Nilsen, J., & Brinton, R. D. (2002). Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. Endocrinology, 143(1), 205-212. https://doi.org/10.1210/endo.143.1.8582
Nilsen J, Brinton RD. Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. Endocrinology. 2002;143(1):205-212. doi:10.1210/endo.143.1.8582
Nilsen, Jon, and Roberta Diaz Brinton. "Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate." Endocrinology, vol. 143, no. 1, 2002, pp. 205-212.
In rat neurons, MPA blocked estrogen protection, progesterone did not
In rat brain cells grown in a dish, progesterone protected neurons from glutamate damage, alone and with estrogen. The synthetic progestin MPA gave no protection and blocked the protection estrogen gave. Researchers used neurons from rat fetuses.
Key Findings
At its most protective concentration, estrogen reduced glutamate-induced release of lactate dehydrogenase (LDH), a marker of cell damage, by approximately 18%. Progesterone reduced it by approximately 22% and 19-norprogesterone by approximately 21%.
Medroxyprogesterone acetate (MPA) alone had no effect on LDH release at either concentration tested.
Progesterone and 19-norprogesterone kept the protection when given with estrogen. No significant decrease in LDH release occurred when MPA was given with estrogen.
Estrogen and all three progestins activated MAPK, a cell-signaling pathway. MPA raised phospho-ERK2 immunoreactivity by approximately 60% and did not antagonize the effect of estrogen on MAPK.
Bcl-2, a protein that helps cells resist death, rose approximately 2.75-fold with estrogen, approximately 3-fold with progesterone and approximately 2.6-fold with 19-norprogesterone. MPA did not raise Bcl-2 and blocked the estrogen-induced increase.
Interpretation
Nilsen and Brinton ran a cell-culture experiment on neurons from the hippocampus of rat fetuses. They measured damage after a brief glutamate exposure. The three progestins split into two groups on protection and on Bcl-2, yet all three switched on MAPK. The authors suggest the choice of progestin in hormone replacement therapy needs attention. The authors say the MPA result fits two clinical studies in which the cognitive benefit of long-term estrogen therapy was lost when MPA was added.
RRM Context
Progesterone is the hormone an ovulatory cycle produces. MPA is a synthetic molecule. Restorative reproductive medicine keeps the two terms apart, and this paper adds evidence from rat neurons that the two can act in opposite directions on estrogen's effect.
Our editorial summary of this paper, not the article's abstract.
Abstract
Estrogen replacement therapy is associated with improvement of cognitive deficits and reduced incidence of Alzheimer's disease. To compare the impact of therapeutically relevant progestins on estrogen-induced neuroprotection, we treated primary hippocampal neuron cultures with 17beta-E2 and progestin, alone and in combination, 48 h before glutamate insult. Estrogen, progesterone, and 19-norprogesterone, alone or in combination, protected against glutamate toxicity. In contrast, medroxyprogesterone acetate (MPA) failed to protect against glutamate toxicity. Not only was MPA an ineffective neuroprotectant but it attenuated the estrogen- induced neuroprotection when coadministered. We addressed the role of MAPK activation in neuroprotection by ovarian steroids. Estrogen and all three progestins tested, alone or in combination, activated MAPK, indicating another mechanism of protection. Bcl-2 expression has been shown to prevent cell death and is up-regulated by 17beta-E2. Progesterone and 19-norprogesterone, alone or in combination with estrogen, increased Bcl-2 expression. In contrast, MPA blocked estrogen-induced Bcl-2 expression when coadministered. These results may have important implications for the effective use of hormone replacement therapy in the maintenance of neuronal function during menopause and aging and for protection against neurodegenerative diseases such as Alzheimer's disease.
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