Differential Effects of Hormone Therapy on Serotonin, Vascular Function and Mood in the KEEPS

Overview

Journal Climacteric

Publisher Informa Healthcare

Date 2015 Dec 15

PMID 26652904

Citations 10

Authors

L Raz

L V Hunter

N M Dowling

W Wharton

C E Gleason

M Jayachandran

L Anderson

S Asthana

V M Miller

Affiliations

Soon will be listed here.

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.

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References

Miller V, Lewis D, Barber D . Gender differences and endothelium- and platelet-derived factors in the coronary circulation. Clin Exp Pharmacol Physiol. 1999; 26(2):132-6. DOI: 10.1046/j.1440-1681.1999.02997.x. View

Guicheney P, Leger D, Barrat J, TREVOUX R, de Lignieres B, Roques P . Platelet serotonin content and plasma tryptophan in peri- and postmenopausal women: variations with plasma oestrogen levels and depressive symptoms. Eur J Clin Invest. 1988; 18(3):297-304. DOI: 10.1111/j.1365-2362.1988.tb01262.x. View

Hodis H, Mack W, Lobo R, Shoupe D, Sevanian A, MAHRER P . Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001; 135(11):939-53. DOI: 10.7326/0003-4819-135-11-200112040-00005. View

Sanchez M, Morissette M, Di Paolo T . Oestradiol modulation of serotonin reuptake transporter and serotonin metabolism in the brain of monkeys. J Neuroendocrinol. 2013; 25(6):560-9. DOI: 10.1111/jne.12034. View

Harman S, Black D, Naftolin F, Brinton E, Budoff M, Cedars M . Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med. 2014; 161(4):249-60. DOI: 10.7326/M14-0353. View

Alberti K, Zimmet P, Shaw J . Metabolic syndrome--a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med. 2006; 23(5):469-80. DOI: 10.1111/j.1464-5491.2006.01858.x. View

Mulvagh S, Behrenbeck T, Lahr B, Bailey K, Zais T, Araoz P . Endothelial function and cardiovascular risk stratification in menopausal women. Climacteric. 2009; 13(1):45-54. DOI: 10.3109/13697130902943287. View

Flaumenhaft R, Nachtigall M, Lowenstein J, Nachtigall L, Nachtigall R, Nachtigall L . Association of oral but not transdermal estrogen therapy with enhanced platelet reactivity in a subset of postmenopausal women. Menopause. 2008; 16(2):407-12. DOI: 10.1097/gme.0b013e3181833886. View

Nobler M, Mann J, Sackeim H . Serotonin, cerebral blood flow, and cerebral metabolic rate in geriatric major depression and normal aging. Brain Res Brain Res Rev. 1999; 30(3):250-63. DOI: 10.1016/s0165-0173(99)00019-3. View

10.

Miller V, Duckles S . Vascular actions of estrogens: functional implications. Pharmacol Rev. 2008; 60(2):210-41. PMC: 2637768. DOI: 10.1124/pr.107.08002. View

11.

Vanhoutte P, Luscher T . Serotonin and the blood vessel wall. J Hypertens Suppl. 1986; 4(1):S29-35. View

12.

Gleason C, Dowling N, Wharton W, Manson J, Miller V, Atwood C . Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med. 2015; 12(6):e1001833. PMC: 4452757. DOI: 10.1371/journal.pmed.1001833. View

13.

Miller V, Hunter L, Chu K, Kaul V, Squillace P, Lieske J . Biologic nanoparticles and platelet reactivity. Nanomedicine (Lond). 2009; 4(7):725-33. PMC: 2785539. DOI: 10.2217/nnm.09.61. View

14.

Schmidt P, Nieman L, Danaceau M, Tobin M, Roca C, Murphy J . Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol. 2000; 183(2):414-20. DOI: 10.1067/mob.2000.106004. View

15.

Kopper N, Gudeman J, Thompson D . Transdermal hormone therapy in postmenopausal women: a review of metabolic effects and drug delivery technologies. Drug Des Devel Ther. 2009; 2:193-202. PMC: 2761184. DOI: 10.2147/dddt.s4146. View

16.

Campagnoli C, Biglia N, Altare F, Lanza M, Lesca L, Cantamessa C . Differential effects of oral conjugated estrogens and transdermal estradiol on insulin-like growth factor 1, growth hormone and sex hormone binding globulin serum levels. Gynecol Endocrinol. 1993; 7(4):251-8. DOI: 10.3109/09513599309152509. View

17.

Jayachandran M, Miller V . Ovariectomy upregulates expression of estrogen receptors, NOS, and HSPs in porcine platelets. Am J Physiol Heart Circ Physiol. 2002; 283(1):H220-6. DOI: 10.1152/ajpheart.00950.2001. View

18.

Sumner B, Grant K, Rosie R, Hegele-Hartung C, Fritzemeier K, Fink G . Effects of tamoxifen on serotonin transporter and 5-hydroxytryptamine(2A) receptor binding sites and mRNA levels in the brain of ovariectomized rats with or without acute estradiol replacement. Brain Res Mol Brain Res. 1999; 73(1-2):119-28. DOI: 10.1016/s0169-328x(99)00243-0. View

19.

Park K, Pepine C . Pathophysiologic mechanisms linking impaired cardiovascular health and neurologic dysfunction: the year in review. Cleve Clin J Med. 2010; 77 Suppl 3:S40-5. DOI: 10.3949/ccjm.77.s3.07. View

20.

Greendale G, Derby C, Maki P . Perimenopause and cognition. Obstet Gynecol Clin North Am. 2011; 38(3):519-35. PMC: 3185244. DOI: 10.1016/j.ogc.2011.05.007. View