Scheduled Phlebotomies Ineffective at Improving Insulin Sensitivity for Women With Hyperandrogenism

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Previous studies have shown that iron lowering therapy by phlebotomy can improve metabolic endpoints in cases of iron overload so, investigators writing in The Journal of Clinical Endocrinology and Metabolism, test this concept in women with hyperandrogenism.

Insulin sensitivity among women with functional hyperandrogenism who received combined oral contraceptives was not improved with bloodletting, a procedure used to lower iron. The findings, from a randomized, parallel, open-label, clinical trial, were published last month in The Journal of Clinical Endocrinology and Metabolism.

It is not uncommon to find increased iron stores in women with functional hyperandrogenism, particularly those with abnormal glucose tolerance. Women with polycystic ovary syndrome (PCOS) tend to have a mild increase in body iron stores. So, in this study, researchers led by Manuel Luque-Ramírez, MD, PhD, of Hospital Universitario Ramón y Cajal in Madrid, hypothesized that iron lowering therapy, such as bloodletting, might improve insulin resistance and glucose metabolism in this group of patients.

Previous studies have suggested that iron depletion can improve glucose tolerance in several metabolic disorders. “Functional hyperandrogenism is a well-known model of insulin resistance in which increased iron depots may play a role,” the authors wrote. “Here, we report the initial findings of a research clinical trial aiming to study the effects of decreasing iron tissue depots by scheduled bloodletting on the cardiometabolic phenotype of women with functional hyperandrogenism, including PCOS and idiopathic hyperandrogenism, submitted to standard treatment with combined oral contraceptives.”

Women (N=33) with functional hyperandrogenism were recruited from the Hospital Universitario Ramón y Cajal in Spain between 2015 and 2019. The women received a combined oral contraceptives of 35 mg ethinyl-estradiol with 2 mg cyproterone acetate. After 3 cycles on the therapy, women were randomized in a 1:1 ratio to receive 3 sessions of 450 g bloodletting (n=17) or not (n=16). The women were assessed for clinical characteristics and insulin sensitivity.

Most women (64%) were premenopausal with functional hyperandrogenism and a minority (36%) had idiopathic hyperandrogenism. The human homeostatic iron regulator protein gene HFE was wild type for 25 participants, 5 were heterozygous carriers of the H63D mutation, and 1 had the C282Y mutation.

Participants in the experimental and control cohorts were on average 25 years old with a body mass index ranging from 29.6 and 28.3 kg/m2. Fasting glucose was 4.8 and 4.9 mmol/L, and Matsuda insulin sensitivity index was 4.2, respectively. Three study participants in the experimental arm and 4 in the control arm were lost by the close of the study.

After 3 months of treatment, plasma ferritin (mean 14 mg/L) and total iron binding capacity (mean 43 mg/dL) increased while plasma hemoglobin decreased (mean -9.5 g/L). There was a statistically significant decrease in BMI (mean −0.40 kg/m2) and fat mass (total body weight, mean −0.65%). All circulating androgens decreased during this period. Fasting glucose decreased slightly (mean -0.13 mmol/L), while plasma glucose increased (mean 0.59 mmol/L).

Ultimately, bloodletting did not alter fasting glucose (odds ratio, 1.007; 95% CI, 0.918-1.263; P =.364), glucose tolerance (odds ratio, 1.055; 95% CI, 0.813-1.370; P =.685), or prediabetes or type 2 diabetes risk (odds ratio, 0.981; 95% CI, 0.712-1.351; P =.906).

A total of 95 adverse events were reported. The most frequent events were low plasma ferritin (<34 ng/mL), transferrin saturation (<15%), hematocrit (<0.36), and hemoglobin (<120 g/L). In all cases, adverse events were elevated among the experimental arm (n=56) compared with the controls (n=39).

This study was limited by its small sample size, likely leading to an underpowered analysis.

These findings do not support the use of scheduled phlebotomies to improve glucose tolerance among women with functional hyperandrogenism being treated with combined oral contraceptives.

“Despite a slight improvement of lipid profile after blood donation has been suggested in patients with the metabolic syndrome, a reduction in iron depots by repeated phlebotomies in patients with hypertriglyceridemia and iron overload did not add any beneficial to a lipid-lowering diet,” the authors wrote.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Ortiz-Flores A E, Martínez-García M Á, Nattero-Chávez L, et al. Iron Overload in Functional Hyperandrogenism: In a Randomized Trial, Bloodletting Does Not Improve Metabolic Outcomes. J Clin Endocrinol Metab. 2021;dgaa978. doi:10.1210/clinem/dgaa978.