Inhibins and activins: clinical advances in reproductive medicine.

Abstract

The discovery of a new hormone is understandably followed by a competitive urgency to seek useful clinical applications. For the glycoprotein hormones inhibin, isolated in 1985 (Ling et al ., 1985; Robertson et al ., 1985), and activin, identified the following year (Vale et al ., 1986), this is no exception. Some 15 years on, we aim to summarize the advances made in understanding the roles of inhibins and activins in human reproduction, and review their current and likely future applications in clinical practice. Inhibins are heterodimeric glycoprotein hormones comprising a common α -subunit and one of two β -subunits ( α β A forming inhibin A, α β B forming inhibin B). Other β -subunits have been identified, but there is currently no evidence for the existence of additional biologically active inhibin species (Burger et al ., 2000). The existence of inhibin was predicted by McCullagh almost 70 years ago, who noted that hypertrophy of the anterior pituitary gland caused by castration could be prevented by injecting a water soluble extract of bovine testis (McCullagh, 1932). However, McCullagh’s ‘inhibin’ hypothesis remained stalled for half a century, until the 1970s, when it was found that FSH from the pituitary gland could be selectively suppressed both in vitro and in vivo by testicular (Franchimont et al ., 1972; Setchell & Jacks, 1974; Keogh et al ., 1976) and follicular fluids (De Jong & Sharpe, 1976). It would take another decade until inhibin was finally isolated and characterized from bovine (Robertson et al ., 1985) and porcine (Ling et al ., 1985) follicular fluid. During the purification of inhibin, a structurally related substance which stimulated FSH secretion was identified. This substance was termed activin (Vale et al ., 1986) and is a dimer of the inhibin β subunit. Three activins exist: activin A ( β A – β A ), activin B ( β B – β B ) and activin AB ( β A – β B ). Inhibins and activins are related to the transforming growth factor beta (TGFβ ) superfamily, sharing structural homology through the β subunit as well as common receptor pathways (Derynck et al ., 1998). Not surprisingly, it has become clear that, in addition to the regulation of FSH secretion, activins and inhibins may have diverse actions in varied tissues, including autocrine regulation of cell proliferation in the male reproductive tract (Risbridger & Cancilla, 2000), erythropoiesis (Yu et al ., 1987) and neural cell survival (Schubert et al ., 1990). Some recent advances in the understanding of activin and inhibin signalling have occurred recently with the identification of two possible inhibin receptors (Chong et al ., 2000; Lewis et al ., 2000). However, full consideration of these findings and the activin receptors and signalling mechanisms is outwith the scope of this review and is available elsewhere (Mathews, 1994; Heldin et al ., 1997; Derynck et al ., 1998; Attisano & Wrana, 2002). While initially problematic, the eventual purification of inhibin led rapidly to the development of a number of immunoassays (Burger, 1993), the most widely used of which was a radioimmunoassay employing a polyclonal antibody raised against purified bovine inhibin, with specificity directed against an epitope on the α subunit (McLachlan et al ., 1986a). This assay became known as the ‘Monash’ assay and was the basis of almost all of the initial studies of inhibin in human reproductive pathophysiology. However, it became apparent that this assay also detected circulating α -subunit free from the β -subunit and of uncertain bioactivity (Schneyer et al ., 1990). Therefore, while the application of the Monash assay led to important advances in our understanding of inhibin in reproductive physiology, some observations, as will be discussed below, were difficult to explain (Bhasin et al ., 1996). The subsequent development of specific two site assays, particularly those peformed by Groome and colleagues (Groome et al ., 1994, 1996), for inhibin A and B, inhibin α -subunit precursors and the activins, clarified those apparent inconsistencies and revealed the specific changes in inhibins and activins in health and disease, as discussed below. Although there are a host of different areas of investigation into inhibins and activins in obstetrics and gynaecology, they centre around three major tissues of origin: the ovary, placenta and testis. Therefore, this review will be structured around these sites of origin, affording a logical discussion linking clinical studies to the physiology of these hormones.