Mutations of Gonadotropins and Gonadotropin Receptors: Elucidating the Physiology and Pathophysiology of Pituitary-Gonadal Function

Abstract

The recent unraveling of structures of genes for the gonadotropin subunits and gonadotropin receptors has provided reproductive endocrinologists with new tools to study normal and pathological functions of the hypothalamic-pituitary-gonadal axis. Rare inactivating mutations that produce distinctive phenotypes of isolated LH or FSH deficiency have been discovered in gonadotropin subunit genes. In addition, there is a common polymorphism in the LH␤ subunit gene with possible clinical significance as a contributing factor to pathologies of LH-dependent gonadal functions. Both activating and inactivating mutations have been detected in the gonadotropin receptor genes, a larger number in the LH receptor gene, but so far only a few in the gene for the FSH receptor. These mutations corroborate and extend our knowledge of clinical consequences of gonadotropin resistance and inappropriate gonadotropin action. The information obtained from human mutations has been complemented by animal models with disrupted or inappropriately activated gonadotropin ligand or receptor genes. These clinical and experimental genetic disease models form a powerful tool for exploring the physiology and pathophysiology of gonadotropin function and provide an excellent example of the power of molecular biological approaches in the study of pathogenesis of diseases. (Endocrine Reviews 21: 2000)

Bioluminescence Resonance Energy Transfer Studies Reveal Constitutive Dimerization of the Human Lutropin Receptor and a Lack of Correlation between Receptor Activation and the Propensity for Dimerization

“…In the experiment shown, the hCG incubation was performed at room temperature to minimize internalization of the hormone-occupied receptor. Using the donor/ acceptor ratio yielding the halfmaximal BRET 2 shown, the effects of a 15-min incubation with hCG at 37C were also examined, but again no changes in BRET 2 were observed. In the other scenario, we examined the effects of a room temperature incubation of the cells with hCG on BRET 2 ratios under conditions where the ratio of hLHR donor and acceptor fusion proteins were held constant, but the total receptor expression levels were varied.…”

“…BRET 2 Assay-HEK293T cells in 6-well plates were transiently co-transfected with vectors encoding Rluc fusion or GFP 2 fusion proteins. In a given experiment, the total amount of plasmid transfected was made constant by the addition of empty vector.…”

“…The BRET 2 ratios reported were corrected by subtracting the ratios obtained when receptor-Rluc was expressed alone. Within a given experiment, each data point was obtained using duplicate wells of cells that were transfected and collected for BRET 2 analyses. Data shown are the mean Ϯ range of the duplicate determinations from one representative experiment (of at least three independent experiments).…”

“…In males the hLHR is expressed predominantly in the testes, stimulating androgen biosynthesis in response to LH. The physiological importance of the LHR to reproductive physiology is underscored by disorders arising from mutations of the hLHR gene (1,2). Thus, whereas constitutively active mutants (CAMs) of the hLHR are associated with gonadotropin-independent precocious puberty in males, loss-of-function mutations of the hLHR result in Leydig cell hypoplasia in males and infertility in females.…”

Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54

“…T he integrity of the pituitary-gonadal axis allows normal sexual differentiation during fetal life and normal puberty and fertility (1)(2)(3). Hypogonadotropic hypogonadism is defined by a defect of gonadal functions manifested by impuberism, partial pubertal development or isolated infertility, caused by a deficiency of follicle-stimulating hormone and luteinizing hormone production.…”