1. The Cycle Steven L. Young MD, PhD Obstetrics & Gynecology UNC School of Medicine Mystery Menstrual

2. Mystery Cycle? Don’t Panic!

3. Overall Objectives 1.Identify normal cycle characteristics 2.Understand the physiologic function of the menstrual cycle. 3.Review the structure, sites of production, action, and physiologic function of major reproductive hormones. 4.Understand how hormone action determines the menstrual cycle.

4. Normal Cycle Characteristics Interval: 24-35 days (mean: 28 days) Duration: 2-7 days (mean: 5 days) Volume: Mean of 35 ml (> 80 ml abnormal) Composition: Nonclotting blood, endometrial debris, dead and living endometrial cells

5. 222426283032343638 40 2 4 6 8 10 12 14 DAYS % INCIDENCE Menstrual Cycle Length

6. Menstrual Cycle Length: mean, median, 5th and 95th percentile by age Mean Median Mean Median 80 70 60 50 40 30 20 10 0 15 20 2530 35 40 45 50 55 60 DAYS CHRONOLOGICAL AGE

7. Overall Objectives 1.Identify normal cycle characteristics 2.Understand the physiologic function of the menstrual cycle. 3.Review the structure, sites of production, action, and physiologic function of major reproductive hormones. 4.Understand how hormone action determines the menstrual cycle.

8.  Only seen in primates  Reproduction Monthly Fertility  Ovary Monthly Mono-Ovulation  Uterus Preparation for Embryo Implantation  Synchronization of Ovary & Uterus Why a Menstrual Cycle?

9. Ovulation Ovarian Cycle Follicular Luteal CYCLE DAY 2 10 12 14 4 6816 281824 2022 26

10. Endometrial Cycle Ovulation Proliferative Secretory CYCLE DAY 2 10 12 14 4 6816 281824 2022 26

11. Synchronization OvulationOvary:FollicularLutealUterus:ProliferativeSecretory CYCLE DAY 2 10 12 14 4 6816 281824 2022 26

12. Overall Objectives 1.Identify normal cycle characteristics 2.Understand the physiologic function of the menstrual cycle. 3.Review the structure, sites of production, action, and physiologic function of major reproductive hormones. 4.Understand how hormone action determines the menstrual cycle.

13. The Characters HormoneStructuralTypeSourceTargets GnRHPeptide (10 aa) Hypothala mus Pituitary FSH & LH Glycoprotein Dimer PituitaryGonad EstrogenProgesteroneAndrogenSteroidGonad(+adrenal) Gonad, Uterus, Prostate, Ext.Genitalia Hypoth & Pit Inhibin Glycoprotein Dimer Gonad Gonad, Pituitary hCGGlycoproteinDimerEmbryoOvary

14. Reproductive Endocrine Circuits hypothalamus pituitary ovary GnRH LHFSH oocyte Estradiol, Progesterone, & Inhibin Uterus & Breast sperm hypothalamus pituitary Testis GnRH LHFSH Testosterone & Inhibin Prostate

15. GnRH  Decapeptide that stimulates LH and FSH production  Released into portal blood vessels for direct action on pituitary.  Must be released in pulsatile fashion to stimulate LH and FSH synthesis and release.

16. Hypothalamic-Pituitary Anatomy

17. LH & FSH Production Require Pulsatile GnRH

18. Gonadotropins FSH, LH, and hCG  Glycoprotein heterodimers Share same alpha subunit with each other Share same alpha subunit with each other and TSH. and TSH.  Stimulate ovary FSH - folliclular development, estrogen FSH - folliclular development, estrogen LH - androgen, ovulation, progesterone LH - androgen, ovulation, progesterone  LH (and probably FSH) are released in pulses corresponding to GnRH pulses.  LH and hCG bind the LH receptor, but hCG has a much longer serum half-life.

19. Steroids: Estradiol & Progesterone  Derived from C27 Cholesterol  Estradiol (C18)  Causes endometrial proliferation  Feeds back to pituitary (low levels supress LH release, high levels trigger LH release)  Induces female secondary sexual characteristics  Breast development, body fat distribution  Progesterone (C21)  Causes Endometrial Differentiation  Stops endometrial proliferation  Allows embryo implantation  High levels suppress pituitary FSH & LH

20. Steroid Inter-conversion Progesterone Androstenedione Pregneneolone Estrone DHEA-S Cholesterol C27 17-OH-Preg 17-OH-Prog Testosterone Estradiol Aldosterone Cortisol C21 C19 C18

21. Inhibins  TGF-  family glycoprotein heterodimer produced primarily in ovarian granulosa cells (Inhibin B) and in luteal cells (Inhibin A)  Inhibits pituitary FSH secretion, also functions in ovary

22. Sertoli Leydig pituitary gonadotrophs sperm hypothalamus (arcuate nucleus) Pulsatile GnRH (portal vessels) LH (+FSH) FSH Inhibin external genitalia, prostate Testosterone - + + - - + Testis

23. oocyte pituitary gonadotrophs hypothalamus (arcuate nucleus) Pulsatile GnRH FSH (+LH) LH Inhibin + + + Theca Granulosa Androgens - - E2 +/- uterus +/-

24. Overall Objectives 1.Identify normal cycle characteristics 2.Understand the physiologic function of the menstrual cycle. 3.Review the structure, sites of production, action, and physiologic function of major reproductive hormones. 4.Understand how hormone action determines the menstrual cycle.

25. Key Events in Cycle  Menstruation (shedding of endometrium) defined as day 1  Proliferative or Follicular Phase  Ovulation (about d14.5 of cycle)  Secretory or Luteal Phase  Endometrium receptive for embryo implantation (d20-24 of cycle).

26. Key Points: d1-5 of cycle Ovarian view = Early Follicular 1.  FSH drives Growth of a follicular cohort 2.Growing follicles:  FSHR, E2, & inhibin & vascularity of theca layer Uterine view = Menstrual / Early Proliferative 1.  E2 causes endometrial proliferation and hypertrophy (from 1mm single layer to 4-5 mm at ovulation). Pituitary View 1.FSH rises beginning a few days before d1 due to falling levels of inhibin A and P and E2 from failing corpus luteum

27. Key Points: d5-13 of cycle Ovarian view = Late Follicular Phase. By day 5-7 falling FSH levels result in selection of the follicle most sensitive to FSH (dominant follicle). The dominant follicle produces increasing amounts of E2 and is destined to ovulate and while all other follicles become atretic. Uterine view = Proliferative Phase. Increasing E2 throughout the proliferative phase causes endometrial proliferation and hypertrophy (from 1mm single layer to about 4-5 mm). Pituitary View. As inhibin and E2 rise, FSH is decreased. At moderate E2 levels there is increased LH storage but inhibited release.

28. Key Points: d14 (Ovulation) Ovarian view The dominant follicle has been able to make more and more E2 since acquiring increased FSH receptors and later LH receptors. A small amount of progesterone production stimulates a significant FSH surge which helps to further increase E2. In response to the LH surge, the oocyte is released and completes meiosis I. After ovulation the granulosa cells and some thecal cells form a corpus luteum which secretes E2 and P. Pituitary View. High E2 (>200 pg/mL) sustained over > 50 hrs causes massive release of LH.

29. Key Points: d15-28 Ovarian view = Luteal phase. Corpus luteum has lifespan of 14 +/- 2 days unless rescued by logarithmic increases in hCG. CL produces E + P + inhibin. CL fails and increasing FSH recruits a new follicular cohort. Uterine view = Secretory. P causes a series of morphological and biochemical changes (differentiation) to allow the endometrium to become receptive to embryo implantation. Without pregnancy, P + E fall with CL atresia, resulting in sloughing of the functionalis layer of endometrium - menstruation. (day 1 of new cycle) Pituitary View. CL-derived E + P + inhibin suppress FSH production. As CL fails, FSH rises.

30. Menstrual Cycle: menses to ovulation Days 1-4Days 5-13Days 13-14 OvarianEarly Follicular Mid to Late Follicular Ovulation Uterine Proliferative (menstrual) Proliferative Hormonal  low E2 & Inhibin,  ing FSH  ing E2 & Inhibin,  ing FSH High E2, LH surge Actions Follicle development and endometrial proliferation Selection of dominant follicle and endometrial proliferation Oocyte maturation & Release

31. Ovarian Steroidogenesis: 2 Cells, 2 Gonadotropins Theca Cell Granulosa Cell B.M. Stroma Follicle FSH-R LH-R Cholesterol Androgens Estrogens Early to Mid-Follicular

32. Ovarian Steroidogenesis: 2 Cells, 2 Gonadotropins Theca Cell Granulosa Cell B.M. Stroma Follicle FSH-R LH-R Cholesterol Androgens Estrogens + Progesterone Late Follicular through Ovulation LH-R Cholesterol

33. Menstrual Cycle: ovulation to menses Days 15-19Days 20-24Days 25-28 OvarianEarly LutealMidlutealLate Luteal Uterine Early Secretory Mid Secretory Late Secretory Decidua Hormonal  ’s  ing P, E2 & Inhibin High P, E2 & Inhibin  ing E2, P, & Inhibin  ing FSH  ing hCG and P Actions Endometrial Differentiation Allow Embryo Implantation prepare for menses and recruit new follicular cohort Maintain CL P production Not PregnantPregnant