MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease

Abstract

Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance.

Figure 1

Sexually dimorphic associations between circulating testosterone levels and increasing metabolic risk. The estimated metabolic risk for different populations suffering from femal androgen excess (Panel A) or male androgen deficiency (Panel B) is shown in relation to testosterone levels. Serum testosterone concentrations of women with androgen excess and men with androgen deficiency overlap and are associated with severe adverse metabolic consequences leading to the concept of the ‘metabolic valley of death’ as a metabolically adverse window of circulating androgen concentrations. Approximate hormone ranges are taken from recent publications using mass spectrometry-based quantification: Healthy women vs PCOS women (200), obese women (30), women with CAH on standard glucocorticoid replacement therapy (201), healthy and obese men (202), men with primary hypogonadism due to Klinefelter syndrome not receiving testosterone supplementation (203), men with secondary hypogonadism due to idiopathic hypogonadotropic hypogonadism and hypopituitarism (204), as well as male-to-female and female-to-male transgender patients (70). No information about the method used to determine serum testosterone in women with type A form of severe insulin resistance was available, but values are included for completeness (205).

Figure 2

Overview of the human androgen biosynthesis pathways. Pregnenolone (PREG), produced by the side-chain cleavage of cholesterol, is the common precursor of all androgen biosynthesis pathways. The classical pathways, proceeding parallel for ∆5- and ∆4-precursors, lead to the formation of testosterone (T), which can be converted to dihydrotestosterone (DHT). The alternate 5α-dione pathway and ‘backdoor’ pathway directly synthesise DHT by-passing T. The 11-oxygenated androgen pathway converts androstenedione (A4) to 11β-hydroxyandrostenedione (11OHA4) by adrenal 11β-hydroxylase (CYP11B1) activity, generating the active androgens 11-keto-testosterone (11KT) and 11-keto-dihydrotestosterone (11KDHT). CYP17A1 capable of both 17α-hydroxylase and 17,20-lyase activity. All androgen receptor-transactivating androgens (T, DHT, 11KT and 11KDHT) are highlighted in bold and white boxes. Enzymes upregulated in PCOS contributing to local and systemic androgen excess (steroid 5α-reductase, 5αRed; 17β-hydroxysteroid dehydrogenase, 17βHSD) are highlighted in bold. Impaired activity of sulfotransferase 2A1 (SULT, underlined) due to mutations of the co-factor synthesising PAPS synthase 2 leads to a PCOS-like phenotype. Androstenedione and T can be converted to the oestrogens estrone (E1) and estradiol (E2), respectively, by aromatase (CYP19A1), whose activity possibly enhances androgen deficiency in obese men. Steroid abbreviations: 3α-diol, 5α-androstanediol; 5α-dione, 5α-androstanedione; 5-diol, androstene-diol; 11KA4, 11-keto-androstenedione; 11OHDHT, 11β-hydroxytestosterone; 17OH-AlloP, 17-hydroxyallopregnanolone; 17OH-DHP, 17-hydroxydihydroprogesterone; 17OH-PREG, 17-hydroxypregnenolone; 17OH-PROG, 17-hydroxyprogesterone; AlloP, allopregnanolone; An, androsterone; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; DHP, 5α-dihydroprogestrone; PROG, progesterone. Enzyme abbreviations: STS, steroid sulfatase; 3β-HSD, 3β-hydroxysteroid dehydrogenase/∆4–5 isomerase; 11βHSD2, 11β-hydroxysteroid dehydrogenase type 2; cytb₅, cytochrome b5.

Figure 3

Differential effects of androgens on adipose tissue and skeletal muscle and implications for global metabolism. Androgens may exert pro-lipogenic effects on adipose tissue, resulting in fat mass expansion. At higher concentrations, as observed in the healthy male range, net anabolic effects on increasing skeletal muscle bulk predominate. However, with circulating androgen levels in the range of female androgen excess and male androgen deficiency, a loss of muscle mass and an increase in abdominal obesity drive the systemic phenotype, and give rise to metabolic and cardiovascular disease. Testosterone (T), dihydrotestosterone (DHT), 11-keto-testosterone (11KT), 11-keto-dihydrotestosterone (11KDHT).