1. Lecture 20 PHYSIOPATHOLOGY OF THE FEMALE REPRODUCTIVE SYSTEM.
HIPOTALAMO-PITUITARY-OVARIAN AXIS.
ENDOMETRIAL CYCLE AND MENSTRUATION
Prof. Vlad TICA, MD, PhD

2. 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

3. 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

4. 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

5. OVULATION FROM A HUMAN OVARY

6. 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

7. 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)

8. 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 GnRH 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

9. HYPOTHALAMIC- PITUITARY-OVARIAN AXIS

10. 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

11. 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

12. 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

13. 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

14. FOLLICULAR PHASE Rapidly 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

15. THE CYCLE OF OVULATION AND MENSTRUATION

16. 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

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

18. 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

19. 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

20. 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

21. ENDOCRINE CONTROL OF THE OVARIAN CYCLE

22. 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

23. 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

24. 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

25. 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

26. 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

28. THANKS !