Steroid hormone synthesis

Steroidogenesis

• Conversion of cholesterol into hormones– Chemical modification

• Ring formation• Reduction of ketone to alcohol

– Structural modification• Removal of carbon side-chains

Site of steroidogenesis

• Mitochondria– Uptake of cholesterol

• Circulation– Lipoproteins

• De Novo synthesis

– Side-chain cleavage• Production of pregnenolone (P5)

– From 27-C molecule to 21-C molecule

• Cytoplasm– Conversion of P5 to progesterone (P4)

• C-21 steroids

– Conversion of progestigens to androgens• C-21 steroids to C-19 steroids

– Conversion of androgens to estrogens• C-19 steroids to C-18 steroids• Armatization of the sterol ring

Steroidogenic cells

• Male– Leydig cells

• Testosterone production– Sertoli cells

• Estradiol production

• Females– Theca cells

• Androgen production– Granulosa cells

• Estradiol production– Progesterone production by both theca and granulosa

cells

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

Pattern of follicular development and changes in blood hormone

concentrations

+ +

LH

+

Ovulation

FSH

Role of gonadotropins

• Production of cAMP– Activation of protein kinase A pathway

• Increased binding of steroidogenic factor-1 (SF-1) to DNA– Transcription factor

• Activation of genes involved in steroidogenesis

Role of gonadotropins

• Increased cholesterol uptake– Increased number of steroidogenic acute

regulate protein (StAR)– Most critical step for androgen synthesis

• Increased enzyme activity– Aromatase expression in the granulosa cells

Action of steroid hormones

• Development of reproductive organs– Fetal– Pubertal

• Determinative

– Adult• Regulatory

• Regulation of gonadotropin secretion– Long feedback loop

Role of androgens in male

• Fetal life– Determinative action

• Development of male genitalia• Defeminization and masculinization

• Adult life– Essential for normal spermatogenesis– Development and function of accessory sex

organs

Gross anatomy of male reproductive organs

• Effects of androgens on the prostate gland and seminal vesicle– Production of seminal

fluid• Differentiation of the

prostate ducts• Blanching of seminal

vesicles

– Loss of androgen• Involution of gland• Loss of secretion

Role of testosterone on spermatogenesis

• Essential for normal spermatogenesis– Proper production of semineferous tubule fluid

• Critical for normal sperm development– Nutrients to developing sperm cells

• Controlled by testosterone in adults

• Intratetsicular concentration of testosterone– Much higher than in

peripheral circulation• Critical for maintenance

of spermatogenesis– Sertoli cell function

• Loss of testosterone– Reduced Sertoli cell function

• Reduced semineferous tubule fluid production• Stage-specific effects

– Later stages (7 and 8)

Gross anatomy of female reproductive organs

Role of estradiol and progesterone in female

• Cyclic changes– Cyclic changes in ovarian structure

• Cyclic changes in uterine structure

• Follicular phase– High estradiol– Low progesterone– Preparation of reproductive tract for fertilization

• Oviduct• Uterus

• 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

• Functional unit of the endometrium– Functionalis

• Proliferation• Secretion• Degeneration• Site of implantation

– Basalis• Regenerative unit

• 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

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

• Effects of progesterone– Differentiation of

endometrium• Inhibition of estradiol-

induced proliferation• Mediated by stroma• Secretion

– Proteins

• Critical for implantation

• Action of progesterone– Increase in cytoplasm of stroma

• Psuedodiciduation

• Effects on other uterine tissues– Myometrium (smooth muscle)

• Excitability and contraction– Depressed by progesterone– Increased by estradiol

• Menstruation– Absence of pregnancy– Initiation of endometrium remodeling

• Alteration of extracellular matrix• Leukocyte infiltration• Death and removal of tissue• Regeneration of tissue

• 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

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