Normal postnatal androgen production and action in isolated micropenis

To try and find out if a defect in androgen biosynthesis or action could be responsible for the incomplete virilisation seen in boys with isolated hypospadias and isolated micropenis, androgen receptor binding was studied in genital skin fibroblasts established from 18 boys with isolated micropenis and 19 boys with isolated hypospadias. The production of gonadotrophint and testosterone was also measured in the boys with micropenis. There was no evidence of gonadotrophin deficiency, or of a defect in testosterone biosynthesis in the boys with micropenis, and there was no evidence of a quantitative or qualitative defect of androgen binding in either group. These isolated abnormalities may be the result of transient defects in androgen synthesis or action, or both, during a critical phase of embryogenesis. Department of Child Health, University of Wales College of Medicine, Cardiff B A J Evans Department of Paediatrics, University of Cambridge, Addenbrookes Hospital, Cambridge CB2 2QQ D M Williams I A Hughes Correspondence to: Professor Hughes. Accepted 9 April 1991 Sexual differentiation in boys follows an orderly sequence of events once the indifferent gonad has developed into a testis. This occurs early in gestation and is under the influence of a testis determining factor, the gene for which is on the short arm of the 'Y chromosome.' 2 Adequate testosterone biosynthesis, the onset of which is probably initially spontaneous3 and which is later controlled by placental human chorionic gonadotropin and pituitary luteinising hormone, is required to induce Wolffian duct development. Male differentiation of the external genitalia is dependent on 5-a-dihydrotestosterone,4 the active reduced metabolite of testosterone, and both androgens promote phallic growth during the remainder ofgestation. The ultimate biological expression of androgen action in target tissues requires the presence of a specific intracellular binding protein that can mediate the effects of androgens on gene expression.' Defects in fetal pituitary secretion of luteinising hormone, testosterone biosynthesis, or androgen action may show themselves as inadequate virilisation of varying severity and sometimes as genital ambiguity. Isolated micropenis and hypospadias are both disorders of inadequate virilisation that are not associated with ambiguity of the genitalia. The former may be the result of congenital hypopituitarism, it may be associated with several dysmorphic syndromes, or it may have no demonstrable cause. Hypospadias is a common isolated malformation with an incidence of 0-2 _-06%.6 The defect is the result of failure of complete fusion of the urethral folds, a process mediated mainly by dihydrotestosterone. A defect in androgen biosynthesis or action may be responsible for both these conditions. We report a study of androgen receptor binding in genital skin fibroblasts established from two groups of boys with isolated micropenis and isolated hypospadias. We also assessed the production of gonadotrophins and testosterone in the group with isolated micropenis. Patients and methods MICROPENIS Eighteen boys with isolated micropenis were studied. Their ages at the time of study ranged from 4-1 to 16-4 years, and eight were prepubertal with bone ages of less than 10 years. The remaining 10 were pubertal, their Tanner stages ranging from 2 to 4. The stretched penile length was measured by the method ofSchonfeld and Beebe and in each case was 2-5 SD or more below the mean value for age.7 All the boys had normal growth velocity and none was obese. Serum samples were collected before and 30, 60, 90, and 120 minutes after an intravenous bolus dose of 100 jig luteinising hormone releasing hormone for measurement of luteinising hormone and follicle stimulating hormone. Each boy then received human chorionic gonadotrophin 2000 units daily intramuscularly for three days. A blood sample was collected on the fourth day for measurement of plasma testosterone concentration. A 2 mm scrotal skin punch biopsy was taken under local anaesthetic to establish genital skin fibroblasts in culture for studies of androgen receptors. Informed parental consent (and where appropriate that of the child) was obtained in each case. HYPOSPADIAS Nineteen boys with isolated hypospadias were studied when they were admitted to hospital for repair. The defects were all classified as glandular or penile. There were no other anomalies of the penis or associated genital abnormalities. A 2 mm foreskin biopsy was obtained at the time of surgery to establish genital skin fibroblasts in culture. METHODS Serum luteinising hormone and follicle stimulating hormone, and plasma testosterone concentrations were measured by radioimmunoassay.8 9 Bone ages were calculated by the method of Tanner and Whitehouse. 10 Primary explants of skin were established in 1033 group.bmj.com on June 21, 2017 Published by http://adc.bmj.com/ Downloaded from