Female sex hormones

Estrogen is a female sex hormone that is produced in the ovaries and, to a lesser degree, in the adrenal glands and adipose tissues. It is essential for the development of primary and secondary sex characteristics, as well as function of the reproductive organs. Estrogen also plays a role in several other processes, including bone metabolism and liver function. While ovarian insufficiency, aromatase deficiency, and hyperprolactinemia result in pathologically low estrogen levels, a decrease in estrogen is a normal feature of menopause. Possible clinical features of estrogen deficiency include menopausal symptoms, vaginal and endometrial atrophy, and osteoporosis. Increased estrogen levels may also have adverse effects, including gynecomastia, thrombosis, and an increased risk of breast and endometrial cancer. Progesterone is a female sex hormone produced by the corpus luteum in nonpregnant women and, in pregnant women, by the corpus luteum graviditatis until the 10th week of gestation, after which the placenta takes over production. Progesterone plays an important role in the preparation of the endometrium for implantation of a fertilized ovum and maintenance of pregnancy. Synthetic progesterone derivatives are called “progestins” and are used as contraceptives and are used in the treatment of conditions resulting from endometrial proliferation (e.g., endometriosis, endometrial cancer).

Ovarian estrogen synthesis

Estrogen synthesis primarily takes place in the ovarian granulosa cells.

• LH stimulates androgen synthesis in ovarian theca cells.
• FSH stimulates conversion of androgens to estrogens.
• Conversion of androgens to estrogens is catalyzed by the aromatase enzyme.

See “Androgens” in "Adrenal gland."

Extra-ovarian estrogen synthesis ^[1]

Estrogen is also produced in other aromatase-containing tissues:

• Fatty tissue
• Placenta
• Testicles
• Adrenal glands

Estrogen types

There are three types of estrogen: estradiol, estrone, and estriol.

• Potency: estradiol > estrone > estriol
• During pregnancy, estrogen concentration increases.
  • Estradiol and estrone: 100-fold increase
  • Estriol: 1000-fold increase (it is secreted by the placenta as unconjugated estriol and a marker of fetal health)
• When estrogen binds to its receptor in the cytoplasm, a hormone-receptor complex is formed that translocates to the nucleus.

Obesity increases the risk of postmenopausal breast cancer. It is hypothesized that this is due to estrogen production in adipose tissue. ^[2]

Measurement of unconjugated estriol (uE3 or free estriol) is part of the prenatal screening for fetal anomalies (i.e., triple screen test and quad screen test). Decreased levels are associated with Down syndrome, Edward syndrome, molar pregnancy, and fetal demise.

Estrogen is a steroid hormone that promotes female sexual development and stimulates the growth and maturation of primary and secondary sex characteristics.

Genitalia/sex characteristics

• Uterus
  • Endometrial proliferation
  • ↑ Myometrial excitability
• Cervix ^[3]
  • ↑ Production of cervical mucus: facilitates passage of sperm
  • Facilitates cervical dilation during labor
• Vagina: proliferation of epithelium
• Pubis: hair growth
• Breast: breast growth

Extragenital tissue ^[4][5]

• Bones: ↑ bone formation by inhibiting bone resorption (induces osteoclast apoptosis)
• Blood vessels: protective effect against atherosclerosis
• Blood clotting: ↑ risk of thrombosis
• Kidneys: ↑ water and sodium retention (may contribute to edema)
• Protein synthesis
  • Slightly ↑ (anabolic effect)
  • ↑ Transport proteins (e.g., SHBG)
• Adipose tissue: female distribution of adipose tissue
• Liver
  • ↓ Bilirubin excretion
  • ↑ HDL and ↓ LDL

Adverse effects of estrogen can arise from high levels secondary to increased endogenous production or medication (e.g., hormone replacement therapy during menopause):

• ↑ Cancer risk
  • Endometrial cancer
  • Breast cancer ^[2][6]
• Thrombosis
• Spider nevi, gynecomastia, and testicular atrophy in individuals with cirrhosis
• Breast hypertrophy, gynecomastia (in men), galactorrhea
• Weight gain (edema)
• Liver toxicity ^[7]
• Nausea and vomiting
• Depressive moods

Although estrogen is a risk factor for the development of some types of cancer, it reduces the risk of colon cancer.

High estrogen levels increase the risk of thrombosis.

• Definition: a condition of increased circulating estrogen
• Etiology
  • ↑ Estrogen production (e.g., due to ovarian tumors, obesity)
  • Excess estrogen supplementation (e.g., due to hormone replacement therapy)
  • ↓ Metabolism and excretion of estrogens (e.g., due to chronic liver disease)
• Clinical features
  • Both sexes: palmar erythema, spider telangiectasias
  • Men
    • Gynecomastia
    • Testicular atrophy
    • Reduced libido
    • Erectile dysfunction, infertility
    • ↓ Body hair (e.g., loss of chest hair, female pattern of pubic hair distribution)
  • Women
    • Menstrual irregularities (see "The menstrual cycle and menstrual cycle abnormalities")
    • Enlargement of the breast and uterus
    • Infertility
    • ↑ Cancer risk (e.g., endometrial cancer)

• Definition: a condition of decreased circulating estrogen
• Etiology
  • Menopause
  • Ovarian insufficiency: idiopathic or secondary to an underlying conditions (e.g., Turner syndrome, polycystic ovary syndrome)
  • Congenital aromatase deficiency (↓ aromatase → ↑ androgens and ↓ estrogen)
  • Hyperprolactinemia (e.g., in pituitary adenomas, hypothyroidism)
  • GnRH agonists
• Clinical features
  • Hot flashes
  • Headaches
  • Reduced libido
  • Breast atrophy
  • ↓ Bone density and secondary osteoporosis
  • Urogenital atrophy
  • Dyspareunia

Production

• In nonpregnant women: granulosa cells of the corpus luteum
• In pregnant women
  • Until the 10^th week of gestation: corpus luteum graviditatis
  • From 10^th week of gestation: placenta (syncytiotrophoblast)

Effects

• The effects of progesterone are mediated via intracellular receptors.
• For the effects of progesterone in pregnancy, see “Placental function” in "The placenta, umbilical cord, and amniotic sac.”

Genitalia/sex characteristics

• Uterus
  • Endometrial glandular secretion and spiral artery development
  • Inhibits endometrial hyperplasia
  • ↓ Estrogen receptor expression
  • ↓ Myometrial excitability
• Cervix: ↓ cervical mucus production → cervical mucus thickening (inhibits entry of spermatozoids to the uterus)
• Breasts: inhibits prolactin (the decrease in progesterone levels after delivery disinhibits prolactin, triggering lactation)

Extragenital effects

• Hypothalamus
  • ↑ Body temperature (basis of basal body temperature contraception method)
  • Inhibits gonadotropin secretion

Role in menstrual cycle

• After ovulation, the ruptured follicle transforms into the corpus luteum, which produces progesterone.
• Progesterone induces changes in internal reproductive organs required for proper implantation of a zygote and inhibits the secretion of FSH and LH, preventing other follicles from developing.
• See "The menstrual cycle and menstrual cycle abnormalities."

Clinical significance

• Associated pathologies: low levels of progesterone are associated with infertility, premature birth, and spontaneous abortion ^[8]
• Clinical use
  • Synthetic progesterone derivatives (progestins) are indicated for the following conditions:
    • Hormonal contraception
    • Treatment of abnormal uterine bleeding
    • Treatment of endometriosis
    • Treatment of endometrial cancer
    • Hormone replacement therapy (prevent endometrial proliferation induced by estrogens)
    • Progesterone withdrawal test
  • See “Reproductive system drugs” in “General endocrinology” for more information about the pharmacology of progestins.

• See “Hormonal contraceptives.”