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----12 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• Mense1. Endometrium is sloughed (progesterone withdrawal)2. Nonclotting menstrual blood mainly comes from artery

(75%)3. Interval: 24-35 days (28 days). duration: 2-6 days. the first

day of menstrual bleeding is consideredy by day 14. Shedding: 30-50 ml

Female Reproductive System

Ovary

UterusFallopian 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 timesof the month

Ovaries

Interaction of thefemale hormonesystem and theirfunctions

• GnRH: anterior pituitary LHand FSH

• LH & FSH: ovary; developmentof ovarian follicles; estrogen andprogesterone 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)Oogenesis7,000,000

20-24 weeks gestation

1,500,000

Birth

400,000

Puberty

Mit

osis

Attrition

300,000-400,000 ova400-500 ovulations in 13-46 years of age

2)Ovarian Follicular Growth(Each ovum is enclosed within a follicle)

Primordial follicle: 50μmovum + one layer of granulosa cells

Primary(preantral )follicle:200μmovum + more layers of granulosa cellsZona pellucid FSH-R aromatase

antral follicle: 500μmovum + granulosa + theca cells + follicular fluid (Estrogens)LH-R cumulus oophorus estrogens

Mature (Graafian) follicle: 15-20mmone follicle outgrows

Follicular phase

Granulosa cells

Zona pellucida

Corona radiata

Antrum

Interstitial tissue

Primodial follicle

Ova

Cumulus oophorus

Primordial Follicle and Mature Follicle

Thecainterna

Theca externa

AntrumTheca

GranulosaOvum

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

TestosteroneO=

OH

OH

HO-

Cholesterol

Estrone

O

HO-

17-Hydroxysteroid Dehydrogenase

LH

aromatase aromataseFSH FSH

Thecal Cells

Granulosa Cells

17 -Hydroxysteroid Dehydrogenase

Estriol

OH

HO-

Peripheral

OH

Cholesterol 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

desmolase desmolase

Lyase

AntrumEstradiol

4)Feedback Control of Gonadotropin Secretion

GnRH

At level of hypothalamus/pituitary:• Circulating estrogens inhibit LH & FSH secretion• Circulating progesterone (low) potentiatesestrogen 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 Cholesterol

ProgesteronePregnenolone

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 desmolase

cAMP

ATPLyase LH receptors increase

in Antral Stage Only -estrogen induced

LH

FSHPregnenolone

EstradiolEstrone

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 estrogensynthesis• 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/F

SH

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 hemorrhagicumCorpus 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

Developingfollicles

Maturefollicle

Luteal Phase of the Ovarian Cycle

Corpus albicans

Mature corpus luteum

Ovulation

Early corpusluteum

• 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

EstrogenProgesteroneInhibin

(-)

(+)

(+)

HypothalamusTermination 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 constrictEndometrium necrosis

40ml blood + 35ml fluid Fibrinolysin → nonclotting

Leukocytes → anti-infection

Ovulation

FSH

LH

Estradiol

Progesterone

Hypothalamus

Anterior Pituitary

Ovarian Events

UterineEndometrium

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

OvarianHormones

GonadotropicHormones

Days of Cycle

Basal BodyTemperature

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 progesteroneEstrogens:

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, externalFemale sex organs

Breasts

Fat/proteindeposition

Skeleton

Electrolytebalance

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 breastFat/Protein deposition• fat deposition in subcutaneous & breast tissues; broadening of thighs/ buttocks• protein deposition in sexual organs, bones; slight increase in total body proteinSkeleton• Increase osteoblastic activity, growth plate unit• Post menopause: decrease osteoblast activity, bone matrix, Ca/P depositsElectrolyte Balance• Increase sodium & water retention – effect is greater during pregnancySkin• Development of thick, soft & smooth skin texture• Vascularization increase bleeding

2)Functions of Progesterone

1. UterusPromotes secretory changes in uterine endometriumDecreases 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 theFemale 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 YinchengTeng Yincheng

M.D., Ph.D., ProfessorM.D., Ph.D., Professor

Dep. of Obstet. & Gynecol.Dep. of Obstet. & Gynecol.

Renji Hospital Affiliated to SJTU School of MedicineRenji Hospital Affiliated to SJTU School of Medicine