Sex hormones modulate circulating antioxidant enzymes: impact of estrogen therapy

Abstract

Objective: Ovarian senescence affects many tissues and produces a variety of symptoms and signs. We hypothesized that estrogens may also influence circulating redox balance by regulating activity of the cellular antioxidative enzyme system. We aimed to explore the impact of surgical estrogen deprivation and replacement (ERT) on the glutathione balance and antioxidant enzymes expression in fertile women.

Study design: Nineteen healthy premenopausal women who underwent total hysterectomy with bilateral salpingo-oophorectomy were evaluated at baseline, 30 days after surgery without ERT and 30 days after ERT. Redox balance was determined by measuring blood reduced (GSH) and oxidized (GSSG) glutathione, as well as the GSSG/GSH ratio. Antioxidant status was evaluated by measuring serum estrogen (E2) levels and mRNA expression of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione S-transferase (GST) in peripheral blood mononuclear cells.

Results: Serum E2 significantly lowered after surgery, and increased in 12 out of 19 patients after 30 days of ERT (Responders). In such patients, an increase in oxidative stress was observed after surgery that resolved after ERT. Oxidative stress was sustained by reduction in the mRNA expression of both SOD and GSH-Px, that recovered after 30 days of therapy in responders. CAT and GST mRNA expression were not modified by surgery and replacement therapy.

Conclusions: Menopause is associated with significant change in antioxidant gene expression that in turn affects circulating redox state. Estrogens replacement therapy is able to prevent and counteract such modifications by acting as regulators of key antioxidant gene expression. These findings suggest that antioxidant genes are, almost in part, under the control of sex hormones, and that pathophysiology of the difference in gender disease may depend on the redox biology.

Keywords: Estrogen replacement therapy; Glutathione; Menopause; Oxidative stress.

Graphical abstract

Fig. 1

(A) Serum level of estrogen (E2) in 19 women that underwent hysterectomy and bilateral oophorectomy at baseline (B), after surgical menopause (SM) and after 30 days of estrogen replacement therapy (ERT). (B–D) Blood level of reduced (GSH) and oxidized (GSSG) glutathione, and GSSG/GSH ratio in 12 women that underwent hysterectomy and bilateral oophorectomy and responded to estrogen replacement therapy (ERT) at baseline (B), 30 days after surgical menopause (SM) and 30 days after ERT. Statistical differences were assessed using one-way ANOVA for repeated measures with Bonferroni's multiple comparison test as post-hoc test.

Fig. 2

Blood level of reduced (GSH) and oxidized (GSSG) glutathione, and GSSG/GSH ratio in responder (n=12) and non responder (n=7) women in surgical menopause to 30 days of estrogen replacement therapy. Data are expressed as mean±standard deviation of the mean. Statistical differences were assessed using Student's t-test for unpaired measures.

Fig. 3

mRNA expression of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione-S-transferase (GST) in peripheral blood mononuclear cell of 12 women that underwent hysterectomy and bilateral oophorectomy and responded to estrogen replacement therapy (ERT) at baseline (B), 30 days after surgical menopause (SM) and 30 days after ERT. Data are expressed as mean±standard deviation of the mean. Statistical differences were assessed using one-way ANOVA for repeated measures with Bonferroni's multiple comparison test as post-hoc test.

Fig. 4

Linear regression analysis between the variations of serum E2 level (ΔE2) and superoxide dismutase (ΔSOD), glutathione peroxidase (ΔGSH-Px) mRNA expression, as well as reduced (ΔGSH) and oxidized (ΔGSSG) glutathione, and GSSG/GSH ratio (ΔGSSG/GSH), expressed as the difference between 30 days after estrogen replacement therapy (ERT) and 30 days after surgical menopause, in 12 women that underwent hysterectomy and bilateral oophorectomy and responded to ERT.