A Syndrome of Gonadotropin Resistance Possibly due to a Luteinizing Hormone Receptor Defect*

Abstract

An 18-yr-old 46,XY man with primary hypogonadism and a microphallus is described whose Leydig cells appear to be partially insensitive to gonadotropin action. The external genitalia were well differentiated though abnormally small. The mean +/- SE baseline plasma testosterone (T) level was 62 +/- 3.9 ng/dl, and androstenedione was 34.5 +/- 7.3 ng/dl. Plasma levels of dehydroepiandrosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, 17-hydroxypregnenolone, corticosterone, deoxycorticosterone, and 17 beta-estradiol were all normal. After the im administration of hCG, plasma T increased insignificantly from 71 to 78 ng/dl, and androstenedione increased from 22 to 47 ng/dl; there was no significant change in the levels of precursor steroids. The mean +/- SE serum FSH level was 17.4 +/- 3.6 mIU/ml, and LH was 15.4 +/- 1.1 mIU/ml (normal, 5-20); both responded briskly to iv GnRH. Exogenous T therapy resulted in normal virilization, whereas therapy with hCG was ineffectual. Testicular biopsy revealed Leydig cells in normal numbers, some spermatogenesis, and thickened tubular basement membranes. In vitro binding studies using [125I]hCG were performed with testicular homogenates from the patient and three normal subjects. With 7.4 fmol labeled hCG, the specific binding (mean +/- SD), expressed as femtomoles of hCG per mg protein, was 1.16 +/- 0.44 compared to 2.49 +/- 0.41 in normal subjects (P less than 0.05). These data demonstrate partial resistance to hCG and suggest that the defect in Leydig cell function may be at the LH receptor or postreceptor level.

Available FSH receptors in adult rat testis in vivo

“…The specific ac¬ tivity of each batch of labelled hormone was deter¬ mined by self-displacement analysis in a radioligand receptor assay employing rat testis homogenate (David et al 1984). The portion of the radioiodinated hormone that was capable of binding specifically to the rat testis was approximately 20%, which was very similar to that reported previously (Cheng, 1975;Ketelslegers & Catt, 1978;Findley & Steinberger, 1983).…”

“…Purified rFSH (NIADDK-rFSH-I-6; biological po¬ tency 100 x NIH-FSH-S1, supplied by the National Pituitary Program, NIH, Bethesda, MD, U.S.A.) was radioiodinated with Na 125I (Amersham Corp., Arlington Heights, IL, U.S.A.) by the Iodogen (Pierce Chemical Co., Rockford, IL, U.S.A.) technique (Fracker & Speck, 1978) and purified by chromato¬ graphy on Sepharose-Concanavalin A (Pharmacia, Piscataway, NJ, U.S.A.) as described previously (David, Yoon, Landin et al 1984). The specific ac¬ tivity of each batch of labelled hormone was deter¬ mined by self-displacement analysis in a radioligand receptor assay employing rat testis homogenate (David et al 1984).…”

New molecular variants of hypothalamus–pituitary–gonad axis genes and their association with early puberty phenotype in Bos taurus indicus (Nellore)

“…Naturally occurring mutations in gonadotropins and gonadotropin releasing hormone receptors were demonstrated to be responsible for human genetic disorders (David et al, 1984;Shenker et al, 1993;Aittomaki et al, 1995;Yano et al, 1995;Kraaij et al, 1995;Kosugi et al, 1995;Laue et al, 1995;Rosenthal et al, 1996;Gromoll et al, 1996;Simoni et al, 1997;De Roux et al, 1997;Layman et al, 1998;Latronico et al, 1998aLatronico et al, ,b, 2000Arnhold et al, 1999;Batista et al, 2000;Kottler et al, 2000), indicating the possibility for them to be strong candidates for reproduction-related phenotypes in other species.…”

“…Upon hormone binding, the receptor activates the adenylcyclase and the phosphatidylinositol mediated signal transduction pathways and both play a crucial role in reproductive physiology including initiation and maintenance of spermatogenesis and ovarian follicle development (Gudermann et al, 1992;Leung et al, 1996;Chan, 1998). Mutations in these receptors that either activate or inactivate their functions were reported in humans as responsible for several reproductive genetic disorders (David et al, 1984;Shenker et al, 1993;Yano et al, 1995;Kraaij et al, 1995;Kosugi et al, 1995;Laue et al, 1995;Aittomaki et al, 1995;Gromoll et al, 1996;Rosenthal et al, 1996;Simoni et al, 1997;De Roux et al, 1997;Layman et al, 1998;Latronico et al, 1998aLatronico et al, , b, 2000Arnhold et al, 1999;Batista et al, 2000;Kottler et al, 2000).…”

Luteinizing Hormone Resistance Syndromes

“…In genetic males, several abnormalities in Leydig cell differentiation or function have been reported to result in varying degrees of male pseudohermaphroditism 4–11 . In these patients, Leydig cells were either nonexistent, hypoplastic, or unresponsive to hCG stimulation.…”