Does low estradiol with normal estrone define aromatase capacity in men?

In adult men, circulating estrogens are primarily synthesized in peripheral tissues such as adipose and striated muscle through the enzymatic aromatization of androgen precursors, rather than via direct testicular secretion. Because circulating estrogen levels are highly dependent on precursor availability, assessing aromatase function requires looking beyond isolated estrogen measurements.

Mechanistic pathways of estrogen synthesis

• Estradiol production: Testosterone is converted directly to estradiol by the enzyme aromatase (CYP19A1). Although only 0.2% to 0.4% of circulating testosterone is aromatized daily, this peripheral conversion accounts for approximately 80% of circulating estradiol in men, with direct testicular secretion contributing only 20%.
• Estrone production: Estrone is primarily generated from the peripheral aromatization of the adrenal/gonadal androgen androstenedione, which has a fractional conversion rate of approximately 1% to 1.5%. Estrone and estradiol also interconvert via the action of 17β-hydroxysteroid dehydrogenase.
• Adipose tissue influence: Adipose tissue highly expresses aromatase. Consequently, variations in body fat mass directly alter whole-body aromatase capacity and circulating estrogen levels.

Clinical evaluation of aromatase capacity

• Substrate confounding: Serum estradiol and estrone concentrations are heavily confounded by clearance rates, hepatic metabolism, sex hormone-binding globulin (SHBG) levels, and substrate availability. A laboratory finding of low estradiol with normal estrone cannot identify a primary defect in aromatase capacity on its own.
• The need for precursor measurement: To determine whether low estradiol represents impaired aromatase activity or simply substrate depletion, concurrent measurement of testosterone is clinically necessary.
• The aromatase index: To properly evaluate the aromatization of estrone, clinicians must measure its direct precursor, androstenedione. This allows for the calculation of the "aromatase index" (the molar ratio of estrone to androstenedione), which serves as an indirect proxy of in vivo aromatase activity.

Bottom line

• An isolated hormone profile showing low estradiol with normal estrone is insufficient to define aromatase capacity; accurate assessment requires concurrent measurement of the precursor substrates testosterone and androstenedione to account for substrate availability.