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

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

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

2.Menstruation Menstruation cyclic endometrium sheds and bleeds due to cyclic ovulation and ovarian hormones changes Mense 1.Endometrium is sloughed (progesterone withdrawal) 2.Nonclotting menstrual blood mainly comes from artery (75%) 3.Interval: days (28 days). duration: 2-6 days. the first day of menstrual bleeding is consideredy by day 1 4.Shedding: ml

Female Reproductive System Ovary Uterus Fallopian tube fertilization site

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

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

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 & LH are essential for the function of the ovaries <8 years old: no FSH & LH >8 years old: FSH & LH culminate monthly cycle Menarche & Puberty - onset of the adult sexual life Function of Anterior Pituitary Gonadotropic Hormones in controlling the Ovarian Cycle

4.The Ovarian Cycle and Hormones

1)Oogenesis 7,000, weeks gestation 1,500,000 Birth 400,000 Puberty Mitosis Attrition 300, ,000 ova ovulations in years of age

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

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

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

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

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

4)Feedback Control of Gonadotropin Secretion GnRH 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 - Inhibin

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

Feedback Control of Gonadotropin Secretion just prior to Ovulation GnRH 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

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

Mammalian Ovarectomy:  FSH, LH within 1-2 days Remove ovaries Pituitary surge: especially of LH Give exogenous estrogen Estrogen Pituitary (-) 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 Estrogen Feedback on Hypothalamus and Anterior Pituitary Give higher dose of estrogen Estrogen Pituitary (+) LH/FSH

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

The Ovary and Process of Ovulation Primordial follicle Ovulation Ovarian vessels Corpus hemorrhagicum Corpus luteum Corpus albicans - 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 in a woman who has a normal 28-day cycle occurs 14 days after the onset of menstruation Developing follicles Mature follicle

Luteal Phase of the Ovarian Cycle Corpus albicans Mature corpus luteum Ovulation Early corpus luteum 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

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

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

FSH LH Estradiol Progesterone Hypothalamus Anterior Pituitary Ovarian Events Uterine Endometrium 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 uterine endometrium. 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. GnRH Ovarian Hormones Gonadotropic Hormones Days of Cycle Basal Body Temperature

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

1)Effects of Estrogens on 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 Uterus, external Female sex organs Breasts Fat/protein deposition Skeleton Electrolyte balance Skin

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

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

2)Functions of Progesterone 1.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

Estrogen Secretion Throughout the Female Sexual Life

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

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