Heterodimers and homodimers of inhibin subunits have different paracrine action in the modulation of luteinizing hormone-stimulated androgen biosynthesis.

TLDR

Inhibin, a gonadal hormone, exists mainly as an alpha‑beta heterodimer that suppresses FSH secretion, while a beta‑beta homodimer stimulates FSH, and both LH‑stimulated androgen production and FSH‑induced inhibin synthesis participate in a closed‑loop feedback between pituitary and gonadal cells. We tested the intragonadal paracrine effects of inhibin heterodimers and homodimers on Leydig cells by culturing primary testis cells and measuring LH‑stimulated androgen production. The alpha‑beta heterodimer increased LH‑stimulated androgen production while the beta‑beta homodimer decreased it, and similar opposing effects were observed in ovarian theca cells, demonstrating that Sertoli and granulosa cells produce these dimers as intragonadal paracrine signals that modulate LH‑stimulated androgen biosynthesis and link the two feedback loops.

Abstract

Inhibin, a gonadal hormone capable of preferential suppression of pituitary follicle-stimulating hormone (FSH) secretion, has recently been purified. The major form of this protein is an alpha beta heterodimer encoded by two separate genes. In contrast to the FSH-suppressing action of the alpha beta heterodimer, the beta beta homodimer stimulates FSH secretion. Luteinizing hormone (LH)-secreting pituitary cells and gonadal androgen-producing cells have long been shown to form a closed-loop feedback axis. Based on recent studies demonstrating the FSH stimulation of inhibin biosynthesis by ovarian granulosa and testis Sertoli cells, an additional closed-loop feedback axis exists between pituitary FSH- and gonadal inhibin-producing cells. Because uncharacterized Sertoli cell factors have been suggested to either stimulate or inhibit androgen production by testicular Leydig cells, we have tested the intragonadal paracrine actions of heterodimers and homodimers of inhibin subunits. In primary cultures of testis cells, the alpha beta heterodimer of inhibin enhances Leydig cell androgen biosynthesis stimulated by LH, whereas the beta beta homodimer suppresses androgen production. Furthermore, similar modulatory actions of inhibin-related proteins were found in cultured ovarian theca-interstitial cells and theca explants treated with LH. In contrast, treatment with the inhibin-related proteins alone did not affect gonadal steroidogenesis. Our data indicate that the inhibin-related gene products synthesized by Sertoli and granulosa cells may form heterodimers or homodimers to serve as intragonadal paracrine signals in the modulation of LH-stimulated androgen biosynthesis and allow cross-communication between the two feedback loops.