The menopause and HRT. HRT and cognitive decline.
ABSTRACT It is biologically plausible that hormone replacement therapy (HRT) would be protective against cognitive decline and Alzheimer's disease (AD). We review observational and randomized trials to determine whether HRT might protect against cognitive decline in cognitively unimpaired and demented women. We also address issues of clinical relevance, including duration and type of treatment and patient characteristics, including type of menopause (surgical versus natural), age, education and menopausal symptoms. Differences in participant characteristics and testing methods limit the ability to draw conclusions across randomized studies of HRT in non-demented women. The available evidence suggests no detrimental effect of HRT on cognitive function and inconsistent benefits on verbal memory and reasoning, frontal functions and speeded attention. Meta-analyses of observational trials suggest that HRT protects against the development of AD, but randomized trials indicate no long-lasting benefit in patients with AD. Evidence is insufficient to recommend HRT to maintain cognitive function.
Article: Effects of two years of conjugated equine estrogens on cholinergic neurons in young and middle-aged ovariectomized monkeys.[show abstract] [hide abstract]
ABSTRACT: The effect of estrogen on the number and size of cholinergic neurons in the basal forebrain was examined in surgically menopausal young and middle-aged cynomolgus monkeys. Young and middle-aged female monkeys were ovariectomized and treated with conjugated equine estrogens (Premarin) at doses that are equivalent to those currently prescribed to postmenopausal women. In the medial septum/diagonal band (MS/DB), no effect of treatment with Premarin was observed in the cholinergic neurons in either ovariectomized young or middle-aged monkeys. However, the number and size of cholinergic neurons in the MS/DB of middle-aged monkeys was greater than that in the young monkeys. In the nucleus basalis of Meynert (NBM) of middle-aged monkeys, the number of cholinergic neurons in the intermediate region (Ch4i) was greater in Premarin-treated monkeys as compared to controls and numbers of neurons in this region were greater at higher levels of estrogen. No effects of estrogen were observed in other NBM regions in the middle-aged monkeys and the size of cholinergic neurons was unaffected by Premarin. These findings suggest that treatment with Premarin has selective beneficial effects on cholinergic neurons in the basal forebrain but that these effects are both age and region specific.Brain research 02/2009; 1264:13-23. · 2.46 Impact Factor
Article: Benzothiophene Selective Estrogen Receptor Modulators Provide Neuroprotection by a novel GPR30-dependent Mechanism.[show abstract] [hide abstract]
ABSTRACT: The clinical benzothiophene SERM (BT-SERM), raloxifene, was compared with estrogens in protection of primary rat neurons against oxygen-glucose deprivation (OGD). Structure-activity relationships for neuroprotection were determined for a family of BT-SERMs displaying a spectrum of ERα and ERβ binding affinity and agonist/antagonist activity, leading to discovery of a neuroprotective pharmacophore, present in the clinically relevant SERMS, raloxifene and desmethylarzoxifene (DMA), for which submicromolar potency was observed for neuroprotection. BT-SERM neuroprotection did not correlate with binding to ER nor classical ER activity, however, both the neuroprotective SERMs and estrogens were shown, using pharmacological probes, to activate the same kinase signaling cascades. The antiestrogen ICI 182,780 inhibited the actions of estrogens, but not those of BT-SERMs, whereas antagonism of the G-protein coupled receptor, GPR30, was effective for both SERMs and estrogens. Since SERMs have antioxidant activity, ER-independent mechanisms were studied using the classical phenolic antioxidants, BHT and Trolox, and the Nrf2-dependent cytoprotective electrophile, sulforaphane. However, neuroprotection by these agents was not sensitive to GPR30 antagonism. Collectively, these data indicate that the activity of neuroprotective BT-SERMs is GPR30-dependent and ER-independent and not mediated by antioxidant effects. Comparison of novel BT-SERM derivatives and analogs identified a neuroprotective pharmacophore of potential use in design of novel neuroprotective agents with a spectrum of ER activity.ACS Chemical Neuroscience 05/2011; 2(5):256-268. · 3.68 Impact Factor
Article: Effects of conjugated equine estrogens on cognition and affect in postmenopausal women with prior hysterectomy.[show abstract] [hide abstract]
ABSTRACT: Different menopausal hormone therapies may have varied effects on specific cognitive functions. We previously reported that conjugated equine estrogens (CEE) with medroxyprogesterone acetate had a negative impact on verbal memory but tended to impact figural memory positively over time in older postmenopausal women. The objective of the study was to determine the effects of unopposed CEE on changes in domain-specific cognitive function and affect in older postmenopausal women with prior hysterectomy. This was a randomized, double blind, placebo-controlled clinical trial. The study was conducted at 14 of 40 Women's Health Initiative (WHI) clinical centers. Participants were 886 postmenopausal women with prior hysterectomy, aged 65 yr and older (mean 74 yr), free of probable dementia, and enrolled in the WHI and WHI Memory Study (WHIMS) CEE-Alone trial for a mean of 3 yr and followed up for a mean of 2.70 yr. Intervention was 0.625 mg of CEE daily or placebo. Annual rates of change in specific cognitive functions and affect, adjusted for time since randomization, were measured. Compared with placebo, unopposed CEE was associated with lower spatial rotational ability (P < 0.01) at initial assessment (after 3 yr of treatment), a difference that diminished over 2.7 yr of continued treatment. CEE did not significantly influence change in other cognitive functions and affect. CEE did not improve cognitive functioning in postmenopausal women with prior hysterectomy. CEE was associated with lower spatial rotational performance after an average of 3 yr of treatment. Overall, CEE does not appear to have enduring effects on rates of domain-specific cognitive change in older postmenopausal women.The Journal of clinical endocrinology and metabolism 11/2009; 94(11):4152-61. · 6.50 Impact Factor