To assess the hypothalamic-pituitary-thyroid axis in two patients with the diagnosis of type I pseudohypoparathyroidism established previously by characteristic clinical features and laboratory findings, including low serum Ca++, high parathyroid hormone concentration, and subnormal urinary cyclic adenosine monophosphate (cAMP) responses to exogenous administration of parathyroid hormone. We determined serum thyroxine, triiodothyronine (T(3)), T(3) resin uptake, and 24-hour thyroidal uptake of 123 I before and after subcutaneous administration of thyroid-stimulating hormone (TSH), 10 U daily for 3 days. Serum TSH levels were determined before and again at 15, 30, 45, and 60 minutes after intravenous administration of thyrotropin-releasing hormone (TRH) (400 microg) after an overnight fast. Values noted in the two patients with type I pseudohypoparathyroidism were compared with those obtained in 10 normal volunteer control subjects. Serum thyroxine (T(4)), triiodothyronine (T(3)), T(3) resin uptake, and 24-hour 123 I uptake values for both patients with type I pseudohypoparathyroidism were within the normal ranges (5.5 to 11.5 microg/dL for T(4), 90 to 190 ng/dL for T(3), 35 to 45% for T(3) resin uptake, and 10 to 35% for 24-hour 123I uptake). Their responses to administration of TSH, however, were all significantly lower in comparison with the mean values for the 10 healthy control subjects. Basal TSH was higher in both patients with type I pseudohypoparathyroidism than in normal subjects, but TSH responses after administration of TRH, although not significantly different from normal, were blunted in relationship to the basal concentrations, as expressed as a percentage increase in TSH as well as a cumulative TSH response. The responses of pituitary thyrotrophs to TRH and the thyroid gland to TSH were both considerably inhibited in the patients with type I pseudohypoparathyroidism in comparison with normal control subjects. This finding may be yet another evidence of the lack of adequate generation of cAMP, an important second messenger needed for normal functioning of most polypeptide hormones, including TRH and TSH, in this syndrome.