Clinical trial NCT03841981: Body Fat As Determinant of Female Gonadal Dysfunction
Official title: Amount, Distribution and Dysfunction of Body Fat As Determinants of Female Gonadal Dysfunction: from Functional Hypothalamic Amenorrhea to the Polycystic Ovary Syndrome
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Polycystic Ovary Syndrome
Hypothalamic Amenorrhea
Keywords: Exercise
Sex steroids
Hyperandrogenism
Adipose tissue
Muscle
Proteome
Gene expression
Adipokine
Cardiovascular risk
Microbiome
Lead sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
Sponsor class: OTHER
Collaborators: name: Instituto de Salud Carlos III
name: University of Alcala
First posted: 2019-02-15
Enrollment: 50
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with exercise-associated functional amenorrhea and polycystic ovary syndrome will be consecutively recruited from our Reproductive Endocrinolgy clinic. Those premenopausal adult women are referred to clinic because of symptoms of functional androgen excess such as hirsutism or menstrual dysfunction.

The control group (Groups IV and V) will include healthy female volunteers recruited - contemporarily with the recruitment of patients - from the hospital's staff and overweight or obese women seeking medical attention in our department.

Brief summary: 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.


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.

Primary outcomes:
measure: Adipokine and myokine signaling identification
timeFrame: Up to 5 years
Secondary outcomes:
measure: Circulating adipokine profile
timeFrame: Up to 5 years
measure: Appetite regulation hormonal profile
timeFrame: Up to 5 years
measure: Association between body mass index and sex steroids
timeFrame: Up to 5 years
measure: Association between percentage of fat mass with respect to total body weight and sex steroids
timeFrame: Up to 5 years
measure: Association between percentage of lean mass with respect to total body weight and sex steroids
timeFrame: Up to 5 years
measure: Association between body fat depots and sex steroids
timeFrame: Up to 5 years
measure: Association between body composition, sex steroids, and insulin resistance.
timeFrame: Up to 5 years
measure: Association between body composition, sex steroids, and lipids.
timeFrame: Up to 5 years
measure: Association between body composition, sex steroids, and office blood pressure.
timeFrame: Up to 5 years
measure: Association between body composition, sex steroids, and ambulatory blood pressure monitoring parameters.
timeFrame: Up to 5 years
measure: Association between body composition, sex steroids, and cardiovascular autonomic function tests.
timeFrame: Up to 5 years
measure: Association between body composition, sex steroids, and carotid intima-media thickness.
timeFrame: Up to 5 years
measure: Association between body composition, sex steroids, and oxidative stress.
timeFrame: Up to 5 years
measure: Association between body composition, sex steroids, and microbiome
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Madrid
country: Spain
facility: Endocrinology and Nutrition
Study officials:
affiliation: Diabetes, Obesity and Human Reproduction Research Group (CIBERDEM), Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
name: Héctor F Escobar-Morreale, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Diabetes, Obesity and Human Reproduction Research Group (CIBERDEM), Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
name: Manuel Luque-Ramírez, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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 Nov;61(11). doi: 10.1002/mnfr.201700425. Epub 2017 Aug 29.
citation: 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.
citation: 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.
citation: Borruel S, Molto JF, Alpanes M, Fernandez-Duran E, Alvarez-Blasco F, Luque-Ramirez M, Escobar-Morreale HF. Surrogate markers of visceral adiposity in young adults: waist circumference and body mass index are more accurate than waist hip ratio, model of adipose distribution and visceral adiposity index. PLoS One. 2014 Dec 5;9(12):e114112. doi: 10.1371/journal.pone.0114112. eCollection 2014.
citation: Luque-Ramirez M, Escobar-Morreale HF. Polycystic ovary syndrome as a paradigm for prehypertension, prediabetes, and preobesity. Curr Hypertens Rep. 2014 Dec;16(12):500. doi: 10.1007/s11906-014-0500-6.
citation: Escobar-Morreale HF, Alvarez-Blasco F, Botella-Carretero JI, Luque-Ramirez M. The striking similarities in the metabolic associations of female androgen excess and male androgen deficiency. Hum Reprod. 2014 Oct 10;29(10):2083-91. doi: 10.1093/humrep/deu198. Epub 2014 Aug 7.
citation: Murri M, Insenser M, Luque M, Tinahones FJ, Escobar-Morreale HF. Proteomic analysis of adipose tissue: informing diabetes research. Expert Rev Proteomics. 2014 Aug;11(4):491-502. doi: 10.1586/14789450.2014.903158. Epub 2014 Mar 31.
citation: Murri M, Insenser M, Escobar-Morreale HF. Metabolomics in polycystic ovary syndrome. Clin Chim Acta. 2014 Feb 15;429:181-8. doi: 10.1016/j.cca.2013.12.018. Epub 2013 Dec 22.
citation: Luque-Ramirez M, Marti D, Fernandez-Duran E, Alpanes M, Alvarez-Blasco F, Escobar-Morreale HF. Office blood pressure, ambulatory blood pressure monitoring, and echocardiographic abnormalities in women with polycystic ovary syndrome: role of obesity and androgen excess. Hypertension. 2014 Mar;63(3):624-9. doi: 10.1161/HYPERTENSIONAHA.113.02468. Epub 2013 Dec 9.
citation: Escobar-Morreale HF. Reproductive endocrinology: Menstrual dysfunction--a proxy for insulin resistance in PCOS? Nat Rev Endocrinol. 2014 Jan;10(1):10-1. doi: 10.1038/nrendo.2013.232. Epub 2013 Nov 26. No abstract available.
citation: Insenser M, Escobar-Morreale HF. Proteomics and polycystic ovary syndrome. Expert Rev Proteomics. 2013 Oct;10(5):435-47. doi: 10.1586/14789450.2013.837665. Epub 2013 Oct 3.
citation: Murri M, Insenser M, Bernal-Lopez MR, Perez-Martinez P, Escobar-Morreale HF, Tinahones FJ. Proteomic analysis of visceral adipose tissue in pre-obese patients with type 2 diabetes. Mol Cell Endocrinol. 2013 Aug 25;376(1-2):99-106. doi: 10.1016/j.mce.2013.06.010. Epub 2013 Jun 18.
citation: Luque-Ramirez M, Martinez-Garcia MA, Montes-Nieto R, Fernandez-Duran E, Insenser M, Alpanes M, Escobar-Morreale HF. Sexual dimorphism in adipose tissue function as evidenced by circulating adipokine concentrations in the fasting state and after an oral glucose challenge. Hum Reprod. 2013 Jul;28(7):1908-18. doi: 10.1093/humrep/det097. Epub 2013 Apr 4.
citation: Insenser M, Montes-Nieto R, Murri M, Escobar-Morreale HF. Proteomic and metabolomic approaches to the study of polycystic ovary syndrome. Mol Cell Endocrinol. 2013 May 6;370(1-2):65-77. doi: 10.1016/j.mce.2013.02.009. Epub 2013 Feb 17.
citation: Borruel S, Fernandez-Duran E, Alpanes M, Marti D, Alvarez-Blasco F, Luque-Ramirez M, Escobar-Morreale HF. Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab. 2013 Mar;98(3):1254-63. doi: 10.1210/jc.2012-3698. Epub 2013 Feb 5.
citation: Montes-Nieto R, Insenser M, Martinez-Garcia MA, Escobar-Morreale HF. A nontargeted proteomic study of the influence of androgen excess on human visceral and subcutaneous adipose tissue proteomes. J Clin Endocrinol Metab. 2013 Mar;98(3):E576-85. doi: 10.1210/jc.2012-3438. Epub 2013 Jan 24.
citation: Alvarez-Blasco F, Luque-Ramirez M, Escobar-Morreale HF. Diet composition and physical activity in overweight and obese premenopausal women with or without polycystic ovary syndrome. Gynecol Endocrinol. 2011 Dec;27(12):978-81. doi: 10.3109/09513590.2011.579658. Epub 2011 May 24.
citation: Insenser M, Escobar-Morreale HF. Application of proteomics to the study of polycystic ovary syndrome. J Endocrinol Invest. 2011 Dec;34(11):869-75. doi: 10.3275/8108. Epub 2011 Nov 21.
citation: Escobar-Morreale HF, Samino S, Insenser M, Vinaixa M, Luque-Ramirez M, Lasuncion MA, Correig X. Metabolic heterogeneity in polycystic ovary syndrome is determined by obesity: plasma metabolomic approach using GC-MS. Clin Chem. 2012 Jun;58(6):999-1009. doi: 10.1373/clinchem.2011.176396. Epub 2012 Mar 16.
citation: Insenser M, Montes-Nieto R, Vilarrasa N, Lecube A, Simo R, Vendrell J, Escobar-Morreale HF. A nontargeted proteomic approach to the study of visceral and subcutaneous adipose tissue in human obesity. Mol Cell Endocrinol. 2012 Nov 5;363(1-2):10-9. doi: 10.1016/j.mce.2012.07.001. Epub 2012 Jul 14.
citation: Murri M, Luque-Ramirez M, Insenser M, Ojeda-Ojeda M, Escobar-Morreale HF. Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Hum Reprod Update. 2013 May-Jun;19(3):268-88. doi: 10.1093/humupd/dms059. Epub 2013 Jan 9.
citation: Martinez-Garcia MA, Montes-Nieto R, Fernandez-Duran E, Insenser M, Luque-Ramirez M, Escobar-Morreale HF. Evidence for masculinization of adipokine gene expression in visceral and subcutaneous adipose tissue of obese women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab. 2013 Feb;98(2):E388-96. doi: 10.1210/jc.2012-3414. Epub 2013 Jan 21.