We are interested in identifying factors that initiate pubertal onset in children. Our long-term goal is to define the developmental physiology of pubertal development in order to gain increased understanding of human disorders of puberty and reproduction. In collaboration with the Reproductive Endocrine Unit at Massachusetts General Hospital (MGH), we are conducting translational research on the neuroendocrine and genetic control of gonadotropin-releasing hormone (GnRH) secretion and its regulation of gonadotropin secretion and gonadal physiology. We use molecular, cellular, and biochemical techniques to identify and characterize biological pathways that may contribute to the reactivation of GnRH secretion at puberty and to explore diagnostic techniques and treatment of disorders of puberty and reproduction.
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 GnRH from the hypothalamus. GnRH secretion is fully active during the neonatal period, quiescent throughout most of childhood, and 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, including anosmia, auditory defects, and skeletal and renal anomalies, have been identified in some individuals.
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.
Our collaboration has resulted in the addition of the NIH as the second site in an existing protocol at MGH for phenotypically characterizing subjects with IHH. We plan to admit males and females 14 years of age or older with clinical signs suggestive of IHH for comprehensive phenotyping that will include neuroendocrine profiling via an luteinizing hormone (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 who are eligible for evaluation.
We are using 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 of other unknown aspects of GnRH biology that may be illuminated through the non-reproductive characteristics of the patients participating in the protocol. Examining the baseline characteristics of subjects with isolated GnRH deficiency will allow us to make genotype-phenotype correlations that will expand our current paradigm of the hypothalamic-pituitary-gonadal axis and may have important implications for human disorders of puberty and fertility.
Human and animal models have revealed several genes responsible for IHH, but more than half of patients with clinical evidence of the disorder do not have a detectable mutation. In addition, affected individuals manifest significant clinical heterogeneity, even among members of the same family harboring the same mutations. Recent evidence 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, as was the case with the identification of mutations in the kisspeptin receptor (KISS1R, or GPR54) in families with IHH, leading to the discovery that kisspeptin (KISS1) is an important gatekeeper of puberty. This is merely one among many critical discoveries made in this field through molecular exploration. We are conducting genetic investigations of subjects with IHH to characterize further the phenotypic effect of previously described genetic variants and to identify novel genes involved in congenital GnRH deficiency, using both candidate gene and whole-exome approaches as well as linkage analysis.
Patients with IHH provide a unique human disease model for elucidating the physiology of GnRH secretion, including the neuroendocrine regulation of GnRH secretion. Examining the genetic characteristics of subjects with isolated GnRH deficiency and correlating these findings with detailed phenotypic characteristics 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 reproduction.
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