Body Fat As Determinant of Female Gonadal Dysfunction

Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

Status: Enrolling

Conditions: Polycystic Ovary Syndrome; Hypothalamic Amenorrhea

Treatments: Diagnostic Test: Sonographic studies; Diagnostic Test: Biochemical, hormonal and metabolic phenotyping; Diagnostic Test: Oral smear and feces specimen; Diagnostic Test: Cardiovascular autonomic function studies; Diagnostic Test: 24-hour Ambulatory blood pressure monitoring; Diagnostic Test: Indirect calorimetry, accelerometer and seven-day dietary recall; Procedure: Percutaneous biopsy; Diagnostic Test: Anthropometric and physical examination

Study type: Observational

Funder types: Other

Identifiers

NCT03841981

PI18/01122

Details and patient eligibility

About

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.

Enrollment: 50 estimated patients

Sex: Female

Ages: 18 to 40 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion 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.

Trial design

50 participants in 5 patient groups

I- Hypothalamic amenorrhea

Description:

10 women with exercise-associated hypothalamic amenorrhea

Treatment:

Diagnostic Test: Anthropometric and physical examination

Procedure: Percutaneous biopsy

Diagnostic Test: Indirect calorimetry, accelerometer and seven-day dietary recall

Diagnostic Test: 24-hour Ambulatory blood pressure monitoring

Diagnostic Test: Cardiovascular autonomic function studies

Diagnostic Test: Oral smear and feces specimen

Diagnostic Test: Biochemical, hormonal and metabolic phenotyping

Diagnostic Test: Sonographic studies

II- Hyperandrogenic polycystic ovary syndrome

Description:

5 lean women with hyperandrogenic polycystic ovary syndrome. 5 women with weight excess and hyperandrogenic polycystic ovary syndrome.

Treatment:

Diagnostic Test: Anthropometric and physical examination

Procedure: Percutaneous biopsy

Diagnostic Test: Indirect calorimetry, accelerometer and seven-day dietary recall

Diagnostic Test: 24-hour Ambulatory blood pressure monitoring

Diagnostic Test: Cardiovascular autonomic function studies

Diagnostic Test: Oral smear and feces specimen

Diagnostic Test: Biochemical, hormonal and metabolic phenotyping

Diagnostic Test: Sonographic studies

III- Non-hyperandrogenic polycystic ovary syndrome

Description:

5 lean women with non-hyperandrogenic polycystic ovary syndrome 5 women with weight excess and non-hyperandrogenic polycystic ovary syndrome

Treatment:

Diagnostic Test: Anthropometric and physical examination

Procedure: Percutaneous biopsy

Diagnostic Test: Indirect calorimetry, accelerometer and seven-day dietary recall

Diagnostic Test: 24-hour Ambulatory blood pressure monitoring

Diagnostic Test: Cardiovascular autonomic function studies

Diagnostic Test: Oral smear and feces specimen

Diagnostic Test: Biochemical, hormonal and metabolic phenotyping

Diagnostic Test: Sonographic studies

IV- Trained women without ovulatory dysfunction

Description:

10 women who exercise as intensively as women with exercise-associated hypothalamic amenorrhea but with normal ovulatory cycles.

Treatment:

Diagnostic Test: Anthropometric and physical examination

Procedure: Percutaneous biopsy

Diagnostic Test: Indirect calorimetry, accelerometer and seven-day dietary recall

Diagnostic Test: 24-hour Ambulatory blood pressure monitoring

Diagnostic Test: Cardiovascular autonomic function studies

Diagnostic Test: Oral smear and feces specimen

Diagnostic Test: Biochemical, hormonal and metabolic phenotyping

Diagnostic Test: Sonographic studies

V- Non-hyperandrogenic healthy women

Description:

10 women matched by age and body mass index with women with polycystic ovary syndrome who do not perform physical activity on a regular basis

Treatment:

Diagnostic Test: Anthropometric and physical examination

Procedure: Percutaneous biopsy

Diagnostic Test: Indirect calorimetry, accelerometer and seven-day dietary recall

Diagnostic Test: 24-hour Ambulatory blood pressure monitoring

Diagnostic Test: Cardiovascular autonomic function studies

Diagnostic Test: Oral smear and feces specimen

Diagnostic Test: Biochemical, hormonal and metabolic phenotyping

Diagnostic Test: Sonographic studies