Physiology of Reproduction(I)

1. Physiology of Reproduction(I) Teng Yincheng M.D., Ph.D., Professor Department Of Obstetrics & Gynecology Renji Hospital Affiliated to SJTU School of Medicine

2. Two Major Phases of Female Reproductive Function • Preparation of the body for conception • Pregnancy

3. 1.Women’s Physiological Stages • Neonatal period: birth---4 weeks • Childhood: 4 weeks----12 years • Puberty: 12 years---18 years • Sexual maturation: 18 year---50 year • Perimenopause: decline of ovarian function (40 years)----1 year postmenopause • Postmenopause:

5. 2.Menstruation • Menstruation cyclic endometrium sheds and bleeds due to cyclic ovulation and ovarian hormones changes • Mense • Endometrium is sloughed (progesterone withdrawal) • Nonclotting menstrual blood mainly comes from artery (75%) • Interval: 24-35 days (28 days). duration: 2-6 days. the first day of menstrual bleeding is consideredy by day 1 • Shedding: 30-50 ml

6. Female Reproductive System Fallopian tube Uterus fertilization site Ovary

7. 3.Female Hormone System(H-P-O axis) 1)Hypothalamus: Gonadotropin-releasing hormone (GnRH); also called LHRH 2)Anterior pituitary: Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) 3) Ovary: Estrogens and progesterone The hormones secrete at different rates during different times of the month

8. Ovaries Interaction of the female hormone system and their functions • GnRH: anterior pituitary  LH • and FSH • LH & FSH: ovary; development • of ovarian follicles; estrogen and • progesterone production • Progesterone: endometrium & • breasts • Estrogen: ovary, uterus, breasts

10. Function of Anterior Pituitary Gonadotropic Hormones in controlling the Ovarian Cycle • Female sexual cycle (menstrual cycle): • Average 28 days/cycle (20-45 days) • A single ovum released from ovaries per month • Uterine endometrium: preparation for implantation of fertilized ovum • FSH & LHare essential for the function of the ovaries • <8 years old: no FSH & LH • >8 years old: FSH & LH culminatemonthly cycle • Menarche & Puberty - onset of the adult sexual life

11. 4.The Ovarian Cycle and Hormones

12. 7,000,000 1,500,000 400,000 Puberty Birth 20-24 weeks gestation 1)Oogenesis Attrition 300,000-400,000 ova 400-500 ovulations in 13-46 years of age Mitosis

13. 2)Ovarian Follicular Growth(Each ovum is enclosed within a follicle) Primordial follicle: 50μm ovum + one layer of granulosa cells Primary(preantral )follicle:200μm ovum + more layers of granulosa cells Zona pellucid FSH-R aromatase antral follicle: 500μm ovum + granulosa + theca cells + follicular fluid (Estrogens) LH-R cumulus oophorus estrogens Mature (Graafian) follicle: 15-20mm one follicle outgrows Follicular phase

14. Primordial Follicle and Mature Follicle Theca Antrum Ovum Granulosa Theca externa Cumulus oophorus Theca interna Interstitial tissue Ova Zona pellucida Primodial follicle Corona radiata Antrum Granulosa cells

15. Ovaries ~20-25 follicles develop each month Maturation of only one follicle each month, atresia of the remainder Controlling factor: vascularity? One follicle outgrows Estrogens Other follicles involute (+) Pituitary FSH & LH FSH & LHReceptors (-) (+) Hypothalamus GnRH One follicle maturation Estrogens

16. LH 17-Hydroxysteroid Dehydrogenase Thecal Cells FSH FSH aromatase aromatase Granulosa Cells O Cholesterol Androstenedione O= OH Testosterone O= OH O 17 -Hydroxysteroid Dehydrogenase HO- HO- Estrone 17-Estradiol OH OH Peripheral Estrogen Synthesis HO- Estriol

18. FSH LH 3)Preantral Thecal and Granulosa Cells & Estrogen Synthesis LDL Granulosa Cells Thecal Cells ATP cAMP Cholesterol Cholesterol Protein Kinase A desmolase desmolase Protein Kinase A cAMP ATP Pregnenolone Progesterone Pregnenolone Progesterone Nucleus 17-Hydroxysteroids Lyase Testosterone Androstenedione Testosterone Androstenedione Aromatase Estrone Aromatase Estradiol Estrone Antrum Estradiol Circulation

19. Inhibin 4)Feedback Control of Gonadotropin Secretion • At level of hypothalamus/pituitary: • Circulating estrogens inhibit LH & FSH secretion • Circulating progesterone (low) potentiates • estrogen feedback effects • Circulating inhibin inhibits FSH secretion • At level of ovary: • Receptors for LH (thecal cells) and FSH (granulosa cells) increase in maturing follicle • Cellular hypertrophy • Proliferation of granulosa/theca increases circulating estrogens that participate in negative feedback GnRH -

20. FSH LH LH receptors increase in Antral Stage Only -estrogen induced Control of Mature Graafian Follicle Estrogen Synthesis FSH Granulosa Cells LDL Thecal Cells ATP cAMP Cholesterol Cholesterol Protein Kinase A desmolase Protein Kinase A desmolase cAMP ATP Pregnenolone Progesterone Pregnenolone LH Progesterone cAMP ATP Nucleus 17-Hydroxysteroids Lyase Testosterone Androstenedione Testosterone Androstenedione Aromatase Estrone Aromatase Antrum Estradiol Estrone Estradiol Circulation

21. GnRH Feedback Control of Gonadotropin Secretion just prior to Ovulation • At level of granulosa and theca: • Theca: increased androgen precursor production • Granulosa: LH/FSH receptors induced; • aromatase induced; increased estrogen • synthesis • Proliferating cells elevate estrogen to critical concentrations • At level of circulation & pituitary: • Increase in circulating estrogen and progesterone • Positive feedback by estrogen on pituitary FSH & LH secretion  FSH/LH “spike” • LH “spike” induces ovulation

22. Estrogen Feedback on Hypothalamus and Anterior Pituitary What explains the differential effect of estradiol on pituitary release of LH/FSH?

23. FSH, LH within 1-2 days (-) (+) Estrogen Pituitary Estrogen Pituitary Remove ovaries Give exogenous estrogen Give higher dose of estrogen Estrogen Feedback on Hypothalamus and Anterior Pituitary Mammalian Ovarectomy: Pituitary surge: especially of LH LH/FSH • Estrogen feedback is time and dose-dependent • Critical plasma level of >200 pg/ml sustained for 2 days is required for positive feedback • Mechanisms differ w/mammalian species

24. Preovulatory Surge of LH • LH is necessary for final follicular growth and ovulation • Two days before ovulation, LH increases 6-10 fold. FSH secretion increases 2-3 fold at the same time • LH surge: caused by positive feedback induced by peak estrogen secretion • LH & FSH act synergistically to cause rapid swelling of the follicle

25. Corpus albicans Corpus hemorrhagicum Corpus luteum The Ovary and Process of Ovulation Ovulation in a woman who has a normal 28-day cycle occurs 14 days after the onset of menstruation Primordial follicle Developing follicles Ovarian vessels Mature follicle - Outer wall of the follicle swells rapidly - Follicular fluid oozes out - Wall of the follicle ruptures - Viscous fluid carries ovum and granulosa cells (corona radiata) into abdominal cavity Ovulation

26. Luteal Phase of the Ovarian Cycle • Luteinization:conversion of thecal & granulosa cells to lutein cells  corpus luteum • Corpus luteum:Secretion of estrogen, • progesterone, inhibin • LH: • stimulates lutein cell formation & growth - enhance corpus luteum secretion • extends corpus luteum lifetime Ovulation Corpus albicans Early corpus luteum Mature corpus luteum

27. Feedback loops • Estrogens feedback at the hypothalamus and pituitary to inhibit LH and FSH secretion • Progesterone potentiates estrogen feedback effects • - Inhibin mainly inhibits FSH secretion Hypothalamus Termination of the ovarian cycle and onset of the next cycle (-) GnRH (+) Anterior Pituitary (-) FSH & LH (+) Ovary Estrogen Progesterone Inhibin

28. 5.Monthly Endometrial Cycle & Menstruation Ovulation Vessels constrict Endometrium necrosis 40ml blood + 35ml fluid Fibrinolysin → nonclotting Leukocytes → anti-infection Estrogen phase (before ovulation) Secrete thin mucus Progestational phase (after ovulation) Secrete uterine milk

29. Basal Body Temperature Hypothalamus GnRH • Summary of the Monthly Cycle • Every 28 days, gonadotropic hormones FSH and LH from anterior pituitary cause new follicles to grow in ovaries. During early growth of the follicles, estrogen is secreted, causing the proliferative changes of uterine endometrium. • One of the follicles is ovulated at the 14th day of cycle. After ovulation, secretory cells of follicle develop into corpus luteum which secretes large quantities of estrogen and progesterone, causing the secretory changes in uterineendometrium. • In another two weeks, corpus luteum degenerates, causing a decrease in progesterone and estrogen. The sudden reduction of ovarian hormones causes menstruation. Then a new cycle follows. • BBT increases after ovulation. Anterior Pituitary Gonadotropic Hormones LH FSH Progesterone Ovarian Hormones Estradiol Ovarian Events Uterine Endometrium Days of Cycle

30. 6.Functions of Ovarian Hormones: Estradiol & Progesterone • Two classes of ovarian sex hormones: • Estrogens and progestins • The most important of the estrogens is estradiol • The most important progestin is progesterone • Estrogens: • Promote proliferation and growth of sex related cells; cause secondary sexual characteristics • Progestins: • Important for preparation of the uterus for pregnancy and the breast for lactation

31. 1)Effects of Estrogenson Primary and Secondary Female Sexual Characteristics Principal Function: cellular proliferation; growth of the tissues of sexual organs; growth of other tissues related to reproduction Estrogen Skin Breasts Electrolyte balance Uterus, external Female sex organs Skeleton Fat/protein deposition

32. 2)Estrogen effects on the Uterus & External Female Sex Organs • Tissue enlargement: fallopian tubes, uterus, vagina, and all external genitalia • Vaginal epithelium: Cuboidal into stratified type; increase resistance to trauma and infection • Facilitate transport of fertilized ovum toward uterus: Increase fallopian cilia number tubelocking • Proliferate endometrial glands in fallopian tubes and uterus: Nourish implanting ovum

33. Estrogen effects on: • Breast • development of ductile system, stroma tissues & fat deposition  mature female breast • Fat/Protein deposition • fat deposition in subcutaneous & breast tissues; broadening of thighs/ buttocks • protein deposition in sexual organs, bones; slight increase in total body protein • Skeleton • Increase osteoblastic activity, growth plate unit • Post menopause: decrease osteoblast activity, bone matrix, Ca/P deposits • Electrolyte Balance • Increase sodium & water retention – effect is greater during pregnancy • Skin • Development of thick, soft & smooth skin texture • Vascularization  increase bleeding

34. 2)Functions of Progesterone • Uterus • Promotes secretory changes in uterine endometrium • Decreases uterus contraction • 2. Fallopian tubes • Promotes secretory changes in mucosal lining • 3. Breasts • Promotes development of lobules, alveoli of breasts: • alveolar cells proliferate, enlarge, and become secretory

35. Estrogen Secretion Throughout the Female Sexual Life

36. Other hormones Thyronine and triodothyronine Congenital adrenal hyperplasia ACTH 21-羟化酶缺陷—皮质激素合成不足---ACTH Progesterone and 17-羟孕酮-------testosterone 女性假两性畸形 Insulin –dependent diabetes millitus

37. THANKS FOR YOUR ATTENTION Teng Yincheng M.D., Ph.D., Professor Dep. of Obstet. & Gynecol. Renji Hospital Affiliated to SJTU School of Medicine