Estrogen

Estrogen, also spelled oestrogen in British English, is a class of sex steroid hormones central to the development and regulation of the female reproductive system and the expression of secondary sexual characteristics. Although typically associated with female physiology, estrogens are produced in all vertebrates and also occur in certain invertebrates. They circulate in both sexes, but at significantly higher concentrations in biological females of reproductive age. Estrogens exert widespread effects on growth, metabolism, reproduction, and numerous other physiological systems.
Structurally, estrogens are steroid hormones capable of diffusing across cell membranes. Their actions are mediated by both nuclear estrogen receptors and membrane-associated rapid-signalling receptors. In addition to their role as endogenous hormones, estrogens are widely used as medications, and synthetic forms appear in the environment as endocrine-disrupting compounds.

Types of Estrogen

Four major naturally occurring estrogens are recognised in humans, each predominant at different stages of life:

• Estrone (E1) – becomes the primary circulating estrogen after menopause.
• Estradiol (E2) – the most potent and abundant estrogen during reproductive years.
• Estriol (E3) – the main circulating estrogen during pregnancy.
• Estetrol (E4) – produced only during pregnancy by the fetal liver.

Estradiol is by far the most active form, being roughly ten times more potent than estrone and approximately one hundred times more potent than estriol in animal studies. During pregnancy, high levels of estriol assume functional dominance, while after menopause estrone becomes the primary form.
Estrogens are synthesised from androgens such as testosterone and androstenedione by the enzyme aromatase. Several minor endogenous estrogens and estrogen metabolites are also produced, including catechol estrogens and hydroxylated derivatives, although their physiological significance is less clearly understood.

Mechanisms of Action

Estrogen functions primarily via the estrogen receptor (ER), a nuclear transcription factor that binds to specific DNA sequences known as hormone response elements. Upon entering the cell by passive diffusion, estrogen binds to ER, promoting receptor dimerisation and activation. This complex influences the transcription of numerous genes, affecting cell growth, differentiation, and metabolic functions.
In addition to classical nuclear signalling, estrogens activate membrane estrogen receptors, including GPER (GPR30), which trigger rapid cellular responses through second messenger pathways. Tissue responses depend heavily on the local distribution of receptor subtypes.

Physiological Functions

Estrogen influences many organ systems, with effects that vary according to sex, age, and hormonal status.
Reproductive System

• Stimulates development of female secondary sexual characteristics, including breast development and areolar pigmentation.
• Thickens the endometrial lining and promotes uterine growth.
• Increases vaginal lubrication and thickens the vaginal epithelium.
• Regulates the menstrual cycle, including the pre-ovulatory surge of luteinising hormone essential for ovulation.
• Supports uterine function during gestation and increases oxytocin receptor expression in the myometrium.
• In males, contributes to the maturation of sperm and supports libido.

Musculoskeletal System

• Increases muscle mass, strength, and regenerative capacity.
• Enhances bone density by reducing bone resorption and promoting bone formation.
• Improves collagen synthesis and connective-tissue turnover.
• Decreases ligament stiffness, providing greater flexibility but increasing susceptibility to certain injuries, such as anterior cruciate ligament tears.

Metabolism

• Exhibits anti-inflammatory effects.
• Promotes peripheral fat deposition in areas such as the hips and thighs while reducing visceral fat.
• Regulates energy expenditure and supports metabolic homeostasis.
• Influences body weight regulation, often exerting more powerful anti-obesity effects than androgens.

Other Structural and Systemic Effects

• Maintains vascular integrity and skin structure.
• Increases hepatic production of various binding proteins and coagulation factors.
• Modulates fluid and salt balance, often contributing to water retention and oedema.
• Influences pigmentation, helping explain darker skin and eye tones frequently observed in females and the lower incidence of melanoma relative to males.
• Supports aspects of lung function in certain species.

Environmental and Medical Aspects

Estrogens occur naturally within organisms but also appear as pharmaceuticals and environmental contaminants. Synthetic and natural estrogens used in menopausal hormone therapy, hormonal contraception, and feminising hormone therapy can enter ecosystems through wastewater, contributing to endocrine disruption in wildlife. These xenoestrogens are part of a larger class of endocrine-disrupting compounds associated with reproductive abnormalities and metabolic disorders in humans and animals.
Medically, estrogens are critical therapeutic agents for managing menopausal symptoms, supporting contraception, and assisting gender-affirming hormone treatment.