Phlebotomy and Polycystic Ovary Syndrome

Study Overview
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Brief Summary
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AIMS To study the effects of the decrease in iron tissue depots after scheduled bloodletting on insulin sensitivity, carbohydrate metabolism, classic and non-classic cardiovascular risk factors in patients with functional hyperandrogenism (polycystic ovary syndrome & idiopathic hyperandrogenism) on standard treatment with combined oral contraceptives (COC) according to usual clinical practice. METHODOLOGY Open label, controlled, parallel, prospective study of 12 months of duration, with 2 randomized arms of follow-up: i) Intervention Group: Patients with functional hyperandrogenism on standard COC treatment randomly allocated to perform scheduled phlebotomies from the third month of treatment to the end of the study (3 times with a 3-month interval between them). ii) Control Group: Patients with functional hyperandrogenism on standard COC treatment randomly allocated to follow-up without bloodletting. The whole group of patients will undergo a comprehensive anthropometric and hormonal assessment, evaluation of classic cardiovascular risk factors (insulin sensitivity and carbohydrate metabolism after a standard oral glucose test- 75 g), lipid profile, ambulatory and office blood pressure monitoring, proinflammatory profile, oxidative stress status, autonomic function assessment, and iron-related metabolism parameters at baseline, after 3-month COC treatment and after reduction of iron tissue depots plus OC in the Intervention Group of patients, and throughout follow-up under treatment with COC in the Control Group of patients. If a significant relationship between circulating hepcidin levels and elevated ferritin concentrations is observed, a study of the potential influence of mutations/polymorphic variants of hepcidin gene on ferritin values will be performed as well.

Official Title
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Effect of Decreasing Iron Tissue Depots on the Cardiovascular Risk of Women With Polycystic Ovary Syndrome

Conditions
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Hyperandrogenism, Metabolic Cardiovascular Syndrome

Intervention / Treatment
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* Procedure: Phlebotomy
* Drug: ethinylestradiol
* Drug: Cyproterone Acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premenopausal women with functional hyperandrogenism defined as: Polycystic ovary syndrome (PCOS): Clinical and biochemical hyperandrogenism plus ovulatory dysfunction or polycystic ovarian morphology. Idiopathic hyperandrogenism: Clinical and biochemical hyperandrogenism with normal ovulatory cycles and normal ovarian morphology. Combined oral contraceptive pill indication for treatment: i) hyperandrogenism-related dermo-cosmetic complaints with psychoemotional impact; ii) endometrial protection; and/or iii) contraception desire. Scheduled phlebotomy acceptation if randomly allocated. Signed informed consent. Exclusion Criteria: Contraindication for blood donation. Plasma ferritin < 76 pmol/l and/or transferrin saturation percent < 15%. Anemia (plasma hemoglobin < 12 g/dl or hematocrit < 36%). Chronic kidney disease (eGFR < 60 ml/min per 1.73 m2). Personal history of dyslipidemia, hypertension, prediabetes, diabetes mellitus, gestational diabetes or cardiovascular events. Treatment with oral contraceptives, antiandrogens, insulin sensitizers, drugs that might interfere with blood pressure regulation, lipid profile or carbohydrate metabolism, and oral/parenteral iron therapy for the previous 3 months to inclusion. Previous surgical treatment for PCOS. History of blood donation for the previous 12 months to inclusion. Current history of infectious disease, inflammatory disease, liver disease, neurologic disease or malignancy. Eating disorders. Body mass index < 18.5 Kg/m2. Hereditary hemochromatosis. Celiac disease or malabsorptive disorder. Contraindication for treatment with combined oral contraceptives. Pregnancy. Current smoking, recreational drug use or excessive alcohol consumption (> 40 g per day).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Premenopausal women with functional hyperandrogenism under combined oral contraceptive pill qd as usual clinical practice who will undergo a scheduled standard phlebotomy every 3 months from month 3 to 12 of follow-up. | Procedure: Phlebotomy<br>* Scheduled standard phlebotomy every three months from month 3 to 12 of follow-up.<br>* Other names: Bloodletting;Drug: ethinylestradiol<br>* 35 mcg ethinylestradiol qd for 21 days per month as usual clinical practice.<br>Drug: Cyproterone Acetate<br>* 2 mg cyproterone acetate qd for 21 days per month as usual clinical practice.<br>|
| Active Comparator: Control<br>Premenopausal women with functional hyperandrogenism under standard combined oral contraceptive pill qd as usual clinical practice. | Drug: ethinylestradiol<br>* 35 mcg ethinylestradiol qd for 21 days per month as usual clinical practice.<br>Drug: Cyproterone Acetate<br>* 2 mg cyproterone acetate qd for 21 days per month as usual clinical practice.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Matsuda index from the circulating glucose and insulin concentrations during and standard oral glucose tolerance test. |  | one year | 
| Percentage of patients with Hb < 12 g/dl or hematocrit <36% throughout the study |  | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the percentage of patients with undiagnosed prediabetes/diabetes between month 0 and 12 of follow-up |  | one year | 
| Change in the Disposition index between month 0 and 12 of follow-up |  | one year | 
| Change in the lipid profile between month 0 and 12 of follow-up |  | one year | 
| Changes in the blood pressure recordings between month 0 and 12 of follow-up |  | one year | 
| Percentage of patients with ferropenia throughout the study |  | one year | 
| Percentage of patients with a hypovolemic event during blood donation |  | one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Functional hyperandrogenism, Polycystic ovary syndrome, Idiopathic hyperandrogenism, Iron tissue depots, Phlebotomy, Insulin resistance, Carbohydrate metabolism, Blood pressure, Autonomic dysfunction, Oxidative stress, Blood clotting tests, Efficacy, Side effects, Randomized clinical trial