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: 4.72). 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 Bookmarks
 · 
49 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Given that the pregnane neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP), is increased following behavioral challenges (e.g., mating), and that there is behavioral-induced biosynthesis of 3α,5α-THP in midbrain and mesocorticolimbic structures, 3α,5α-THP likely has a role in homeostasis and motivated reproduction and reproduction-related behaviors (e.g., affect, affiliation). The role of pregnane xenobiotic receptor (PXR), involved in cholesterol metabolism, for these effects is of continued interest. We hypothesized that there would be differences in brain levels of 3α,5α-THP following varied behavioral experiences, an effect abrogated by knockdown of PXR in the midbrain. Proestrous rats were infused with PXR antisense oligonucleotides (AS-ODNs) or vehicle to the ventral tegmental area before different behavioral manipulations and assessments. Endpoints were expression levels of PXR in the midbrain, 3α,5α-THP, and ovarian steroids (estradiol, progesterone, dihydroprogesterone) in the midbrain, striatum, hippocampus, hypothalamus, prefrontal cortex, and plasma. Across experiments, knocking down PXR reduced PXR expression and 3α,5α-THP levels in the midbrain and hippocampus. There were differences in terms of the behavioral manipulations, such that paced mating had the most robust effects to increase 3α,5α-THP levels and reduce open field exploration and social interaction. An additional question that was addressed is whether brain-derived neurotrophic factor (BDNF) is a downstream factor for regulating effects of behavioral-induced 3α,5α-THP biosynthesis. Rats infused with PXR AS-ODNs had lower levels of BDNF in the hippocampus. Thus, PXR may be a regulator of mating-induced 3α,5α-THP formation and behavioral changes and neural plasticity, such as BDNF.
    Psychopharmacology 05/2014; · 4.06 Impact Factor
  • [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; · 7.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Studies show increased autism risk among children born to mothers experiencing obstetrical complications. Although this is usually interpreted as suggesting that the obstetrical complications could be causing autism, it is possible that a single factor could be responsible for both complications and autism. We hypothesized that low levels of the hormone progesterone is responsible since it is supplied to the fetus maternally and does not only support pregnancy but also promotes brain development. Following a review of the literature, we report findings from a survey of mothers of autistic children (n=86) compared to mothers of typically-developing children (n=88) regarding obstetrical histories, including five obstetrical risk factors indicative of low progesterone. Using this analysis, the ASD group had significantly more risk factors than controls (1.21±0.09 vs. 0.76±0.08, p<.0001), suggesting low progesterone. Thus, results suggest that low progesterone may be responsible for both obstetrical complications and brain changes associated with autism and that progesterone levels should be routinely monitored in at-risk pregnancies. Our hypothesis also suggests that ensuring adequate levels of progesterone may decrease the likelihood of autism.
    Medical Hypotheses 01/2014; · 1.18 Impact Factor