Differential effects of hormone therapy on serotonin, vascular function and mood in the KEEPS

Abstract

Background Serotonin (5-hydroxytryptamine, 5-HT) is modulated by sex steroid hormones and affects vascular function and mood. In the Kronos Early Estrogen Prevention Cognitive and Affective Ancillary Study (KEEPS-Cog), women randomized to oral conjugated equine estrogens (oCEE) showed greater benefit on affective mood states than women randomized to transdermal 17β-estradiol (tE2) or placebo (PL). This study examined the effect of these treatments on the platelet content of 5-HT as a surrogate measure of 5-HT synthesis and uptake in the brain.

Methods The following were measured in a subset (n = 79) of women enrolled in KEEPS-Cog: 5-HT by ELISA, carotid intima-medial thickness (CIMT) by ultrasound, endothelial function by reactive hyperemic index (RHI), and self-reported symptoms of affective mood states by the Profile of Mood States (POMS) questionnaire.

Results Mean platelet content of 5-HT increased by 107.0%, 84.5% and 39.8%, in tE2, oCEE and PL groups, respectively. Platelet 5-HT positively correlated with estrone in the oCEE group and with 17β- estradiol in the tE2 group. Platelet 5-HT showed a positive association with RHI, but not CIMT, in the PL and oCEE groups. Reduction in mood scores for depression-dejection and anger-hostility was associated with elevations in platelet 5-HT only in the oCEE group (r = −0.5, p = 0.02).

Conclusions Effects of oCEE compared to tE2 on RHI and mood may be related to mechanisms involving platelet, and perhaps neuronal, uptake and release of 5-HT and reflect conversion of estrone to bioavailable 17β-estradiol in platelets and the brain.

Keywords:

• Conjugated equine estrogen
• 17β-estradiol
• 5-hydroxytryptamine
• Kronos Early Estrogen Prevention Study
• platelet

Acknowledgements

We gratefully acknowledge the dedicated efforts of all the investigators and staff at the KEEPS clinical centers, the KEEPS Data Coordinating Center at KLRI, study coordinator, Teresa G. Zais (deceased), and Robert D. Litwiller for technical assistance collecting the blood. Above all, we recognize and thank the KEEPS participants for their dedication and commitment to the programs of the Mayo Clinic Women’s Health Research Center.

Author contributions

Dr Raz: conceptualization of the study, analysis and interpretation of the data, drafting the manuscript. Larry Hunter: data collection, analysis and revising the manuscript. Dr Dowling: data collection, interpretation of data and revising the manuscript. Dr Wharton: data collection, interpretation of data and revising the manuscript. Dr Gleason: data collection, interpretation of data and revising the manuscript. Dr Jayachandran: analysis and interpretation of the data, revising the manuscript. Layne Anderson: data collection. Dr Asthana: design or conceptualization of the study, interpretation of data and revising the manuscript. Dr Miller: design or conceptualization of the study, interpretation of data and revising the manuscript.

Conflict of interest

The authors report no conflict of interest.

Source of funding

The Aurora Foundation to the Kronos Longevity Research Institute, NIH HL90639, NS066147, HD65987, AG029624, P50 AG033514, UL1 RR024150 and the Mayo Foundation. Study medications for KEEPS were supplied in part by Bayer Health Care and by Abbott Pharmaceuticals. UL1 RR024150 is from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.