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The hypothalamic-pituitary regulation of TSH secretion in vivo during aging was examined in male SpragueDawley rats. Parameters that were assessed include the circadian pattern of serum TSH, changes in plasma TSH after iv or pituitary administration of TRH at several dosages, and the possible influence of circulating levels of corticosterone, T 3 , and T 4 on pituitary sensitivity to TRH-mediated TSH secretion. Concentrations of circulating TSH, serum T 3 , and T 4 were determined by RIA. The fractions of T3 and T 4 not bound to serum proteins (free T 3 and T 4 ) were determined by equilibrium dialysis. The concentration of serum corticosterone was assayed fluorometrically. The principal findings are as follows. 1) The circadian periodicity of serum TSH in 2-month-old rats, characterized by a zenith at 1000 h and a nadir at 2200 h, is progressively abolished by 24 months of age, whereas the average serum TSH concentration remains unchanged during this portion of the lifespan. In contrast, the circadian periodicity of serum corticosterone is very similar between 2-24 months of age, with a zenith at 1800 h and a nadir at 0600 h. Plasma corticosterone levels are, however, significantly higher in the 24-monthold rats between 0600-1800 h. 2) Increases in plasma TSH after TRH administration are very similar for all ages. However, at the lowest employed dosages of TRH, the TSH secretory response of the 12-and 24-month-old rats is significantly greater than that of the 2-month-old rats. 3) Both total and free levels of serum T 3 and T 4 decrease during aging, most significantly between 2-12 months of age. These studies indicate that pituitary sensitivity to TRH-mediated TSH secretion is not altered during aging, and suggest that differences in the regulation of TSH during aging may reflect very specific alterations in hypothalamic and/or neural functions. Expression of such neuroendocrine deficiencies may cause impairments in the metabolic responsiveness of peripheral tissues during aging. (Endocrinology 104: 1136,1979) P REVIOUS reports of the effects of aging on pituitary responsiveness to TRH are controversial. Snyder and Utiger reported a decline in the maximal TSH response to injected TRH in aged human males (1) but were unable to demonstrate a similar result in aged females (2). Sakoda et al. (3) found no significant difference in TRH-mediated TSH release between young and aged human subjects in groups of mixed sex. In contrast, Ohara et al. (4) reported a significantly higher TSH response to TRH stimulation for the aged group of mixed sex when TRH was injected at relatively low doses.The interpretation of these varied results is difficult, since separate dose-response curves were not determined for each age group, and/or the influence of those variables regulating pituitary sensitivity to TRH was not assessed. Therefore, in these studies, an aging effect cannot be differentiated on the basis of one or more of the following: 1) an altered maximal capacity of pituitary response, 2) a shift in the intrinsic sensit...