Familial Incomplete Male Pseudohermaphroditism Associated with Impaired Nuclear Androgen Retention. STUDIES IN CULTURED SKIN FIBROBLASTS

Abstract

A B S T R A C T The androgen resistance syndromes are generally felt to be due to quantitative or qualitative abnormalities of the androgen receptor. Some patients with testicular feminization have no demonstrable fibroblast cytosol androgen binding, whereas others have androgen binding in cultured fibroblasts that is thermolabile or fails to be stabilized by sodium molybdate. I describe here familial incomplete testicular feminization associated with reduced nuclear androgen retention. Fibroblasts, cultured from pubic skin biopsies of two phenotypic female 46XY siblings, were assayed for whole cell and nuclear uptake of [3H] Although whole cell binding studies at 370C showed minimally diminished androgen binding in the patients' cells compared with binding at 220C, Griffin (1979. J. Clin. Invest. 64: 1624-1631.) has demonstrated thermolability of the androgen receptors in fibroblasts also cultured from these patients. The observations with intact cells coupled with the diminished cytosol 8S peak of [3H]dihydrotestosterone on sucrose gradients indicate that these patients have cytosol androgen receptors that are qualitatively abnormal physicochemically, the physiologic consequence of which is failure of nuclear androgen localization. Thus, although the underlying defect in the pathogenesis of the androgen resistance in these patients appears to reside in the androgen receptor, the crucial biologic manifestation of the molecular lesion is impaired nuclear androgen retention. These experiments, therefore, suggest that assessment of nuclear [3H]dihydrotestosterone uptake is an effective indicator of the functional integrity of the androgen receptor system in patients with various forms of androgen insensitivity and provides additional insights to those obtained by thermolability or cytosol sucrose gradient studies.

A mutation that causes lability of the androgen receptor under conditions that normally promote transformation to the DNA-binding state.

“…Dihydrotesterone binding and intracellular localization of dihydrotestosterone are normal in intact The nature of the process by which steroid hormone-receptor complexes acquire the capacity to bind to nuclear components is unknown. Nuclear localization studies after whole cells are exposed to radiolabeled hormone have been used to identify mutations of the glucocorticoid receptor in cultured lymphoid cell lines (12), and impaired nuclear retention of androgen has been described by Eil (13) in fibroblasts from patients with androgen resistance. However, normal localization of the hormone in nuclei from intact cells, as occurred in this patient, does not necessarily imply that the steroid-receptor complex is bound to DNA or other nuclear components and could be a passive reflection of the amount of steroid-receptor complex in the cytosol (7).…”

Androgen directs apparent cytoplasmic and nuclear distribution of rat cardiovascular androgen receptors.

“…1516 Characteristic receptor defects include: 1) absent or diminished tissue receptor content; 17 " 19 2) altered physical properties that apparently affect function; 19 " 21 and 3) impaired capacity for nuclear retention. 22 These studies establish that the presence of cytoplasmic androgen binding components in a presumed target tissue is not necessarily correlated with functionality. The results of these studies raise concern about the physiologic significance of previously described cardiovascular androgen binding components.…”

β‐Glucuronidase activity is present in the microscopic epididymis of the Tfm/Y mouse

“…In some cases there appears to be total absence of androgen receptors, and in others receptors are present but demonstrate inadequate androgen binding (Pinsky et al, 1981). In one family reported by Eil (1983), whole cell androgen binding was in the normal range, but nuclear binding was virtually undetectable. Elsewhere, Eil et a1 (1982) reported altered binding of androgen receptors of such patients to a DNA-cellulose chromatographic column.…”