Genetic DisorderNCT01500447
Inherited Reproductive Disorders
An observational study of Genetic Disorder and Infertility, run by National Institute of Environmental Health Sciences (NIEHS) at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 6 weeks to 120 years
- Conditions the study is for
- Genetic Disorder, Infertility, Hypogonadism
- How many people
- 850 participants
- Where
- 2 sitesUnited States
- Study dates
- 25 Apr 2012to not given
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 weeks to 120 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Primary Clinical, self-referred or physician-referred subjects
Who may be able to join
- The essential inclusion criteria include:
- 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
- abnormally early development of puberty, or
- normal puberty with subsequent development of low gonadotropin levels, or
- individuals with features indicating an increased risk of hypogonadotropic hypogonadism.
- Family members: both affected and unaffected family members are strongly encouraged to participate.
Who cannot join
- 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).
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States2 sites, 2 recruiting
- Recruiting
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR), 800-411-1222 ext. TTY dial 711, ccopr@nih.gov
- Recruiting
NIEHS Clinical Research Unit (CRU)
Research Triangle Park, North Carolina, 27713
Natalie Shaw, M.D., 984-287-3716, natalie.shaw@nih.gov
About this study
Official title: The Molecular Basis of Inherited Reproductive Disorders
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.
Read more
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.
Read the 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 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
- Genetic Disorder, Infertility, Hypogonadism, Amenorrhea
- Keywords
- Hypogonadotropic Hypogonadism, Kallmann Syndrome, Delayed Puberty, Hypothalamic Amenorrhea, Precocious Puberty, Natural History
- Medical subject headings
- Genetic Diseases, Inborn, Infertility, Hypogonadism, Amenorrhea, Kallmann Syndrome, Puberty, Delayed, Puberty, Precocious
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Central Precious Puberty | CPP subjects | |
| Hypogonadotropic Hypogonadism | IHH, KS, GnRH Deficiency, BAM syndrome (arhinia), HA, CDP subjects |
What is being measured
The primary outcome is the main question the study is designed to answer.
The main outcome is the identification of known and novel genetic variants in individuals representing the complete spectrum of idiopathic hypogonadotropic hypogonadism.
The main outcome is the identification of known and novel genetic variants in individuals representing the complete spectrum of idiopathic hypogonadotropic hypogonadism.
Measured: Ongoing/exploratory
Secondary outcomes (1)
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.
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.
Measured: Ongoing/exploratory
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Dec 2011 (estimated)
- Study start25 Apr 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Genetic DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Cross-sectional
- Enrolment
- 850 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Institute of Environmental Health Sciences (NIEHS)
- Sponsor type
- US National Institutes of Health
- Collaborators
- Massachusetts General Hospital
- Responsible party
- Sponsor
- Investigators
- Natalie D Shaw, M.D., Principal investigator, National Institute of Environmental Health Sciences (NIEHS)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01500447
- Sponsor's protocol ID
- 120049
- Other IDs
- 12-E-0049
- Status last verified
- 3 Jun 2026
- First submitted
- 21 Dec 2011
- Last updated
- 26 Oct 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: 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.
Publications
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.
PubMed 32870266Meader 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.
PubMed 32480405
Study at a glance
From the registry record, last updated by the sponsor on 26 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Molecular Basis of Inherited Reproductive Disorders
- ClinicalTrials.gov ID
- NCT01500447
- Acronym / sponsor ID
- 120049
- Conditions
- Genetic Disorder, Infertility, Hypogonadism, Amenorrhea
- Keywords
- Hypogonadotropic Hypogonadism, Kallmann Syndrome, Delayed Puberty, Hypothalamic Amenorrhea, Precocious Puberty, Natural History
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 850 participants (estimated)
- Lead sponsor
- National Institute of Environmental Health Sciences (NIEHS)US National Institutes of Health
- Collaborators
- Massachusetts General Hospital
- Study start
- 25 Apr 2012 (actual)
- First posted
- 28 Dec 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 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.
Study design
- Observational model
- Case only
- Time perspective
- Cross-sectional
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Central Precious Puberty | – | –CPP subjects |
| Hypogonadotropic Hypogonadism | – | –IHH, KS, GnRH Deficiency, BAM syndrome (arhinia), HA, CDP subjects |
Who may qualify
- Ages
- 6 weeks to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Primary Clinical, self-referred or physician-referred subjects
Key inclusion criteria (6 listed)
- 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
- abnormally early development of puberty, or
- normal puberty with subsequent development of low gonadotropin levels, or
- individuals with features indicating an increased risk of hypogonadotropic hypogonadism.
- Family members: both affected and unaffected family members are strongly encouraged to participate.
Key exclusion criteria (4 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
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.
1 secondary outcome
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
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Oct 2026.
- Derived from this study: PubMed 32870266Delaney 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.
- Derived from this study: PubMed 32480405Meader 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Natalie D Shaw, M.D. principal investigator
National Institute of Environmental Health Sciences (NIEHS)
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Genetic Disorder and Infertility, run by National Institute of Environmental Health Sciences (NIEHS) at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 26 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact NIEHS Join A Study Recruitment Group ((855) 696-4347, myniehs@nih.gov), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01500447, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Oct 2026.