Article

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.

0 Followers
 · 
79 Views
 · 
0 Downloads
    • "However, hormones are still commonly prescribed on and off-label for non-cognitive indications, and some hormone formulations may impart a cognitive benefit for some women. There is emerging evidence that progestins and progesterone do not equivalently influence neurobiological mechanisms of cognitive function, and that progesterone is likely to be more beneficial and carry fewer risks than its synthetic counterparts (Fischer et al., 2014; Jodhka et al., 2009; Maki, 2012; Singh and Su, 2013a). Despite this distinction, there is currently little evidence on the cognitive effects of progesterone in postmenopausal women. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The effects of postmenopausal hormone treatment on cognitive outcomes are inconsistent in the literature. Emerging evidence suggests that cognitive effects are influenced by specific hormone formulations, and that progesterone is more likely to be associated with positive outcomes than synthetic progestin. There are very few studies of unopposed progesterone in postmenopausal women, and none that use functional neuroimaging, a sensitive measure of neurobiological function. In this study of 29 recently postmenopausal women, we used functional MRI and neuropsychological measures to separately assess the effects of estrogen or progesterone treatment on visual and verbal cognitive function. Women were randomized to receive 90 days of either estradiol or progesterone counterbalanced with placebo. After each treatment arm, women were given a battery of verbal and visual cognitive function and working memory tests, and underwent functional MRI including verbal processing and visual working memory tasks. We found that both estradiol and progesterone were associated with changes in activation patterns during verbal processing. Compared to placebo, women receiving estradiol treatment had greater activation in the left prefrontal cortex, a region associated with verbal processing and encoding. Progesterone was associated with changes in regional brain activation patterns during a visual memory task, with greater activation in the left prefrontal cortex and right hippocampus compared to placebo. Both treatments were associated with a statistically non-significant increase in number of words remembered following the verbal task performed during the fMRI scanning session, while only progesterone was associated with improved neuropsychological measures of verbal working memory compared to placebo. These results point to potential cognitive benefits of both estrogen and progesterone. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Psychoneuroendocrinology 05/2015; 59. DOI:10.1016/j.psyneuen.2015.04.020 · 5.59 Impact Factor
  • Source
    • "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; 35(3). DOI:10.1016/j.yfrne.2014.01.002 · 7.58 Impact Factor
  • Source
    • "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
Show more