Abstract
Animal experiments have consistently shown that estrogen receptor β (ERβ)-selective ligands have antidepressant and anxiolytic effects. In humans, endogenous ligands for ERβ include 5α-androstane-3β, 17β-diol (3βAdiol) and androstenediol (Δ5-diol). We determined, for the first time, the exact serum levels of 3βAdiol and Δ5-diol in young healthy volunteers using liquid chromatography–tandem mass spectrometry (LC–MS/MS). We investigated the effect of the menstrual cycle on the levels of these steroids in women; then, we performed a gender comparison. Blood samples were collected from 48 subjects: 23 women (mean age = 28.4±7.8 years) and 25 men (mean age = 31.4±7.8 years). We collected the blood samples of women at three time-points in the menstrual cycle: the early follicular phase, ovulatory or mid-cycle phase, and mid-luteal phase. A total of 92 blood samples were analyzed using LC–MS/MS. The levels of two well-studied steroids, namely dehydroepiandrosterone (DHEA) and 17β-estradiol (E2), were simultaneously measured. Depression rating scale (Hamilton Rating Scale for Depression, Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology) scores were also recorded at the time of blood sampling. Significant differences in the levels of 3βAdiol and E2 and in the depression rating scale scores were observed over the duration of the menstrual cycle of the women. The levels of 3βAdiol and Δ5-diol were significantly lower in women than in men. E2 levels were higher in women than in men, and DHEA levels did not differ significantly between men and women. Further, women had higher scores than men on the Hamilton Rating Scale for Depression. Sex differences in depressive symptoms can be explained by 3βAdiol and Δ5-diol levels, and the effect of the menstrual cycle on mood can be explained by 3βAdiol and E2 levels, not by Δ5-diol level.
Highlights
The physiological functions of the novel estrogenic steroids 5α-androstane-3β, 17β-diol (3βAdiol) [1, 2] and androstenediol (Δ5-diol) [3] have been clarified in recent studies
This study presents the first comprehensive data on the natural estrogen receptor β (ERβ) ligands, 3βAdiol and Δ5-diol, and provides deeper insight into the association between the serum levels of these steroids and depressive symptoms in young healthy adults
The high cost of the LC–MS/MS assay and the limited number of facilities where this assay can be performed are issues that need to be addressed in the future
Summary
The physiological functions of the novel estrogenic steroids 5α-androstane-3β, 17β-diol (3βAdiol) [1, 2] and androstenediol (Δ5-diol) [3] have been clarified in recent studies. Selective stimulation of ERβ, not ERα, produces antidepressant effects [5,6,7]. 3βAdiol and Δ5-diol have been identified as endogenous ERβ-selective agonists [4, 8]. Results of animal experiments strongly suggest that 3βAdiol [9,10,11] and Δ5-diol [3] are antidepressants. Studies on these steroids in human subjects are few
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