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Inherited Reproductive Disorders

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Collaborator:
Massachusetts General Hospital
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
ClinicalTrials.gov Identifier:
NCT01500447
First received: December 21, 2011
Last updated: November 11, 2014
Last verified: July 2014
  Purpose

Background:

- During puberty, children begin to develop into adults. Problems with the hormones released during puberty can affect the reproductive system. Some people have low hormone levels that severely delay or prevent puberty. Others start puberty abnormally early. Other people may have a normal puberty but develop reproductive disorders later in life. Researchers want to study people with reproductive disorders to learn more about how these disorders may be inherited.

Objectives:

- To learn how reproductive system disorders may be inherited.

Eligibility:

  • People with one of the following problems:
  • Abnormally early puberty
  • Abnormally late or no puberty
  • Normal puberty with hormonal problems that develop later in life
  • People who have not yet had puberty but have symptoms that indicate low hormone levels.

Design:

  • Participants will provide a blood sample for testing. They will complete a questionnaire about their symptoms. They will also have a scratch-and-sniff test to study any problems with their ability to smell.
  • Participant medical records will be reviewed. Participants will also provide a family medical history.
  • Family members of those in the study may be invited to participate.
  • Treatment will not be provided as part of this study.

Condition
Genetic Disorder
Infertility
Hypogonadism
Amenorrhea

Study Type: Observational
Study Design: Time Perspective: Prospective
Official Title: The Molecular Basis of Inherited Reproductive Disorders

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • The main outcome is the identification of known and novel genetic variants in individuals representing the complete spectrum of idiopathic hypogonadotropic hypogonadism.

Secondary Outcome Measures:
  • Phenotypic correlations, made by comparing the results of the genotypic analysis with clinical and/or biochemical characteristics, as well as discovery of genes worthy of further functional analysis.
  • The inheritance patterns of IHH, as well as whether these patterns are gene-specific, will be clarified through the genetic investigation of families harboring these mutations.

Estimated Enrollment: 500
Study Start Date: December 2011
Detailed Description:

The key initiating factors for reproductive development remain among the great mysteries of pediatric and reproductive endocrinology. The onset of puberty is initiated by pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. The neuroendocrine events leading to increased GnRH secretion and the resultant onset of puberty remain largely unknown.

Isolated deficiency of GnRH results in the rare clinical syndrome of idiopathic hypogonadotropic hypogonadism (IHH), where decreased secretion of GnRH results in impaired gonadotropin secretion. The resultant hypogonadism presents with delayed, incomplete, or absent sexual maturation. Human and animal models have identified a number of genes responsible for IHH, but more than half of patients with clinical evidence of the disorder do not have a detectable mutation. In addition, there is significant clinical heterogeneity among affected individuals, including members of the same family harboring the same mutations. Careful human phenotyping of such patients and families has expanded our understanding of this spectrum of disorders to include oligo-digenic inheritence, as well as reversibility of the condition, and has provided insight into developmental pathways involved in the ontogeny of GnRH neurons.

Genetic analysis of subjects with unknown mutations is likely to yield important insights into additional pathways involved in the regulation of GnRH secretion. Here, we propose a genetic investigation of subjects with IHH to characterize further the phenotypic effect of previously described genetic variants, as well as to identify novel genes involved in congenital GnRH deficiency. In collaboration with the Reproductive Endocrine Unit at the Massachusetts General Hospital, we will use both candidate gene and whole exome approaches, as well as linkage analysis. The collaboration will allow for sufficient statistical power to conduct such an investigation.

This protocol will utilize the disease model of IHH to increase our understanding of the physiology of GnRH secretion, including the neuroendocrine regulation of GnRH pulsatility. Examining the genetic characteristics of subjects with isolated GnRH deficiency will reveal insights into the mechanisms underlying the reawakening of the hypothalamic-pituitary-gonadal axis at puberty, providing opportunities for new diagnostic capabilities and therapeutic interventions for disorders of puberty and fertility.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • The essential inclusion criteria include:

    1. failure to go through a normal, age-appropriate, spontaneous puberty and low sex steroid levels in the setting of low/normal gonadotropins, or
    2. abnormally early development of puberty, or
    3. normal puberty with subsequent development of low gonadotropin levels, or
    4. pre-pubertal individuals with features suggestive of hypogonadotropic hypogonadism.
    5. Family members: both affected and unaffected family members are strongly encouraged to participate.

      EXCLUSION CRITERIA:

      Since hypogonadotropic hypogonadism is a rare condition, this protocol remains open to enrollment so that we may study all subjects that are both qualified and interested in participating.

      Because HH represents a spectrum, where associated clinical findings may provide phenotypic clues to the assessment of inheritability and underlying physiology, exclusion criteria are very limited:

  • Patients who have additional pituitary deficiencies, effectively ruling out isolated GnRH deficiency, whether these deficiencies are congenital or acquired (e.g. secondary to malignancy, infection, or irradiation).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01500447

Contacts
Contact: Angela Delaney, M.D. (301) 496-3025 delaneya@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Chile
University of Chile Recruiting
Santiago, Chile
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
Principal Investigator: Angela Delaney, M.D. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
ClinicalTrials.gov Identifier: NCT01500447     History of Changes
Other Study ID Numbers: 120049, 12-CH-0049
Study First Received: December 21, 2011
Last Updated: November 11, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Hypogonadotropic Hypogonadism
Kallmann Syndrome
Delayed Puberty
Infertility
Hypothalamic Amenorrhea
Early Puberty
Late Puberty
Hypogonadism
Amenorrhea
Endocrine Diseases

Additional relevant MeSH terms:
Amenorrhea
Disease
Hypogonadism
Infertility
Endocrine System Diseases
Genital Diseases, Female
Genital Diseases, Male
Gonadal Disorders
Menstruation Disturbances
Pathologic Processes

ClinicalTrials.gov processed this record on November 20, 2014