Female Reproductive Physiology PDF

Female Reproductive System Regulation of the Menstrual Cycle Pregnancy and Lactation Vihang A. Narkar Institute of Molecular Medicine 713-500-3585 [email protected]  LECTURE OUTLINE Components of the female reproductive sy...

Female Reproductive System Regulation of the Menstrual Cycle Pregnancy and Lactation Vihang A. Narkar Institute of Molecular Medicine 713-500-3585 [email protected]  LECTURE OUTLINE Components of the female reproductive system. Menstrual cycle. Hormonal regulation in female reproductive system. Synthesis of steroid hormones (Estrogen & Progesterone). Physiological effects of steroid hormones. Puberty and Menopause. Overview of female reproductive system-related disorders. Clinical uses of steroid hormones or related drugs.  RECOMMENDED READING Joel Michael’s Fundamentals of Medical Physiology, Sec X (Chapters 84, 85, 87, 88) Guyton’s Medical Physiology, Chapters 81, 82  COMPONENTS OF THE FEMALE REPRODUCTIVE SYSTEM  Female Reproductive System HYPOTHALAMUS HORMONE REGULATORY ANTERIOR NEURONAL COMPONENT PITUTARY FEMALE REPRODUCTIVE ORGANS REPRODUCTIVE ORGANS OVARIES Ovaries are responsible for the production of ova. Approximately 1 million ova are present at birth. Approximately 300-400K ova remain at puberty (Primordial follicles). Between the age of 13-46 years 300-400 ova mature/develop. One ovum is released every month (ovulation) at the mid-point of the menstrual cycle. The ovum is released through complete maturation of primordial follicles during the menstrual cycle. Steroid hormones (estrogen & progesterone) are synthesize and released from the ovaries. REPRODUCTIVE ORGANS FALLOPIAN TUBE Captures the ovum released by the ovary. Travels to the uterus. UTERUS Also called the womb. It is lined by the endometrium. The fertilized ovum is lodged in the uterus in the endometrial bed. Endometrium itself undergoes cyclic proliferation/expansion and degradation during the menstrual cycle. CERVIX VAGINA/BIRTH CANAL  Hormones involved in the Female Reproductive System Gonadotropin-releasing hormone [HYPOTHALAMUS] Follicular Stimulating Hormone Luteinizing Hormone [Anterior Pituitary] [Anterior Pituitary] Estrogen [Granulosa cells/Follicles] INHIBIN Progesterone RELAXIN [Corpus Luteum/Lutein cells]  MENSTRUAL CYCLE (OVARIAN+ENDOMETRIAL)  Ovarian Cycle OR Menstrual Cycle (Overview) Monthly rhythmic changes in the rate of secretion of gonadotropins and the female sex hormones. These hormones cause cyclic changes in ovaries (ovarian follicles) and endometrium (geared towards reproduction). Average length is 28 days (20-45 days). Key events are (i) the release of the ovum from the ovaries and (ii) preparation of endometrium for the potential implantation of fertilized ovum. Gonadotrophic hormones (FSH and LH), are required for ovulation as well as progression of the menstrual cycle.  Ovarian Cycle OR Menstrual Cycle (Overview) Ovaries are dormant in pre-pubertal age, due to lower circulating gonadotropin hormones. Beginning at 9-10 years of age, gonadotropin hormones in circulation gradually increase to initiate menstrual cycle between 11-16 years of age (Puberty). First few menstrual cycles may not result in ovulation because hormones levels (LH & FSH) are still low. Menarche. Cyclic increase and decrease in FSH and LH is responsible for cyclic ovarian changes during each menstrual cycle.  Ovarian Cycle OR Menstrual Cycle Ovarian cycle is divided into three phases: (I) FOLLICULAR PHASE, (II) OVULATION PHASE and the (III) LUTEAL PHASE. Endometrial cycle is divided in to three phases: (I) PROLIFERATIVE PHASE, (II) SECRETORY PHASE, and the (III) MENSTRUAL PHASE.  FOLLICULAR PHASE Multiple ova, each surrounded by single layer of granulosa cells exists at birth. At this stage the ovum is called the primordial follicle. In childhood, the granulosa cells secrete oocyte-inhibition factor that keeps ovum in its primordial state. At puberty, FSH & LH increases and releases the inhibition. Starting with the beginning of each menstrual cycle the primordial follicles gradually mature. There are different stages of maturation. The growth involves granulosa cell proliferation, appearance of thecal cell layer surrounding the granulosa cells. Granulosa cells produce and secrete estrogen. LH is responsible for thecal cell proliferation. Follicular Phase (~day 1-14)  FSH, LH, E  OVULATION Ovulation is caused by a sudden increase in LH (6- 8 fold) and FSH (2-3 fold), 2 days before the ovulation. This increase in LH/FSH is driven by estrogen- dependent positive feedback to anterior pituitary at the mid-point in the cycle. LH specifically causes granulosa and thecal cells to secrete more progesterone and less estrogen. Ovulation (~day 14) Spike in LH, FSH, E  LUTEAL PHASE After ovulation, the granulosa cells of the follicle are converted to lutein cells in a process called luteinization. Lipid accumulation imparts yellowish appearance. The resulting mass of cells is called Corpus luteum. Highly vascularized Lutein cells produce Progesterone and estrogen. Corpus luteum can grow approximately 1.5 cm in diameter in 7-8 days post-ovulation. Within 12 days after ovulation the corpus luteum disintegrates loosing its secretory function. Corpus luteum ➔Corpus albicans ➔connective tissue.   FSH, LH  E, P Luteal Phase (~day 15-28)  E, P  FSH, LH  Follicular Development 1o (Primordial) Follicle: 1o Oocyte plus 1 layer of granulosa cells. Growing Follicle: Granulosa cells proliferate Theca Folliculi: Differentiated stromal cells. Inner layer is theca internal. highly vascularized. Maturing Follicle: Increase in fluid causes a central cavity (antrum).  Follicular Development Graafian Follicle: Fluid production continues. Bulges into peritoneal cavity. Oocyte on stalk. Ruptured Follicle: Oocyte ejected into peritoneum. Ingrowth and differentiation of granulosa and thecal cells. Corpus Luteum: Active steroid-producing tissue. If no pregnancy, regresses after 2 weeks.  ENDOMETRIAL CYCLE 1st = Proliferation of endometrium (11 days): Rapid re-epithelialization and growth. Epithelial and stromal growth. Driven by estrogen. 2nd = Secretory changes (12 days): Endometrium becomes highly secretory and glandular with excessive vascularization. Highly nutritious mass rich in lipid and glucose. Driven by progesterone + estrogen. 3rd = Desquamation/Degradation (5 days): Marks the beginning of the menstrual cycle. This occurs if ovum is not fertilized and implanted, and no pregnancy occurs. Signaled by drop in progesterone and estrogen.  Hormones in the Female Reproductive System Gonadotropin-releasing hormone [HYPOTHALAMUS] Follicular Stimulating Hormone Luteinizing Hormone [Anterior Pituitary] [Anterior Pituitary] Estrogen [Granulosa cells/Follicles] INHIBIN Progesterone RELAXIN [Corpus luteum/Lutein cells] Comparison of hormone levels & the stages of Menstrual cycle GONADOTROPIN-RELEASING HORMONE (GNRH) Secreted by the medio-basal hypothalamic region neurons. Transported by hypothalamic- PULSATIVE RELEASE hypo physical portal system to the anterior pituitary gland. Secreted in pulsating fashion. (Few minutes every 1-3 hours). Continuous release has inhibitory effect on the anterior pituitary CONTINUOUS RELEASE hormones. FOLLICULAR STIMULATING HORMONE (FSH) & LUTEINIZING HORMONE (LH) Secreted by the anterior pituitary glands. Secretion is controlled by GnRH. Release of FSH & LH are also pulsatile. The primary effect of FSH & LH is on the maturation of the ovarian follicles. FSH is responsible for the proliferation and expansion of granulosa cells (particularly Graafian follicle) and for stimulating estrogen synthesis and secretion by these cells. LH is responsible for (i) ovulation, (ii) luteinization of the granulosa and thecal cells, and (iii) formation of corpus luteum. LH also stimulates progesterone synthesis and release form thecal cells. ESTROGEN & PROGESTERONE Estrogen is secreted by the granulosa cells upon stimulation by FSH. Estrogen levels gradually increase during the mestrual cycle, typically peaking during ovulation. Progesterone is secreted by the thecal cells. Rise in progesterone is more gradual than estrogen, and typically peaks during the LUTEAL phase. In the absence of pregnancy levels of both estrogen and progesterone drop at the end of the menstrual cycle. The cyclical process begins all over again. In successful pregnancy, the synthesis of estrogen/progesterone is taken over by placental-fetal unit. Estrogen promotes secretory and motility functions of the female reproductive tact in order to facilitate fertilization. Progesterone functions to maintain pregnancy by decreasing fluid secretion and motility of the uterus. Hormone Levels and Stages of Menstrual cycle Negative and Positive Feedback Control of Hormone Secretion Effect of progesterone on the pulse generator  Summary of the hormonal, follicular and uterine changes during the menstrual cycle Day of Endocrinology Follicular Development Uterine Endometrial Development Cycle 1-6 FSH, LH ↑ 15-20 primordial follicles Menstruation occurs. Early E2, P low develop into unilaminar follicles. Follicular Phase 7-14 FSH ↓ (-ve feedback at A.P) Unilaminar follicle →Multilaminar Proliferative Phase: Proliferation of Late E2 ↑ (due to FSH stimulation follicle →Fluid-filled vesicles which functionalis and proliferation and Follicular of the ovary) can later mature into an antrum elongation of non-secreting Phase endometrial glands 13 & 14 LH and FSH ↑ (+ve feedback 1 follicular develops pre-dominantly. Functionalis & endometrial glands Pre-ovulation to A.P) Develops an antrum → Griffin at maximum size. Endometrial glands & Ovulation LH & FSH then ↓ Follicle. still non-secretory. At ovulation, the oocyte expelled into peritoneal cavity and taken up by oviduct. 15-21 P and E2 produced Granulosa and thecal cells of Secretory Phase: Early by corpus luteum. dominant follicle stay in ovary and P stimulates endometrial glands to Luteal Corpus luteum evolves become corpus luteum. secrete glycogen, mucus. Phase due to pre-ovulatory surge of LH. LH & FSH ↓ (due to -ve feedback of P on hypothalamus) 22-28 w/o fertilization, corpus Corpus luteum undergoes atresia. As P & E2 ↓, endometrium undergoes Late luteum degenerates. Corpus luteum devolves into Involution. At days 25-26, Luteal P & E2 ↓ (lowest at day 28). corpus albicans (white scar). vasoconstriction → ischemia → Phase FSH begins to rise. apoptosis of functionalis. SYNTHESIS OF STEROID HORMONES  Three types of cells involved: Granulosa cells, Luteal cells and Thecal cells. Thecal cells produce androgens (androstenedione and testosterone). These androgens diffuse to the Granulosa cells, where they are converted to estrone and estradiol by the enzyme aromatase. Theca luteal cells produce progesterone.  Interactions between the Theca and Granulosa Cells FSH receptors are expressed only on granulosa cells. During follicular phase activation of the FSH receptors leads to synthesis of LH receptors in both granulosa and thecal cells. Activation of FSH receptors also leads to synthesis of aromatase in granulosa cells. Activation of LH receptors on the thecal cells leads to the up regulation of the enzymes that convert cholesterol to pregnenolone and progesterone to androgens. Androgens are synthesized in thecal cells, diffuse to granulosa cells and are converted to estrogen. Both thecal and granulosa cells produce pregnenolone from cholesterol. However, this primarily occurs in thecal cells because they have relatively high access to LDL from blood supply. No progesterone produced during follicular phase. But, as LH response increases, level of pregnenolone increases, leading to progestin production. Steroidogenesis PHYSIOLOGICAL EFFECTS OF STEROID HORMONES Physiological Effects of ESTROGEN FEMALE MATURATION: Sexual maturation & growth. Development of female reproductive organs. Secondary sexual characteristics. Breast development: Stromal and ductal tissue growth. Bone development: Especially growth at puberty. Closing of epiphysis of the long bone at puberty. Skin pigmentation. Co-ordinates endometrial growth along with Progesterone. METABOLIC/CARDIOVASCULAR EFFECTS: Skin and blood vessel development. Prevents bone resorption by increasing apoptosis of osteoclasts & antagonizing pro-osteoclastic effects of PTH and IL-6. Increase leptin production by adipose tissue. What is Leptin? Lipid Regulation: HDL, LDL, and cholesterol,  Triglycerides  Physiological effects – Cont’d BLOOD COAGULATION: Increases blood coagulation: Proteins involved in clotting, fibrinolysis, and blood pressure control are regulated by Estrogen. Results in enhanced clotting. May result in thromboembolism and exaggerated hypertension in women over 35, especially smokers and pre-hypertensive. OTHER EFFECTS: Stimulates central components of stress system: Increase corticotrophin-releasing hormone and sympathetic system. Edema Na and water retention. Can modulate sympathetic regulation of sympathetic tone. Physiological Effects of PROGESTERONE Endometrial maturation Alveolar and secretory apparatus in the breast. Maturation and secretory changes in endometrium. Metabolic effect: Increased fat deposition, increased response to insulin, increased liver glycogen storage in liver. Can also act on the MR to decrease renal Na absorption. Competitive antagonist of aldosterone. Central (hypothalamic) regulation of body temperature. Regulates respiratory centers. Depressant and hypnotic effects through the central mechanism. PUBERTY & MENOPAUSE  Puberty & Pulse Generator Onset of adult sex life. Caused by an increase in gonadotrophic hormone secretion by the pituitary beginning around 8th year of life. Usually culminating in the onset of menstruation (11-16 years). While the ovaries and the pituitary are fully functional in childhood, the hypothalamus does not release sufficient GnRH. This is due to lack of signals from the higher brain centers (limbic system??).  Menopause At the age of 40-50 yr, the sexual cycle becomes irregular, and ovulation fails to occur during many cycles. Period during which the cycles cease and the female sex hormones diminish rapidly to almost none at all is called Menopause. The cause is the depletion of the ovaries of the primordial follicles. As the # of primordial follicles diminish, their maturation throughout the cycle ceases. This decreases the production of estrogen, resulting in the loss of LH/FSH surge that is required for ovulation. Hot flashes, irritability, fatigue, anxiety. Bone loss, cardiovascular complications. OVERVIEW-FEMALE REPRODUCTIVE DISORDERS INFERTILITY MENSTRUAL ABNORMALITIES: Amenorrhea, Dysmenorrhea, Premature Syndrome, Polycystic Ovary Syndrome. ENDOMETRIOSIS VAGINITIS, CERVICITIS, PELVIC INFLAMMATORY DISEASE. CANCER: BREAST, ENDOMETRIAL, FALLOPIAN TUBE, OVARIAN, UTERINE, VAGINAL  Infertility Infertility may be caused by any defect or malfunction of the hypothalamic - pituitary - ovarian axis, such as certain neurologic diseases. Other possible cause include: Cervical factors (infection and possibly cervical antibodies that immobilize sperm, abnormal mucus), Ovarian factors (lack of ovulation), Tubal and pelvic factors, Uterine abnormalities. Intervention aim to correct the underlying abnormality or dysfunction: e.g. Within the hypothalamic-pituitary-ovarian complex: Hormone therapy, Progesterone replacement for progesterone deficiency. e.g. Surgical restoration may correct certain anatomic causes of infertility, such as fallopian tube obstruction, artificial insemination, in vitro (test tube) fertilization.  Endometriosis A painful disorder in which endometrium that typically lines the inside of the uterus grows outside of the uterus (called as endometrial implant). Endometriosis most commonly occurs in ovaries, bowel or the tissue lining the pelvis. The endometrial implant continues to respond to menstrual hormones in a cyclic fashion i.e. thickening, break down and bleeding with each menstrual cycle. When endometriosis involves the ovaries, cysts called endometriomas may form. Endometriosis can cause pain — sometimes severe — especially during period. Fertility problems also may develop. Fortunately, effective treatments are available. Common signs and symptoms of endometriosis may include: painful periods (dysmenorrhea), pain with bowel movements or urination, excessive bleeding, infertility, and other symptoms such as fatigue, diarrhea, constipation, bloating or nausea, especially during menstrual periods.  Polycystic ovary syndrome Polycystic ovary syndrome (PCOS) is a common endocrine system disorder among women of reproductive age. Polycystic ovaries become enlarged and contain numerous small fluid-filled sacs which surround the eggs. Polycystic ovary syndrome signs and symptoms often begin soon after a woman first begins having periods. In some cases, PCOS develops later during the reproductive years, for instance, in response to substantial weight gain. Infrequent or prolonged menstrual periods, excess hair growth, acne, and obesity can all occur in women with polycystic ovary syndrome. Excessive ovarian or adrenal production of androgen is though to be the cause of PCOS.  Breast Cancer Cancer arises in the glandular and ductal cells in the breast. Non-epithelial cell cancers of the stroma are less common. Risk factors: Family history, Diet, Mutations (BRACA1/2 gene mutations). Breast cancers can be estrogen/progestin +ve, HER2 +ve, or receptor –ve in type. Treatment options include: Surgery, Radiation therapy and chemotherapy/hormone therapy. Commonly used drugs: Tamoxifen/Roloxifen (ER receptor modulators), aromatase inhibitors (Anastrozole), Trastruzumab (HER2 monoclonal antibody). Clinical uses of steroid hormones or related drugs. PRIMARY HYPOGONADISM POST-MENOPOSAL HORMONE REPLACEMENT HORMONAL CONTRACEPTIVES Comparison of hormone levels & the stages of Menstrual cycle  HORMONAL CONTRACEPTIVES Women take contraceptives for 21 of the 28 day cycle (and placebo/iron pills for the remaining 7 days). Combination (estrogen + progestin) or progestin only. Monophasic: fixed combination oral contraceptives. Multiphasic: (i) varying dose pills, (ii) lower total steroid levels, (iii) no increased risk of endometrial breakthrough. Progestin-only pills: Where estrogen is contraindicated. Mechanisms of action Feedback at the levels of the hypothalamus (GnRH) and the gonadotropins (suppression of FSH and LH levels) Low FSH levels suppress foliculogenesis. Low LH levels prevent the LH surge (inhibit ovulation). Progestin only pills do not effectively inhibit ovulation. These cause mucus thickening, reduced motility, impaired implantation. Have substantially higher failure rate than combined pills