A case is made for the involvement of pituitary prostaglandins (PGs) in the regulation of thyrotropin (TSH) secretion by citing recent evidence that TSH release in vivo and in vitro is enhanced by treatment with exogenous PGs and is inhibited by drugs (e.g., indomethacin) that block PG synthesis. Pharmacological studies were then performed to test the hypothesis that hypothalamic PGs also affect TSH secretion indirectly via the appropriate hypothalamic hormones that regulate pituitary secretion. The inhibition of thyroidectomy-induced TSH secretion was used as an endpoint in choosing the best of several drugs purported to inhibit PG synthesis. The established effectiveness of indomethacin and aspirin were used for reference in testing the following drugs: naproxen, mefenamic acid, tranylcypromine, and phenelzine. Only naproxen was found to be effective, but since it was no more potent than indomethacin, the latter drug was used for subsequent work. Indomethacin was stereotaxically implanted into several hypothalamic regions known to regulate TSH secretion, and sequential plasma samples were analyzed for TSH by radioimmunoassay. Bilateral implants of indomethacin in the anterior hypothalamic area increased TSH secretion throughout the 72 hr period of study. Sham inplants at this site and indomethacin implants in other nearby sites were ineffective. These findings suggest that endogenous PGs play an inhibitory role in the hypothalamic regulation of pituitary secretion.Over the past couple of decades it has become well recognized that the prostaglandins (PGs) can exert a wide variety of endocrine and metabolic effects. In particular, these ubiquitous fatty acids have recently been shown to affect the secretion of each of the hormones of the anterior pituitary gland (1, 2). In some instances, the effects of the PGs are direct ones in that they affect the pituitary itself. In contrast, others of the known effects are indirect in that they are exerted at the hypothalamus on factors which in turn alter pituitary secretion. Figure 1. In these experiments, various PGs and TRH (or appropriate vehicles) were infused sequentially directly into the anterior pituitaries of pentobarbital-anesthetized female rats, and plasma samples were assayed for TSH by radioimmunoassay. 83