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Phlebotomy and Polycystic Ovary Syndrome

Primary Purpose

Hyperandrogenism, Metabolic Cardiovascular Syndrome

Status

Completed

Phase

Not Applicable

Locations

Spain

Study Type

Interventional

Intervention

Phlebotomy

ethinylestradiol

Cyproterone Acetate

About this trial

This is an interventional treatment trial for Hyperandrogenism focused on measuring 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

Eligibility Criteria

18 Years - 45 Years (Adult)FemaleDoes not accept healthy volunteers

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).

Sites / Locations

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)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Intervention

Control

Arm Description

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.

Premenopausal women with functional hyperandrogenism under standard combined oral contraceptive pill qd as usual clinical practice.

Outcomes

Primary Outcome Measures

Change in the Matsuda index from the circulating glucose and insulin concentrations during and standard oral glucose tolerance test.

Percentage of patients with Hb < 12 g/dl or hematocrit <36% throughout the study

Secondary Outcome Measures

Change in the percentage of patients with undiagnosed prediabetes/diabetes between month 0 and 12 of follow-up

Change in the Disposition index between month 0 and 12 of follow-up

Change in the lipid profile between month 0 and 12 of follow-up

Changes in the blood pressure recordings between month 0 and 12 of follow-up

Percentage of patients with ferropenia throughout the study

Percentage of patients with a hypovolemic event during blood donation

Full Information

NCT ID

NCT02460445

First Posted

May 27, 2015

Last Updated

July 25, 2022

Sponsor

Manuel Luque Ramírez

Collaborators

Instituto de Salud Carlos III

1. Study Identification

Unique Protocol Identification Number

NCT02460445

Brief Title

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

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Completed

Study Start Date

January 2015 (Actual)

Primary Completion Date

June 2020 (Actual)

Study Completion Date

June 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Manuel Luque Ramírez

Collaborators

Instituto de Salud Carlos III

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

37 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Intervention

Arm Type

Experimental

Arm Description

Arm Title

Control

Arm Type

Active Comparator

Arm Description

Premenopausal women with functional hyperandrogenism under standard combined oral contraceptive pill qd as usual clinical practice.

Intervention Type

Procedure

Intervention Name(s)

Phlebotomy

Other Intervention Name(s)

Blood donation, Bloodletting

Intervention Description

Scheduled standard phlebotomy every three months from month 3 to 12 of follow-up.

Intervention Type

Drug

Intervention Name(s)

ethinylestradiol

Intervention Description

35 mcg ethinylestradiol qd for 21 days per month as usual clinical practice.

Intervention Type

Drug

Intervention Name(s)

Cyproterone Acetate

Intervention Description

2 mg cyproterone acetate qd for 21 days per month as usual clinical practice.

Primary Outcome Measure Information:

Title

Change in the Matsuda index from the circulating glucose and insulin concentrations during and standard oral glucose tolerance test.

Time Frame

one year

Title

Percentage of patients with Hb < 12 g/dl or hematocrit <36% throughout the study

Time Frame

one year

Secondary Outcome Measure Information:

Title

Change in the percentage of patients with undiagnosed prediabetes/diabetes between month 0 and 12 of follow-up

Time Frame

one year

Title

Change in the Disposition index between month 0 and 12 of follow-up

Time Frame

one year

Title

Change in the lipid profile between month 0 and 12 of follow-up

Time Frame

one year

Title

Changes in the blood pressure recordings between month 0 and 12 of follow-up

Time Frame

one year

Title

Percentage of patients with ferropenia throughout the study

Time Frame

one year

Title

Percentage of patients with a hypovolemic event during blood donation

Time Frame

one year

Other Pre-specified Outcome Measures:

Title

Subclinical chronic inflammation

Time Frame

one year

Title

Oxidative stress

Time Frame

one year

Title

Autonomic vascular function

Time Frame

one year

Title

Blood clotting test

Time Frame

one year

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

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).

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Manuel Luque Ramírez, M.D., Ph.D.

Organizational Affiliation

Assistant in Endocrinology. Member of the Diabetes, Obesity and Human Reproduction Research Group from the lnstituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)

Official's Role

Principal Investigator

Facility Information:

Facility Name

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)

City

Madrid

ZIP/Postal Code

28034

Country

Spain

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

All data sets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

IPD Sharing Time Frame

With publication

IPD Sharing Access Criteria

Data are available from PI on reasonable request (manuel.luque@salud.madrid.org)

Citations:

PubMed Identifier

33462622

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. Erratum In: J Clin Endocrinol Metab. 2022 Aug 18;107(9):e3973.

Results Reference

result

PubMed Identifier

34764381

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.

Results Reference

result

PubMed Identifier

35807149

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.

Results Reference

result

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Phlebotomy and Polycystic Ovary Syndrome

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