Which estrogen predominates in the circulation of postmenopausal women?

Estrone Predominates in Postmenopausal Circulation

Estrone (E1) is the predominant circulating estrogen after menopause, not estradiol (E2). 1, 2, 3

Estrogen Metabolism After Menopause

Primary Estrogen Source and Conversion Pathway

• Estrone is produced primarily through peripheral aromatization of androstenedione (a weak androgen secreted by the adrenal glands and residual ovarian stroma), accounting for approximately 24.6% of circulating estrone. 1, 2

• Androstenedione serves as the principal precursor substrate for estrogen synthesis in postmenopausal women, with peripheral tissues (adipose tissue, muscle, liver, skin) converting it to estrone via the aromatase enzyme. 1, 2

• Estradiol is derived predominantly from estrone conversion rather than direct peripheral aromatization, with estrone-to-estradiol conversion accounting for 21.5% of the circulating estradiol pool. 1

• Direct conversion of testosterone to estradiol contributes minimally (only 2.5% of the estradiol pool), and direct aromatization of androstenedione to estradiol is also insignificant. 1

Quantitative Hormone Levels

• Median estrone concentrations in postmenopausal women are 181.2 pmol/L (range 88.7–347.6 pmol/L), whereas median detectable estradiol is only 22.0 pmol/L (range 11.0–58.7 pmol/L). 3

• Estradiol falls below the limit of detection (11 pmol/L or 3 pg/mL) in 66.1% of postmenopausal women, whereas estrone remains detectable in 99.1% of women, confirming estrone as the principal circulating estrogen. 3

• Estrone levels are 8–10 times higher than estradiol levels in the typical postmenopausal woman, reflecting the metabolic hierarchy where estrone is the primary product and estradiol is a secondary metabolite. 3

Clinical Implications

Body Weight and Estrogen Levels

• Obesity increases estrogen production rates through enhanced peripheral aromatization in adipose tissue, with positive correlations between body weight and both peripheral estrone and estradiol levels. 4, 2, 5

• Percent ideal body weight strongly correlates with estrone and estradiol concentrations, but age itself does not independently affect estrogen levels once menopause is established. 5

• Sex hormone-binding globulin (SHBG) decreases significantly in menopause and further declines with obesity, thereby increasing the fraction of "free" (bioavailable) estradiol available to target tissues. 2

Residual Ovarian Contribution

• The postmenopausal ovary continues to produce androgens (primarily testosterone and androstenedione), with significant ovarian-peripheral gradients observed in 75% of women for testosterone and 45% for androstenedione. 4

• Direct ovarian estrogen secretion is minimal but present in some women, with significant ovarian-peripheral gradients for estradiol in 35% and for estrone in 25% of postmenopausal subjects. 4

Androgen Decline with Age

• Dehydroepiandrosterone (DHEA) and DHEA-sulfate decline significantly with advancing age (P < 0.001), reflecting age-related changes in adrenal 17,20-desmolase activity. 5

• Delta-4 androgens (androstenedione and testosterone) do not decline with age in postmenopausal women, maintaining stable substrate availability for peripheral aromatization. 5

Progesterone and Progestins

• Circulating progestin levels (progesterone and 17-hydroxyprogesterone) remain at follicular-phase concentrations and do not change with age in postmenopausal women, reflecting loss of corpus luteum function but stable adrenal production. 5

Cancer Risk Context

• The absence of progesterone opposition allows estrone and estradiol to exert unopposed proliferative effects on breast and endometrial tissue, contributing to increased cancer risk in obese postmenopausal women. 2

• Weight loss reverses obesity-related increases in estrogen levels and decreases in SHBG, normalizing the hormonal milieu and potentially reducing cancer risk. 2