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Progesterone Antagonizes the Permissive Action of Estradiol on Tumor Necrosis Factor--Induced Apoptosis of Anterior Pituitary Cells

Centro de Investigaciones en Reproducción (M.C., G.J., V.Z., S.Z., L.F., D.P., A.S.), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires C1121ABG, Argentina; and Gene Therapeutics Research Institute (M.G.C.), Cedars Sinai Medical Center and David Geffen School of Medicine, University of California, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Adriana Seilicovich, Centro de Investigaciones en Reproducción, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, piso 10, Buenos Aires 1121, Argentina. E-mail: adyseili{at}fmed.uba.ar.

We previously reported that TNF--induced apoptosis of lactotropes is estrogen dependent and predominant at proestrus. Here we observed that TNF- (50 ng/ml) failed to induce apoptosis of anterior pituitary cells from ovariectomized rats cultured in the presence of progesterone (10^–6 M). However, progesterone blocked the apoptotic effect of TNF- in anterior pituitary cells and lactotropes cultured with 17ß-estradiol (10^–9 M). In addition, 17ß-estradiol induced apoptosis of somatotropes and triggered the proapoptotic action of TNF- in these cells, effects completely blocked by ICI 182 780 (10^–6 M), an estrogen receptor antagonist. Progesterone reverted the permissive effect of 17ß-estradiol on TNF--induced apoptosis of somatotropes. TNF- induced apoptosis of somatotropes from rats killed at proestrus but not at diestrus. The antiprogestine ZK 98 299 (10^–6 M) completely inhibited the protective action of progesterone on TNF--induced apoptosis of anterior pituitary cells, lactotropes, and somatotropes. Although progesterone can interact with glucocorticoid receptors, dexamethasone (10^–6 M) had no effect on TNF--induced apoptosis of anterior pituitary cells, lactotropes, and somatotropes. Our results show that progesterone, by interacting with progesterone receptors, antagonizes the permissive action of estrogens on TNF--induced apoptosis of lactotropes and somatotropes. These observations suggest that the steroid milieu may modulate the apoptotic response of anterior pituitary cells during the estrous cycle.

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