Hormonal Regulation of Puberty and Fertility

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.

- 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