In postmenopausal women, does estrone become the dominant estrogen and reflect peripheral aromatization or altered clearance?

Context and Background

During the reproductive years, ovaries directly secrete estradiol ($E_2$) as the primary circulating estrogen. However, during the menopausal transition, ovarian follicular depletion leads to a dramatic drop in ovarian estrogen synthesis. Consequently, the female endocrine landscape shifts from active ovarian secretion to peripheral, extragonadal synthesis, making estrone ($E_1$) the dominant circulating estrogen in postmenopausal women.

Clinical and Mechanistic Evidence

• Peripheral Aromatization: In postmenopausal women, estrogen production relies almost entirely on the conversion of adrenal androgens. The adrenal cortex continues to secrete androstenedione, which is converted into estrone ($E_1$) by the aromatase enzyme ($CYP19A1$) located in peripheral tissues, primarily adipose tissue, skeletal muscle, and the liver.
• Adiposity and Synthesis: Because adipose tissue is a major site for aromatase expression, increased adiposity and body mass index (BMI) are directly associated with higher rates of peripheral conversion, leading to elevated baseline estrone levels.
• Interconversion Dynamics: The relationship between estrone ($E_1$) and the more potent estradiol ($E_2$) is tightly regulated by the 17$\beta$-hydroxysteroid dehydrogenase ($17\beta\text{-HSD}$) enzyme family.
  • $17\beta\text{-HSD1}$ catalyzes the reduction of the weaker estrone ($E_1$) into the highly active estradiol ($E_2$).
  • $17\beta\text{-HSD2}$ catalyzes the reverse oxidation reaction, converting active $E_2$ back to the less potent $E_1$.
• Clearance and Conjugation: Estrogen clearance heavily influences circulating levels. Estrogens undergo Phase I cytochrome P450-mediated hydroxylation, followed by Phase II conjugation to facilitate excretion.
  • Sulfation and Desulfation: Estrone is reversibly conjugated by sulfotransferases (such as $SULT1E1$ and $SULT1A1$) into estrone sulfate ($E_1S$), which serves as a long-lived circulating reservoir. The enzyme steroid sulfatase ($STS$) hydrolyzes $E_1S$ back into active estrone as needed.
  • Genetic Variations: Polymorphisms in genes encoding these metabolic enzymes (including $SULT1A1$, $UGT1A4$, $HSD17B1$, and $HSD17B2$) can alter individual conversion and clearance rates. These variations frequently result in atypical clinical presentations, such as elevated estrone co-existing with optimal or stable estradiol levels.

Bottom line

The claim is fully supported by scientific evidence. In postmenopausal women, the depletion of ovarian function shifts the dominant estrogen from estradiol to estrone, which is synthesized via the peripheral aromatization of adrenal androstenedione. An elevated estrone level co-occurring with optimal estradiol is a clinically recognized phenomenon that reflects either an increased conversion of estradiol to estrone via $17\beta\text{-HSD2}$ activity, accelerated recycling from the estrone sulfate reservoir, or genetic variations in Phase II conjugation and clearance pathways.