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CompletedNCT02460445Updated Jul 27, 2022

Phlebotomy and Polycystic Ovary Syndrome

An interventional study of Phlebotomy and ethinylestradiol in Hyperandrogenism and Metabolic Cardiovascular Syndrome, sponsored by Manuel Luque Ramírez. Completed at 1 site in Spain. Open to female participants aged 18 Years to 45 Years. Per ClinicalTrials.gov, last updated 2022-07-27.

Sponsored by Manuel Luque Ramírez · Not applicable, Interventional, and Treatment

Phase
Not applicable
Study type
Interventional
Enrollment
37
Allocation
Randomized
Ages
18 Years to 45 Years
Sex
Female
01

Study 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.

02

Conditions studied

  • 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
03

Who can participate

Ages eligible
18 Years to 45 Years
Sexes eligible
Female
Accepts healthy volunteers
No

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

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).
04

Study design

Phase
Not applicable
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
37 participants (actual)

Study arms

  • Experimental
    Intervention

    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 · Drug: ethinylestradiol · Drug: Cyproterone Acetate

  • Active comparator
    Control

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

    Drug: ethinylestradiol · Drug: Cyproterone Acetate

Interventions

  • ProcedurePhlebotomy

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

    Also known as: Blood donation, Bloodletting

  • Drugethinylestradiol

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

  • DrugCyproterone Acetate

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

05

What researchers measure

Primary outcomes

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

    Time frame: one year

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

    Time frame: one year

Secondary outcomes

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

    Time frame: one year

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

    Time frame: one year

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

    Time frame: one year

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

    Time frame: one year

  5. Percentage of patients with ferropenia throughout the study

    Time frame: one year

  6. Percentage of patients with a hypovolemic event during blood donation

    Time frame: one year

Other outcomes

  1. Subclinical chronic inflammation

    Time frame: one year

  2. Oxidative stress

    Time frame: one year

  3. Autonomic vascular function

    Time frame: one year

  4. Blood clotting test

    Time frame: one year

06

Study locations

1 site
  • 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)
    Madrid, 28034, Spain
07

References and documents

Publications

  • 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. doi: 10.1210/clinem/dgac314. PubMed 33462622 ↗
  • 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. PubMed 34764381 ↗
  • 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. PubMed 35807149 ↗

Individual participant data

Plan to share: Yes — 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.

Supporting information: Study protocol, Sap, Icf, Csr, Analytic code

08

Registry details

Key details

Study ID
NCT02460445
Lead sponsor
Manuel Luque Ramírez
Collaborators
Instituto de Salud Carlos III
Responsible party
Manuel Luque Ramírez (Member of the Diabetes, Obesity and Human Reproduction Research Group, Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM., Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal) — Sponsor-investigator
First posted
Jun 2, 2015
Start date
Jan 2015
Primary completion
Jun 2020
Completion
Jun 2020
Last update
Jul 27, 2022

Study contacts

Manuel Luque Ramírez, M.D., Ph.D.
principal investigator · Assistant in Endocrinology. Member of the Diabetes, Obesity and Human Reproduction Research Group from the lnstituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Jul 2022. You cannot join it, but the record below documents what was studied.

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