Smith-Lemli-Opitz syndrome: in vivo and in vitro study of testicular function in a prepubertal patient with ambiguous genitalia

The pathogenesis of the development of ambiguous genitalia reported in some 46,XY patients with Smith-Lemli-Opitz syndrome is not understood. Presumab ly, it is related to the 7-dehydrocholesterol reductase deficiency present in these patients. In this study we have evaluated testicular function, bot h in vivo and in vitro, in a 46,XY patient with ambiguous genitalia, reared as a girl. The diagnosis was based on clinical features, low serum cholest erol and high serum 7-dehydrocholesterol levels. Serum hormone values, dete rmined during the first month of age, showed normal basal testosterone (1.9 5 ng/ml), LH (0.91 U/l) and FSH (2.51 U/l). However, serum testosterone did not increase after hCG administration (1.98 ng/ml). On the other hand, the patient had a positive biological response to exogenous testosterone (decr ease in sex hormone-binding globulin serum levels). She was orchidectomized at the age of 33 mo. Testicular cells were dispersed and maintained in cul ture for 6 d. These cells showed a very good capacity to secrete testostero ne into the culture medium (X +/- SD, 26.1 +/- 11.7 vs. 4.36 +/- 1.70 pmol/ 10(6) cells/24 h in a control group of testicular cells prepared from teste s collected at necropsy). The patient's cells failed to respond to LH stimu lation (18.6 +/- 4.0 pmol/10(6) cells/24 h), although they did respond to o ther stimuli. It is concluded that the severe cholesterol deficiency of thi s patient did not impair the capacity of the testes to synthesize testoster one. However, the LH/hCG receptor or its subsequent message was activated n either in vivo nor in vitro. This finding suggests that the foetal testes m ight have failed to respond to placental hCG at the time of male external g enital differentiation. This failure could have been responsible for the am biguous genitalia present in this patient.