Although TRH stimulates the release of uncombined alpha-subunit into the circulation in patients with primary hypothyroidism, it is not clear whether alpha-subunit is released from the thyrotrophs in euthyroid subjects. We hypothesized that spontaneous fluctuations in circulating alpha-subunit released from gonadotrophs by GnRH in normal adults could obscure the detection of small changes in alpha-subunit after TRH administration. We, therefore, examined alpha-subunit responses to TRH in five euthyroid men with idiopathic hypogonadotropic hypogonadism (IHH), who produce little or no GnRH, five normal men, and four postmenopausal women. Mean (+/- SEM) basal serum alpha-subunit levels were significantly (P less than 0.05) less in men with IHH (0.26 +/- 0.07 microgram/L) than in the normal men (0.80 +/- 0.20 microgram/L) or postmenopausal women (3.54 +/- 0.60 microgram/L). alpha-Subunit levels rose after TRH administration in all men with IHH to a peak level of 0.86 +/- 0.25 ng/ml; TSH levels also increased from 1.9 +/- 0.4 to 13.0 +/- 5.6 mU/L. The increment in TSH and alpha-subunit levels was highly positively correlated (r = 0.96). alpha-Subunit levels also increased 2-fold in normal men given TRH, whereas alpha-subunit levels in postmenopausal women were unchanged. We conclude that thyrotrophs release alpha-subunit into the circulation in normal men and euthyroid men with IHH. Thus, both thyrotrophs and gonadotrophs appear to contribute to circulating alpha-subunit in men with IHH; however, most of the uncombined alpha-subunit in normal men appears to be from gonadotrophs.