Hormonal Regulation of Puberty and Fertility

  • participants needed
  • sponsor
    National Institute of Environmental Health Sciences (NIEHS)
Updated on 27 January 2021
testosterone level
hormone levels
hypogonadotropic hypogonadism
klinefelter syndrome
secondary hypogonadism


  • 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.

We will 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.

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.

Condition Endocrine disorder, Adolescence, Hypogonadism, Female Genital Diseases, Amenorrhea, Infertility, Hypomenorrhea, Gynecological Infections, Menstrual Disorders, endocrinopathy, endocrine disorders, endocrine disease, endocrine diseases, sterility, unable to conceive
Clinical Study IdentifierNCT01511588
SponsorNational Institute of Environmental Health Sciences (NIEHS)
Last Modified on27 January 2021


Yes No Not Sure

Inclusion Criteria

Since hypogonadotropic hypogonadism is a rare condition, with an incidence of
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

Exclusion Criteria

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
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