How and where is estradiol (estrogen steroid hormone) produced in women and men?

Estradiol Production in Women and Men

Primary Sources in Women

In premenopausal women, the ovaries are the principal source of estradiol, secreting 70-500 mcg daily depending on menstrual cycle phase, functioning as a circulating endocrine hormone. 1

Ovarian Production

• The ovarian follicle serves as the primary estradiol production site in cycling women, with secretion varying dramatically across the menstrual cycle 1
• Ovarian granulosa cells contain aromatase enzyme, which converts androgens (C19 steroids) to estrogens (C18 steroids) 2
• Follicle-stimulating hormone (FSH) regulates ovarian aromatase expression through cyclic AMP via promoter II 3

Postmenopausal Shift

• After menopause, the ovaries cease estrogen production, and the primary source becomes peripheral conversion of adrenal androgens 1
• Androstenedione secreted by the adrenal cortex is converted to estrone in peripheral tissues, which is then reduced to estradiol 1
• Estrone and estrone sulfate become the most abundant circulating estrogens in postmenopausal women, serving as a reservoir for more active estrogen formation 1

Primary Sources in Men

In men, estradiol is not produced by gonads as an endocrine hormone but rather synthesized locally in extragonadal tissues through aromatization of testosterone, functioning primarily as a paracrine or intracrine factor. 3

Extragonadal Production Sites

• Adipose tissue is the major site of estradiol production in men, with aromatase expression increasing with body weight and advancing age 2
• Bone tissue produces local estradiol through aromatase activity in osteoblasts and chondrocytes 2, 3
• Brain tissue synthesizes estradiol locally via aromatase, important for cognitive and hypothalamic functions 2
• Vascular endothelium and aortic smooth muscle cells contain aromatase and produce local estradiol 3

Enzymatic Conversion Mechanism

The enzyme aromatase (CYP19) is the critical catalyst that converts androgens to estrogens in all tissues, and its tissue-specific regulation determines local estradiol concentrations. 2

Aromatase Distribution

• Aromatase is found in ovarian granulosa cells, placental syncytiotrophoblast, adipose fibroblasts, skin fibroblasts, bone, brain, and vascular tissues 2
• In the brain specifically, testosterone enters cells and is converted to estradiol by aromatase, which then binds estrogen receptors to promote neural differentiation 4
• This conversion is particularly important in males, where testosterone serves as the precursor for local estradiol production 5

Tissue-Specific Promoter Regulation

• Aromatase expression is controlled by different promoters in different tissues: promoter II in ovary, promoter I.1 in placenta, promoter I.4 in skin and adipose tissue 2, 3
• Adipose tissue can switch between promoters (II/I.3 and I.4) in response to different stimuli like prostaglandin E2 versus glucocorticoids 2
• This complex regulation allows tissue-specific control of estradiol production independent of circulating hormone levels 3

Local vs. Systemic Production

In postmenopausal women and men, circulating estradiol levels are reactive rather than proactive—they reflect local tissue production that escapes into circulation rather than directing estrogen action. 3

Paracrine/Intracrine Function

• Local tissue estradiol concentrations can be at least one order of magnitude greater than circulating levels due to in situ synthesis 3
• Breast tissue, for example, can have estradiol concentrations far exceeding plasma levels through local aromatase activity 3
• This local production is responsible for maintaining bone mineralization, cognitive function, and unfortunately breast cancer development in postmenopausal women 3

Clinical Implications

• Circulating estradiol levels in postmenopausal women and men do not accurately reflect tissue estrogen exposure or action 3
• Adipose tissue contribution to circulating estrogen increases with obesity, potentially causing endometrial hyperplasia and cancer in anovulatory or postmenopausal women 2
• Excessive aromatase expression in adipose fibroblasts surrounding breast carcinomas creates elevated local estrogen concentrations promoting tumor growth 2

Metabolic Interconversions

Estradiol, estrone, and estriol exist in dynamic equilibrium through reversible metabolic conversions, primarily occurring in the liver. 1

Conversion Pathways

• Estradiol converts reversibly to estrone, and both can convert to estriol (the major urinary metabolite) 1
• Estrone sulfate serves as a circulating reservoir that can be converted back to more active estrogens 1
• Estriol arises from estrone and cannot be converted back to estradiol, making it a terminal metabolite 6, 7

Enterohepatic Recirculation

• Estrogens undergo sulfate and glucuronide conjugation in the liver, biliary secretion into intestine, hydrolysis in gut, and reabsorption 1
• This recirculation maintains circulating estrogen pools and prolongs hormonal effects 1

Sex Differences in Estradiol Function

While both sexes produce estradiol through similar enzymatic pathways, the biological significance differs dramatically—serving as a primary endocrine hormone in premenopausal women versus a local paracrine/intracrine factor in men and postmenopausal women. 5, 3

• The concept of estrogen as solely a "female hormone" is an oversimplification, as estradiol regulates critical biological processes in both males and females through tissue-specific mechanisms 5
• In males, local estradiol production in bone is paramount for slowing bone loss, despite low circulating levels 2