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History of Changes for Study: NCT01500447
Inherited Reproductive Disorders
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Study Record Versions
Version A B Submitted Date Changes
1 December 22, 2011 None (earliest Version on record)
2 January 20, 2012 Contacts/Locations, Eligibility and Study Status
3 February 8, 2012 Conditions and Study Status
4 March 14, 2012 Contacts/Locations and Study Status
5 March 20, 2012 Contacts/Locations and Study Status
6 October 27, 2012 Study Status
7 December 15, 2012 Study Status
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9 May 23, 2013 Outcome Measures and Study Status
10 October 1, 2013 Study Status
11 March 14, 2014 Study Status
12 August 16, 2014 Outcome Measures, Conditions and Study Status
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14 October 23, 2014 Contacts/Locations and Study Status
15 November 11, 2014 Sponsor/Collaborators and Study Status
16 July 25, 2015 Eligibility and Study Status
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18 October 30, 2015 Contacts/Locations and Study Status
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20 July 28, 2016 Study Status
21 August 31, 2016 References and Study Status
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27 April 21, 2017 Study Design and Study Status
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35 January 18, 2018 Sponsor/Collaborators and Study Status
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37 March 27, 2018 Contacts/Locations and Study Status
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39 June 23, 2018 Contacts/Locations and Study Status
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42 August 8, 2018 Oversight and Study Status
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44 October 25, 2018 Study Status
45 November 28, 2018 Study Status
46 April 2, 2019 Study Description and Study Status
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48 July 6, 2019 Study Status and Eligibility
49 July 9, 2019 Outcome Measures, Eligibility, Study Design, Contacts/Locations, Groups and Interventions, Conditions and Study Status
50 July 11, 2019 Contacts/Locations and Study Status
51 July 12, 2019 Study Status
52 July 16, 2019 Contacts/Locations, References, Eligibility, Outcome Measures, Study Design, Conditions and Study Status
53 August 12, 2019 Study Status and Study Identification
54 August 13, 2019 Sponsor/Collaborators, Study Status, References and Contacts/Locations
55 August 14, 2019 Contacts/Locations and Study Status
56 September 7, 2019 Study Description and Study Status
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60 January 3, 2020 Study Description and Study Status
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70 May 15, 2020 Contacts/Locations, Eligibility and Study Status
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75 June 20, 2020 Eligibility, Study Design and Study Status
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78 June 27, 2020 Study Description and Study Status
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105 October 7, 2021 Outcome Measures, Eligibility, Oversight and Study Status
106 October 12, 2021 Study Status and Oversight
107 October 13, 2021 Study Description and Study Status
108 October 14, 2021 Study Description and Study Status
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110 October 16, 2021 Study Description and Study Status
111 November 2, 2021 Study Description and Study Status
112 December 9, 2021 Study Description and Study Status
113 December 15, 2021 Conditions and Study Status
114 December 16, 2021 Study Description and Study Status
115 December 30, 2021 Study Description and Study Status
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177 May 31, 2022 IPDSharing, Eligibility and Study Status
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204 September 13, 2022 Contacts/Locations, Eligibility, Study Design and Study Status
205 September 14, 2022 Study Description and Study Status
206 September 16, 2022 Study Status
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Study NCT01500447
Submitted Date:  December 22, 2011 (v1)

Open or close this module Study Identification
Unique Protocol ID: 120049
Brief Title: Inherited Reproductive Disorders
Official Title: The Molecular Basis of Inherited Reproductive Disorders
Secondary IDs: 12-CH-0049
Open or close this module Study Status
Record Verification: November 2011
Overall Status: Recruiting
Study Start: December 2011
Primary Completion:
Study Completion:
First Submitted: December 21, 2011
First Submitted that
Met QC Criteria:
December 22, 2011
First Posted: December 28, 2011 [Estimate]
Last Update Submitted that
Met QC Criteria:
December 22, 2011
Last Update Posted: December 28, 2011 [Estimate]
Open or close this module Sponsor/Collaborators
Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Responsible Party:
Collaborators: Massachusetts General Hospital
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring:
Open or close this module Study Description
Brief Summary:

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.
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.

Open or close this module Conditions
Conditions: Endocrine Diseases
Genetic Disorder
Infertility
Hypogonadism
Amenorrhea
Keywords: Hypogonadotropic Hypogonadism
Kallmann Syndrome
Delayed Puberty
Infertility
Hypothalamic Amenorrhea
Open or close this module Study Design
Study Type: Observational
Time Perspective: Prospective
Biospecimen Retention:
Biospecimen Description:
Enrollment: 500 [Anticipated]
Number of Groups/Cohorts 0
Open or close this module Groups and Interventions
Open or close this module Outcome Measures
Open or close this module Eligibility
Minimum Age:
Maximum Age:
Sex: All
Gender Based:
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.

      The target enrollment goal is 500 subjects, including patients and their family members. However, given the observational nature of this natural history study, our goal is to continue to reevaluate and revise this number, based on recruitment and enrollment results.

      Blood testing allows the immortalization of lymphocytes to provide a long-term supply of genetic material and the opportunity to study mRNA. If cell lines are not available, genome amplification may be performed to create additional material for genomic analyses. We may also perform a whole genome/exome analysis on a subset of DNA samples depending on the geno-/phenotyping results, to explore new genes associated with reproductive disorders. Serum and plasma samples may be obtained to measure various hormones, proteins, and/or chemistries if the clinical history and findings suggest any associated endocrine abnormalities. This will aid in refining the complete phenotypic spectrum of IHH and strengthen our ability to determine genotype/phenotype correlations.

      Infants and children will be studied, because in some cases children may have a specific phenotype such as microphallus, cryptorchidism, cleft palate, anosmia etc. that may strongly suggest that they carry a gene mutation. However, because IHH is often silent until the time of puberty, the absence of such identifiers does not mean that a child is not affected. Performing mutation analysis in such children can be very important. The discovery for example of a mutation in a child whose parent is clearly affected demonstrates vertical transmission of the genetic defect in the family - i.e. dominant inheritance. This would have important genotype-phenotype implications for the family as a whole.

      In a different type of example, a child might not be affected, but his/her data might be essential for the overall genetic approach. An example of this is linkage analysis in which unaffected individuals (children or adults) often provide power statistically for the determination of linkage. The statistical considerations cannot be predicted ahead of time, and have to be considered on an individual pedigree basis.

      The study investigators and family members will speak to the child about the study protocol. Any child who is able to read with good comprehension will read and sign the assent form and a parent will sign the consent form as a demonstration of their willingness to participate. For children not able to read, parents will sign the consent form.

      All participants-children and adults-are given the option of removing their sample from the study at any time. Contact information for study investigators, staff, and the Clinical Center Patient Representative is provided, should they wish to remove their sample.

      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).

Subjects contacting MGH or NIH for consideration for this study will be given the option of having the study performed at either study site, and will have the option of consenting to the NIH study remotely, so that their DNA may be included in this protocol.

All subjects will be provided with a copy of the consent to read over. Time will be given to meet with the subject, describe the study, and review the procedures involved with the study. This will be followed by a time where the prospective subject can express any questions or concerns he/she may have regarding the study and have those issues addressed by one of the investigators. The consent will be signed by the subject and by a designated investigator. A copy of the signed consent will be given to the subject prior to the initiation of any study procedures. We will not include any bloods for analysis unless we have a signed consent for that subject. Total enrollment for this study will be 500 subjects.

Open or close this module Contacts/Locations
Central Contact Person: Angela Delaney, M.D.
Telephone: (301) 496-3025
Email: delaneya@mail.nih.gov
Locations: United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
[Recruiting]
Bethesda, Maryland, United States, 20892
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Citations: Donahoe PK, Noonan KM, Lage K. Genetic tools and algorithms for gene discovery in major congenital anomalies. Birth Defects Res A Clin Mol Teratol. 2009 Jan;85(1):6-12. doi: 10.1002/bdra.20546. PubMed 19107955
Zeggini E, Damcott CM, Hanson RL, Karim MA, Rayner NW, Groves CJ, Baier LJ, Hale TC, Hattersley AT, Hitman GA, Hunt SE, Knowler WC, Mitchell BD, Ng MC, O'Connell JR, Pollin TI, Vaxillaire M, Walker M, Wang X, Whittaker P, Xiang K, Jia W, Chan JC, Froguel P, Deloukas P, Shuldiner AR, Elbein SC, McCarthy MI; International Type 2 Diabetes 1q Consortium. Variation within the gene encoding the upstream stimulatory factor 1 does not influence susceptibility to type 2 diabetes in samples from populations with replicated evidence of linkage to chromosome 1q. Diabetes. 2006 Sep;55(9):2541-8. Erratum in: Diabetes. 2006 Nov;55(11):3197. Kunsun, Xiang [corrected to Xiang, Kunsan]. PubMed 16936202
Alkuraya FS. Homozygosity mapping: one more tool in the clinical geneticist's toolbox. Genet Med. 2010 Apr;12(4):236-9. doi: 10.1097/GIM.0b013e3181ceb95d. Review. PubMed 20134328
Links: Description: NIH Clinical Center Detailed Web Page
Available IPD/Information:

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