Inherited Reproductive Disorders
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|ClinicalTrials.gov Identifier: NCT01500447|
Recruitment Status : Recruiting
First Posted : December 28, 2011
Last Update Posted : June 3, 2021
|First Submitted Date||December 21, 2011|
|First Posted Date||December 28, 2011|
|Last Update Posted Date||June 3, 2021|
|Actual Study Start Date||April 25, 2012|
|Primary Completion Date||Not Provided|
|Current 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. [ 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 hypogonadotropic hypogonadism
|Original Primary Outcome Measures||Not Provided|
|Current 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. [ Time Frame: Ongoing/exploratory ]
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.
|Original Secondary Outcome Measures||Not Provided|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title||Inherited Reproductive Disorders|
|Official Title||The Molecular Basis of Inherited Reproductive Disorders|
- 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.
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 Design||Observational Model: Case-Only
Time Perspective: Cross-Sectional
|Target Follow-Up Duration||Not Provided|
|Sampling Method||Non-Probability Sample|
|Study Population||Primary Clinical, self-referred or physician-referred subjects|
|Publications *||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). pii: dgaa331. doi: 10.1210/clinem/dgaa331.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Original Estimated Enrollment
|Study Completion Date||Not Provided|
|Primary Completion Date||Not Provided|
The essential inclusion criteria include:
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:
|Ages||6 Weeks and older (Child, Adult, Older Adult)|
|Accepts Healthy Volunteers||No|
|Listed Location Countries||United States|
|Removed Location Countries||Chile|
|Other Study ID Numbers||120049
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Institute of Environmental Health Sciences (NIEHS) )|
|Study Sponsor||National Institute of Environmental Health Sciences (NIEHS)|
|Collaborators||Massachusetts General Hospital|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||June 1, 2021|