Studies in Patients with Congenital GnRH Deficiency

National Institute Of Environmental Health Sciences

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Abstract

In this study we are performing phenotype/genotype studies in women with congenital deficiency in the secretion or responsiveness to gonadotropin releasing hormone (GnRH). Isolated GnRH deficiency is a rare disorder, with an estimated incidence of 1/50,000. Patients present with failure of normal pubertal development and hypogonadotropic hypogonadism (low LH, FSH and estradiol or testosterone), indicative of a hypothalamic or, less frequently, pituitary abnormality. The disorder is referred to as isolated hypogonadotropic hypogonadism (IHH). Approximately 50% of these patients lack a sense of smell (Kallmann Syndrome, KS) while the other half are normosmic (nIHH). Studies in KS/nIHH patients have been particularly informative in helping us understand the GnRH requirements for normal reproductive function and have led to development of a physiologic regimen of GnRH replacement in men and women. While pulsatile GnRH serves as treatment for patients interested in conceiving or in their potential to conceive, these patients have provided a clinical model that allows us to address key questions in reproductive physiology . When synthetic GnRH first became available for clinical study, there was not yet an adequate understanding of the physiology of GnRH secretion in the human to support its potential therapeutic application. As a result, early attempts at ovulation induction were unsuccessful. It was soon appreciated that an episodic mode of delivery was essential for normal pituitary stimulation by GnRH. Studies which defined the frequency of pulsatile GnRH secretion in normal women at different stages of the menstrual cycle were key to designing a physiologic program of pulsatile GnRH administration that resulted in successful ovulation induction in patients with GnRH deficiency. Additional studies demonstrated that while replacement of GnRH using the subcutaneous route was adequate to reproduce normal physiology in GnRH-deficient men, the intravenous route is superior in women. We have now determined that the dose of GnRH that induces ovulation of a single dominant follicle, followed by normal luteal phase dynamics for the majority of women is 75 ng/kg administrated intravenously. Moreover, normal gonadotropin and gonadal steroid dynamics are faithfully re-created using a frequency that mimics the frequency in normal women and changes across the cycle from once per hour to once every four hours. Replacement of GnRH induces ovulation in approximately 95% of GnRH-deficient women. However, a subset of women with KS/nIHH do not ovulate in response to the physiologic 75 ng/kg dose. Thirty-seven women with KS/nIHH who received a physiologic replacement regimen of pulsatile GnRH (75 ng/kg at a physiologic frequency) were studied during their first cycle of GnRH replacement. In those who ovulated in the first 20 days of treatment, LH, FSH and estradiol levels rose quickly to the range of normal women in the early follicular phase. Patients with LH and/or FSH below the 25th centile of ovulatory patients were defined as pituitary resistant; 90% of these patients ovulated with a longer treatment duration or a higher dose of GnRH. Surprisingly, mutations in GNRHR were found in search for genes conferring pituitary resistance in patients with KS/nIHH. With GnRH treatment, three patients demonstrated FSH levels above the 75th centile of the ovulatory women, providing evidence of ovarian resistance once GnRH was replaced. With GnRH treatment, three patients demonstrated FSH levels above the 75th centile of the ovulatory women, providing evidence of ovarian resistance once GnRH was replaced. None of the three had evidence of mutations in genes known to be associated with GnRH deficiency although some are known to be present in the ovary, again providing fertile ground for future gene discovery. This study is being conducted in patients identified by the PI with the support of investigators at Massachusetts General Hospital as is part of the PIs long-term collaborative efforts.