Lecture 20 1 PHYSIOPATHOLOGY OF THE FEMALE REPRODUCTIVE

Lecture 20 1. PHYSIOPATHOLOGY OF THE FEMALE REPRODUCTIVE SYSTEM. 2. HIPOTALAMO-PITUITARYOVARIAN AXIS. 3. ENDOMETRIAL CYCLE AND MENSTRUATION Prof. Vlad TICA, MD, Ph. D

OVARIAN CYCLE �As graafian follicle develops, primary oocyte completes meiosis I �One daughter cell (secondary oocyte) receives cytoplasm �Other daughter, now a small polar body degenerates �Secondary oocyte arrests at metaphase II �Only fertilized ova complete meiosis II

OVARIAN CYCLE �Secondary oocyte is part of the graafian follicle �Granulosa cells form a layer around outside of follicle �Oocyte sits on a mound of this layer the cumulus oophorus �Corona radiata – ring of granulosa cells enclosing the secondary oocyte �Zona pellucida – gelatinous layer between oocyte and radiata forms barrier to sperm penetration

OVULATION � 10 -14 days after start of menstruation �Only 1 follicle survives �Others become atretic follicles (degenerate) �Surviving graafian follicle forms bulge on surface of ovary �Secretes increasing levels of estrogen �Graffian follicle releases secondary oocyte �Into uterine tube at ovulation

OVULATION FROM A HUMAN OVARY

FERTILIZATION �If a sperm passes through the corona radiata and zona pellucida and enters the cytoplasm of the occyte �now the oocyte completes meiosis II �with formation of another polar body �If not fertilized within 2 days, secondary oocyte degenerates

OVARIAN CYCLE �Following ovulation empty follicle under the influence of LH becomes a corpus luteum �which secretes progesterone and estradiol �Non-fertile cycle, becomes corpus albicans (non-functional remnant)

PITUITARY-OVARIAN AXIS �Hormonal interactions between anterior pituitary and ovaries �Anterior pituitary secretes luteinizing hormone (LH) and follicle-stimulating hormone (FSH) �Both promote cyclic changes in the ovaries �Both are controlled by Gn. RH from hypothalamus �FSH secretion slightly greater during early phase of menstrual cycle �LH secretion greatly exceeds FSH secretion prior to ovulation �Not clearly understood but believed to result from negative feedback effects

HYPOTHALAMIC- PITUITARY-OVARIAN AXIS

MENSTRUAL (MONTHLY) CYCLE �Approximately month-long cycle of ovarian activity �humans, apes, old world monkeys �Menstruation – characterized by shedding of endometrial lining accompanied by bleeding �And sexual receptivity anytime throughout the cycle �Nonprimate female mammals have estrous cycles �no shedding of endometrium and receptivity is limited �estrous animals that bleed (dogs and cats) is due to high estrogen that accompanies receptive period

MENSTRUAL CYCLE �In humans is about 28 days �Day 1 is taken to be the first day of menstruation �Days 1 thru ovulation constitutes the follicular phase �Time from ovulation to menstruation is luteal phase �Endometrial changes are called: menstrual, proliferative and secretory phases

FOLLICULAR PHASE �Lasts from day 1 to ~13 �Dominated by growth and death of a cohort of primary follicles into secondary follicles �with one survivor becoming a graafian follicle �which will undergo ovulation �As follicles grow granulosa cells secrete increasing amounts of estradiol �Reaching peak about day 12

FOLLICULAR PHASE �Follicular growth and estradiol secretion dependent on FSH �FSH and estradiol induce formation of FSH receptors in granulosa cells �Follicles increasingly sensitive to the same level of FSH �At same time – FSH and estradiol recruit LH receptors in graafian follicle

FOLLICULAR PHASE �Rapidly rising estradiol secretion: �Hypothalamus increases pulses of Gn. RH �Anterior pituitary sensitivity to Gn. RH increases: �results in greater LH secretion �Positive feedback between estrogen and anterior pituitary �results in LH surge, peaks 16 hrs before ovulation and causes ovulation

THE CYCLE OF OVULATION AND MENSTRUATION

THE LUTEAL PHASE �After ovulation – LH causes empty follicle to become corpus luteum �which secretes Estrogen and Progesterone �Progesterone levels rise and peak about a week after ovulation �Development of new follicles and another ovulation inhibited by: �high progesterone and estrogen exert strong negative feedback on LH and FSH �inhibin from corpus luteum further suppresses FSH

THE LUTEAL PHASE �No fertilization → �corpus luteum regresses �Estrogen and Progesterone levels decline �with menstruation and new cycle of follicle development

CYCLIC CHANGES IN THE ENDOMETRIUM �Driven by cyclic changes in estrogen and progesterone levels �Proliferative phase (menstration cycle) occurs during follicular phase - ↑ levels of estrogen �stimulates growth of endometrial lining and development of spiral arteries �causes cervical mucus to become thin and watery to allow sperm penetration

CYCLIC CHANGES IN THE ENDOMETRIUM �Secretory phase occurs during luteal phase – endometrium becomes ready for implantation �Progesterone stimulates development of uterine glands �Progesterone and Estrogen cause endometrium to become thick, vascular, and spongy �Progesterone causes cervical mucus to thicken and become sticky

CYCLIC CHANGES IN THE ENDOMETRIUM �Menstrual phase results from drop in Progesterone and Estrogen following corpus luteum degeneration �Low progesterone: constriction of spiral arteries �Blood flow stops followed by necrosis and sloughing of endometrium

ENDOCRINE CONTROL OF THE OVARIAN CYCLE

FACTORS AFFECTING MENSTRUAL CYCLE �Release of Gn. RH is regulated not only by hormonal feedback but also by input from higher brain centers �Olfactory system can send activity to hypothalamus in response to pheromones � Can cause the “dormitory effect” in which cycles of roommates become synchronized

FACTORS AFFECTING MENSTRUAL CYCLE �Limbic system input to the hypothalamus: �In times of stress can cause functional amenorrhea (cessation of menstruation) �Also occurs in very thin or athletic females with low body weight � may be related to reduced leptin secretion by small adipocytes

CONTRACEPTIVE METHODS �Oral contraceptive pills – synthetic estrogen and progesterone �Taken daily for 3 weeks after menstrual period �Mimic corpus luteum, so that negative feedback inhibits ovulation �Placebo pills taken in 4 th wk to permit menstruation

RHYTHM METHOD �Involves daily measurement of oral basal body temperature (BT) upon awakening because: �ovarian steroids cause BT changes �declining Estrogen on day of LH surge causes a slight drop in BT �rising Progesterone on day after LH peak causes elevated BT

MENOPAUSE �Cessation of ovarian activity and menstruation roughly ~50 years �Ovaries depleted of follicles produce no estrogen �LH and FSH are high because of no negative feedback �Lack of Estrogen from ovaries most responsible for: �Hot flashes, osteoporosis, and increased risk of atherosclerosis

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