Effect of Iron Depletion by Bloodletting vs. Observation on Oxidative Stress Biomarkers of Women with Functional Hyperandrogenism Taking a Combined Oral Contraceptive: A Randomized Clinical Trial

Manuel Luque-Ramírez, Andrés E Ortiz-Flores, María Ángeles Martínez-García, María Insenser, Alejandra Quintero-Tobar, Sara De Lope Quiñones, Elena Fernández-Durán, María Lía Nattero-Chávez, Francisco Álvarez-Blasco, Héctor Francisco Escobar-Morreale, Manuel Luque-Ramírez, Andrés E Ortiz-Flores, María Ángeles Martínez-García, María Insenser, Alejandra Quintero-Tobar, Sara De Lope Quiñones, Elena Fernández-Durán, María Lía Nattero-Chávez, Francisco Álvarez-Blasco, Héctor Francisco Escobar-Morreale

Abstract

Women with functional hyperandrogenism show both increased markers of oxidative stress and a mild iron overload. Combined oral contraceptives (COC) may worsen redox status in the general population. Since iron depletion ameliorates oxidative stress in other iron overload states, we aimed to address the changes in the redox status of these women as a consequence of COC therapy and of bloodletting, conducting a randomized, controlled, parallel, open-label clinical trial in 33 adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. After three months of treatment with a COC, participants were randomized (1:1) to three scheduled bloodlettings or observation for another nine months. After taking a COC, participants showed a mild decrease in their plasma electrochemical antioxidant capacity, considering fast-acting antioxidants [MD: −1.51 (−2.43 to −0.60) μC, p = 0.002], and slow-acting antioxidants [MD: −1.90 (−2.66 to −1.14) μC, p < 0.001]. Women submitted to bloodletting showed a decrease in their non-enzymatic antioxidant capacity levels (NEAC) throughout the trial, whereas those individuals in the control arm showed a mild increase in these levels at the end of the study (Wilks’ λ: 0.802, F: 3.572, p = 0.041). Decreasing ferritin and plasma hemoglobin during the trial were associated with worse NEAC levels. COC may impair redox status in women with functional hyperandrogenism. Decreasing iron stores by scheduled bloodletting does not override this impairment.

Keywords: hyperandrogenism; iron; oxidative stress.

Conflict of interest statement

M.L.-R. has received consulting fees and honoraria for speaking from Novo Nordisk and Merck, and was involved in clinical trials supported by AstraZeneca, Cortendo AB, InsudPharma, and Neurocrine. A.E.O.-F. was involved in a clinical trial supported by Cortendo AB. M.L.N.-C. has received consulting fees and honoraria for speaking from Novo Nordisk and Sanofi Aventis, and was involved in clinical trials supported by AstraZeneca, Cortendo AB, Diamyd Medical, InsudPharma, and Neurocrine. F.A.-B. has received consulting fees and honoraria for speaking from Novo Nordisk, AstraZeneca, Menarini, and Lilly-Boehringer, and was involved in clinical trials supported by AstraZeneca and Diamyd Medical. E.F.-D. and A.Q.-T. were involved in clinical trials supported by AstraZeneca, Cortendo AB, Diamyd Medical, InsudPharma, and Neurocrine. H.F.E.-M. was involved in a clinical trial supported by AstraZeneca, and has received consulting fees from InsudPharma. All authors have read the journal’s authorship agreement and policy on disclosure of potential conflicts of interest, and no other potential conflict of interest are reported.

Figures

Figure 1
Figure 1
Flow chart of the study. The figure includes the numbers of participants randomly assigned to the arms of the study, those receiving the intended intervention, and the losses and exclusions, together with their reasons, occurring after randomization.
Figure 2
Figure 2
Short-term effects of combined oral contraceptive on oxidative stress biomarkers. The box indicates the 25th and 75th percentiles, the solid and short dashed lines within the box mark the median and mean, respectively. Whiskers below and above the box indicate the 10th and 90th percentiles. * Statistically significant change in mean values from month −3 to 0.
Figure 3
Figure 3
Changes in circulating ferritin in each arm of the trial throughout the study. Data are shown as mean of the differences and 95% CI.
Figure 4
Figure 4
Changes in oxidative stress biomarkers throughout the experimental phase of the trial. We show data as means (SEM) of the patients remaining at each visit of the trial, even though we conducted intention-to-treat statistical analyses. Data were submitted to a repeated-measures general linear model. † Statistically significant interaction between the visits and the arm of the study.
Figure 5
Figure 5
Changes in plasma non-enzymatic antioxidant activity throughout the experimental phase of the trial as a function of the changes in plasma ferritin and hemoglobin grouped by tertiles. We show data as means (SEM) of the patients remaining at each visit of the trial even though we conducted intention-to-treat statistical analyses. Data were submitted to a repeated-measures general linear model introducing the upper tertile (T3) vs. mid and lower tertiles (T1 + 2) as between-subjects factors. † Statistically significant interaction between the visits and tertile subgroups.

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