Why do some women in menopause still have substantial estradiol (estrogen) levels while others have almost none?

Why Some Menopausal Women Have Substantial Estradiol While Others Have Almost None

After menopause, estradiol levels vary significantly between women primarily due to differences in peripheral conversion of androgens to estrogens in extragonadal tissues, particularly adipose tissue.

Physiological Basis for Estradiol Variation in Menopause

Normal Estradiol Production

• In premenopausal women, the ovarian follicles are the primary source of estradiol, producing 70-500 mcg daily depending on menstrual cycle phase 1, 2, 3
• During perimenopause, estradiol levels may fluctuate markedly but are generally preserved until late perimenopause 4
• After menopause, ovarian production of estradiol essentially ceases

Post-Menopausal Estradiol Sources

• After menopause, most endogenous estrogen is produced by conversion of androstenedione (secreted by the adrenal cortex) to estrone in peripheral tissues 1, 2, 3
• This peripheral conversion becomes the dominant source of estrogen, making estrone and estrone sulfate the most abundant circulating estrogens in postmenopausal women 1
• Extragonadal sites of estrogen production include:
  • Adipose tissue (especially breast adipose tissue)
  • Bone (osteoblasts and chondrocytes)
  • Vascular endothelium
  • Brain 5

Factors Contributing to Estradiol Variation

Adipose Tissue

• Adipose tissue is a major site of aromatase activity, which converts androgens to estrogens 5
• Women with higher body fat typically have higher estradiol levels due to increased peripheral conversion
• The enzyme aromatase (CYP19) in adipose tissue is responsible for converting androstenedione to estrone, which can then be converted to estradiol 5

Adrenal Function

• Variations in adrenal production of androstenedione affect the substrate available for peripheral conversion to estrogens
• Some women maintain higher adrenal androgen production after menopause than others

Genetic Factors

• Genetic variations in aromatase expression and activity contribute to differences in peripheral estrogen production 5
• Tissue-specific regulation of CYP19 (aromatase) expression is achieved through distinct promoters, each regulated by different hormonal factors 5
• Follicle atresia (which leads to menopause) is partially explained by genetic factors 6

Age at Menopause

• Women who experience earlier menopause (before age 45) may have different hormonal profiles than those with later menopause 7
• The median age of menopause is 51 years in the general population, but approximately 47 years in women with chronic kidney disease 7

Clinical Implications

Hormone Measurement

• Single measurements of FSH and estradiol during perimenopause have limited diagnostic value due to significant hormonal fluctuations 4, 8
• Serial measurements of FSH, LH, and estradiol provide more reliable information about menopausal status 8

Symptom Variation

• Women with lower estradiol levels typically experience more severe menopausal symptoms 9
• Symptoms related to estrogen deficiency include vasomotor symptoms (hot flashes, night sweats) and urogenital atrophy 8

Long-term Health Implications

• Women with lower estradiol levels post-menopause may have increased risk for:
  • Osteoporosis and fractures 7
  • Cardiovascular disease 7
  • Cognitive changes 5

Important Considerations for Clinicians

• Circulating estrogen levels in postmenopausal women reflect rather than direct estrogen action, as they originate from extragonadal sites where estrogen acts locally 5
• Local tissue estrogen concentrations (e.g., in breast tissue) can be up to ten times higher than circulating levels due to local synthesis 5
• When evaluating menopausal status, consider the entire clinical picture rather than relying solely on a single hormone measurement 8
• For women with premature or early menopause, primary prevention of cardiovascular disease and screening for risk factors are warranted 7