Inherited Reproductive Disorders

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. 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. Human and animal models have identified a number of genes
responsible for IHH, but more than half of patients with clinical evidence of the disorder do
not have a detectable mutation. In addition, there is significant clinical heterogeneity
among affected individuals, including members of the same family harboring the same
mutations. Careful human phenotyping of such patients and families has expanded our
understanding of this spectrum of disorders to include oligo-digenic inheritence, as well as
reversibility of the condition, and has provided insight into developmental pathways involved
in the ontogeny of GnRH neurons.

Genetic analysis of subjects with unknown mutations is likely to yield important insights
into additional pathways involved in the regulation of GnRH secretion. Here, we propose a
genetic investigation of subjects with IHH to characterize further the phenotypic effect of
previously described genetic variants, as well as to identify novel genes involved in
congenital GnRH deficiency. In collaboration with the Reproductive Endocrine Unit at the
Massachusetts General Hospital, we will use both candidate gene and whole exome approaches,
as well as linkage analysis. The collaboration will allow for sufficient statistical power to
conduct such an investigation.

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.
Examining the genetic 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.

- The essential inclusion criteria include:

1. failure to go through a normal, age-appropriate, spontaneous puberty and low sex
steroid levels in the setting of low/normal gonadotropins (due to substantial
variability among patient presentations, this will be based on the clinical
judgement of the Investigator), or

2. abnormally early development of puberty, or

3. normal puberty with subsequent development of low gonadotropin levels, or

4. pre-pubertal individuals with features suggestive of hypogonadotropic
hypogonadism.

5. Family members: both affected and unaffected family members are strongly
encouraged to participate.

EXCLUSION CRITERIA:

Since hypogonadotropic hypogonadism is a rare condition, this protocol remains open to
enrollment so that we may study all subjects that are both qualified and interested in
participating.

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 affect GnRH secretion, such as
corticosteroids or continuous opiate administration (or were taking them at the time
of diagnosis).