No abstract

Continuously superfused rat anterior pituitary cells were used to study the effects of prostaglandins (PGs) and a thromboxane (TX) on the secretion of TSH. Indomethacin, a blocker of PG synthetase, inhibited the amount of TSH secreted in response to TRH. This reduction in TRH responsiveness was overcome by administration of PGE2 in combination with the TRH. Arachidonic acid, a prostanoid precursor, increased the amount of TSH released by TRH. Superfusion with TXB2 or imadazole, an inhibitor of TX synthetase, did not change TSH secretion. PGs A2, B2, D2, F1 alpha, F2 alpha, and endoperoxide analogs U-44069 and U-46619 had no effect on hormone release. PGE1 and E2 both increased TRH-stimulated TSH, but neither compound affected basal output; PGI2 was found to stimulate TSH release. Somatostatin inhibited TRH-induced TSH, but failed to block the effects of the PGs. These studies demonstrate that PGs, but no TXs, play a role in TSH secretion. PGE1 and PGE2 appear to modulate TRH responsiveness, while PGI2 directly stimulates hormone output.

The first portion of this paper is devoted to an overview of the normal function of the hypothalamo-pituitary-thyroid axis. This section emphasizes areas of current research interest and it identifies several sites and mechanisms that are potentially important interfaces with toxins or toxic mechanisms. We then describe an in vitro technique for the continuous superfusion of enzymatically dispersed pituitary cells; this approach is particularly valuable in studying the dynamics of the TSH responses to the factors known (or suspected) to regulate TSH secretion in vivo. Using this technique, we have found that 10(-5)M prostaglandin (PG)I2 stimulates TSH secretion without altering the response to TRH (10(-8)M), and that this stimulation is not due to its rapid conversion to 6-keto PGF1 alpha. In contrast PGs of the E series (PGE1 and PGE2, 10(-5)M) increase responsiveness to TRH but have no effect alone. We found no effects of any of the other prostanoids tested (PGs A2, B2, F1 alpha, F2 alpha, thromboxanes A2 and B2, and the endoperoxide analog, U-44069. Somatostain (10(-9)M inhibits TRH-induced TSH secretion, but does not alter the responsiveness to PGI2. These findings suggest that somatostatin blocks TSH secretion at a point that is functionally prior to the involvement of the PGs, and perhaps does so by blocking synthesis or limiting availability of selected PGs.

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