Androgens and Androgen Responsiveness in the Feminizing Testis Syndrome. Comparison of Complete and “Incomplete” Forms¹

Abstract

The metabolic response to androgens was studied in a patient with the complete syndrome of testicular feminization in whom the conversion of testosterone to dihydrotestosterone by skin homogenates was below normal. The subject not only failed to manifest an anabolic response to chorionic gonadotropin and testosterone propionate, but also failed to respond to dihydrotestosterone and dihydrotestosterone acetate. Steroid dosages were those sufficient to induce maximal anabolism in normal men or women. The anticipated anabolic effect of estradiol benzoate was readily demonstrated. It is accordingly proposed that the resistance to androgen resulted from an abnormality of specific androgen retention by target cell nuclei or in the subsequent chain of intracellular events initiated by androgen. It is suggested that the remarkable degree of breast development in the complete syndrome is the result of the unopposed action of estrogen of testicular origin, acting upon mammary primordia not subjected to antenatal inhibition by androgen. The diagnosis of "incomplete testicular feminization" was presumed in a pubertal male pseudohermaphrodite on the basis of absent miillerian derivatives, early breast development, and evidence compatible with androgen insensitivity. Two experimental observations supported the concept of end organ resistance to the effects of androgen. The degree of development of secondary sex characteristics was seemingly poor considering the nearly adult male level of plasma testosterone. Delayed, if any, anabolic response resulted from chorionic gonadotropin stimulation in spite of a rise in plasma testosterone from 233 to 770 ng/100 ml. That no more than partial androgen resistance existed was indicated by the observation that an anabolic response was induced by both dihydrotestosterone acetate and testosterone propionate at plasma levels of unconjugated steroid over 1000-2000 ng/100 ml. Intracellular formation of dihydrotestosterone from testosterone was normal. No abnormality in the plasma concentration of androgenic intermediary metabolites was demonstrated in either patient. The comparative studies suggest that complete and incomplete forms of the feminizing testes syndrome exist which may differ in the degree or nature of androgen resistance. (J Clin Endocr 32: 625, 1971) T HE COMPLETE syndrome of testicular feminization is clinically characterized by a female phenotype with normal feminization, absent miillerian derivatives, and sparse or absent sexual hair in association with an XY karyotype and cryptorchid testes. Resistance to the effects of androgen has been demonstrated in such subjects by failure of testosterone admin-

Metabolic clearance rate and blood production rate of testosterone and dihydrotestosterone in normal subjects, during pregnancy, and in hyperthyroidism

“…The acetates of dihydrotestosterone, etiocholanolone, and isoandrosterone are more difficult to separate than the free compounds. A contamination of dihydrotestosterone with other metabolites of testosterone and androstenedione could partially explain the similar MCRDHT values found by Mahoudeau and ourselves and the discordance in the values for the (p) BBETDHT and (pD) EBDET Studies made in vivo and in vitro suggest that the conversion of testosterone into dihydrotestosterone by the target organs is reduced in the testicular feminization syndrome (32)(33)(34)(35). In the three patients with this syndrome the over-all conversion of testosterone into dihydrotestosterone was within the limits for males.…”

Sex hormone binding globulin response to testosterone. An androgen sensitivity test

“…These studies in fibroblasts grown in culture, however, are complex, expensive and time-consuming. Nitrogen retention after an¬ drogen administration has also been proposed as a clinical test of androgen sensitivity (Rosenfield et al 1971). It requires, however, several days of nitro¬ gen balance under very careful control conditions.…”

Incomplete androgen insensitivity: asymmetry in morphology and steroid profile and metabolism of the gonads. An analysis of a case

“…Chromosome analysis of short-term cul¬ tured lymphocytes revealed the karyotype 46,XY (Q-and G-banding). The clinical diagnosis of incomplete testicu¬ lar feminization was based on these findings together with the histologie picture of the gonads, in accordance with the definition given by Rosenfield et al (1971). Bilateral gonadectomy was performed by laparotomy.…”