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: 17β-estradiol; 5-hydroxytryptamine; Conjugated equine estrogen; Kronos Early Estrogen Prevention Study; platelet.

Figure 1

Flow chart defining the KEEPS-Cog cohort participating in this study. Total number of participants (n = 79) in whom sufficient serum and platelets were available for analysis is reported by treatment group in placebo (PL), transdermal (tE2) or oral (oCEE) estrogen preparations.

Figure 2

Levels of 5-HT in serum (left panel) and platelet lysates (right panel) at baseline (BL) and after 48 months (48m) of treatment with placebo (PL), transdermal 17β estradiol (tE2) or oral conjugated equine estrogens(oCEE). Asterisk denotes statistical significant difference from BL (p = 0.002*).

Figure 3

Correlations of serum estrone (E1), estradiol (E2), sex hormone binding globulin (SHBG) and testosterone (T) with platelet lysate levels of 5-HT in women receiving placebo (PL) and transdermal (tE2, 17β-estradiol; Climera, 50 μg/day) or oral (oCEE; Premarin, 0.45 mg/day) hormone preparations. Each dot represents an individual. .

Figure 4

Relationship between platelet 5-HT and endothelial function as measured by flow-mediated reactive hyperemia index (RHI) via pulse volume digital tonometry at 48m. Correlations are presented by treatment in placebo (PL, n = 21), transdermal (tE2, n = 14) and oral (oCEE, n = 13) groups. Each symbol represents data from an individual.

Figure 5

Associations of peripheral platelet 5-HT levels (pg/mg protein) with components of mood by treatment group at 48m. A lower self-reported mood score represents improved mood. Consistent significant associations were found between increases in platelet 5-HT and decreases in scores for depression-dejection and anger-hostility (less depression-dejection and anger-hostility) in the oCEE group at follow up (r = −0.52, p = 0.02).