Clinical trial NCT02460445: Phlebotomy and Polycystic Ovary Syndrome
Official title: Effect of Decreasing Iron Tissue Depots on the Cardiovascular Risk of Women With Polycystic Ovary Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hyperandrogenism
Metabolic Cardiovascular Syndrome
Keywords: 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
Lead sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
Sponsor class: OTHER
Collaborators: name: Instituto de Salud Carlos III
First posted: 2015-06-02
Enrollment: 37
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. 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.
2. Combined oral contraceptive pill indication for treatment: i) hyperandrogenism-related dermo-cosmetic complaints with psychoemotional impact; ii) endometrial protection; and/or iii) contraception desire.
3. Scheduled phlebotomy acceptation if randomly allocated.
4. Signed informed consent.

Exclusion Criteria:

1. Contraindication for blood donation.
2. Plasma ferritin \< 76 pmol/l and/or transferrin saturation percent \< 15%.
3. Anemia (plasma hemoglobin \< 12 g/dl or hematocrit \< 36%).
4. Chronic kidney disease (eGFR \< 60 ml/min per 1.73 m2).
5. Personal history of dyslipidemia, hypertension, prediabetes, diabetes mellitus, gestational diabetes or cardiovascular events.
6. 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.
7. Previous surgical treatment for PCOS.
8. History of blood donation for the previous 12 months to inclusion.
9. Current history of infectious disease, inflammatory disease, liver disease, neurologic disease or malignancy.
10. Eating disorders. Body mass index \< 18.5 Kg/m2.
11. Hereditary hemochromatosis.
12. Celiac disease or malabsorptive disorder.
13. Contraindication for treatment with combined oral contraceptives.
14. Pregnancy.
15. Current smoking, recreational drug use or excessive alcohol consumption (\> 40 g per day).

Primary outcomes:
measure: Change in the Matsuda index from the circulating glucose and insulin concentrations during and standard oral glucose tolerance test.
timeFrame: one year
measure: Percentage of patients with Hb < 12 g/dl or hematocrit <36% throughout the study
timeFrame: one year
Secondary outcomes:
measure: Change in the percentage of patients with undiagnosed prediabetes/diabetes between month 0 and 12 of follow-up
timeFrame: one year
measure: Change in the Disposition index between month 0 and 12 of follow-up
timeFrame: one year
measure: Change in the lipid profile between month 0 and 12 of follow-up
timeFrame: one year
measure: Changes in the blood pressure recordings between month 0 and 12 of follow-up
timeFrame: one year
measure: Percentage of patients with ferropenia throughout the study
timeFrame: one year
measure: Percentage of patients with a hypovolemic event during blood donation
timeFrame: one year
Other outcomes:
measure: Subclinical chronic inflammation
timeFrame: one year
measure: Oxidative stress
timeFrame: one year
measure: Autonomic vascular function
timeFrame: one year
measure: Blood clotting test
timeFrame: one year
Locations:
city: Madrid
country: Spain
facility: Diabetes, Obesity and Human Reproduction Research Group, Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)
Study officials:
affiliation: Assistant in Endocrinology. Member of the Diabetes, Obesity and Human Reproduction Research Group from the lnstituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)
name: Manuel Luque Ramírez, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ortiz-Flores AE, Martinez-Garcia MA, Nattero-Chavez L, Alvarez-Blasco F, Fernandez-Duran E, Quintero-Tobar A, Escobar-Morreale HF, Luque-Ramirez M. Iron Overload in Functional Hyperandrogenism: In a Randomized Trial, Bloodletting Does Not Improve Metabolic Outcomes. J Clin Endocrinol Metab. 2021 Mar 25;106(4):e1559-e1573. doi: 10.1210/clinem/dgaa978.
citation: Luque-Ramirez M, Ortiz-Flores AE, Nattero-Chavez L, Martinez-Garcia MA, Insenser M, Alvarez-Blasco F, Fernandez-Duran E, Quintero-Tobar A, de Lope Quinones S, Escobar-Morreale HF. Bloodletting has no effect on the blood pressure abnormalities of hyperandrogenic women taking oral contraceptives in a randomized clinical trial. Sci Rep. 2021 Nov 11;11(1):22097. doi: 10.1038/s41598-021-01606-7.
citation: Luque-Ramirez M, Ortiz-Flores AE, Martinez-Garcia MA, Insenser M, Quintero-Tobar A, De Lope Quinones S, Fernandez-Duran E, Nattero-Chavez ML, Alvarez-Blasco F, Escobar-Morreale HF. 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. J Clin Med. 2022 Jul 3;11(13):3864. doi: 10.3390/jcm11133864.