Female Sex Hormones

Biosynthesis and physiological role

All sex hormones are steroid in nature. In the ovaries, biosynthesis is described by the two-cell theory: the theca cells produce androgens, and the granulosa cells take them up and convert them into estradiol via an aromatization reaction.

During the follicular phase of the cycle, the hypothalamus pulsatilely releases gonadotropin-releasing hormone, which stimulates the production of follicle-stimulating hormone (FSH) by the pituitary gland. FSH triggers follicular growth and estrogen secretion, which prepare the endometrium for implantation. Mid-cycle, the estrogen peak triggers a surge in luteinizing hormone (LH) and ovulation. A corpus luteum forms at the site of the ruptured follicle and secretes progesterone. If fertilization does not occur, the corpus luteum degenerates, hormone levels drop sharply, and menstruation begins.

In the postmenopausal period, the ovaries cease function. Adipose tissue becomes the primary source of estrogens, where the enzyme aromatase converts adrenal androgens into estrone and estradiol.

Mechanism of action and receptors

Due to their high lipophilicity, estrogens easily penetrate the cell via simple diffusion. In the cytoplasm, the hormone binds to a specific receptor. Following this, the inhibitory heat shock protein (chaperone) dissociates, forming a dimer that translocates into the cell nucleus. There, the receptor complex interacts with DNA, initiating transcription and the synthesis of specific proteins.

There are two types of receptors encoded by different genes:

• ER$\alpha$: located in the uterus, vagina, ovaries, mammary glands, bone tissue, vascular endothelium, and hypothalamus.
• ER$\beta$: localized in the prostate gland, ovaries, lungs, blood vessels, and brain.

Drug classification

Estrogen preparations are divided into two main groups based on origin:

1. Natural: estradiol, its esters, and estriol.
2. Synthetic: ethinylestradiol and mestranol (a prodrug).

Synthetic analogues exhibit high oral bioavailability because they are metabolized more slowly and accumulate in adipose tissue. They serve as the basis for combined oral contraceptives (COCs).

Natural estrogens are more commonly used for hormone replacement therapy (HRT). To reduce the metabolic load on the liver, natural estradiol is often prescribed as transdermal patches or gels. Estriol has a selective effect on the urogenital tract and, when properly dosed (short receptor-binding time), does not cause endometrial proliferation.

Side effects

Administration of exogenous estrogens requires strict monitoring due to the risk of serious complications:

• Hemostatic system: hypercoagulation, which significantly increases the risk of thrombosis and thromboembolism.
• Water-electrolyte balance: sodium and water retention leading to edema and weight gain.
• Gastrointestinal and hepatobiliary systems: nausea, anorexia, increased lithogenicity of bile (risk of cholelithiasis).
• Oncology: stimulation of cell proliferation can provoke cancer in estrogen-dependent tissues (mammary glands, endometrium).
• CNS: mood swings, increased frequency of migraine attacks.

Class and exam questions

What else to study on this topic

• Enterohepatic circulation of estrogens and its clinical significance
• The "Depot" system and the role of estrone sulfotransferase
• Mechanism of action of selective estrogen receptor modulators
• Pharmacokinetics of injectable estradiol esters
• Clinical presentation of climacteric syndrome in estrogen deficiency

Other topics in the section "Hormone preparations, their synthetic substitutes, and antagonists"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.