P2‐248: Continuous and cyclic progesterone differentially affect estrogen regulation of Alzheimer‐like pathology in female 3xTg‐AD mice
Year: 2009
Type: article
Abstract: Women have a higher risk for Alzheimer's disease (AD) than men, presumably because of the depletion of estrogen and progesterone at menopause. However, the use of estrogen plus progestin hormone therapy (HT) to reduce the risk of AD in post-menopausal women has proven controversial and less successful than anticipated. One hypothesized problem is the use of continuous hormone delivery rather than a cyclic pattern that mimics natural hormonal fluctuations. We recently demonstrated that continuous progesterone treatment attenuated the beneficial effects of estradiol treatment on beta amyloid accumulation in female AD transgenic mice. However, the effects of variable progesterone treatment exposure are unknown. This study compared the effects of continuous versus cyclic progesterone treatment in regulating AD-like neuropathology in female 3xTg-AD mice. Adult female 3xTg-AD mice received sham surgery or were ovariectomized then immediately treated for with one of the following hormone regimes: a) sham+placebo, b) OVX+placebo, c) OVX+E2 (continuous estradiol, d) OVX+P4 (continuous progesterone), e) OVX+E2+P4, f) OVX+p4 (cyclic progesterone), and g) OVX+E2+p4. These treatments were achieved using subcutaneous, slow-release pellets including either a 90-day, E2 or P4 pellet, and/or a 10-day, P4 pellet inserted on the 20th day every 30 days for 90 days. Following hormone treatment, hippocampal-dependent working memory was assessed in the Y-maze, levels of beta amyloid protein were quantified by immunohistochemical load, and levels of tau hyperphosphorylation were quantified by counts of tau-immunoreactive cells. Consistent with our previous findings, we observed that constant P4 attenuated the effects of E2 on beta amyloid accumulation and working memory but had beneficial effects on lowering tau hypoerphosphorylation. Further, we observed that cyclic progesterone treatment, which more closely mimics women's natural, monthly hormone fluctuation, had a synergistic effect with estradiol to reduce beta amyloid accumulation specifically in the subiculum and frontal cortex, reduce deficits in working memory and lower tau hyperphosphorylation. These results demonstrate in an animal model of AD that continuous progesterone attenuates whereas cyclic progesterone augments the protective benefits of estrogen in reducing AD-related neuropathology. These findings question the current use of continuous progestin in HT and suggest the need to clinically evaluate cyclic progesterone in HT.
Source: Alzheimer s & Dementia
Institution: University of Southern California
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1984438417