferation of the cells of: a) Female sex organs (ovaries, fallopian tubes, uterus, vagina, and external genitalia) b) Other tissues associated with reproduction: in the breast, they stimulate development of stroma tissue and ductile system. 3. Development of secondary sexual characters in females; hair distribution, voice, body shape & deposition of fats in the subcutaneous tissue, (breasts, hips, thighs). 4. Bones: A) Stimulates osteoblastic activity, but at the same time they cause B) closure of the bone epiphyses ➔ growth spurt at puberty which last only a few years. NB: menopause ➔ ↓ density of bones ➔ ↑ risk of bone fracture. 5. It increase total body protein and metabolic rate (weak anabolic effect). 6. On blood: Hypercoagulability effect ➔ ↑ risk thromboembolism. Functions of Estrogen 3 1. Plays a critical role in the menstrual cycle: follicular & proliferative phases 2. Facilitates the effect of oxytocin on the uterus (makes it more excitable). 3. Makes the cervical mucus more thin and vaginal epithelium cornified. 4. Increases lipido. 5. Formation of some plasma proteins by the liver: increase hepatic production of: a) TBG (thyroid binding globulins). b) Angiotensinogens. c) Clotting factors (that is why estrogen therapy causes thrombosis). 6. Other effects: a) Salt and water retention b) Vasodilatation (by increasing NO production) c) Decreases cholesterol level in plasma (= cardio-protective effect) Functions of Progesterone ❑Progesterone is concerned mainly with the final preparation of he uterus for implantation of the zygote and the breasts for lactation 1) Promotes secretory changes in the uterine endometrium (as well as the lining of the fallopian tubes) during the second half of monthly cycle. 2) It reduces the excitability and motility of the uterine smooth muscle. 3) Enlargement and proliferation of breast alveolar cells. They become secretory, although they do not produce milk. Milk formation is achieved through the effect of prolactin, which is antagonized by the action of both estrogen and progesterone. Responsible for preovulatory increases in body temperature by about 0.50 F which takes place a few hours before ovulation. (It ↑ the metabolic rate3). Makes mucus in the cervix and vagina more thick3. Stimulates the respiratory center → hyperventilation → low plasma PCO2 during pregnancy & the luteal phase3. In large doses, it inhibits the action of aldosterone & causes natriuresis3. Regulation of Female Monthly Cycle 1. Estrogen Strongly inhibits secretion of LH and FSH through either a direct pituitary effect, or the hypothalamic secretion of GnRH. However, estrogen has a positive feedback effect on LH immediately before ovulation, triggers ovulation and transformation of the granulosa and thecal cells to luteal cells. 2. Progesterone Acts synergistically with estrogen, but it has a weak inhibitory effect by itself. 3. Inhibin Secreted by the granulosa cells of the ovarian corpus luteum inhibits secretion of FSH and, to a lesser extent, LH. Once the levels of LH fall to minimal values two days before the onset of menstruation, the corpus luteum involutes, estrogen and progesterone secretion decline toward zero. Formation of LH and FSH increases in the absence of inhibition as menstruation begins, initiating the development of a new group of follicles. Puberty and Menarche Puberty means the onset of adult sexual life, and menarche means the beginning of the cycle of menstruation. Puberty is caused by a gradual increase in gonadotropic hormone secretion (FSH & LH) by the pituitary if it is appropriately stimulated. This is beginning in about the 8th year of life, culminating in the onset of puberty and menstruation between11 and 16 years (average, 13 years). Throughout childhood, in the absence of these hormones, the ovaries remain inactive. This is probably NOT because hypothalamus is not capable of secreting this hormone, rather because lacking of the appropriate signal from some other area of the brain -perhaps somewhere in the limbic system- Menopause Menopause is the period during which the monthly cycles of the female cease and the ovarian hormones fall to minimal levels. The cessation of the cycling is the result of the presence of an inadequate number of primary follicles in the ovary to respond to of FSH. As a result, the estrogen secretion is inappropriate for triggering the LH surge, and ovulation does not occur. After several irregular anovulatory cycles, estrogen production declines to near zero. Without inhibition, the rate of FSH (mainly) and LH secretion proceeds at very high levels for many years after menopause Menopause The loss of estrogens often causes marked physiological changes in the function of the body, including (1) “hot flushes” characterized by extreme flushing of the skin, (2) psychic sensations of dyspnea, (3) irritability, (4) fatigue, (5) anxiety, (6) decreased strength and calcification of bones throughout the body. Treated with daily administration of estrogen in small quantities, but this may increase the risk for cardiovascular disease. Female Fertility Fertile period of each monthly cycle. The ovum remains viable and capable of being fertilized no longer than 24 hours after it is expelled from the ovary. A few sperm can remain fertile in the female reproductive tract for up to 5 days. Therefore, sperm must be available soon after ovulation if fertilization is to take place. For fertilization to take place, intercourse must occur 4 – 5 days before ovulation up to a few hours after ovulation. Method of Contraception 1. Avoid of intercourse near the time of ovulation. It has high failure rate; 20 to 25 percent per year, because of: a) Difficulty to predict the exact day of ovulation. b) Can be used only when the periodicity of the menstrual cycle is regular. Prediction of ovulation: a) Ovulation usually occurs within the 14th day before the upcoming cycle. Variation of the duration of the cycle is due to variation in follicular phase, while luteal phase is constant. E.g. if the periodicity of the cycle is 40 days, ovulation usually occurs within 1 day of the 26th day of the cycle. b) Anticipation of raised body temperature (by 0.5 F0) is another way to detect ovulation. Method of Contraception 2. Hormonal suppression Administration of either estrogen or progesterone during the first half of the menstrual cycle can inhibit ovulation by preventing the preovulatory surge of LH, which is essential for ovulation. The reason for this inhibition is not fully understood; however, it is suggested that they could prevent what might be the initiating signal for ovulation a sudden depression of estrogen secretion that leads to the LH surge. Synthetic estrogens & progestins are used because unlike the natural hormones, they resist the destructive propensity of the liver, thus allowing oral administration. References John E. Hall. Pocket companion to Guyton and Hall textbook of medical physiology. 13th ed. 2016. Elsevier, p593 – John E. Hall. Guyton and Hall textbook of medical physiology. 13th ed. 2016. Elsevier.