Where is estradiol produced in males and females?

Sites of Estradiol Production in Males and Females

In females, the ovaries are the primary source of estradiol during reproductive years, while in males and postmenopausal females, estradiol is produced through peripheral conversion of testosterone via aromatase in adipose tissue, brain, bone, and other extragonadal sites. 1, 2, 3

Female Estradiol Production

Premenopausal Women

• The ovarian follicle secretes 70-500 mcg of estradiol daily, varying by menstrual cycle phase, making it the principal source of circulating estrogen. 1
• Estradiol functions as a true endocrine hormone, circulating to act on distant target tissues throughout the body. 3

Postmenopausal Women

• After menopause, the ovaries cease estrogen production, and estradiol is primarily generated through peripheral aromatization of androstenedione (from the adrenal cortex) to estrone, which is then reduced to estradiol. 1, 3
• Estrone and estrone sulfate become the most abundant circulating estrogens in postmenopausal women. 1
• Adipose tissue becomes the predominant site of estrogen synthesis, with aromatase expression increasing as a function of body weight and advancing age. 2, 3

Male Estradiol Production

Primary Production Sites

• In males, estradiol is not produced by the testes as a primary secretory product but rather through peripheral conversion of testosterone to estradiol via the aromatase enzyme. 4, 3
• Adipose tissue serves as the major site of aromatization, with increased conversion in obese men leading to elevated estradiol levels. 5, 2
• The brain contains aromatase in specific regions including the preoptic area and hypothalamus, where testosterone is locally converted to estradiol. 6, 5

Physiological Significance in Males

• Estradiol in men is essential for modulating libido, erectile function, and spermatogenesis, despite being traditionally considered a "female" hormone. 4
• Estrogen receptors and aromatase are abundant in the brain, penis, and testis—organs critical for male sexual function. 4

Extragonadal (Peripheral) Production Sites in Both Sexes

Tissue-Specific Aromatization

• Aromatase enzyme is found in multiple human tissues beyond the gonads: adipose tissue, skin fibroblasts, bone (osteoblasts and chondrocytes), vascular endothelium, aortic smooth muscle cells, and numerous brain regions. 2, 3
• In these extragonadal sites, estradiol acts locally as a paracrine or intracrine factor rather than as a circulating endocrine hormone. 3

Brain Production

• The brain produces estradiol locally through aromatase-mediated conversion of testosterone, particularly in sexually dimorphic regions like the preoptic area. 6, 5
• Androgen receptor activation by testosterone stimulates aromatase synthesis, resulting in increased local estradiol production within sexually dimorphic brain nuclei. 6, 5
• Aromatase inhibitor studies demonstrate that blocking brain estradiol production prevents normal masculine behavioral development despite high testosterone levels, confirming the critical role of local brain estradiol synthesis. 6, 5
• Regional differences exist in estradiol concentration within the brain, with sex-specific patterns in the prefrontal cortex, amygdala, and hippocampus. 7

Adipose Tissue

• Adipose tissue aromatase expression accounts for the majority of extraglandular estrogen formation and increases with body weight and age. 2, 3
• In obese individuals, sufficient estradiol can be produced through peripheral aromatization to cause endometrial hyperplasia and cancer in anovulatory or postmenopausal women. 2
• In obese men, increased adipose aromatization elevates estradiol levels, which suppresses LH secretion and reduces testosterone production, contributing to secondary hypogonadism. 5

Bone and Vascular Tissue

• Local estrogen biosynthesis in bone via aromatase activity is paramount in slowing postmenopausal bone loss in both sexes. 2, 3
• Vascular endothelium and aortic smooth muscle cells produce estradiol locally, contributing to cardiovascular health. 2, 3

Clinical Implications

Circulating vs. Local Estradiol

• In postmenopausal women and men, circulating estradiol levels are reactive rather than proactive—they reflect local tissue production rather than directing estrogen action. 3
• Local tissue estradiol concentrations can be one order of magnitude greater than circulating levels, particularly in breast tissue, bone, and brain. 3

Sex-Specific Considerations

• Serum estradiol concentrations do not necessarily reflect brain tissue concentrations, with regional and sex-specific differences in uptake and storage. 7
• Estradiol levels were undetectable in the prefrontal cortex of intact males but detectable in all other brain regions, suggesting less local production in males than females in certain brain areas. 7

Common Pitfalls

• Clinicians often fail to measure free testosterone in obese men with low total testosterone, missing that increased aromatization may be contributing to secondary hypogonadism. 5
• Assuming circulating estradiol levels accurately represent tissue-level estrogen action in postmenopausal women and men leads to misinterpretation of estrogen's physiological effects. 3