Symptoms and General Pathology

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Neoplasms

Gland and Hormone Related Diseases

Nervous System Diseases

Musculoskeletal Diseases

Mouth and Tooth Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Syndrome

Infertility

Polycystic Ovary Syndrome

Anosmia

Cleft Palate

Cleft Lip

Hypogonadism

Puberty, Precocious

Amenorrhea

Cryptorchidism

Kallmann Syndrome

Gonadal Disorders

Endocrine System Diseases

Mouth Diseases

Stomatognathic Diseases

Congenital Abnormalities

Mouth Abnormalities

Stomatognathic System Abnormalities

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Jaw Abnormalities

Jaw Diseases

Maxillofacial Abnormalities

Craniofacial Abnormalities

Musculoskeletal Abnormalities

Menstruation Disturbances

Disorders of Sex Development

Disorder of Sex Development, 46,XY

Urogenital Abnormalities

Male Urogenital Diseases

Genetic Diseases, Inborn

Precocious Puberty

Patients with reproductive disorders with or without cleft lip/palate will be recruited for:

* completion of medical questionnaire and review of medical records
* family tree (including questions on reproductive disorders and cleft lip/palate)
* specimen collection (DNA/RNA) from: serum/plasma/saliva/urine/buccal swab/hair follicles/sperm/skin biopsy
* smell testing
* hearing test
* bone density
* brain MRI
* kidney, testicular/ovarian ultrasound

Family members of Patients will be recruited for:

* completion of medical questionnaire
* specimen collection (DNA/RNA) from: serum/plasma/saliva/urine/buccal swab/hair follicles/sperm/skin biopsy
* smell testing

Emmanuelle Paccou

Michela Adamo, MD

Nelly Pitteloud, M.D.

The purpose of this study is to explore the genetic basis of reproductive disorders and cleft lip and/or palate.

The World Health Organization estimates approximately 10% of couples experience some sort of infertility problem.

In humans, puberty is the process through which we develop reproductive capacity.

The timing of puberty varies greatly in the general population and is influenced by both genetic and environmental factors. In extreme cases of pubertal delay, puberty progresses only partially or not at all and results in the clinical picture of congenital hypogonadotropic hypogonadism (CHH), either accompanied by anosmia in 50% of cases (Kallmann syndrome \[KS\]) or by normal sense of smell (nCHH), with a male: female ratio of 4:1.

CHH is due to GnRH deficiency (incidence 1: 4,000-10,000) and result in the failure of sexual maturation and infertility. It is genetically heterogeneous, with multiple patterns of inheritance and several associated loci. In the clinical spectrum of GnRH deficiency, CHH may also be associated with a cleft lip/palate (CL/P) in 5 to 7% of cases. However, this prevalence increases up to 40% in CHH patients carrying a mutation in a CL/P gene, suggesting a genetic overlap between CHH and CL/P.

Disorders of puberty have provided insight into the biology of reproduction and genetic technologies have enabled us to deepen understanding in this field. The focus of this study is to better understand the genetic control of puberty and human reproduction as well as its link with CL/P.

Increasing understanding of the molecular basis (genes) of inherited reproductive disorders and CL/P may enable investigators to:

* improve diagnostic testing and treatments for these problems
* develop new diagnostic tests and therapies for patients
* enhance counseling for patients and families with reproductive disorders
* enhance counseling for patients and families with cleft lip/palate

whole blood, serum/plasma, white blood cells, DNA

Genetics of Reproductive Disorders (Including Kallmann Syndrome) and Cleft Lip and/or Palate

The Genetics of Neuroendocrine Reproductive Disorders and of the Cleft Lip and/or Palate

The investigators aim to discover genes associated with reproductive disorders by identifying rare sequence variants (mutations) in patients

The investigators will use a variety of scientific approaches to assess the functional impact of the identified rare sequence variants (mutations)

The investigators will examine family pedigrees and study family members to determine the inheritance patterns (how the disorder is transmitted in the family)

The investigators will study the phenotypic spectrum (how the disorder presents clinically) in patients with identified rare sequence variants (mutations)

Swiss National Science Foundation

Centre Hospitalier Universitaire Vaudois

Professor of Medicine, Chief of Service

Hyperandrogenism

Hypoglycemic Agents

All Drugs and Chemicals

Vasoconstrictor Agents

Respiratory System Agents

Insulin

Insulin, Globin Zinc

Hormones

Epinephrine

Racepinephrine

Epinephryl borate

10 women with exercise-associated hypothalamic amenorrhea

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

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

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

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

* Weight and height.
* Waist-to-hip ratio.
* Body composition: Bioelectrical impedance and \[Dual energy X-ray absorptiometry (DEXA)\].

Anthropometric and physical examination

Indirect calorimetry, accelerometer and seven-day dietary recall

* 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.

Biochemical, hormonal and metabolic phenotyping

* 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.

Sonographic studies

A\&D TM2430EX oscillometric devices (A\&D Company Limited, Tokyo, Japan).

24-hour Ambulatory blood pressure monitoring

Subcutaneous fat tissue and muscle tissue for proteomics an gene expression studies.

Percutaneous biopsy

Parasympathetic and sympathetic responses to deep breathing, Valsalva's maneuver and orthostatism.

Cardiovascular autonomic function studies

Oral smear and feces specimen

Elena Fernández Durán

Héctor F Escobar-Morreale, PhD, MD

Manuel Luque-Ramírez, PhD, MD

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.

Serum Plasma Whole blood samples Subcutaneous adipose tissue by percutaneous biopsy Muscle tissue by percutaneous biopsy Feces Oral smear

Body Fat as Determinant of Female Gonadal Dysfunction

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

The investigators will deposit any datasets and supplemental materials to a generalist repository. The investigators will refer to the deposited material as an item in the bibliography of any manuscript and number the reference appropriately within the text.

At fasting and after an oral glucose challenge: Circulating concentrations of Leptin, Adiponectin, Chemerin, Lipocalin-2, Adipsin, Plasminogen Activator Inhibitor (PAI)-1, Monocyte Chemoattractant Protein (MCP)-1, and Soluble Leptin Receptor by multianalyte profiling on the Luminex Magpix system (Luminex Technologies, Austin, USA.).

At fasting and after an oral glucose challenge: Circulating concentrations of Amylin, C-Peptide, Ghrelin, Gastric Inhibitory Peptide (GIP), Glucagon-Like Peptide (GLP)-1, Glucagon, IL-6, Insulin, Pancreatic Polypeptide (PP), Peptide YY, Tumor Necrosis Factor (TNF)-α by multianalyte profiling on the Luminex Magpix system (Luminex Technologies, Austin, USA.).

Body mass index in in kg/m\^2. Sex steroids (including circulating total testosterone, estradiol, androstenedione, dehydroepiandrosterone-sulphate and estrone) measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Free testosterone will be calculated from total testosterone and sex hormone binding globulin levels.

Fat mass% by bioelectric impedanciometry and DEXA. Sex steroids (including circulating total testosterone, estradiol, androstenedione, dehydroepiandrosterone-sulphate and estrone) measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Free testosterone will be calculated from total testosterone and sex hormone binding globulin levels.

Lean mass% by bioelectric impedanciometry and DEXA. Sex steroids (including circulating total testosterone, estradiol, androstenedione, dehydroepiandrosterone-sulphate and estrone) measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Free testosterone will be calculated from total testosterone and sex hormone binding globulin levels.

Adipose tissue depots will be estimated using a Toshiba Nemio XG SSA-580A Diagnostic Ultrasound System. Minimum sc and preperitoneal fat thicknesses will be measured at the level of the xyphoid process. Maximum sc fat thickness will be measured at the level of the umbilicus. Intraperitoneal fat thickness will be measured placing a probe transversally in the midline of abdomen, 2 cm above the umbilicus. Three measures of ip fat thickness will be obtained: the distance from the fascia of rectus abdominis muscle to the vertebral column, the distance from the peritoneum to the vertebral column, and the distance from the linea alba to the vertebral column. Perirenal fat thickness will be estimated as the distance from the perirenal fascia to the renal surface. Sex steroids will be measured as previously described.

Fat mass, lean mass and body fat depots will be measured as previously described. Fasting glucose and insulin levels will be used for calculating the homeostasis model assessment of insulin resistance (HOMA-IR), and the composite insulin sensitivity index will be estimated from the glucose and insulin concentrations measured during the oral glucose tolerance test. Sex steroids will be measured as previously described.

Fat mass, lean mass and body fat depots will be measured as previously described. Circulating HDL-cholesterol and phospholipid levels will be measured by enzymatic methods after precipitation of plasma with phosphotungstic acid and Mg2+. Total cholesterol and triglyceride levels will be determined by enzymatic methods. LDL-cholesterol concentrations will be estimated by Friedewald's equation. Circulating apolipoprotein (Apo) AI, Apo B100, and lipoprotein (a) levels will be determined by kinetic immunonephelometry. Sex steroids will be measured as previously described.

Fat mass, lean mass and body fat depots will be measured as previously described. Office blood pressure will be determined as the mean of three manual sphygmomanometer readings in the sitting position. Sex steroids will be measured as previously described.

Fat mass, lean mass and body fat depots will be measured as previously described. Twenty-four-hour ambulatory blood pressure monitoring will be performed using an A\&D TM2430EX oscillometric device (A\&D Co., Ltd., Tokyo, Japan). The cuff (12 × 22 cm for lean participants, 14 × 30 cm for overweight or obese participants) will placed on the nondominant arm in every woman. The period from 0700 to 2300 h will be considered daytime, and from 2300 until 0700 h the next day will be considered nighttime, reflecting the usual sleeping habits of Spaniards. Systolic, diastolic, and mean blood pressure as well as heart rate will be measured every 20 min during daytime and every 30 min during nighttime. Sex steroids will be measured as previously described.

Fat mass, lean mass and body fat depots will be measured as previously described. Cardiovascular autonomic function will be assessed by the blood pressure and heart rate responses to active standing, and Ewing and Clarke's tests. Sex steroids will be measured as previously described.

Fat mass, lean mass and body fat depots will be measured as previously described. Imaging will be conducted using a high-resolution 7.5-MHz phased-array transducer by the same trained operator in all the participants. Sex steroids will be measured as previously described.

Fat mass, lean mass and body fat depots will be measured as previously described. Oxidative stress profile will be measured by enzymatic assays: Plasma thiobarbituric acid reactive substances, total antioxidant capacity, nitrotyrosine, protein carbonyl groups and erythrocyte glutathione peroxidase levels. Sex steroids will be measured as previously described.

Participants will be instructed to collect fecal and salivary samples. DNA samples wil be used for massive sequencing of 16S ribosomal DNA (rDNA) amplicons in a MiSeq platform (Illumina). The bacterial diversity will be estimated by using Shannon, Chao 1, Jaccard, and Sorensen indexes with their SDs. Taxonomic affiliations will be assigned by using the RDP_classifier from the Ribosomal Database Project (RDP), and readings with RDP score value \<0.8 will be assigned to the upper taxonomic rank, leaving the last rank as unidentified. Sex steroids will be measured as previously described.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Genetics of Reproductive Disorders (Including Kallmann Syndrome) and Cleft Lip and/or Palate	NCT01601171	Kallmann Syndro... Hypogonadotropi... Hypothalamic Am... Polycystic Ovar... Precocious Pube... Cleft Lip and P... Cleft Palate Cleft Lip		-	Centre Hospitalier Universitaire Vaudois
Body Fat as Determinant of Female Gonadal Dysfunction	NCT03841981	Polycystic Ovar... Hypothalamic Am...	Anthropometric ... Indirect calori... Biochemical, ho... Sonographic stu... 24-hour Ambulat... Percutaneous bi... Cardiovascular ... Oral smear and ...	18 Years - 40 Years	Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

Spots Global Cancer Trial Database for hypothalamic amenorrhea