To ascertain if androgen insensitivity causes severe oligospermia or azoospermia we studied three unrelated, phenotypically normal men with long histories of infertility. The mean plasma concentrations and production rates of testosterone were 14.3 ng per milliliter and 10.1 mg per day, respectively, values approximately twice the average found in normal men. Serum luteinizing hormone concentrations were elevated in two of the three subjects. The specific high-affinity dihydrotestosterone binding capacity of cultured genital-skin fibroblasts was 8, 0 and 10 fmol per milligram of cellular protein, values half (or less) of those from normal men and women but similar to values in subjects with partial androgen insensitivity manifested by incomplete testicular feminization or Reifenstein syndrome. The low amount of androgen receptor and the combination of high serum gonadotropins and plasma testosterone production rates suggest that the defective spermatogenesis in these infertile men was the consequence of androgen insensitivity.

To ascertain the frequency of androgen resistance as the cause of male infertility and to determine whether endocrine abnormalities are a universal feature of the disorder, we measured the androgen receptor in fibroblasts cultured from the genital skin of 28 unrelated phenotypically normal men with idiopathic azoospermia or oligospermia. The amounts of androgen receptor were compared with those in genital skin fibroblasts from a variety of other subjects, including 10 men with azoospermia of known cause, 5 normal men, 28 subjects with disorders of androgen formation of metabolism of known cause, and 28 persons with documented disorders of the androgen receptor (testicular feminization and Reifenstein syndrome). The mean androgen receptor Bmax (amount of high affinity binding) was 12 fmol/mg protein or greater in 10 infertile men with azoospermia of known cause and in 6 infertile men with mild oligospermia. In fibroblasts from 1 to 4 individuals with severe oligospermia of unknown cause (less than 1 million/ml) and 8 of 18 subjects with idiopathic azoospermia, the androgen receptor Bmax was less than 12 fmol/mg protein. The mean value in these 9 men was not significantly different from that in subjects with testicular feminization or Reifenstein syndrome. Serum concentrations of testosterone and LH were normal in 6 of these 9 infertile men, and plasma production rates of testosterone were elevated in only 2 of the 6 men studied in whom the Bmax values in genital skin fibroblasts were less than 12 fmol/mg protein. We conclude that androgen resistance may be the cause of a significant fraction (40% or more) or idiopathic male infertility due to azoospermia or severe oligospermia, and that this disorder may not be manifested by a functional defect in the pituitary-testicular axis.

Gynecomastia developed in three men 1-30 yr after the occurrence of testicular atrophy due to mumps orchitis. At the time of study, these men were 63-68 yr of age. In these men the mean plasma production rate of testosterone was 816 microgram/24 h, a value 20% of that found in normal elderly men without gynecomastia. The plasma production rate of androstenedione averaged 1317 microgram/24 h. The mean production rates of 17 beta-estradiol and estrone in these subjects were 33 and 48 microgram/24 h, values comparable to those of normal young men. Extraglandular formation of estrogen from plasma prehormones accounted for all of the 17 beta-estridiol and most of the estrone produced by these elderly men with gynecomastia. Serum gonadotropin concentrations were elevated in these men, probably because plasma testosterone production rates were decreased. These findings are consistent with the view that the capacity of Leydig cells to secrete testosterone was impaired after mumps orchitis in these subjects, but the capacity to form estrogen was not similarly impaired, since most estrogen is formed in extraglandular sites. Thus, the impairment in Leydig cell testosterone secretion after mumps orchitis together with the normal increase in extraglandular aromatization that accompanies aging bring about a striking reduction in the ratio of testosterone to estrogen production rates, and gynecomastia may result.

Four patients with androgen insensitivity had plasma LH and FSH measured at 20-min intervals for 24 h and at 15- to 30-min intervals for 3 h after the injection of LRH. Twenty-four-hour mean testosterone (T), estradiol, and androstenedione (delta 4) levels were also measured. Patients with androgen insensitivity had significantly elevated LH levels (P less than 0.05) and an increase in the number of LH secretory episodes (P less than 0.001) compared to normal subjects. The amplitude of the LH secretory episodes, expressed as the absolute increment, was significantly higher than normal controls (P less than 0.005). The LH response to LRH (absolute increment) was twice that of normal, but was not significantly different from normal subjects. The 24-h mean FSH levels were normal in three of the patients and elevated in one. This patient had the mildest degree of androgen insensitivity on clinical exam and the greatest degree of testicular atrophy. The 24-h mean T, estradiol, and delta 4 levels were higher than normal, but only the delta 4 was significantly increased (P less than 0.05). To determine if the elevated LH levels were in response to a decrease in the free T level, we measured T-binding capacity (TBG), TBG was higher than normal controls but was not significantly different, suggesting that elevated LH levels were probably in response to a decrease in T action at the hypothalamic-pituitary level. This was further supported by the inability of prolonged dihydrotestosterone administration to affect LH secretion in one of the patients with the Reifenstein syndrome.

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