Biosynthesis and Physiological Role
All sex hormones are steroid-based. In the ovaries, biosynthesis is described by the two-cell theory: the theca interna cells produce androgens, while granulosa cells take them up and convert them into estradiol via aromatization.
During the follicular phase of the cycle, the hypothalamus pulsatilely releases gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary to secrete follicle-stimulating hormone (FSH). FSH triggers follicular growth and estrogen secretion, preparing the endometrium for implantation. Mid-cycle, the estrogen peak triggers a luteinizing hormone (LH) surge and ovulation. The ruptured follicle transforms into the corpus luteum, which secretes progesterone. If fertilization does not occur, the corpus luteum regresses, hormone levels drop precipitously, and menstruation ensues.
During postmenopause, 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 high lipophilicity, estrogens easily cross the cell membrane via simple diffusion. In the cytoplasm, the hormone binds to a specific receptor. This causes the dissociation of an inhibitory heat shock protein (chaperone), leading to receptor dimerization and translocation into the cell nucleus. Inside the nucleus, the receptor complex interacts with DNA, initiating transcription and the synthesis of specific proteins.
There are two main receptor subtypes 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.
Classification of Agents
Estrogen preparations are divided into two main groups based on their origin:
- Natural: estradiol, its esters, and estriol.
- Synthetic: ethinyl estradiol and mestranol (a prodrug).
Synthetic analogs feature high oral bioavailability because they are metabolized more slowly and accumulate in adipose tissue. They serve as the foundation for combined oral contraceptives (COCs).
Natural estrogens are more commonly used for hormone replacement therapy (HRT). To reduce hepatic workload, natural estradiol is frequently administered via transdermal patches or gels. Estriol has a selective effect on the urogenital tract and, when properly dosed (short receptor-binding duration), does not cause endometrial proliferation.
Adverse Effects
Administration of exogenous estrogens requires strict monitoring due to the risk of serious complications:
- Hemostatic system: hypercoagulability, significantly increasing the risk of thrombosis and thromboembolism.
- Water-electrolyte balance: sodium and water retention, leading to edema and weight gain.
- Gastrointestinal tract and hepatobiliary system: nausea, anorexia, increased bile lithogenicity (risk of cholelithiasis).
- Oncology: stimulation of cellular proliferation can trigger malignancies in estrogen-dependent tissues (mammary glands, endometrium).
- Central nervous system: mood swings, exacerbation of migraine attacks.