A review of estrogens used in menopausal hormone therapy

To provide an overview of endogenous and therapeutic estrogens, their receptor biology, clinical applications, and evolving safety considerations, with emphasis on how estrogen type, timing, and route of administration influence outcomes in menopausal hormone therapy (MHT).

Emerging research shows that estrogen receptor (ER)α, ERβ, and G protein-coupled estrogen receptor mediate distinct and sometimes opposing physiological effects. Updated analyses support the timing hypothesis, showing that starting MHT closer to menopause may yield cardiovascular and neurological benefits not observed with later initiation. Comparative studies demonstrate that estradiol has a more favorable thrombotic and metabolic profile than conjugated equine estrogens. Newer agents such as estetrol provide selective ERα activation with reduced hepatic stimulation and promising effects on vasomotor symptoms, bone turnover, and metabolic markers. Estriol has gained attention for its safety and effectiveness in treating genitourinary syndrome of menopause.

Estrogen therapy reflects a nuanced approach informed by receptor selectivity, pharmacologic diversity, and timing of initiation. Estradiol-based and transdermal formulations remain preferred for systemic therapy, while low-dose vaginal estrogen is first line for urogenital symptoms. Novel estrogens and deeper mechanistic insights continue to refine therapeutic options, supporting more targeted and safer use of estrogen across the menopausal transition.