The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 13 No. 6 • December 2010


Delay in Administering Hormone Replacement Therapy in
Postmenopausal Women Results in Loss of Estrogen Protection:
Possible Prevention by Cholinergic Nervous System

A new paper1 makes a plausible suggestion for a mechanism that may explain why it is that, if delayed too long after menopause, estrogen loses its ability to protect against cardiovascular disease and age-associated cognitive impairment.

As has been widely discussed recently, the discrepant findings on whether estrogen replacement therapy provides protective benefits to women with respect to cardiovascular risk and also risk of cognitive decline has resulted in a realization that an excessive delay in replacing estrogen/progesterone results in a loss of protective effects. In fact, in studies in which women received hormone replacement containing conjugated estrogens or conjugated estrogens and a synthetic progestagen, delayed treatment resulted in increased risk of cardiovascular disease.

The new study1 found in that in rats 9 and 15 months post-ovariectomy, estrogen replacement (17-beta estradiol) was still able to induce a significant increase in the magnitude of LTP (long term potentiation, a critical process in learning and memory) in the hippocampus, whereas in rats 19 months post-ovariectomy, the magnitude of LTP in hippocampal slices from the estrogen treated rats no longer differed from that seen in the vehicle-treated controls.

The researchers surmise that “[t]he inability of E2 [estrogen] to increase synaptic plasticity and spine density reported here and hippocampal learning reported by others after prolonged E2 deprivation might be explained by decreased hippocampal cholinergic function.” They note that “an extensive literature has documented a key role of cholinergic innervation in mediating the beneficial effects of E2 on spatial learning.” Moreover, they explain, OVX [ovariectomy] leads to a significant decrease in ChAT [choline acetyltransferase] mRNA in basal forebrain cholinergic neurons and acetylcholine release in the hippocampus beyond that of normal aging. Thus, a threshold may exist at which cholinergic function is so severely depleted that E2’s effects on synaptic function and learning cannot be elicited. In support of this idea, a recent elegant study showed that pharmacological inhibition of acetylcholinesterase in vivo rescued the ability to E2 to enhance cognitive function in aged rats 19 to 24 mon post-OVX.” It is well known that the cholinergic nervous system suffers age-related decline, one mechanism being the demonstrated reduced ability of older brains of humans to transport choline into the brain.

This is a hypothesis and has not been directly tested yet. However, there is considerable supportive evidence (as noted above). If cholinergic dysfunction is the cause of the loss of estrogenic protective effects after a “critical period” post-menopause, then a possible “fix” for this problem is to take supplemental choline (from, for example, our sugar-free choline formulation) and a cholinesterase inhibitor, such as is found in a galantamine-containing product. This might work even to restore estrogen protective effects after the “critical period” (the “use by” date) has passed.

Reference

  1. Smith et al. Duration of estrogen deprivation, not chronological age, prevents estogen’s ability to enhance hippocampal synaptic physiology. Proc Natl Acad Sci USA 107(45):19543-8 (2010).

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