Testicular seminoma in a patient with a constitutively activating mutation of the luteinizing hormone/chorionic gonadotropin receptor

Abstract

A white man who had been diagnosed, 35 years previously at the age of 27 months, to have precocious puberty, was later determined to have familial male-limited precocious puberty (FMPP), on the basis of his family history, increased serum testosterone, prepubertal concentrations of follicle stimulating hormone and luteinizing hormone, and Leydig cell hyperplasia. Recently, this diagnosis was confirmed by molecular genetic analysis that demonstrated the presence of a heterozygous constitutive activating mutation of the luteinizing hormone/chorionic gonadotropin receptor. This dominant gain-of-function Asp578Gly mutation has been shown constitutively to activate the receptor in the absence of the agonist, leading to enhanced synthesis of cAMP and, in turn, to increased, sustained production of testosterone. In 1994, this patient was found to have a testicular seminoma. He represents the first case of a testicular germ cell tumor described in an FMPP patient, raising the possibility of a potentially harmful effect of prolonged increased concentrations of sex hormones, with onset early in life, upon the cellular components of the testes.

Venous sampling can be crucial in identifying the testicular origin of idiopathic male luteinising hormone-independent sexual precocity

“…DNA sequencing of the affected tissue identified the Asp564Gly mutation, which was also present in the patient's peripheral blood cells; this is in stark contrast to the Asp578His patients, whose testicular mutation did not appear in their peripheral blood cells. Previously, a case of testicular germ cell tumour in an FMPP patient caused by an activating mutation Asp578Gly was published [10]. This patient was diagnosed at the age of 27 months and he developed a testicular seminoma 35 years later.…”

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

“…Recently, an FMPP patient with testicular seminoma was reported (322). The occurrence of these relatively rare disorders could be attributed to chance but could also be the effect of continuous stimulation by increased levels of androgens.…”

Developmental Exposures of Male Rats to Soy Isoflavones Impact Leydig Cell Differentiation1

“…Also, high intratesticular testosterone was found to suppress spermatogonial proliferation in the radiationdamaged rat testis [85]. Other reports have established that elevated serum testosterone levels increased the risk for testicular germ cell tumors in human subjects [86,87]. On the other hand, a number of studies have shown that isoflavones may act within the seminiferous epithelium to impact spermatogenesis without concomitant endocrine changes [88,89].…”