Effect of danazol on gonadal steroidogenesis in patients with a complete form of testicular feminization

The clinical applicability of danazol has been postulated to depend upon its antigonadotropic and androgenic properties. However, the true mechanism of action of danazol has not been fully elucidated, and experimental evidence indicates that the major pharmacologic action of this drug may be related to the direct inhibition of multiple enzymes of gonadal steroidogenesis. In the present study, the hypothesis that danazol directly inhibits gonadal steroidogenesis was tested during the course of endocrine studies on three sisters with a complete form of testicular feminization. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and testosterone (T) levels were determined following short-term administration of varying doses of danazol. In these patients, the absence of androgen receptors and the expected inability of danazol to serve as a metabolic precursor of estrogens would minimize possible antigonadotropic effects of this drug and allow the evaluation of its direct action on the secretion of steroids by the gonads in vivo. During the experiments, there was a highly significant and dose-related suppression of serum T levels in all patients. E2 levels decreased slightly. Both LH and FSH levels showed no consistent decline and remained within the range of normal. In one patient, LH and FSH levels declined significantly during treatment, but in the other two patients serum concentrations of LH remained stable or even increased while T levels fell. In spite of the fall in steroid levels, a compensatory increase in gonadotropins did not always occur. In conclusion, danazol effectively suppresses peripheral T levels in patients with a complete form of testicular feminization. Such suppression is dose related and can occur in the absence of a decline in LH serum concentrations, possibly as a result of a direct action on gonadal steroidogenesis.l