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Involvement of Reticulum Endoplasmic Stress in the Physiopathology of Polycystic Ovary Syndrome (PI12/1984)

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ClinicalTrials.gov Identifier: NCT02302326
Recruitment Status : Active, not recruiting
First Posted : November 27, 2014
Last Update Posted : February 15, 2019
Sponsor:
Information provided by (Responsible Party):
Antonio Hernandez Mijares, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana

Brief Summary:
The main objective of the present project is to evaluate the relevance of reticulum stress in the pathogenesis of polycystic ovary syndrome (PCOS), focusing particularly on the underlying mechanisms of insulin resistance, which is the origin of metabolic comorbidities. Furthermore, the investigators will assess the potential of insulin sensitizers as a treatment to control endoplasmic reticulum stress markers in PCOS patients.

Condition or disease Intervention/treatment Phase
Polycystic Ovary Syndrome Drug: Metformin Dietary Supplement: Myo-inositol + folic acid Not Applicable

Detailed Description:
To do this, the investigators will evaluate anthropometric, biochemical and hormone parameters, lipid profile and cardiovascular risk markers (using enzymatic and biochemical techniques, nephelometry, enzyme-linked immunosorbent assay, radioimmunoassay), and markers of endoplasmic reticulum stress and the insulin pathway and inflammatory and apoptotic parameters (by means of Western blot, Real Time- Polymerase Chain Reaction (RT-PCR), Luminex® xMAP® Technology ) in patients with and without PCOS. The investigators' second objective is to evaluate (using the abovementioned methodology) the efficacy of different insulin sensitizers (myoinositol and metformin) administered to PCOS patients during a 3-month period after which the investigators will analyze different parameters of oxidative stress and mitochondrial function (using Clark electrode and fluorometric techniques).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Involvement of Reticulum Endoplasmic Stress in the Physiopathology of Polycystic Ovary Syndrome: Possible Therapeutic Implications of Insulin Sensitizers.
Study Start Date : January 2013
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: Metformin
PCOS women began treatment with ER 500 mg metformin per day, and the dose was increased to 1000 mg after 2 weeks, and to 1700 mg/d after a further 2 weeks, and was maintained at this dose for a total of 12 weeks.
Drug: Metformin
Dose: metformin (1700 mg / day) for 12 weeks

Experimental: Myo-inositol + folic acid
PCOS women received a dietary supplement (Ovusitol® : 4 g myo-inositol plus 400 micrograms of folic acid) for 12 weeks
Dietary Supplement: Myo-inositol + folic acid
Dose: Ovusitol® (4 g myo-inositol plus 400 micrograms of folic acid/day) for 12 weeks

No Intervention: Healthy women
Healthy untreated women adjusted for age and body mass index



Primary Outcome Measures :
  1. Changes in markers of endoplasmic reticulum stress in controls and pcos women before and after metformin/Myo-inositol + folic acid administration [ Time Frame: 3 months ]
    Markers of endoplasmic reticulum stress (78-kDa glucose-regulated protein (GRP78), ubiquitous translation initiation factor 2α (eIF2α), double-stranded RNA-activated protein kinase (PERK), inositol requiring enzyme 1 (IRE1α), X-box binding protein 1 (XBP-1)) were assessed by Western Blot and Real Time- Polymerase Chain Reaction (RT-PCR) in polymorphonuclear cells

  2. Changes in markers of the insulin pathway in controls and pcos women before and after metformin/Myo-inositol + folic acid administration [ Time Frame: 3 months ]
    Markers of the insulin pathway (c-Jun N-terminal kinase (JNK), insulin receptor substrate (IRS)) were assessed by Western Blot and Real Time- Polymerase Chain Reaction (RT-PCR) in polymorphonuclear cells

  3. Changes in inflammatory parameters in controls and pcos women before and after metformin/Myo-inositol + folic acid administration [ Time Frame: 3 months ]
    Inflammatory parameters (nuclear factor κB (NF-κB), interleukin-6 (IL6), tumor necrosis factor α (TNFα)) were assessed by Western Blot, Real Time- Polymerase Chain Reaction (RT-PCR), or Luminex® xMAP® Technology in polymorphonuclear cells and serum

  4. Changes in apoptotic parameters in controls and pcos women before and after metformin/Myo-inositol + folic acid administration [ Time Frame: 3 months ]
    Apoptotic parameters (transcription factor C/EBP homologous protein (CHOP) and caspase 12) were assessed by Western Blot and Real Time- Polymerase Chain Reaction (RT-PCR) in polymorphonuclear cells


Secondary Outcome Measures :
  1. Changes in anthropometric parameters in controls and pcos women before and after metformin/Myo-inositol + folic acid administration [ Time Frame: 3 months ]
    Anthropometric (weight, height, body mass index and waist) and blood pressure parameters were evaluated

  2. Changes in biochemical parameters in controls and pcos women before and after metformin/Myo-inositol + folic acid administration [ Time Frame: 3 months ]
    Glucose levels were measured using enzymatic techniques. Insulin was measured by an enzymatic luminescence technique. IR was calculated by homeostasis model assessment (HOMA). Total cholesterol and triglycerides were measured by employing enzymatic assays, and high density lipoprotein cholesterol (HDLc) concentrations were recorded with an autoanalyser using a direct method. Low-density lipoprotein cholesterol (LDLc) concentration was calculated using the Friedewald method. Luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone were measured by specific radioimmunoassays. Dehydroepiandrosterone-sulfate (DHEAS), sex hormone-binding globulin (SHBG), androstenedione and testosterone were measured by specific chemiluminescence techniques. High-sensitive C-reactive protein (hsCRP) was quantified by a latex-enhanced immunonephelometric assay

  3. Changes in mitochondrial function parameters in controls and pcos women before and after metformin/Myo-inositol + folic acid administration [ Time Frame: 3 months ]
    Oxidative stress markers ( mitochondrial oxygen (O2) consumption, membrane potential, glutathione, reactive oxygen species (ROS) and hydrogen peroxide levels, mitochondrial mass) were assessed by Clark electrode and fluorometric techniques

  4. Changes in endothelial function parameters in controls and pcos women before and after metformin/Myo-inositol + folic acid administration [ Time Frame: 3 months ]
    Interactions between leukocytes and human umbilical vein endothelial cells were evaluated by flow chamber microscopy (leukocyte rolling velocity, leukocyte rolling flux and leukocyte adhesion). The vascular cell adhesion molecule 1 (VCAM-1), Intercellular adhesion molecule 1 (ICAM-1) and E-selectin were evaluated in serum by Luminex® 200 flow analyzer system



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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Women diagnosed with PCOS using the Rotterdam criteria
  • Women of reproductive age

Exclusion Criteria:

  • Organic, malignant, haematological, infectious or inflammatory disease
  • History of ischaemic heart disease (stroke or thromboembolism)
  • Diabetes mellitus,
  • Secondary causes of obesity (hypothyroidism, Cushing's syndrome)
  • Severe hypertension.
  • Smoking or alcohol habit

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02302326


Locations
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Spain
Antonio Hernández
Valencia, Spain, 46017
Sponsors and Collaborators
Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana
Investigators
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Principal Investigator: Antonio Hernández, Phd, MD FISABIO - University Hospital Dr Peset

Publications:
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Responsible Party: Antonio Hernandez Mijares, PhD, MD, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana
ClinicalTrials.gov Identifier: NCT02302326     History of Changes
Other Study ID Numbers: AHM-MET-2013-01
First Posted: November 27, 2014    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019

Keywords provided by Antonio Hernandez Mijares, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana:
reticulum endoplasmic stress
Polycystic Ovary Syndrome
mitochondrial function
insulin resistance
inflammation
myoinositol
metformin
oxidative stress

Additional relevant MeSH terms:
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Inositol
Syndrome
Polycystic Ovary Syndrome
Disease
Pathologic Processes
Ovarian Cysts
Cysts
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Gonadal Disorders
Endocrine System Diseases
Metformin
Folic Acid
Vitamin B Complex
Hypoglycemic Agents
Physiological Effects of Drugs
Hematinics
Vitamins
Micronutrients
Nutrients
Growth Substances