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.


CONCLUSIONS
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.


CONCLUSIONS
Serotonergic mediation of estrogen has important clinical implications and warrants further evaluation.
Rybaczyk
Leszek A
LA
Integrated Biomedical Science Graduate Program, The Ohio State University, 1190 Graves Hall, 333 West 10th Avenue, Columbus, OH 43210-1218, USA. rybaczyk.1@osu.edu
Bashaw
Meredith J
MJ
Pathak
Dorothy R
DR
Moody
Scott M
SM
Gilders
Roger M
RM
Holzschu
Donald L
DL