Hormonal Regulation of Puberty and Fertility
Hormonal Regulation of Puberty and Fertility
Background:

 - 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.

 Objectives:

 - To study disorders of GnRH production.

 Eligibility:

 -  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.

 Design:

 -  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.
-  INCLUSION CRITERIA:

 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.

 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