Dr. Ron’s Research Review – February 11, 2015

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This week’s research review focuses on the critical period hypothesis of estradiol.

Soon after the WHI results were published, Sherwin, Maki and others proposed the “critical period hypothesis,” which states that a precise window of opportunity exists for beneficial hormone therapy following menopause.
If hormone therapy is initiated after a significant period of time (i.e. 10 years) has elapsed following menopause, outside the window of opportunity, then the beneficial effects of estradiol on cognitive decline could be significantly attenuated.

A recent study showed that galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats. Galanthamine is a cholinesterase inhibitor used to treat memory impairment associated with Alzheimer's disease. This could be of particular benefit to older women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment.  (Gibbs et al., 2011)

During the menopause transition, hormonal measurements of FSH and E2 are of little diagnostic value because of their unpredictable variability. (Burger, 2011)

Dr. Ron


 

Articles

Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats.
            (Gibbs et al., 2011) Download
We hypothesize that beneficial effects of estradiol on cognitive performance diminish with age and time following menopause due to a progressive decline in basal forebrain cholinergic function. This study tested whether galanthamine, a cholinesterase inhibitor used to treat memory impairment associated with Alzheimer's disease, could enhance or restore estradiol effects on cognitive performance in aged rats that had been ovariectomized in middle-age. Rats were ovariectomized at 16-17 months of age. At 21-22 months of age rats began receiving daily injections of galanthamine (5mg/day) or vehicle. After one week, half of each group also received 17ss-estradiol administered subcutaneously. Rats were then trained on a delayed matching to position (DMP) T-maze task, followed by an operant stimulus discrimination/reversal learning task. Treatment with galanthamine+estradiol significantly enhanced the rate of DMP acquisition and improved short-term delay-dependent spatial memory performance. Treatment with galanthamine or estradiol alone was without significant effect. Effects were task-specific in that galanthamine+estradiol treatment did not significantly improve performance on the stimulus discrimination/reversal learning task. In fact, estradiol was associated with a significant increase in incorrect responses on this task after reversal of the stimulus contingency. In addition, treatments did not significantly affect hippocampal choline acetyltransferase activity or acetylcholine release. This may be an effect of age, or possibly is related to compensatory changes associated with long-term cholinesterase inhibitor treatment. The data suggest that treating with a cholinesterase inhibitor can enhance the effects of estradiol on acquisition of a DMP task by old rats following a long period of hormone deprivation. This could be of particular benefit to older women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment. Potential mechanisms for these effects are discussed.


 

Estrogen neuroprotection and the critical period hypothesis.
            (Scott et al., 2012) Download
17beta-Estradiol (estradiol or E2) is implicated as a neuroprotective factor in a variety of neurodegenerative disorders. This review focuses on the mechanisms underlying E2 neuroprotection in cerebral ischemia, as well as emerging evidence from basic science and clinical studies, which suggests that there is a "critical period" for estradiol's beneficial effect in the brain. Potential mechanisms underlying the critical period are discussed, as are the neurological consequences of long-term E2 deprivation (LTED) in animals and in humans after natural menopause or surgical menopause. We also summarize the major clinical trials concerning postmenopausal hormone therapy (HT), comparing their outcomes with respect to cardiovascular and neurological disease and discussing their relevance to the critical period hypothesis. Finally, potential caveats, controversies and future directions for the field are highlighted and discussed throughout the review.

Unpredictable endocrinology of the menopause transition: clinical, diagnostic and management implications.
            (Burger, 2011) Download
The approach to menopause can be divided into the early (E) and late (L) menopausal transitions (MT) on the basis of menstrual irregularity (EMT) and subsequent observation of at least one episode of 60 or more days amenorrhoea (LMT). In total, 40-60% of cycles in the LMT are anovulatory, often with low oestradiol (E2) and high follicle-stimulating hormone concentrations. The ovulatory cycles have variable endocrine characteristics, none of which is specific to EMT or LMT. Hormonal measurements of FSH and E2 are thus of little diagnostic value because of their unpredictable variability. Symptoms during the transitions may result from high or low E2 and can often be satisfactorily managed with low-dose oral contraceptives, which suppress pituitary-ovarian function.


 

References

Burger, HG (2011), ‘Unpredictable endocrinology of the menopause transition: clinical, diagnostic and management implications.’, Menopause Int, 17 (4), 153-54. PubMedID: 22120939
Gibbs, RB, et al. (2011), ‘Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats.’, Horm Behav, 60 (5), 607-16. PubMedID: 21889940
Scott, E, et al. (2012), ‘Estrogen neuroprotection and the critical period hypothesis.’, Front Neuroendocrinol, 33 (1), 85-104. PubMedID: 22079780