Role of Sex Steroids in β Cell Function, Growth, and Survival

Abstract

The gonads have long been considered endocrine glands, producing sex steroids such as estrogens, androgens, and progesterone (P4) for the sole purpose of sexual differentiation, puberty, and reproduction. Reproduction and energy metabolism are tightly linked, however, and gonadal steroids play an important role in sex-specific aspects of energy metabolism in various physiological conditions. In that respect, gonadal steroids also influence the secretion of insulin in a sex-specific manner. This review presents a perspective on the physiological roles of estrogens, androgens, and P4 via their receptors in pancreatic β cells in the gender-specific tuning of insulin secretion. I also discuss potential gender-specific therapeutic avenues that this knowledge may open in the future.

Keywords: androgen; estrogen; insulin; islet; progesterone; β cells.

Figure 1. Steroidogenesis of sex hormones in classical steroidogenic tissues

Steroids are synthesized in the gonads and adrenal glands from cholesterol. The first reaction catalyzed by cytochrome P450 side-chain cleavage (P450scc) in the mitochondria produces pregnenolone. Progestagens are the first steroids synthesized. In the Leydig cells of the testis, the cytochrome P-450_17α catalyses two key steps in the biosynthesis of androgens from pregnanes, the 17α hydroxylation step and the subsequent 17–20 lyase reaction and produces dehydroepiandrosterone (DHEA). Leydig cells express high levels of 3β-hydroxysteroid-dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase (17β-HSD), and DHEA is converted to the final product, testosterone, via the intermediates androstenediol and androstenedione. In target tissues, testosterone is converted to dihydrotestosterone (DHT) by the action of 5α-reductase (5α-R). In thecal cells of the ovary, pregnenolone is converted to P4 by the 3β-HSD. Cytochrome P-450_17α then catalyzes P4 transformation into androstenedione. Aromatase is expressed by granulosa cells (as well as adipose tissue and bone in both sexes), and produces estradiol (E2) and estrone (E1) from testosterone and androstenedione.

Figure 2. Effect of estrogens and ERs on β-cell function, growth and survival

17β-estradiol binds ERα, ERβ and the GPER in islet β-cell to promote the effects described. Selective ligands for the three receptors have the same effect of their cognate receptor.

Figure 3. The testicular/islet axis in insulin secretion

Testosterone secreted by the testicles binds AR in β-cells, which amplifies (+) the insulinotropic effect of the β-cell GLP-1 receptor (GLP-1R) that is activated by islet-derived GLP-1 and GLP-1R agonists (GLP-1RA). Gut GLP-1 acts in a paracrine manner on GLP-1Rs in the guts portal vein to relay signals via the vagal nerve to the brain which then signals to the islets (gut/brain/islet axis) to enhance insulin secretion (+).

Figure 4. Effect of androgen excess in fetal and adult female islets

Testosterone excess in the adult female activates AR in β-cells leading to insulin hypersecretion and hyperinsulinemia. Fetal testosterone excess programs β-cells in utero via AR: This leads to basal hyperinsulinemia but decreased insulin secretion in response to glucose in adult females. Thus, the combination of fetal and adult androgen excess in females may result in the β-cell dysfunction observed in adult females with PCOS.