Testicular Feminization Associated with a Thermolabile Androgen Receptor in Cultured Human Fibroblasts

Abstract

A B S T R A C T Evidence for a qualitative abnormality in the androgen receptor was obtained by studies of temperature sensitivity. The binding of [3H]dihydrotestosterone (17,8-hydroxy-5a-androstan-3-one) was studied in monolayers of cultured genital skin fibroblasts from genetic males with abnormal sexual differentiation resulting from androgen resistance. Binding in cells from eight patients with a female phenotype (complete and incomplete testicular feminization) fell from half-normal levels at the usual assay temperature of 37°C to levels <20% of normal when cells were incubated at 42°C. This thermal inactivation was rapidly reversed when the assay temperature was lowered to 37°C, was not associated with altered dihydrotestosterone metabolism, and was also demonstrable with [3Hlmethyltrienolone as the binding ligand. Binding increased to overlap the normal range when the assay temperature was lowered to 26°C. The patients with receptor-deficient testicular feminization include three pairs of siblings; the pedigrees in two of these families are compatible with X-linkage.Only minor changes in the amount of binding at elevated temperatures were observed in cells from 10 control subjects and from 2 male pseudohermaphrodites with normal levels ofandrogen receptors. In 10 patients with androgen resistance and partial receptor deficiency associated with a predominantly male phenotype (Reifenstein syndrome and infertile men), dihydrotestosterone binding also did not change consistently with elevated temperature. Binding was approximately half-normal at 370C and either increased or decreased slightly at 420C.

Incomplete Androgen Insensitivity Associated with a Thermolabile Androgen Receptor.

“…The presence of thermolabile androgen receptor (qualitatively abnormal androgen receptor) made the diagnosis convincing. Thermolabile androgen receptors have been observed in complete AIS [4,5], incomplete AIS [6], the Reifeinstein syndrome [7] and the infertile male syndrome [8], indicating that patients with thermolabile androgen receptors span a wide spectrum. Further study is required to elucidate these forms of phenotypic heterogeniety in patients with thermolabile androgen receptors.…”

Abnormality of Intracellular 5α-Dihydrotestosterone Binding in Simple Hypospadias: Studies on Equilibrium Steroid Binding in Sonicates of Genital Skin Fibroblasts

“…The decrease in receptor number in a given HS subject might reflect either a decreased number of binding sites or relative instability of thc receptor or the steroid-receptor complex. Apparent receptor instability has been reported in male pseudohermaphroditism ( 12,19). Clearly, the androgen receptor is moderately unstable under the present assay conditions, at least until equilibrium betwecn receptor and steroid is reached.…”

Primary cortisol resistance associated with a thermolabile glucocorticoid receptor in a patient with fatigue as the only symptom.

“…Furthermore, therapy with pharmacologic glucocorticoid doses without the development of the stigmata of Cushing's syndrome has been linked with steroid resistance in receptor defective lymphocytes in patients with acute leukemia (31). Principally, it appears that alterations in the sensitivity to glucocorticoids can be traced to biochemical lesions at the receptor level (4,32). In some cases, however, unresponsiveness to glucocorticoids occurs despite seemingly normal receptor functions and receptor concentration (33).…”

“…She had no previous history ofdisease. The menopause Receivedfor publication 4 April 198S and in revisedform 24 June 1986.…”