Lecture 20Lecture 20

PHYSIOPATHOLOGY OF THE PHYSIOPATHOLOGY OF THE FEMALE REPRODUCTIVE SYSTEM. FEMALE REPRODUCTIVE SYSTEM.

HIPOTALAMO-PITUITARY-OVARIAN HIPOTALAMO-PITUITARY-OVARIAN AXIS. AXIS.

ENDOMETRIAL CYCLE AND ENDOMETRIAL CYCLE AND MENSTRUATIONMENSTRUATION

Prof. Vlad TICA, MD, PhDProf. Vlad TICA, MD, PhD

OVARIAN CYCLEAs 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 CYCLESecondary 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

OVULATION10-14 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 CYCLEFollowing ovulation empty follicle under the influence

of LH becomes a corpus luteumwhich secretes progesterone and estradiolNon-fertile cycle, becomes corpus albicans (non-

functional remnant)

PITUITARY-OVARIAN AXISHormonal 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 GnRH from hypothalamusFSH secretion slightly greater during early phase

of menstrual cycleLH secretion greatly exceeds FSH secretion prior

to ovulationNot clearly understood but believed to result from

negative feedback effects

HYPOTHALAMIC- PITUITARY-OVARIAN AXIS

MENSTRUAL (MONTHLY) CYCLEApproximately 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 CYCLEIn 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 PHASELasts from day 1 to ~13

Dominated by growth and death of a cohort of primary follicles into secondary follicleswith one survivor becoming

a graafian follicle

which will undergo ovulation

As follicles grow granulosa cells secrete increasing amounts of estradiolReaching peak about day 12

FOLLICULAR PHASEFollicular 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 PHASERapidly rising estradiol

secretion:

Hypothalamus increases pulses of GnRH

Anterior pituitary sensitivity to GnRH 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 PHASEAfter 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 PHASENo 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 GnRH 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 4th wk to permit menstruation

RHYTHM METHODInvolves 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

MENOPAUSECessation 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

THANKS !