Hypogonadotropic HypogonadismNCT00494169
Investigation of the Genetic Causes of Kallmann Syndrome and Reproductive Disorders
An observational study of Hypogonadotropic Hypogonadism and Kallmann Syndrome, run by Massachusetts General Hospital at 1 site in United States.
Trial summary
The aims of this study are: 1) to identify genes that play a role in human pubertal development and reproduction, 2) to characterize the phenotypic spectrum of patients with these gene defects, and 3) to discern the mode of inheritance for disorders caused by these gene defects. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Hypogonadotropic Hypogonadism, Kallmann Syndrome, Puberty, Delayed
- How many people
- 4,042 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 1999to Feb 2022
- Phase
- Observational
- Are there results?
- None posted in the registry
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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Subjects who 1. fail to go through a normal, age-appropriate, spontaneous puberty, and abnormal hormone levels. 2. have abnormally early development of puberty (Precocious Puberty) 3. Family members of these patients.
Who may be able to join
- Failure to go through a normal, age-appropriate, spontaneous puberty, and abnormal hormone levels OR
- Children with abnormally early development of puberty (Precocious Puberty) OR
- Family members of these patients.
Who cannot join
- pituitary tumor
- high prolactin levels
Trial locations and contacts
1 site in 1 country.
United States1 site
Massachusetts General Hospital
Boston, Massachusetts, 02114
About this study
Official title: Molecular Basis of Inherited Reproductive Disorders
The aims of this study are: 1) to identify genes that play a role in human pubertal development and reproduction, 2) to characterize the phenotypic spectrum of patients with these gene defects, and 3) to discern the mode of inheritance for disorders caused by these gene defects. We are specifically interested in genes that cause Kallmann syndrome, idiopathic hypogonadotropic hypogonadism (IHH), precocious (early) puberty, and delayed puberty. Individuals do not have to travel to Boston to participate in this study.
Read the detailed description
Overview:
Our work is divided into two main areas of investigation:
- the discovery of new, yet-undiscovered genes for conditions of early (i.e. precocious) puberty, delayed puberty, and/or absence of pubertal development (i.e. Kallmann syndrome/hypogonadotropic hypogonadism). Identification of new genes requires either a single large family or a collection of smaller families.
- a detailed examination of the genes already implicated in causing these conditions.
There are several other important aspects about our program:
- This analysis will detect DNA abnormalities only in those DNA segments being screened. The turnaround time to process a sample is approximately 12-24 months. We must receive a signed consent form in order to begin analysis on a blood sample.
- Our laboratory is located in Massachusetts General Hospital, Boston MA and is largely funded by the National Institutes of Health. We are a research laboratory and not a CLIA certified clinical laboratory.
- Even if a participant is the only member of his/her family affected by one of the conditions mentioned above, obtaining blood samples on other family members, including parents and siblings is often important to our work.
- It is every individual's responsibility to notify the research team he/she would like to obtain research results. Research results will be relayed to the participant's healthcare provider and must be confirmed in a clinical laboratory before being relayed to the participant or used for medical care.
Study Procedures and Risks
- You will be asked to give approximately 3-5 tablespoons of blood for this research project. There is a risk of bruising and a very small amount of bleeding associated with blood drawing.
- You will be asked to fill out a medical history checklist, indicating the presence or absence of clinical features that may be associated with abnormalities in pubertal development.
- Since absence of puberty is sometimes associated with limited or no smell ability, you may be asked to try to identify the odors in a scratch and sniff test. This will take about 15 minutes.
- Your family history can give us clues to determine how your condition was inherited. Therefore, a detailed family history, at least back to your grandparents will be obtained by a researcher.
Benefits:
There are no direct benefits to you from participation in this study. Some genes for this condition are known, other genes have yet to be discovered. If this study discovers what genes are responsible, it will help to further the understanding of this disorder. It is possible that the genetic cause of your reproductive disorder may be learned. This information can be shared with you at your request, as explained above.
When contacting us, please include in your message a description of your diagnosis, your pubertal history (age when you hit pubertal hallmarks, e.g., growth spurt; body hair; voice deepening and genital growth for men; menstruation and breast development for women) and your reproductive history.
- Conditions
- Hypogonadotropic Hypogonadism, Kallmann Syndrome, Puberty, Delayed, Puberty, Precocious, GnRH Deficiency
- Keywords
- Idiopathic Hypogonadotropic Hypogonadism, Kallmann Syndrome, Puberty, Pituitary Abnormalities, Hypothalamus, GnRH deficiency
- Medical subject headings
- Hypogonadism, Kallmann Syndrome, Puberty, Delayed, Puberty, Precocious, Idiopathic Hypogonadotropic Hypogonadism
What is being measured
The primary outcome is the main question the study is designed to answer.
Identification of DNA abnormalities
Measured: 5/2015
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jun 2007 (estimated)
- Study startJan 1999
- Primary completionFeb 2022
- Study completionFeb 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (38)Papers the sponsor has linked to this study.
- Other trials for Hypogonadotropic HypogonadismStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- 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-control
- Time perspective
- Cross-sectional
- Enrolment
- 4,042 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Stephanie B. Seminara, MD, Massachusetts General Hospital
- Investigators
- Stephanie B Seminara, MD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00494169
- Sponsor's protocol ID
- U54HD028138
- Status last verified
- Jun 2022
- First submitted
- 28 Jun 2007
- Last updated
- 30 Jun 2022
- Results posted
- No
- Data monitoring committee
- No
Publications
Kallmann FJ, Schoenfeld WA. The genetic aspects of primary eunuchoidism. American Journal of Mental Deficiency 158:203-236, 1944.
Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R, Carrozzo R, Maestrini E, Pieretti M, Taillon-Miller P, Brown CJ, Willard HF, Lawrence C, Graziella Persico M, Camerino G, Ballabio A. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature. 1991 Oct 10;353(6344):529-36. doi: 10.1038/353529a0.
PubMed 1922361Legouis R, Hardelin JP, Levilliers J, Claverie JM, Compain S, Wunderle V, Millasseau P, Le Paslier D, Cohen D, Caterina D, et al. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell. 1991 Oct 18;67(2):423-35. doi: 10.1016/0092-8674(91)90193-3.
PubMed 1913827Burris TP, Guo W, McCabe ER. The gene responsible for adrenal hypoplasia congenita, DAX-1, encodes a nuclear hormone receptor that defines a new class within the superfamily. Recent Prog Horm Res. 1996;51:241-59; discussion 259-60.
PubMed 8701082de Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison G, Milgrom E. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med. 1997 Nov 27;337(22):1597-602. doi: 10.1056/NEJM199711273372205. No abstract available.
PubMed 9371856Layman LC, Cohen DP, Jin M, Xie J, Li Z, Reindollar RH, Bolbolan S, Bick DP, Sherins RR, Duck LW, Musgrove LC, Sellers JC, Neill JD. Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat Genet. 1998 Jan;18(1):14-5. doi: 10.1038/ng0198-14. No abstract available.
PubMed 9425890Crowley WF Jr, Pitteloud N, Seminara S. New genes controlling human reproduction and how you find them. Trans Am Clin Climatol Assoc. 2008;119:29-37; discussion 37-8.
PubMed 18596868Balasubramanian R, Plummer L, Sidis Y, Pitteloud N, Martin C, Zhou QY, Crowley WF Jr. The puzzles of the prokineticin 2 pathway in human reproduction. Mol Cell Endocrinol. 2011 Oct 22;346(1-2):44-50. doi: 10.1016/j.mce.2011.05.040. Epub 2011 Jun 1.
PubMed 21664414Au MG, Crowley WF Jr, Buck CL. Genetic counseling for isolated GnRH deficiency. Mol Cell Endocrinol. 2011 Oct 22;346(1-2):102-9. doi: 10.1016/j.mce.2011.05.041. Epub 2011 Jun 1.
PubMed 21664415Pitteloud N, Meysing A, Quinton R, Acierno JS Jr, Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes F, Seminara S, Hughes VA, Ma J, Bouloux P, Mohammadi M, Crowley WF Jr. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol. 2006 Jul 25;254-255:60-9. doi: 10.1016/j.mce.2006.04.021. Epub 2006 Jun 9.
PubMed 16764984Pallais JC, Bo-Abbas Y, Pitteloud N, Crowley WF Jr, Seminara SB. Neuroendocrine, gonadal, placental, and obstetric phenotypes in patients with IHH and mutations in the G-protein coupled receptor, GPR54. Mol Cell Endocrinol. 2006 Jul 25;254-255:70-7. doi: 10.1016/j.mce.2006.04.019. Epub 2006 Jun 6.
PubMed 16757106Pitteloud N, Acierno JS Jr, Meysing A, Eliseenkova AV, Ma J, Ibrahimi OA, Metzger DL, Hayes FJ, Dwyer AA, Hughes VA, Yialamas M, Hall JE, Grant E, Mohammadi M, Crowley WF Jr. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6281-6. doi: 10.1073/pnas.0600962103. Epub 2006 Apr 10.
PubMed 16606836Pitteloud N, Acierno JS Jr, Meysing AU, Dwyer AA, Hayes FJ, Crowley WF Jr. Reversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J Clin Endocrinol Metab. 2005 Mar;90(3):1317-22. doi: 10.1210/jc.2004-1361. Epub 2004 Dec 21.
PubMed 15613419Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, Seminara SB, Mendonca BB, Kaiser UB, Latronico AC. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med. 2008 Feb 14;358(7):709-15. doi: 10.1056/NEJMoa073443.
PubMed 18272894Cerrato F, Seminara SB. Human genetics of GPR54. Rev Endocr Metab Disord. 2007 Mar;8(1):47-55. doi: 10.1007/s11154-007-9027-3.
PubMed 17334928
Study at a glance
From the registry record, last updated by the sponsor on 30 Jun 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Molecular Basis of Inherited Reproductive Disorders
- ClinicalTrials.gov ID
- NCT00494169
- Acronym / sponsor ID
- U54HD028138
- Conditions
- Hypogonadotropic Hypogonadism, Kallmann Syndrome, Puberty, Delayed, Puberty, Precocious, GnRH Deficiency
- Keywords
- Idiopathic Hypogonadotropic Hypogonadism, Kallmann Syndrome, Puberty, Pituitary Abnormalities, Hypothalamus, GnRH deficiency
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 4,042 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Study start
- Jan 1999
- Primary completion
- Feb 2022 (actual)
- Study completion
- Feb 2022 (actual)
- First posted
- 29 Jun 2007 (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.
The aims of this study are: 1) to identify genes that play a role in human pubertal development and reproduction, 2) to characterize the phenotypic spectrum of patients with these gene defects, and 3) to discern the mode of inheritance for disorders caused by these gene defects. We are specifically interested in genes that cause Kallmann syndrome, idiopathic hypogonadotropic hypogonadism (IHH), precocious (early) puberty, and delayed puberty. Individuals do not have to travel to Boston to participate in this study.
Detailed description
Overview:
Our work is divided into two main areas of investigation:
- the discovery of new, yet-undiscovered genes for conditions of early (i.e. precocious) puberty, delayed puberty, and/or absence of pubertal development (i.e. Kallmann syndrome/hypogonadotropic hypogonadism). Identification of new genes requires either a single large family or a collection of smaller families.
- a detailed examination of the genes already implicated in causing these conditions.
There are several other important aspects about our program:
- This analysis will detect DNA abnormalities only in those DNA segments being screened. The turnaround time to process a sample is approximately 12-24 months. We must receive a signed consent form in order to begin analysis on a blood sample.
- Our laboratory is located in Massachusetts General Hospital, Boston MA and is largely funded by the National Institutes of Health. We are a research laboratory and not a CLIA certified clinical laboratory.
- Even if a participant is the only member of his/her family affected by one of the conditions mentioned above, obtaining blood samples on other family members, including parents and siblings is often important to our work.
- It is every individual's responsibility to notify the research team he/she would like to obtain research results. Research results will be relayed to the participant's healthcare provider and must be confirmed in a clinical laboratory before being relayed to the participant or used for medical care.
Study Procedures and Risks
- You will be asked to give approximately 3-5 tablespoons of blood for this research project. There is a risk of bruising and a very small amount of bleeding associated with blood drawing.
- You will be asked to fill out a medical history checklist, indicating the presence or absence of clinical features that may be associated with abnormalities in pubertal development.
- Since absence of puberty is sometimes associated with limited or no smell ability, you may be asked to try to identify the odors in a scratch and sniff test. This will take about 15 minutes.
- Your family history can give us clues to determine how your condition was inherited. Therefore, a detailed family history, at least back to your grandparents will be obtained by a researcher.
Benefits:
There are no direct benefits to you from participation in this study. Some genes for this condition are known, other genes have yet to be discovered. If this study discovers what genes are responsible, it will help to further the understanding of this disorder. It is possible that the genetic cause of your reproductive disorder may be learned. This information can be shared with you at your request, as explained above.
When contacting us, please include in your message a description of your diagnosis, your pubertal history (age when you hit pubertal hallmarks, e.g., growth spurt; body hair; voice deepening and genital growth for men; menstruation and breast development for women) and your reproductive history.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Subjects who 1. fail to go through a normal, age-appropriate, spontaneous puberty, and abnormal hormone levels. 2. have abnormally early development of puberty (Precocious Puberty) 3. Family members of these patients.
Key inclusion criteria (3 listed)
- Failure to go through a normal, age-appropriate, spontaneous puberty, and abnormal hormone levels OR
- Children with abnormally early development of puberty (Precocious Puberty) OR
- Family members of these patients.
Key exclusion criteria (2 listed)
- pituitary tumor
- high prolactin levels
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
Identification of DNA abnormalities
Time frame: 5/2015
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jun 2022.
- BackgroundKallmann FJ, Schoenfeld WA. The genetic aspects of primary eunuchoidism. American Journal of Mental Deficiency 158:203-236, 1944.
- Background: PubMed 1922361Franco B, Guioli S, Pragliola A, Incerti B, Bardoni B, Tonlorenzi R, Carrozzo R, Maestrini E, Pieretti M, Taillon-Miller P, Brown CJ, Willard HF, Lawrence C, Graziella Persico M, Camerino G, Ballabio A. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature. 1991 Oct 10;353(6344):529-36. doi: 10.1038/353529a0.
- Background: PubMed 1913827Legouis R, Hardelin JP, Levilliers J, Claverie JM, Compain S, Wunderle V, Millasseau P, Le Paslier D, Cohen D, Caterina D, et al. The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules. Cell. 1991 Oct 18;67(2):423-35. doi: 10.1016/0092-8674(91)90193-3.
- Background: PubMed 8701082Burris TP, Guo W, McCabe ER. The gene responsible for adrenal hypoplasia congenita, DAX-1, encodes a nuclear hormone receptor that defines a new class within the superfamily. Recent Prog Horm Res. 1996;51:241-59; discussion 259-60.
- Background: PubMed 9371856de Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison G, Milgrom E. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med. 1997 Nov 27;337(22):1597-602. doi: 10.1056/NEJM199711273372205. No abstract available.
- Background: PubMed 9425890Layman LC, Cohen DP, Jin M, Xie J, Li Z, Reindollar RH, Bolbolan S, Bick DP, Sherins RR, Duck LW, Musgrove LC, Sellers JC, Neill JD. Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat Genet. 1998 Jan;18(1):14-5. doi: 10.1038/ng0198-14. No abstract available.
- Background: PubMed 18596868Crowley WF Jr, Pitteloud N, Seminara S. New genes controlling human reproduction and how you find them. Trans Am Clin Climatol Assoc. 2008;119:29-37; discussion 37-8.
- Background: PubMed 21664414Balasubramanian R, Plummer L, Sidis Y, Pitteloud N, Martin C, Zhou QY, Crowley WF Jr. The puzzles of the prokineticin 2 pathway in human reproduction. Mol Cell Endocrinol. 2011 Oct 22;346(1-2):44-50. doi: 10.1016/j.mce.2011.05.040. Epub 2011 Jun 1.
- Background: PubMed 21664415Au MG, Crowley WF Jr, Buck CL. Genetic counseling for isolated GnRH deficiency. Mol Cell Endocrinol. 2011 Oct 22;346(1-2):102-9. doi: 10.1016/j.mce.2011.05.041. Epub 2011 Jun 1.
- Results publication: PubMed 16764984Pitteloud N, Meysing A, Quinton R, Acierno JS Jr, Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes F, Seminara S, Hughes VA, Ma J, Bouloux P, Mohammadi M, Crowley WF Jr. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol. 2006 Jul 25;254-255:60-9. doi: 10.1016/j.mce.2006.04.021. Epub 2006 Jun 9.
- Results publication: PubMed 16757106Pallais JC, Bo-Abbas Y, Pitteloud N, Crowley WF Jr, Seminara SB. Neuroendocrine, gonadal, placental, and obstetric phenotypes in patients with IHH and mutations in the G-protein coupled receptor, GPR54. Mol Cell Endocrinol. 2006 Jul 25;254-255:70-7. doi: 10.1016/j.mce.2006.04.019. Epub 2006 Jun 6.
- Results publication: PubMed 16606836Pitteloud N, Acierno JS Jr, Meysing A, Eliseenkova AV, Ma J, Ibrahimi OA, Metzger DL, Hayes FJ, Dwyer AA, Hughes VA, Yialamas M, Hall JE, Grant E, Mohammadi M, Crowley WF Jr. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6281-6. doi: 10.1073/pnas.0600962103. Epub 2006 Apr 10.
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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. This study is not recruiting at the moment.
Stephanie B Seminara, MD principal investigator
Massachusetts General Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Hypogonadotropic Hypogonadism and Kallmann Syndrome, run by Massachusetts General Hospital at 1 site 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 3 inclusion and 2 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: finished, as of the sponsor's last update on 30 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Identification of DNA abnormalities (time frame: 5/2015). 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 NCT00494169, which also lists 38 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 30 Jun 2022.