Follitropin (FSH) deficiency in an infertile male due to FSHβ gene mutation.: A syndrome of normal puberty and virilization but underdeveloped testicles with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations

We studied a man who sought medical attention at age 28 years because of infertility in both his first and second marriages. His sexual development appeared to have been normal, with normal puberty and virilization, and normal libido and sexual potency. At examination, his testicles were small and soft; otherwise he had a normal physical appearance. Evaluations revealed azoospermia, undetectable in serum before and after 100 mu g of intravenously administered gonadotrophin releasing hormone, but moderately elevated lutropin concentration with a brisk rise after gonadotrophin releasing hormone. The a subunit concentration was normal before and after gonadotrophin releasing hormone; that of inhibin B was very low. Analysis of the follitropin beta gene, exon 3, revealed a Cys(82) --> Arg mutation (TGT --> CGT). Judging from studies of the biosynthesis of the chorionic gonadotrophin beta subunit one may conclude that inability to form the first intramolecular disulphide bond in the follitropin beta subunit results in an abnormal tertiary structure during follitropin beta biosynthesis with extensive intracellular degradation of the products, inability to associate with the a subunit and defective glycosylation, as well as inability to form a biologically active hormone. This first male case of follitropin deficiency thus defines a new syndrome of male infertility.