Adrenocortical Carcinoma with Feminization and Hypertension Associated with a Defect in 11β-Hydroxylation

Abstract

An investigation of steroid metabolism in a 28-year-old male with metastatic adrenocortical carcinoma, who exhibited feminization, hypertension, edema and acne, has yielded information on the role of steroids in the production of these signs and symptoms. Initially, when feminization was the only finding, the patient excreted abnormally large amounts of estrogens and normal amounts of 17-ketosteroids and 17-hydroxycorticosteroids. Later, hypertension, edema and acne appeared in association with abnormally high and rapidly rising levels of estrogens and tetrahydro-11-deoxycortisol, but normal levels of tetrahydrocortisol, tetrahydrocortisone, androsterone and etiocholanolone. ACTH administration caused a disproportionately marked increase in the excretion of estrogens and tetrahydro-11-deoxycortisol. Estrogen excretion also increased upon the administration of methopyrapone (2-methyl-l,2-bis[3-pyridyl]-l-propanone), an 11β-hydroxylase inhibitor. These studies of steroid excretion suggested: 1) that the tumor possessed an overactive aromatizing enzyme system and a defect in 11β-hydroxylation to account for the overproduction of estrogens with feminization, and 2) that overproduction of the usual androgens and corticoids was not involved in the initiation of the hypertensive phase. In support of the first conclusion it was demonstrated directly by incubating neoplastic tissue with radioactive steroid precursors that the tumor possessed most of the biosynthetic enzymes known to occur in normal adrenocortical tissue, but that there was a relative deficiency in 11β-hydroxylation and an overactive aromatization. The incubation results suggested that an verproduction of deoxycorticosterone might have been responsible for the hypertensive phase of the disease, but this was not proved in vivo. On the basis of both the in vivo and in vitro results, the most probable pathways utilized for steroid production in this patient were designated. The excretion of 17-ketosteroids and 17-hydroxycorticosteroids reached abnormally high levels terminally without producing any significant changes in the clinical manifestations. Treatment with o,p′-DDD(2,2-bis[4-chlorophenyl, 2-chlorophenyl]-1,1-dichloroethane) was partially effective in lowering steroid excretion, but had no demonstrable effect or tumor growth. Amphenone (3,3-bis[p-aminophenyl] butanone-2) was ineffective in both regards.