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Hormonal Regulation of Puberty and Fertility

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01511588
Recruitment Status : Recruiting
First Posted : January 18, 2012
Last Update Posted : March 29, 2018
Massachusetts General Hospital
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )

January 13, 2012
January 18, 2012
March 29, 2018
December 20, 2011
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The main outcome is the identification of novel GnRH secretory patterns or non-reproductive phenotypic characteristics in individuals representing the complete spectrum of idiophatic hypogonadotropic hypogonadism.
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Complete list of historical versions of study NCT01511588 on Archive Site
Secondary outcomes are the recognition of specific pubertal phenotypes, as well as discovery of the roles of newly identified genes contributing to IHH in GnRH development and biology, for those subjects who also enroll in our genetics protocol.
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Hormonal Regulation of Puberty and Fertility
The Role of Gonadotropin Pulsations in the Regulation of Puberty and Fertility


- The body produces gonadotropin-releasing hormone (GnRH) about every 2 hours. GnRH travels through the bloodstream to the pituitary gland, where it stimulates the gland to produce hormones called gonadotropins. These hormones stimulate the testicles or ovaries. The testicles produce testosterone and develop sperm. The ovaries produce estrogen and prepare for ovulation. Normal estrogen and testosterone levels are required for puberty. Some people, however, have either low levels or total lack of GnRH. This can cause problems with puberty and fertility. Researchers want to study people with low or no GnRH to better understand how it affects puberty and fertility.


- To study disorders of GnRH production.


  • Adult men and women at least 18 years of age with low or no gonadotropin levels.
  • Adolescents between 14 and 18 years of age with low or no gonadotropin levels.


  • Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected.
  • Participants will have tests to look at their hormone levels. Blood samples may be collected after taking different drugs, including insulin and cortisone. A 24-hour urine sample will be collected.
  • Participants will have imaging studies to look at bone and brain development. They will also have ultrasounds of the kidneys, abdomen, and reproductive organs.
  • Tests of smell and hearing will be used to look for abnormalities in these senses.

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. GnRH secretion is fully active during the neonatal period, quiescent throughout most of childhood, and is reactivated at the time of puberty to induce sexual maturation and subsequent fertility. 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. In addition, non-reproductive phenotypes of this spectrum have been identified in some individuals, including anosmia, auditory defects, skeletal and renal anomalies. More severe syndromic forms of IHH have also been associated with rare congenital malformations, such as the Bosma arhinia microphthalmia (BAM) syndrome.

Defining the physiology of GnRH is critical to understanding the clinical heterogeneity of isolated GnRH deficiency, particularly in light of emerging gene discoveries that elucidate genotype-phenotype correlations. Careful human phenotyping of patients with mutations in genes known to cause IHH has provided insight into developmental pathways involved in the ontogeny of GnRH neurons, but the neuroendocrine regulation of this system is not well understood.

Here, we propose the addition of the NIH as the second site to an existing protocol at Massachusetts General Hospital to phenotypically characterize subjects with IHH, including severe syndromic forms. We plan to admit males and females 14 years of age or older with clinical signs suggestive of IHH for comprehensive phenotyping to include neuroendocrine profiling via an LH pulsatility study, as well as identification of other non-reproductive findings. Combining our effort with the established protocol and recruitment mechanisms at MGH will allow us to maximize the number of subjects with this rare disorder that can be evaluated.

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, as well as other unknown aspects of GnRH biology, which may be illuminated through the non-reproductive characteristics of these patients. Examining the baseline 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.

Observational Model: Case-Only
Time Perspective: Prospective
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  • Endocrine Disease
  • Infertility
  • Hypogonadism
  • Amenorrhea
  • Adolescents
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*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
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Since hypogonadotropic hypogonadism is a rare condition, with an incidence of 1/10,000 to 1/86,000 for isolated GnRH deficiency (34, 35), this protocol remains open to enrollment so that we may study all subjects that are both qualified and interested in participating.

Males or females who are greater than or equal to 14 years old with clinical findings of HH as outlined above will be included. In certain circumstances, a patient under the age of 14 years may be considered for baseline evaluation if there is sufficient evidence suggestive of HH, such as any two of the following: anosmia, history of cryptorchidism or microphallus.


-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 cause HH, such as corticosteroids or continuous opiate administration.
  • Pregnancy or lactation
Sexes Eligible for Study: All
14 Years and older   (Child, Adult, Senior)
Contact: Angela Delaney, M.D. (301) 496-3025
United States
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National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Massachusetts General Hospital
Principal Investigator: Angela Delaney, M.D. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institutes of Health Clinical Center (CC)
December 13, 2017