Cognitive-impairing effects of medroxyprogesterone acetate in the rat: independent and interactive effects across time
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The synthetic progestin medroxyprogesterone acetate (MPA), widely used in hormone therapy (HT) and as the contraceptive Depo Provera, is implicated in detrimental cognitive effects in women. Recent evidence in aged ovariectomized (Ovx) rodents shows that short-term MPA treatment impairs cognition and alters the GABAergic system.
Using rats, we evaluated the long-lasting cognitive and GABAergic effects of MPA administered in young adulthood (Early-MPA), modeling contraception, and how this early exposure interacts with later MPA treatment (Late-MPA), modeling HT.
Early-MPA treatment involved weekly anti-ovulatory MPA injections (3.5 mg) from 4 to 8 months of age in ovary-intact rats. At 10 months old, rats were Ovx and weekly MPA injections were re-initiated and continued throughout testing for Late-MPA treatment.
On the water radial-arm maze, all MPA-treated groups showed working memory impairment compared to Controls (p < 0.05); Early + Late-MPA rats were impaired on multiple dimensions of working memory (p < 0.05). On the Morris maze, Late-MPA rats showed greater overnight forgetting compared to Controls (p < 0.05). At study conclusion, MPA was detected in serum in all MPA-treated groups except Early-MPA, confirming treatment and clearance from serum in Early-MPA rats. In animals with detectable serum MPA, higher MPA levels were associated with less dorsal-hippocampal glutamic acid decarboxylase, the synthesizing enzyme for GABA (p = 0.0059).
Findings suggest that MPA treatment leads to long-lasting cognitive impairments in the rodent, even in the absence of circulating MPA in animals given prior MPA treatment, which may relate to the GABAergic system. Further research defining the parameters of the negative impact of this widely used progestin on brain and cognition is warranted.
KeywordsHormone therapy Contraceptive Cognition Progestins Menopause Aging Learning and memory
This research was funded by grants awarded to HAB-N from the National Institute on Aging (AG028084), state of Arizona, ADHS and the Arizona Alzheimer’s Disease Core Center. LP recognizes support by the NIH Grant AG027956 and an endowment (BK-0031) from the Welch Foundation. We are grateful to Dr. Xiaoqian Liu for performing the LC–APCI-MS/MS assay and to Dr. Craig Enders for his expert statistical consultation. The authors have nothing to disclose regarding financial disclosures. The experiments comply with the current laws of the country in which they were performed.
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