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Recruiting NCT03841981

Body Fat as Determinant of Female Gonadal Dysfunction

— Observational Polycystic Ovary Syndrome Hypothalamic Amenorrhea

For patients and families

In plain language

An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.

What is being studied
The protocol lists: Anthropometric and physical examination, Indirect calorimetry, accelerometer and seven-day dietary recall, Biochemical, hormonal and metabolic phenotyping, Sonographic studies.
Who it may be relevant to
Registry conditions: Polycystic Ovary Syndrome, Hypothalamic Amenorrhea. Basic parameters: 18 years — 40 years · Female.
What needs checking
Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
Where it takes place
Spain
Next step
Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →

Unsure about the terms? Read our patient guide →

Official title

Amount, Distribution and Dysfunction of Body Fat as Determinants of Female Gonadal Dysfunction: From Functional Hypothalamic Amenorrhea to the Polycystic Ovary Syndrome

Overview

Reproduction requires from women enough energy depots to warrant an adequate nutritional supply to the fetus. Hence, adipose tissue is able to communicate with female hypothalamic-pituitary-ovary axis. The hypothesis of the project is that abnormalities in the quantity (absolute and relative to lean body mass), distribution and/or function of adipose tissue are associated with functional forms of female gonadal dysfunction in predisposed women, in a spectrum of anomalies that go from hypothalamic amenorrhea to the polycystic ovary syndrome (PCOS). To challenge this hypothesis, the investigators will study 5 groups of 10 women each: women with exercise-associated hypothalamic amenorrhea, women without ovulatory dysfunction that exercise equally, non-hyperandrogenic patients with PCOS, hyperandrogenic patients with PCOS, and healthy control women comparable to those with PCOS. The aims of the study will be: Primary objective: To identify novel signalling factors originating from adipose tissue and muscle using targeted and nontargeted evaluation of the proteome and of gene expression of superficial subcutaneous fat, deep subcutaneous fat (which mimics visceral adipose tissue) and skeletal muscle. Secondary objectives: 1. To study the serum adipokine profile - including those identified by the primary objective - and circulating gut hormones during fasting and after a glucose load in the 5 groups of women, and their associations with sexual hormones and body fat distribution. 2. To study body composition and body fat distribution in these women and their relationships with: 2.1, Sex steroid profiles. 2.2. Classic cardiovascular risk factors: carbohydrate metabolism, lipid profiles and blood pressure. 2.3 Markers of low-grade chronic inflammation. 2.4. Oxidative stress markers. 2.5. Cardiovascular autonomic function. 2.6. Surrogate markers of subclinical atherosclerosis. 2.7. Circulating concentrations of endocrine disruptors. 2.8. Oral and gut microbiome. The results will provide a better understanding of the mechanisms linking body energy depots with the female reproductive axis and, hopefully, the identification of potential biomarkers for the diagnosis and treatment of the disorders studied here.

Interventions

  • Diagnostic test Anthropometric and physical examination
    * Weight and height. * Waist-to-hip ratio. * Body composition: Bioelectrical impedance and \[Dual energy X-ray absorptiometry (DEXA)\].
  • Diagnostic test Indirect calorimetry, accelerometer and seven-day dietary recall
    Energy availability assessment.
  • Diagnostic test Biochemical, hormonal and metabolic phenotyping
    * Lipid profile. * Oral glucose tolerance test: plasma glucose and insulin, insulin sensitivity indices, gastrointestinal hormones, adipokines, oxidative stress markers. * Sex steroid profile. * Hypothalamic-pituitary-adrenal axis study. * Ferrokinetic study. * Subclinical chronic inflammatory markers.
  • Diagnostic test Sonographic studies
    * Polycystic ovarian morphology. * Carotid intima-media thickness. * Eco-FAT: Ultrasound measurements of adipose tissue depots including sc, preperitoneal, intraperitoneal (ip), mesenteric, and perirenal fat thickness.
  • Diagnostic test 24-hour Ambulatory blood pressure monitoring
    A\&D TM2430EX oscillometric devices (A\&D Company Limited, Tokyo, Japan).
  • Procedure Percutaneous biopsy
    Subcutaneous fat tissue and muscle tissue for proteomics an gene expression studies.
  • Diagnostic test Cardiovascular autonomic function studies
    Parasympathetic and sympathetic responses to deep breathing, Valsalva's maneuver and orthostatism.
  • Diagnostic test Oral smear and feces specimen
    Microbiome studies.

Primary outcome measures

  • Adipokine and myokine signaling identification [Time frame: Up to 5 years]
Secondary outcome measures (12)
  • Circulating adipokine profile [Time frame: Up to 5 years]
  • Appetite regulation hormonal profile [Time frame: Up to 5 years]
  • Association between body mass index and sex steroids [Time frame: Up to 5 years]
  • Association between percentage of fat mass with respect to total body weight and sex steroids [Time frame: Up to 5 years]
  • Association between percentage of lean mass with respect to total body weight and sex steroids [Time frame: Up to 5 years]
  • Association between body fat depots and sex steroids [Time frame: Up to 5 years]
  • Association between body composition, sex steroids, and insulin resistance. [Time frame: Up to 5 years]
  • Association between body composition, sex steroids, and lipids. [Time frame: Up to 5 years]
  • Association between body composition, sex steroids, and office blood pressure. [Time frame: Up to 5 years]
  • Association between body composition, sex steroids, and ambulatory blood pressure monitoring parameters. [Time frame: Up to 5 years]
  • Association between body composition, sex steroids, and cardiovascular autonomic function tests. [Time frame: Up to 5 years]
  • Association between body composition, sex steroids, and carotid intima-media thickness. [Time frame: Up to 5 years]

Eligibility criteria

Inclusion criteria

Group I

  • Body mass index between 18.5 and 25.0 kg/m2.
  • Group 1 ovulatory dysfunction \[World Health Organization (WHO) classification\].
  • Normal/low gonadotrophin levels \[follicle-stimulating hormone (FSH) and luteinizing (LH) < 10 IU/l\] and low estradiol (< 50 pg/ml).
  • Moderate-vigorous intensity physical activity (> 5 hours per week) plus low energy availability (< 30 kcal/per kg of lean mass).
  • Exclusion of secondary etiologies
  • Informed consent signed.

Group II:

  • Polycystic ovary syndrome phenotype I, II and III \[National Institute of Health (NIH)-2012\] with hyperandrogenemia (http://prevention.nih.gov/workshops/2012/resources.aspx).
  • Body mass index between 18.5 and 40.0 kg/m2.
  • Informed consent signed.

Group III:

  • Polycystic ovary syndrome phenotype IV (NIH-2012) (http://prevention.nih.gov/workshops/2012/resources.aspx).
  • Body mass index between 18.5 and 40.0 kg/m2.
  • Informed consent signed.

Group IV:

  • Body mass index between 18.5 and 25.0 kg/m2.
  • Regular menses.
  • Normal gonadotropins and estradiol levels at follicular phase.
  • Moderate-vigorous intensity physical activity (> 5 hours per week) with normal energy availability (> 30 kcal/per kg of lean mass).
  • Informed consent signed.

Group V:

  • No signs or symptoms of hyperandrogenism.
  • No exercise or mild intensity physical activity.
  • Regular menses.
  • Body mass index between 18.5 and 40.0 kg/m2.
  • Informed consent signed.

Exclusion Criteria (Groups I-V)

  • Oral drugs interfering with ovulation (glucocorticoids, antipsychotics, antidepressants, contraceptives, sex steroids and/or opioids) for the previous 6 months to study inclusion.
  • Current pregnancy or lactation, or during the previous 6 months to study inclusion.
  • Asherman's syndrome or outflow tract disorders.
  • Current smoking or alcohol intake > 40 g per day.
  • Previous diagnosis of glucose intolerance, hypertension, dyslipidemia, known heart or lung diseases, kidney disease, liver disease, celiac disease or any other malabsorptive condition, chronic inflammatory disease or malignancy.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model
Case-control

Study locations

Spain · 1 center
  • Endocrinology and Nutrition — Madrid

Publications

  • Ortiz-Flores AE, Luque-Ramirez M, Fernandez-Duran E, Alvarez-Blasco F, Escobar-Morreale HF. Diagnosis of disorders of glucose tolerance in women with polycystic ovary syndrome (PCOS) at a tertiary care center: fasting plasma glucose or oral glucose tolerance test? Metabolism. 2019 Apr;93:86-92. doi: 10.1016/j.metabol.2019.01.015. Epub 2019 Jan 30. PMID 30710572
  • Luque-Ramirez M, Jimenez-Mendiguchia L, Garcia-Cano A, Fernandez-Duran E, de Dios Rosa V, Nattero-Chavez L, Ortiz-Flores AE, Escobar-Morreale HF. Certified testosterone immunoassays for hyperandrogenaemia. Eur J Clin Invest. 2018 Dec;48(12):e13029. doi: 10.1111/eci.13029. Epub 2018 Oct 8. PMID 30229887
  • Insenser M, Murri M, Del Campo R, Martinez-Garcia MA, Fernandez-Duran E, Escobar-Morreale HF. Gut Microbiota and the Polycystic Ovary Syndrome: Influence of Sex, Sex Hormones, and Obesity. J Clin Endocrinol Metab. 2018 Jul 1;103(7):2552-2562. doi: 10.1210/jc.2017-02799. PMID 29897462
  • Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018 May;14(5):270-284. doi: 10.1038/nrendo.2018.24. Epub 2018 Mar 23. PMID 29569621
  • Escobar-Morreale HF. The Role of Androgen Excess in Metabolic Dysfunction in Women : Androgen Excess and Female Metabolic Dysfunction. Adv Exp Med Biol. 2017;1043:597-608. doi: 10.1007/978-3-319-70178-3_26. PMID 29224112
  • Montes-Nieto R, Insenser M, Murri M, Fernandez-Duran E, Ojeda-Ojeda M, Martinez-Garcia MA, Luque-Ramirez M, Escobar-Morreale HF. Plasma thiobarbituric acid reactive substances (TBARS) in young adults: Obesity increases fasting levels only in men whereas glucose ingestion, and not protein or lipid intake, increases postprandial concentrations regardless of sex and obesity. Mol Nutr Food Res. 2017 N PMID 28722287
  • Escobar-Morreale HF, Martinez-Garcia MA, Montes-Nieto R, Fernandez-Duran E, Temprano-Carazo S, Luque-Ramirez M. Effects of glucose ingestion on circulating inflammatory mediators: Influence of sex and weight excess. Clin Nutr. 2017 Apr;36(2):522-529. doi: 10.1016/j.clnu.2016.01.015. Epub 2016 Jan 29. PMID 26874912
  • Insenser M, Montes-Nieto R, Martinez-Garcia MA, Escobar-Morreale HF. A nontargeted study of muscle proteome in severely obese women with androgen excess compared with severely obese men and nonhyperandrogenic women. Eur J Endocrinol. 2016 Mar;174(3):389-98. doi: 10.1530/EJE-15-0912. Epub 2015 Dec 15. PMID 26671973

Identifiers

NCT: NCT03841981 · PI18/01122

Primary sources (government registries)

View this study on ClinicalTrials.gov ↗