1. Menstrual Cycle Fawaz Edris MD, FRCSC, FACOG, RDMS, AAACS Maternal Fetal Medicine Reproductive Endocrinology & Infertility

2. Introduction Hypothalamus – Pituitary – Ovaries - Endometrium Hormonal changes  functional and morphological changes in ovaries  ovulation  endometrial changes  implantation or menstruation Hypothalamus – pituitary axis Menstrual Cycle = Ovarian + Endometrial + Cervical + Vaginal + Breast + Psychological + Others

3. Ovarian Cycle Estrogen. Estrogen. Estrdiol (Ovary - Follicles) + Estrone (Androstendione – Aromatization) Low in early proliferate phase Rise 1 week before ovulation Maximum 1 day before LH surge Marked drop Rise again to its maximum 5-7 days after ovulation (mid-luteal) Baseline before menstruation

4. Ovarian Cycle Progestins. Progestins. Progesterone (conversion from adrenal pregnenolone + pregnenolone sulphate) + 17-OHP Minimal during follicular phase Just before ovulation start to increase (from lutenized graafian follicle) – Hence need for LH/hCG during IVF Rise to its maximum 5-7 days after ovulation (mid-luteal) – elevated BBT Baseline before menstruation If pregnancy  continuecontinue

5. Ovarian Cycle Androgens Directly (small amount) from ovaries + adrenals Indirectly (most amount) (metabolism from Androstenedione from ovaries & adrenals) SHBG Binds most Estrogens & Androgens Prolactin Levels do not change strikingly during cycle

6. Follicular Development Primordial follicles (development – differentiation – maturation) Primordial follicles Mature graffian follicle(s) produced Follicle rupture and release ovum Ruptured follicle luteinize and produce corpus luteumcorpus luteum

7. Follicular Development During each cycle a cohort of follicles are recruited One usually mature (18-25mm) – remain go into atresia Mature follicle is estrogen dependent Increase local FSH – continue to grow despite drop of mid- follicular FSHdrop  FSH enhance FSH receptors  increased E2  enhance FSH & LH receptors  LH enhance androgen  aromatization to E2increased E2 aromatization to E2  LH receptors increase the response to mid-cycle LH surge which is important for final maturation, ovulation, and luteal progesterone production Atresic follicles are androgen dependent Decreased local FSH – cant grow LH induced androgen will not aromatize and will lead to atresia

8. Ovulation LH surge  structural and biochemical changes to the growing follicle(s) Dissolution of the entire follicular wall particularly at the surface of the ovary takes place (proteolytic enzymes)(proteolytic enzymes) Detachment (less attachment) of the oocyte along with the cumulus from the remain of the follicle Oocyte adheres to the surface of the ovary for extended time allowing fallopian tube contractions to bring the ovary into close contact with the tubal epithelium Tubal muscular contraction +/- tubal cilia movement contribute to the entry of & transportation of the ovum along the tube

9. Ovulation At birth, primary oocyte are in the prophase of first meiotic division Few hours before ovulation, meiotic division takes places, and secondary oocyte along with a polar body are produced (each 23 chromosomes) After fertilization, second polar body is formed

10. Corpus Luteum LH  granulosa cells of ruptured follicle undergo luteinization Luteinized granulosa cells + surrounding theca cells + capillaries + CT  CL CL  ++++ progesterone & + E2 Life span of CL = 9 - 10 days (unless pregnant)  corpus albicans (avascular scar)

11. Endometrial Cycle Endometrium is responsive to Progestins + Androgens + Estrogens  menstruation & implantation & pregnancy Functionally the endometrium is divided to 2 zones: Outer portion (functionalis) Cyclical changes in morphology & function during menstrual cycle Sloughed off during menstruation Occupied by spiral arteries (coiled) Inner portion (basalis) Relatively unchanged during menstrual cycle Provide stem cells for the renewal of the funcionalis Occupied by basal arteries (straight)

12. Endometrial Cycle Histophysiology of the endometrium is divided into there stages: Histophysiology Menstrual phase Proliferative or estrogenic phase Secretory or progestational phase

13. Menstrual Phase First day of menstruation is day 1 of the cycle Last 4-5 days Disruption and disintegration of the endometrial glands & stroma Leukocyte infiltration RBC extravasaion Sloughing of the funtionalis Compression of the basalis Renewed tissue growth within the basalis

14. Proliferative Phase Endometrial proliferation or growth secondary to estrogenic stimulation By the end of this stage: Cellular proliferation & endometrial growth reached maximum Numerous mitotic activity Spiral arteries are elongated and convoluted Endometrial glands are straight with narrow lumen containing glycogen

15. Secretory Phase Following ovulation  progesterone secretion by CL stimulates the glandular cells to produce glycogen, mucus, and others Glands become tortuous and filled Stroma become edematous Mitosis are rare Spiral arteries extend into superficial layer If pregnancy doesn’t occur by day 23 CL regress Secretion of Progesterone and E2 decline Endometrial involution 1 day before menstruation, marked constriction of spiral arteriols takes place  ischemia of endometrium  lukocyte infiltration & RBC extravasation Prostaglandin effects  Pain

16. Cervical Cycle Although part of the uterus but different in many ways: The mucosa does not undergo cyclical desquamation Instead there are changes in the cervical mucus Estrogen makes it thinner and alkaline  Thinnest at ovulation time (spinnbarkeit 8-12cm)  Promote sperm survival and transport Progesterone makes it thicker and cellular Histologically Estrogen gives it fern like patternfern After ovulation & during pregnancy  fail to fern

17. Vaginal Cycle Estrogen Cornified epithelium Cornified Progesterone Thick mucus secretion Epithelial proliferation Infiltration by leukocytes

18. Breast Cycle Estrogen Proliferation of the mammary ducts Progesterone Growth of lobules and alveoli Distention of the ducts + hyperemia and edema of the interstitial breast tissue  Breast swelling, tenderness, and pain  Starts 10 days before menstruation and disappears with menstruation

19. Other Cyclical Changes Temperature Progesterone Emotional Psychological

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