Insights into Female Reproductive Hormones and Ovarian Cycle

1. Female reproductive hormones

2. Gross anatomy of female reproductive organs

3. Ovarian hormone production • Cyclic changes • Cyclic changes in ovarian structure • Ovaries • Characterized as an organ of constant change • A series of dynamic changes in a very predictable manner during the reproductive cycle. • Cyclic changes in uterine structure

4. Cyclic changes • Development of large fluid-filled structures called follicles • Rupture of the ovulatory follicle and release of the oocyte (ovulation) • Formation of a corpus luteum from remnants of the ovulated follicle.

5. Destruction of the corpus luteum (CL) • Prostaglandin F2alpha (PGF2a) near the end of the cycle if pregnancy is not initiated • Demise of the CL • Development of an ovulatory follicle and release of the oocyte at ovulation • Series of events takes place in the predictable manner • Once every three weeks in cows • Once every four weeks in humans

6. Follicular Phase Luteal Phase

7. CL CH C Ovulation Ovulation Adapted from Lucy et al., 1992 Pattern of follicular development and changes in blood hormone concentrations Ovulation Ovulation • The pattern of follicular development in human and cattle resembles that of a wave (follicular wave) • One cohort of follicles emerges in the beginning • One of the follicles within the cohort becomes the dominant follicle and continues to grow • After reaching its growth plateau, the dominant follicle begins to shrink, and a new cohort emerges shortly thereafter

8. Pattern of follicle development in cattle and humans LH LH Ovulation Ovulation + + + + + + E E E E E E FSH E E E E Adopted from Ginther et al., 1996 Ireland et al., 2000 FSH=follicle stimulating hormone LH=luteinizing hormone

9. Structure of ovarian follicle Granulosa cells Basement membrane Antrum Oocyte Theca externa Theca interna

10. Synthesis of estrogens • Theca cells • Androgen production • Granulosa cells • Estradiol production • Progesterone production by both theca and granulosa cells

11. Structure of ovarian follicle Granulosa cells Basement membrane Antrum Oocyte Theca externa Theca interna

12. Two-cell, two-gonadotropin theory • Ovarian steroidogenesis • LH acts on theca cells to produce androgens • FSH acts on granulosa cells to produce estradiol using thecal androgens • FSH • Essential for normal granulosa cell development and function • Expression of LH receptors in large follicle

13. Theca cells cAMP FSH LH Granulosa cells

14. LH Ovulation + + + FSH Pattern of follicular development and changes in blood hormone concentrations

15. Role of estradiol • Proliferation of endometrium • Transcription and translation • Thickening of stroma • Mitosis • Stimulated by growth factors from stroma • Growth and differentiation • Increased metabolic activity • Expression of progesterone receptors

16. Effects of progesterone • Differentiation of endometrium • Inhibition of estradiol-induced proliferation • Mediated by stroma • Secretion • Proteins • Critical for implantation

17. Uterine endometrium • Mucosal lining of the uterus • Inner-most lining • Well-developed in human compared to other species • Placentation • Menstruation (shedding of endomertial tissue) • Spiral arteries • Hemorrhage (changes in blood flow) • Renewal of endometrium during each reproductive cycle

18. Hormone-induced changes in endometrium • Cyclic in nature • Re-epithelialization • Menstrual-postmenstrual transition • Endometrial proliferation • Estradiol • Epithelial secretion • Estradiol and progesterone • Premestrual ischemia • Loss of blood supply to epithelia • Menstruation

19. Role of estradiol • Proliferation of endometrium • Transcription and translation • Thickening of stroma • Mitosis • Stimulated by growth factors from stroma • Growth and differentiation • Increased metabolic activity • Expression of progesterone receptors

20. Luteal structures • After ovulation • The oocyte is released from the preovulatory follicle • Theca and granulosa cells remaining in the follicular wall undergo dramatic changes • Formation of a corpus luteum. • A shift from producing estradiol (granulosa) and androgen (theca) to producing large amounts of progesterone

21. Luteal structures • Three structures • Corpus hemorrhagicum (CH) • Corpus Luteum (CL) • Corpus Albicans (CA) • These names refer to the same structure (luteal) but with differing features characteristic of different stages of the reproductive cycle

22. Luteal structures • The corpus hemorrhagicum (bloody body) • During the early part of the luteal phase of the reproductive cycle • Appears red • Small blood vessels within the follicle rupture during ovulation • Collapse of follicular wall into many folds after leakage of follicular fluid into many folds CH CH Early CH Developing CH

23. Luteal structures • The corpus luteum (yellow body) • Found during the middle part of the luteal phase of the reproductive cycle • The major source of progesterone • Some have a CL with a very large fluid-filled cavity, whereas others have a CL without a distinguishable cavity CL CL with cavity CL CL without cavity

24. Luteal structures • The corpus albicans (white body) • A white, fibrous tissue • Remains of the CL • Loss of ability to produce progesterone • Death of cells in the CL • It eventually completely loses the ability to produce progesterone • Leads to follicular phase CA CA Early CA Advanced CA

25. Effects of progesterone • Differentiation of endometrium • Inhibition of estradiol-induced proliferation • Mediated by stroma • Secretion • Proteins • Critical for implantation

26. Regulation of luteal function • Luteal cells • Small (around 25 % of total cells in the CL) • Very small contribution to basal production of progesterone • Responds to LH and produce progesterone (5 to 20 X above the basal level) • Large (around 10 % of total cells in the CL) • Very high • No significant response to LH

27. Hormonal factors • LH • Extremely crucial during development • May not be necessary during the middle of luteal phase • Estradiol • Only in some species (i.e. rabbits) • Prolactin • During early stage of pregnancy in rats and mice

28. Action of progesterone • Increase in cytoplasm of stroma • Psuedodiciduation

30. Effects on other uterine tissues • Myometrium (smooth muscle) • Excitability and contraction • Depressed by progesterone • Increased by estradiol

31. Menstruation • Absence of pregnancy • Initiation of endometrium remodeling • Alteration of extracellular matrix • Leukocyte infiltration • Death and removal of tissue • Regeneration of tissue

32. Menstruation • Withdraw of steroid hormones • Constriction of arterioles and coiled arteries • Ischemia • Precedes bleeding • Bleeding • Relaxation of arteries • Induction of hypoxia-reperfusion injury (formation of hematoma) • Detachment of tissue fragments

33. Effects of steroid hormones on female reproductive tract • Oviduct • Secretion of oviductal fluid • Nutrients for the oocytes • Sperm survival and capacitation • Early embryonic development • Cervix • Estradiol • Relaxation of muscle • Secretion of watery mucus • Progesterone • Tightening of muscle • Secretion of thick mucus