An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

BACKGROUND: In humans, serotonin has typically been investigated as a neurotransmitter. However, serotonin also functions as a hormone across animal phyla, including those lacking an organized central nervous system. This hormonal action allows serotonin to have physiological consequences in systems outside the central nervous system. Fluctuations in estrogen levels over the lifespan and during ovarian cycles cause predictable changes in serotonin systems in female mammals. DISCUSSION: We hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution. Here, we integrate data from endocrinology, molecular biology, neuroscience, and epidemiology to propose that serotonin may mediate the effects of estrogen. In the central nervous system, estrogen influences pain transmission, headache, dizziness, nausea, and depression, all of which are known to be a consequence of serotonergic signaling. Outside of the central nervous system, estrogen produces changes in bone density, vascular function, and immune cell self-recognition and activation that are consistent with serotonin's effects. For breast cancer risk, our hypothesis predicts heretofore unexplained observations of the opposing effects of obesity pre- and post-menopause and the increase following treatment with hormone replacement therapy using medroxyprogesterone. SUMMARY: Serotonergic mediation of estrogen has important clinical implications and warrants further evaluation

Quinolinate and related excitotoxins: mechanisms of neurotoxicity and disease relevance

There are many ways in which neuronal damage can be produced in the brain, including the overactivation of depolarizing receptors, exposure to high levels of pro-inflammatory proteins such as cytokines, or miscellaneous toxins, but the kynurenine pathway has emerged as a novel but potentially major factor in regulating neuronal viability or death. It is the major route for the metabolism of the essential amino acid tryptophan, which is oxidized by indoleamine-2,3-dioxygenase (IDO) to a series of compounds which can activate, block, or modulate conventional neurotransmitter receptors. Quinolinic acid is an agonist at N-methyl-d-aspartate receptors, kynurenic acid is an antagonist at these and other glutamate receptors, and other kynurenine metabolites are highly redox-active. Superimposed on the discovery of this neuromodulatory pathway have been observations that activity in the pathway is linked to neurological and psychiatric disorders, correlating with disease state (as in Huntington’s disease) or cognitive function (as following bypass surgery). Together, the data accumulated to date make a strong case for this hitherto obscure pathway being a major factor in determining cell damage, death, or recovery in health and disease

Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial

Background Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drugs ability to prevent type 2 diabetes in individuals at high risk of developing the condition