Gonadotropin-independent familial sexual precocity with premature Leydig and germinal cell maturation (familial testotoxicosis): effects of a potent luteinizing hormone-releasing factor agonist and medroxyprogesterone acetate therapy in four cases.
Four boys with sexual precocity are described in whom pubertal concentrations of plasma testosterone were associated with premature Leydig and germinal cell maturation without activation of the hypothalamic-pituitary gonadotropin unit. Extensive laboratory evaluation localized the source of testosterone secretion to the testes, and testicular biopsy revealed maturation of Leydig cells and spermatogenic elements. These events appear to be nongonadotropin-dependent in view of the absence of a pubertal pattern of pulsatile LH secretion, persistence of a prepubertal LH response to LRF even after long standing sexual precocity, prepubertal basal levels of LH and undetectable hCG, and the absence of biologically active LH-hCG by bioassay. Indirect immunofluorescence studies failed to demonstrate an immunoglobulin in the patients' sera that bound to Leydig cells or seminiferous tubules of normal adult human testes. The potent LRF analog D-Trp6-Pro9-NEt-LRF did not result in suppression of plasma testosterone or Leydig cell function even after 3 months of daily treatment in two patients which provides additional support of pituitary gonadotropin independence and of the lack of a direct effect of the analog on Leydig cell function. Oral medroxyprogesterone acetate treatment in two patients was associated with a striking decrease in both plasma testosterone concentration and height velocity. In the only patient in whom a complete family history could be obtained (three of four patients were adopted), sexual precocity was noted in the maternal grandfather. As this familial syndrome is characterized by a prepubertal hypothalamic-pituitary gonadotropin unit and apparent gonadotropin-independent maturation of Leydig cells and germinal epithelium, possibly due to an intratesticular inborn error, we propose the term "familial testotoxicosis" to describe this group of sexually precocious boys.
D002675:Child, Preschool; D006063:Chorionic Gonadotropin; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007985:Leydig Cells / Q000502:physiology*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008525:Medroxyprogesterone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017258:Medroxyprogesterone Acetate; D010507:Periodicity; D011629:Puberty, Precocious / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D013094:Spermatozoa / Q000254:growth & development*; D013737:Testis / Q000166:cytology; D013739:Testosterone / Q000097:blood; D017329:Triptorelin Pamoate / Q000031:analogs & derivatives*
D006063:Chorionic Gonadotropin; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; C019176:Tryptal; D007986:Luteinizing Hormone; D017258:Medroxyprogesterone Acetate; D008525:Medroxyprogesterone