Estrogen Production in Reproductive-age Women

Where is estrogen coming from in Premenopausal women?

(1) The ovaries (follicle granulosa cells) before ovulation (follicular phase) are the main source of estrogen (predominantly ESTRADIOL), which functions as a circulating hormone

(2) A small amount of estrogen is produced in peripheral tissue (E.g. skin, fat, muscle) by the conversion of circulating androgens (via aromatase enzyme)

(3) The placenta produces ESTRIOL during pregnancy

Feedback mechanism of Estrogen Production during reproductive cycle

ESTRADIOL production is under the cyclical endocrine control of two PITUITARY gonadotrophins, LH and FSH - which are released by hypothalamic GnRH (which is subject to negative estrogen feed-back from the ovaries )

-   By negative-feedback - high-level Estrogen causes a decrease in FSH/LH production by inhibiting hypothalamic GnRH (Gonadotropin Releasing Hormone) production.

FSH/LH ▲ ➔ Estrogen ▲ 

Estrogen ▲  ▲  ▲  ➔  GnRH ▼ ➔  FSH/LH▼➔  Estrogen ▼

(Rising levels of Estrogen in the blood begins follicle/egg development)

Luteinizing hormone (LH) -binds with LH receptors tostimulate follicle thecal cells to produce mainly ANDROSTENEDIONE,which is supplied to the neighboring follicle granulosa cells as a substrate with which to make ESTRADIOL;

Follicle-stimulating hormone (FSH)

-   FSH stimulates the growth of immature ovarian follicles - by pronounced proliferation of granulosa cells.

-   FSH stimulates granulosa cells of ovarian follicle (a collection of fluid around eggs) to secrete estrogens -mainly ESTRADIOL;

-    Follicle granulosa cells have FSH-sensitive aromatase activity and proliferate in response to estrogens:

•   Proliferation is inhibited by androgens;

•   FSH regulates transcription of the aromatase gene (CYP19A1) in ovarian granulosa cells.

•   Substrate ANDROSTENEDIONE is supplied by ovarian theca cells and is converted to ESTRONE by aromatase - followed by conversion of ESTRONE to ESTRADIOL ▲ by 17β-HSD enzyme.

•   Estrogen stimulates the uterine endometrium to proliferate and to synthesize PROGESTERONE receptors (PR's) ▲  in the cytosol;

•   After ovulation (2^nd half of menstrual cycle, called the luteal phase), estrogen ▼ production/secretion from the ovarian granulosa cells decreases;

The rise in ESTRADIOL causes expression of LH receptors ▲  on maturing follicles, which also indirectly increases ESTRADIOL▲  production.    By stimulating theca cells to provide more substrate ANDROSTENEDIONE. ESTRADIOL continues its positive feedback loop supplying LH receptors for LH activation to provide more ANDROSTENEDIONE substrate for additional estrogen production, until high estrogen levels inhibit hypothalamic GnRH,causing a decrease in FSH production and a subsequent decrease in estrogen production;

Normal Female Estrogen Production fluctuates during reproductive years

Normal, average estrogen levels (measured in pg/ml) vary for a woman at different times throughout her reproductive years.