• presence of ovulation and/or pregnancy [ Time Frame: 1 pulsatile GnRH cycle ] [ Designated as safety issue: No ]
  

In comparison to the use of exogenous gonadotropins, pulsatile administration of GnRH has many theoretical advantages for ovulation induction, including; 1) the ability to use the patients' own gonadotropins for ovarian stimulation; 2) the ability to treat anovulatory defects at their appropriate level, which most commonly is hypothalamic; 3) the ability to maintain normal ovarian-pituitary feedback mechanisms to restrain endogenous FSH secretion, as occurs normally in species that ovulate a single egg per cycle; 4) a resultant decrease in the risks of multiple gestations and hyperstimulation; and 5) a decreased need for intensive monitoring of ovarian function with an attendant decrease in costs.

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 by our group and others which defined the frequency of pulsatile GnRH secretion in normal women at different stages of the menstrual were then 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 which replacement of GnRH using the subcutaneous route was adequate to reproduce normal physiology in GnRH-deficient men, the intravenous route was superior in women. We have now determined the dose of GnRH which is appropriate for the majority of women as 75 ng/kg, a dose which induces ovulation of a single dominant follicle, followed by normal luteal phase dynamics.

A number of investigators including us have sought to define the specific subgroups likely to achieve the greatest benefit from this form of therapy. However, there are many questions which remain unanswered and that we are currently addressing. We are specifically interested in understanding why there is variability in the dose of GnRH required by apparently GnRH-deficient women and have recently determined that one of our patients who required a significantly higher dose of GnRH to reproduce normal cycle dynamics, had a mutation of the GnRH receptor rather than a deficiency of GnRH itself. We have recently determined that the response of gonadotropin free a-subunit may help to refine the phenotype in patients with idiopathic hypogonadotropic hypogonadism.

In addition, we are actively recruiting patients with polycystic ovarian syndrome (PCOS). Patients with PCOS have a more variable response to pulsatile GnRH than do other subsets of anovulatory patients and we are seeking to determine the specific patient characteristics, which predict success. This is important as this group of patients are particularly challenging in terms of ovulation induction with gonadotropins, being susceptible to ovarian hyperstimulation, cycle cancellation and/or multiple gestation. One of the major factors associated with anovulation is insulin resistance with compensatory hyperinsulinemia. Improving insulin resistance, using an insulin-sensitizing agent as metformin, has been shown to improve ovulatory function in patients with PCOS undergoing ovulation induction with clomiphene or exogenous gonadotropins. The combination of metformin with pulsatile GnRH will be addressed in this population.

It is important to note that minors have been included in this protocol, as many patients are extremely anxious to know whether they respond normally to pulsatile GnRH even though they may not be interested in conceiving at the time. This is particularly true of patients who have survived childhood cancers and associated surgery and/or radiation in whom a normal response to pulsatile GnRH can be a very positive experience. Minors with PCOS will not be administered Metformin as part of this protocol.