Does estrone become the dominant circulating estrogen after menopause and can reduced conversion to estradiol cause low-estrogen symptoms?

The transition into postmenopause is defined by a fundamental shift in the hormonal landscape, where the cessation of ovarian function necessitates a change in how the body produces and processes estrogens.

Clinical evidence of estrogen dominance shift

In the reproductive years, 17β-estradiol (E2) is the primary and most potent circulating estrogen. However, postmenopause triggers a significant reversal in the ratio of circulating estrogens. Evidence from ultrasensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) confirms that while both levels drop, E2 declines more precipitously than estrone (E1).

• Ratio Reversal: In postmenopausal women, serum E1 typically ranges from 20–180 pmol/L, whereas E2 often falls between <4–36 pmol/L.
• Prevalence: E2 levels often fall below the limit of detection in standard assays, while E1 remains consistently quantifiable, establishing it as the dominant circulating estrogen.

Mechanistic basis of local conversion

The physiological impact of these hormones is not determined solely by circulating levels but by "intracrinology"—the local conversion of hormones within specific tissues. The enzyme 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is the primary catalyst responsible for converting the relatively weak estrone into the highly potent estradiol.

• Tissue-Level Activity: This conversion allows target tissues (such as the brain, bone, and vaginal epithelium) to maintain bioactive E2 levels even when ovarian production has ceased.
• Enzymatic Efficiency: Genetic variations in the HSD17B1 gene, such as the rs605059 polymorphism, can alter the efficiency of this enzyme. Research indicates that women with specific genotypes that may result in less efficient E1-to-E2 conversion experience higher-severity vasomotor symptoms (hot flashes).

Clinical implications for symptoms

When the local conversion of E1 to E2 is reduced, the "reservoir" of circulating estrone cannot be effectively utilized to meet the tissue's demand for potent estradiol. This deficiency at the cellular level manifests as classic low-estrogen symptoms.

• Symptom Severity: High-severity symptoms have been directly correlated with elevated E1 levels in the presence of inefficient conversion, suggesting that it is the lack of local E2—not just the presence of E1—that drives clinical discomfort.
• Bioavailability: Because E2 is significantly more potent at the estrogen receptor than E1, any bottleneck in the conversion process results in a more profound estrogenic deficiency.

Bottom line

In postmenopause, the body relies on the peripheral conversion of adrenal androgens into estrone, making it the dominant circulating estrogen. The severity of menopause symptoms is influenced by the efficiency of local enzymes in converting this estrone into bioactive estradiol; a reduction in this conversion capacity is a key contributor to significant low-estrogen effects.