Body Fat as Determinant of Female Gonadal Dysfunction

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.

Conditions

• Polycystic Ovary Syndrome
• Hypothalamic Amenorrhea

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.

Sponsors & Collaborators

• Instituto de Salud Carlos III

  collaborator OTHER_GOV

• University of Alcala

  collaborator OTHER

• Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

  lead OTHER

Principal Investigators

• Héctor F Escobar-Morreale, PhD, MD · 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

• Manuel Luque-Ramírez, PhD, MD · 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

Eligibility

Min Age

18 Years

Max Age

40 Years

Sex

FEMALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2020-01-31

Primary Completion

2025-06-30

Completion

2025-12-31

Countries

• Spain

Study Locations