Metabolic benefits afforded by estradiol and testosterone in both sexes: clinical considerations

Abstract

Testosterone (T) and 17β-estradiol (E2) are produced in male and female humans and are potent metabolic regulators in both sexes. When E2 and T production stops or decreases during aging, metabolic dysfunction develops and promotes degenerative metabolic and vascular disease. Here, we discuss the shared benefits afforded by E2 and T for metabolic function human females and males. In females, E2 is central to bone and vascular health, subcutaneous adipose tissue distribution, skeletal muscle insulin sensitivity, antiinflammatory immune function, and mitochondrial health. However, T also plays a role in female skeletal, vascular, and metabolic health. In males, T's conversion to E2 is fundamental to bone and vascular health, as well as prevention of excess visceral adiposity and the promotion of insulin sensitivity via activation of the estrogen receptors. However, T and its metabolite dihydrotestosterone also prevent excess visceral adiposity and promote skeletal muscle growth and insulin sensitivity via activation of the androgen receptor. In conclusion, T and E2 are produced in both sexes at sex-specific concentrations and provide similar and potent metabolic benefits. Optimizing levels of both hormones may be beneficial to protect patients from cardiometabolic disease and frailty during aging, which requires further study.

Figure 1. Origin of T and E₂ in males and females.

(A) In males, all T is produced by Leydig cells of the testis. Most E₂ (80%) is formed via aromatization of circulating T in the periphery. The testes directly produce approximately 20% of circulating E₂. (B) In females of reproductive age, the granulosa cells of the ovaries produce E2, the major circulating estrogen. T is produced by the ovary (25%), the adrenal gland (25%), and in peripheral tissues (50%) following conversion from circulating androstenedione (A4, an androgen that is equally produced by the ovary and the adrenal gland). (C) After menopause, estrone (E₁) becomes the major circulating estrogen and is produced by aromatization from A4 (mainly produced by the adrenal gland) in adipose tissue. E₁ serves as a reservoir of E₂. T is mainly produced by the ovaries (50%) and peripheral conversion of A4 (40%). 17β-HSD, 17β-hydroxysteroid dehydrogenase.

Figure 2. T and E₂ concentrations in males and females.

(A) Circulating T and E₂ in males and females over the life span. (B) Ratio of T to E₂ in males and females. Data in both panels derived from the CDC’s NHANES sex steroids data from 2013–2014 and 2015–2016 databases using sex steroids data from 2013–2014 and 2015–2016 for 7201 males and 7561 females (156, 157). In these data, total hormone (free and protein-bound) was measured using isotope dilution liquid chromatography–tandem mass spectrometry (ID-LC-MS/MS). We binned data from participants ages 6 years and up into decades and plotted as 95% confidence intervals (shown as lighter shading around averaged line). Data outside of the reported range of values were excluded (E₂: 2.117 to 1220 pg/mL and T: 4.1 to 15,500 pg/mL).

Figure 3. Cardiometabolic effect of E₂ and T in females.

E₂’s effects on immune, vascular, lipid, islet, adipose, muscle, and bone biology are represented on the right, while T’s effects on vascular, adipose, muscle, and bone biology are represented on the left.

Figure 4. Cardiometabolic effect of T and E₂ in males.

In males, T is converted to E₂ and DHT. T’s effects that are mediated via conversion to E₂ on immune, vascular, lipid, islet, adipose, muscle, and bone biology as well as sexual function are represented on the right, while T’s effects mediated via direct action or conversion to DHT on vascular, lipid, islet adipose, muscle, and bone biology are represented on the left. DHT, dihydrotestosterone.