Mutations of the G protein-coupled receptors of the hypothalamo-pituitary-gonadal axis. Where do we stand?

Gonadal function is controlled by the two gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), produced by the pituitary gland under regulation of the hypothalamic hormone gonadotropin-releasing hormone (GnRH). LH, FSH and GnRH act through binding to specific receptors, which are members of the G protein-coupled receptor family. In recent years, it has become evident that germline mutations of the gonadotropin and GnRH receptors are involved in some forms of hypogonadism and pathologic pubertal maturation. Moreover, as these hormones have tropic and growth-promoting roles in their target organ, it has been hypothesized that somatic activating mutation of their receptors might be involved in the generation of gonadal and pituitary tumors. This hypothesis is further supported by the relatively frequent finding of activating mutations of the closely related thyroid-stimulating hormone (TSH) receptor in hyperfunctioning thyroid adenomas. The clinical manifestations of genomic mutations of the gonadotropin receptors have been reviewed recently and special emphasis has been given to the possibility that such mutations could be much more frequent than suspected and discovered so far (1–3). However, the search for mutations of G proteincoupled receptors of the gonadotropic axis has been much less rewarding than the analogous exercise in the thyroid field. At this stage, one wonders whether the phenotypes associated with such mutations, especially gain-of-function mutations, have been correctly postulated. The clinical picture associated with inactivating mutations of the gonadotropin receptors is obvious and consists essentially of hypergonadotropic hypogonadism, resulting in primary amenorrhea (in cases of both LH and FSH receptor mutations) in females and Leydig cell hypoplasia with pseudohermaphroditism (LH receptor) and variable suppression of fertility (FSH receptor) in males. Recently, inactivating mutations of the GnRH receptor gene have been described in cases of hypogonadotropic hypogonadism (4, 5). Activating mutations are more subtle. Whereas constitutive LH receptor activation is found in familial and sporadic cases of male-limited pseudoprecocious puberty (testotoxicosis), the only known activating mutation of the FSH receptor was found in a hypophysectomized patient with normal spermatogenesis in spite of undetectable serum gonadotropin concentrations (6). It is noteworthy that activating mutations of the LH receptor do not produce a phenotype in females. This lack of phenotype is puzzling, because transgenic mice overexpressing a highly bioactive LH analog have cycle irregularities and develop polycystic ovaries and ovarian tumors, and the males have subfertility and reduced testicular volume (7), whereas symptoms of LH receptor hyperactivation cease after puberty in boys with testotoxicosis. The effect of constitutive activation is even more veiled in the case of the FSH receptor, and the still unique case of a naturally occurring mutation of this type was discovered only because of the fortuitous coincidence of hypophysectomy. Ever since that discovery, many efforts have been devoted to the search for other cases of activating FSH receptor mutations, but the possible phenotype remains obscure. We and others have screened several potential candidates for a chronic FSH-like hyperactivity, such as boys and men with megalotestis, women with familial tendency to produce twins and triplets, and women with premature ovarian exhaustion. In no case could activating mutations of the FSH receptor be demonstrated. Thus, considering that activating mutations of the LH receptor have no phenotype in women and in men after puberty, it seems that gain-offunction mutations of both gonadotropin receptors are basically clinically irrelevant and escape diagnosis. Why? Continuous exposure to hormone stimulation leads to a decreased response, a process known as desensitization. In vitro, Leydig cells, granulosa cells and Sertoli cells progressively lose the capacity to respond to sustained gonadotropin stimulation. This process of receptor loss (down-regulation) is the consequence of both phosphorylation and sequestration of the hormone receptor complexes within the cell and reduced receptor protein synthesis as a result of decresed transcription, reduced mRNA half-life, or both (8). In this way, the cell defends itself from potentially dangerous hyperstimulation and responsivity to the hormone is tightly regulated. There are no in vivo data on the downregulation of constitutively active gonadotropin receptors, but transgenic mice, in which a constitutively active European Journal of Endocrinology (1998) 139 145–147 ISSN 0804-4643