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The membrane progesterone receptors (mPR, -, -, -, -) are known to mediate rapid non-genomic progesterone functions in different cell types. However, the functions of these receptors in the pituitary have not been reported to date. Here we show that the expression of mPR was the highest among the mPRs in the rat anterior pituitary gland. Immunostaining of mPR was detected in somatotrophs, gonadotrophs and lactotrophs. Interestingly, 63% of mPR-positive cells within the pituitary were lactotrophs suggesting that mPR is involved in controlling prolactin (PRL) secretion in the pituitary. To test this hypothesis, rat pituitaries were incubated (1h) with either progesterone (P4) or the mPR specific agonist Org OD 02-0. PRL secretion was then measured by radioimmunoassay (RIA). Results of this experiment revealed that both P4 and Org OD 02-0 decreased PRL secretion. Moreover, results from the GH3 cell line (CCL-82.1 ) showed that P4 and Org OD 02-0 inhibited PRL release, but the nuclear PR agonist R5020 was ineffective. Our investigation of the cellular mechanisms behind mPR activity indicated that both P4 and Org OD 02-0 decreased cAMP accumulation, while R5020 was ineffective. In addition, the Org OD 02-0-effect on PRL release was blocked by pretreatment with pertussis toxin, an inhibitor of Go/Gi proteins. Because TGF1 is a potent inhibitor of PRL secretion in lactotrophs, we lastly evaluated whether TGF1 was activated by progesterone and whether this effect was mediated by mPR. Our results showed that P4 and Org OD 02-0, but not R5020 increased active TGF1 levels. This effect was not observed when cells were transfected with mPR-siRNA. Taking together, these data provide new evidence that mPR mediates the progesterone inhibitory effect on PRL secretion through both: the decreases in cAMP levels and the activation of TGF1 in the lactotroph population. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.