Gonadotroph Adenomas in Men Produce Biologically Active Follicle-Stimulating Hormone*

Abstract

Gonadotroph adenomas may exhibit qualitative and quantitative defects in gonadotropin biosynthesis and secretion. Hypersecretion of immunoreactive FSH dimers by these adenomas occurs frequently; however, it has not been known whether this FSH is biologically active. Using the granulosa cell aromatase bioassay and a highly specific immunoradiometric assay for FSH, we studied the serum bioactivity and bio- to immunoactivity (B/I) ratios of 14 men with FSH-secreting adenomas and compared these values to those of 11 age-matched normal men. In addition, three adenoma patients received TRH (400 micrograms, iv). The mean basal serum FSH level (international units per L), as measured by both bio- and immunoassays, and the FSH B/I ratios were significantly higher (P less than 0.02, by Kolmogorov-Smirnov test) in the adenoma patients than in normal men (mean +/- SEM; adenoma patients: bioactivity, 68.8 +/- 10.4; immunoreactivity, 34.8 +/- 13.7; B/I ratio, 3.4 +/- 0.6; normal men: bioactivity, 5.8 +/- 1.2; immunoreactivity, 6.4 +/- 0.8; B/I ratio, 0.90 +/- 0.1). Both bio- and immunoactive FSH rose after TRH injection, resulting in maintenance of the B/I (mean +/- SEM; pre-TRH: bio-FSH, 63.7 +/- 22.4; immuno-FSH, 28.0 +/- 14.1; B/I ratio, 2.8 +/- 1.2; post-TRH: bio-FSH, 125.6 +/- 42.7; immuno-FSH, 45.8 +/- 21.8; B/I ratio, 3.5 +/- 1.6). When gonadotroph adenoma cells from three separate patients were cultured and their conditioned media (n = 3) studied, relatively large amounts of both bio- and immuno-FSH were detected. Furthermore, the major isoelectric profile of bio-FSH (pH 4.9-3.0) in the conditioned medium from two such adenomas was shown by chromatofocusing to be comparable to that of purified human pituitary FSH (pH 5.2-3.6). We conclude that gonadotroph adenomas in men secrete FSH that is biologically active, both basally and in response to TRH.

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

“…Whether a gain-of-function mutation of the FSH receptor gene would produce a similar phenotype in human remains to be seen. With the present knowledge this seems unlikely, since men with pituitary adenomas secreting large amounts of FSH have no testicular phenotype (304).…”

Testicular enlargement in a patient with a FSH-secreting pituitary adenoma

“…Thus, it is plausible that a gonadotropinoma producing elevated serum levels of FSH in a male could exert a trophic effect on the testicles. Using in vitro assays for FSH bioactivity (aromatase activity in rat granulosa cells or Sertoli cells), FSH from gonadotroph pituitary adenomas have been shown to have normal or even elevated biological activity compared to FSH from healthy controls [8,9].…”

Ovarian hyperstimulation syndrome caused by an FSH-secreting pituitary adenoma

“…The cellular machinery for biosynthesis and processing of FSH is intact, and functional FSH is secreted despite aberrant tumor growth. 6 It should, however, be mentioned that the unassociated LHβ and FSHβ subunits exhibit no intrinsic biological activity and that formation of a heterodimer with the α subunit is essential for biological activity. As 70-100% of nonfunctioning adenomas secrete free subunits, these tumors usually show no biological activity.…”