Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
850 participants
OBSERVATIONAL
2012-04-25
Brief Summary
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\- 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
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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 inheritance, 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 effects of previously described genetic variants, as well as to identify novel genes involved in congenital GnRH deficiency. We will use 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.
Conditions
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Keywords
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Study Design
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CASE_ONLY
CROSS_SECTIONAL
Study Groups
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Central Precious Puberty
CPP subjects
No interventions assigned to this group
Hypogonadotropic Hypogonadism
IHH, KS, GnRH Deficiency, BAM syndrome (arhinia), HA, CDP subjects
No interventions assigned to this group
Eligibility Criteria
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Inclusion Criteria
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.
Exclusion Criteria
* 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).
6 Weeks
120 Years
ALL
No
Sponsors
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Massachusetts General Hospital
OTHER
National Institute of Environmental Health Sciences (NIEHS)
NIH
Responsible Party
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Principal Investigators
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Natalie D Shaw, M.D.
Role: PRINCIPAL_INVESTIGATOR
National Institute of Environmental Health Sciences (NIEHS)
Locations
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National Institutes of Health Clinical Center
Bethesda, Maryland, United States
NIEHS Clinical Research Unit (CRU)
Research Triangle Park, North Carolina, United States
Countries
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Central Contacts
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Facility Contacts
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For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Role: primary
Natalie Shaw, M.D.
Role: primary
References
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Delaney A, Burkholder AB, Lavender CA, Plummer L, Mericq V, Merino PM, Quinton R, Lewis KL, Meader BN, Albano A, Shaw ND, Welt CK, Martin KA, Seminara SB, Biesecker LG, Bailey-Wilson JE, Hall JE. Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea. J Clin Endocrinol Metab. 2021 Mar 8;106(3):e1441-e1452. doi: 10.1210/clinem/dgaa609.
Meader BN, Albano A, Sekizkardes H, Delaney A. Heterozygous Deletions in MKRN3 Cause Central Precocious Puberty Without Prader-Willi Syndrome. J Clin Endocrinol Metab. 2020 Aug 1;105(8):2732-9. doi: 10.1210/clinem/dgaa331.
Related Links
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NIH Clinical Center Detailed Web Page
Other Identifiers
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12-E-0049
Identifier Type: -
Identifier Source: secondary_id
120049
Identifier Type: -
Identifier Source: org_study_id