Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling

Abstract

The impact of progestins on estrogen-inducible mechanisms of neuroprotection was investigated. Previously, we showed that estrogen and progesterone are neuroprotective against excitotoxicity, whereas the synthetic progestin medroxyprogesterone acetate (MPA; Provera) is not. Here, we demonstrate that 17␤-estradiol (E 2) and progesterone (P4) treatment of hippocampal neurons attenuated the excitotoxic glutamate-induced rise in intracellular calcium concentration. Although MPA had no effect alone, MPA completely antagonized E 2-induced attenuation of intracellular calcium concentration. Activation of extracellular receptor kinase (ERK) is required for estrogen-induced neuroprotection and calcium regulation. Paradoxically, E 2, P4, and MPA all elicited similar rapid and transient activation of ERK, presenting a contradiction between the dependence on ERK for gonadal hormone-induced neuroprotection and the lack of neuroprotection induced by MPA. Subcellular analysis of ERK demonstrated that the phospho-ERK signal is transduced to the nucleus only by E 2 and P4, not by MPA. These results indicate that the profile of nuclear translocation of ERK is consistent with the neuroprotective profile. Further, the E 2-induced nuclear translocation of ERK was blocked by coadministration of MPA. Results of this study reveal that nuclear ERK induction by ovarian steroids is predictive of the neuroprotective effects of estrogen and progestin treatments, revealing a hitherto unrecognized divergence of progestin signaling through the src͞ MAPK pathway. These results have much broader implications encompassing the impact of progestins on estrogen-mediated effects in multiple tissues. The recent results from the Women's Health Initiative trial, which used MPA as the progestinal agent, indicate that differences between progestin formulations are crucial to health outcomes in women.N eurologic benefits of estrogen replacement therapy in humans include reversal of estrogen deficiency-induced memory dysfunction and reduced risk of Alzheimer's disease (AD) (1-5). Recently, the Cache County Study confirmed a reduced risk of AD in elderly women on hormone replacement therapy (HRT) (6). Because progestins are added to HRT to prevent hyperplasia of the endometrium (7) and resulting uterine cancer (8), possible impacts of progestins need to be determined. Numerous studies have found contradictory effects of estrogen͞ progestin use and breast cancer (9), coronary heart disease (10), and cognition (11,12). Although some of these studies used the same hormone formulation [conjugated estrogens (Premarin) with medroxyprogesterone acetate (MPA; Provera)], many did not determine or subdivide the type of progestin used (9-14), raising the possibility that the apparent discrepancies in outcomes are due to the differences in cellular responses induced by different progestins. Such concerns have been underscored by the termination of the combined regimen arm of the Women's Health Initiative trial (11,12,15).In earlier work, we found that 17␤-estradiol (E 2...

Estrogen Receptor Protein Interaction with Phosphatidylinositol 3-Kinase Leads to Activation of Phosphorylated Akt and Extracellular Signal-Regulated Kinase 1/2 in the Same Population of Cortical Neurons: A Unified Mechanism of Estrogen Action

“…The intensity of pERK1/2 signal increased gradually from 10 to 30 min with a time-dependent increase. We further observed that E 2 induced pERK translocation to the nucleus, which was consistent with previous observations from our group (Nilsen and Brinton, 2003b). Nuclear localization of pERK1/2, which was evident at the first time point of 10 min, was sustained at 20 and 30 min.…”

“…Primary cultures of cortical neurons were obtained from embryonic day 18 rat fetuses as described previously (Nilsen and Brinton, 2003b;Brewer et al, 2006). Briefly, cortical cells were dissected and treated with 0.02% trypsin in HBSS (Invitrogen) for 5 min at 37°C and dissociated by repeated passage through a series of fire-polished constricted Pasteur pipettes.…”

“…Mechanistically, E 2 activates a myriad of signaling cascades in neurons, including mitogen-activated protein kinase (MAPK) (Watters et al, 1997;Singer et al, 1999;Singh et al, 1999;Nilsen and Brinton, 2003b), phosphatidylinositol-3 kinase (PI3K) (Singh, 2001;Cardona-Gomez et al, 2002), G-protein-regulated signaling (Kelly et al, 2002), c-Fos (Rudick and Woolley, 2000), protein kinase C (PKC) (Cordey et al, 2003), and Ca 2ϩ influx (Cordey et al, 2003;Wu et al, 2005). Each of these have been associated with E 2 regulation of neuronal function and survival (Singh et al, 1994;McEwen et al, 1997;Mor et al, 1999;Woolley, 1999;Brinton, 2001;McEwen, 2001;Brinton, 2002, 2003a).…”

“…In parallel, E 2 -dependent MAPK activation phosphorylates cAMP response element-binding protein (CREB), which increases transcription of genes related to morphogenesis, including spinophilin (Zhao et al, 2005), and the anti-apoptotic proteins Bcl-2 (Nilsen and Brinton, 2003a) and Bcl-xl (Pike, 1999), required for neuroprotection. Both the phosphorylated Akt (pAkt) and phosphorylated extracellular signalregulated kinase 1/2 (pERK1/2) pathways are activated within minutes of E 2 exposure and have been associated with a membrane site of E 2 action (Nilsen and Brinton, 2003b;ToranAllerand et al, 2005;Wu et al, 2005).…”

Frontiers proposal. National Institute on Aging “bench to bedside: estrogen as a case study”

“…In some model systems, progestogens such as medroxyprogesterone acetate (MPA) are associated with outcomes very different from those associated with progesterone (Nilsen and Brinton 2003). At the same time, there is increasing evidence that progesterone has neuroprotective effects that may be very useful clinically (Stein 2007).…”