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The Differences in Neuroprotective Efficacy of Progesterone and Medroxyprogesterone Acetate Correlate with Their Effects on Brain-Derived Neurotrophic Factor Expression

Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, 3400 Camp Bowie Boulevard, Fort Worth, Texas 76107-2699, USA.
Endocrinology (Impact Factor: 4.64). 04/2009; 150(7):3162-8. DOI: 10.1210/en.2008-1247
Source: PubMed

ABSTRACT Whereas hormone therapy is used for the treatment of menopausal symptoms, its efficacy in helping reduce the risk of other diseases such as Alzheimer's disease has been questioned in view of the results of recent clinical trials that appeared inconsistent with numerous basic research studies that supported the beneficial effects of hormones. One possible explanation of this discrepancy may lie in the choice of hormone used. For example, we and others found that progesterone is neuroprotective whereas medroxyprogesterone acetate (MPA), the synthetic progestin used in hormone therapy, is not. Because our data suggest that progesterone-induced protection is associated with the induction of brain-derived neurotrophic factor (BDNF) levels and, importantly, can be blocked by inhibiting the neurotrophin signaling, we determined whether progesterone and medroxyprogesterone acetate differed in their ability to regulate BDNF levels in the explants of the cerebral cortex. We found that progesterone elicited an increase in both BDNF mRNA and protein levels, whereas medroxyprogesterone acetate did not. Furthermore, using both a pharmacological inhibitor of the progesterone receptor (PR) and PR knockout mice, we determined that the effects of progesterone were mediated by the classical PR. Our results underscore the fact that not all progestins have equivalent effects on the brain and suggest that the selection of the appropriate progestin may influence the success of hormone therapy formulations used in treating the menopause and/or reducing the risk for diseases associated with the postmenopausal period.

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    • "bed that in cerebral cortical explants , the difference in neuroprotective effi - cacy between progesterone and MPA may have been attributed to their differential regulation of BDNF . Specifically , while proges - terone increased both the mRNA and protein levels of BDNF in the cerebral cortex , MPA treatment resulted in a substantial inhibition ( Jodhka et al . , 2009 ) . Combined with the observation that proges - terone ' s protective effects may be dependent on neurotrophin sig - naling ( Kaur et al . , 2007 ) , this inhibition of BDNF expression by MPA may actually suggest that it have adverse consequences to brain function . Similarly , the Brinton laboratory has shown in hip - pocampal cultures"
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    ABSTRACT: Studies have shown differences in specific cognitive ability domains and risk of Alzheimer's disease between the men and women at later age. However it is important to know that sex differences in cognitive function during adulthood may have their basis in both organizational effects, i.e., occurring as early as during the neuronal development period, as well as in activational effects, where the influence of the sex steroids influence brain function in adulthood. Further, the rate of cognitive decline with aging is also different between the sexes. Understanding the biology of sex differences in cognitive function will not only provide insight into Alzheimer's disease prevention, but also is integral to the development of personalized, gender-specific medicine. This review draws on epidemiological, translational, clinical, and basic science studies to assess the impact of sex differences in cognitive function from young to old, and examines the effects of sex hormone treatments on Alzheimer's disease in men and women.
    Frontiers in Neuroendocrinology 01/2014; 35(3). DOI:10.1016/j.yfrne.2014.01.002 · 7.58 Impact Factor
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    • "bed that in cerebral cortical explants , the difference in neuroprotective effi - cacy between progesterone and MPA may have been attributed to their differential regulation of BDNF . Specifically , while proges - terone increased both the mRNA and protein levels of BDNF in the cerebral cortex , MPA treatment resulted in a substantial inhibition ( Jodhka et al . , 2009 ) . Combined with the observation that proges - terone ' s protective effects may be dependent on neurotrophin sig - naling ( Kaur et al . , 2007 ) , this inhibition of BDNF expression by MPA may actually suggest that it have adverse consequences to brain function . Similarly , the Brinton laboratory has shown in hip - pocampal cultures"
    [Show abstract] [Hide abstract]
    ABSTRACT: Studies have shown differences in specific cognitive ability domains and risk of Alzheimer’s disease between the men and women at later age. However it is important to know that sex differences in cognitive function during adulthood may have their basis in both organizational effects, i.e., occurring as early as during the neuronal development period, as well as in activational effects, where the influence of the sex steroids influence brain function in adulthood. Further, the rate of cognitive decline with aging is also different between the sexes. Understanding the biology of sex differences in cognitive function will not only provide insight into Alzheimer’s disease prevention, but also is integral to the development of personalized, gender-specific medicine. This review draws on epidemiological, translational, clinical, and basic science studies to assess the impact of sex differences in cognitive function from young to old, and examines the effects of sex hormone treatments on Alzheimer’s disease in men and women.
    Frontiers in Neuroendocrinology 01/2014; · 7.58 Impact Factor
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    • "Most of the work comparing the neural effects of progesterone and MPA has examined the neuroprotective properties of these two progestagens . These studies typically find that progesterone results in neuroprotection whereas MPA antagonizes the neuroprotective properties of E 2 (Jodhka et al., 2009; Nilsen and Brinton, 2003). More recently, studies have investigated the effects of these two progestagens after long-term exposure, and although they sometimes result in divergent neural outcomes, natural progesterone does not seem to be more beneficial than MPA. "
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