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Inherited Reproductive Disorders

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01500447
Recruitment Status : Recruiting
First Posted : December 28, 2011
Last Update Posted : July 19, 2022
Massachusetts General Hospital
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Environmental Health Sciences (NIEHS) )

Tracking Information
First Submitted Date December 21, 2011
First Posted Date December 28, 2011
Last Update Posted Date July 19, 2022
Actual Study Start Date April 25, 2012
Primary Completion Date Not Provided
Current Primary Outcome Measures
 (submitted: October 7, 2021)
The main outcome is the identification of known and novel genetic variants in individuals representing the complete spectrum of idiopathic hypogonadotropic hypogonadism. [ Time Frame: Ongoing/exploratory ]
The main outcome is the identification of known and novel genetic variants in individuals representing the complete spectrum of idiopathic hypogonadotropic hypogonadism.
Original Primary Outcome Measures Not Provided
Change History
Current Secondary Outcome Measures
 (submitted: October 7, 2021)
Phenotypic correlations, made by comparing the results of the genotypic analysis with clinical and/or biochemical characteristics, as well as the discovery of genes worthy of further functional analysis. [ Time Frame: Ongoing/exploratory ]
Phenotypic correlations, made by comparing the results of the genotypic analysis with clinical and/or biochemical characteristics, as well as the discovery of genes worthy of further functional analysis.
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title Inherited Reproductive Disorders
Official Title The Molecular Basis of Inherited Reproductive Disorders
Brief Summary


- 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.


- To learn how reproductive system disorders may be inherited.


  • 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.


  • 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.
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. In particular, hypogonadotropic hypogonadism (HH) exists along a genetic and phenotypic spectrum that includes milder forms of GnRH dysregulation, precocious and delayed puberty, and onset of reproductive dysfunction after puberty.

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. We will use both candidate gene and whole exome approaches, as well as linkage analysis.

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.

Study Type Observational
Study Design Observational Model: Case-Only
Time Perspective: Cross-Sectional
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Non-Probability Sample
Study Population Primary Clinical, self-referred or physician-referred subjects
  • Genetic Disorder
  • Infertility
  • Hypogonadism
  • Amenorrhea
Intervention Not Provided
Study Groups/Cohorts
  • Central Precious Puberty
    CPP subjects
  • Hypogonadotropic Hypogonadism
    IHH, KS, GnRH Deficiency, BAM syndrome (arhinia), HA, CDP subjects
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: June 23, 2020)
Original Estimated Enrollment
 (submitted: December 22, 2011)
Study Completion Date Not Provided
Primary Completion Date Not Provided
Eligibility 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 (due to substantial variability among patient presentations, this will be based on the clinical judgement of the Investigator), or
  2. abnormally early development of puberty, or
  3. normal puberty with subsequent development of low gonadotropin levels, or
  4. individuals with features indicating an increased risk of hypogonadotropic hypogonadism.
  5. Family members: both affected and unaffected family members are strongly encouraged to participate.


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).
  • Patients who are taking medications known to affect GnRH secretion, such as corticosteroids or continuous opiate administration (or were taking them at the time of diagnosis).
Sexes Eligible for Study: All
Ages Child, Adult, Older Adult
Accepts Healthy Volunteers No
Contact: NIEHS Join A Study Recruitment Group (855) 696-4347
Contact: Janet E Hall, M.D. (984) 287-3647
Listed Location Countries United States
Removed Location Countries Chile
Administrative Information
NCT Number NCT01500447
Other Study ID Numbers 120049
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
Plan Description: .This study does not meet the criteria of a clinical trial, therefore ICMJE does not require a data sharing statement.@@@@@@The study will comply with the NIH Genomic Data Sharing Policy, if in the future, it meets the Policy s criteria for large scale human genomic data.
Current Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Environmental Health Sciences (NIEHS) )
Original Responsible Party Not Provided
Current Study Sponsor National Institute of Environmental Health Sciences (NIEHS)
Original Study Sponsor Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Collaborators Massachusetts General Hospital
Principal Investigator: Janet E Hall, M.D. National Institute of Environmental Health Sciences (NIEHS)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date May 27, 2022