Bloodletting has no effect on the blood pressure abnormalities of hyperandrogenic women taking oral contraceptives in a randomized clinical trial

Abstract

Normoferritinemic women with functional hyperandrogenism show a mild iron overload. Iron excess, hyperandrogenism, and cardioautonomic dysfunction contribute to blood pressure (BP) abnormalities in these patients. Furthermore, combined oral contraceptives (COC) prescribed for hyperandrogenic symptoms may worse BP recordings. Iron depletion by phlebotomy appears to lower BP in other acquired iron overload conditions. We aimed to determine the effect of iron depletion on the office BP, ambulatory BP monitoring, and frequency of hypertension in patients with functional hyperandrogenism submitted to standard therapy with COC. We conducted a phase 2 randomized, controlled, parallel, open-label clinical trial (NCT02460445) in adult women with functional hyperandrogenism including hyperandrogenic polycystic ovary syndrome and idiopathic hyperandrogenism. After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to three scheduled bloodlettings or observation for another 9 months. Main outcome measures were the changes in office BP, 24-h-ambulatory BP, and frequency of hypertension in both study arms. From June 2015 to June 2019, 33 women were included in the intention-to-treat analyses. We observed an increase in mean office systolic BP [mean of the differences (MD): 2.5 (0.3-4.8) mmHg] and night-time ambulatory systolic BP [MD 4.1 (1.4-6.8) mmHg] after 3 months on COC. The percentage of nocturnal BP non-dippers also increased, from 28.1 to 92.3% (P < 0.001). Office and ambulatory BP did not change throughout the experimental period of the trial, both when considering all women as a whole or as a function of the study arm. The frequency of the non-dipping pattern in BP decreased during the experimental period [OR 0.694 (0.577-0.835), P < 0.001], regardless of the study arm. Decreasing iron stores by scheduled bloodletting does not override the BP abnormalities caused by COC in women with functional hyperandrogenism.

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, and Neurocrine. A.E. O.-F. was involved in a clinical trial supported by Cortendo AB. 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, 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, and Neurocrine. H.F. E.-M. was involved in a clinical trial supported by AstraZeneca, and has received consulting fees from InsudPharma. All other authors have no conflict of interest.

© 2021. The Author(s).

Figures

Figure 1

Flow chart of the study.

Figure 2

Changes in office blood pressure and ambulatory blood pressure monitoring recordings throughout the trial. Data are shown as means (SEM) of the patients remaining at each visit of the trial (figures above the x-axis) even though we conducted intention-to-treat statistical analyses. *Significant changes observed during the run-in phase in the whole group of participants after introducing the presence of obesity as between-subjects covariate. To analyze changes during the experimental phase, data were submitted to a repeated-measures general linear model.

Figure 3

Influence of functional hyperandrogenism (hyperandrogenic PCOS vs idiopathic hyperandrogenism) on systolic blood pressure. Data are shown as means (SEM) of the patients remaining at each visit of the trial (figures above the x-axis) even though we conducted intention-to-treat statistical analyses. *Interaction with the visit of the study during the run-in period. †Interaction with the visit of the study and arm of treatment during the experimental phase of the trial.

Figure 4

Percentage changes in the Ewing’s cardioautonomic function tests throughout the trial. Data are shown as means (SEM) of the patients remaining at each visit of the trial (figures above the x-axis) even though we conducted intention-to-treat analyses. Left side columns show the changes occurred during the run-in period (from months − 3 to 0). Central columns show the percentage change occurred from months 0 to 6 of the experimental period. Right side columns show the percentage change observed from months 0 to 9 of the experimental period.