Ovulatory dysfunction accounts for 20-30% of all infertility and 40% of female infertility. Ovulation induction agents such as clomiphene citrate and menopausal gonadotropins have been used historically with some success. However, a significant percentage of patients do not respond to clomiphene, and the attendant risks of multiple gestation and hyperstimulation with gonadotropin therapy confine its use to centers capable of intensive ultrasound and estradiol monitoring. A significant advance in the field of ovulation induction has been the introduction of pulsatile GnRH which has resulted in high rates of ovulation and conception in patients with primary and secondary hypothalamic amenorrhea. The risks of multiple gestation and hyperstimulation secondary to pulsatile GnRH appear to be lower than those seen with gonadotropin therapy, although these outcomes have not been compared directly.
Specific Aim #1 of this Project proposes such a direct comparison between pulsatile GnRH and exogenous gonadotropins in women with hypothalamic amenorrhea, specifically looking at the endpoints of ovulatory and conception rates, risk of multiple gestation and hyperstimulation, and costs.
In Specific Aim #2, we propose to investigate the potential expansion of the indications for pulsatile GnRH to patients with hypogonadotropic amenorrhea due to structural CNS abnormalities, cranial irradiation, or pituitary tumors (acquired hypogonadotropic hypogonadism), and to design outpatient tests to predict responsiveness in this subset of amenorrheic patients. The goal of Specific Aim #3 will be to optimize the use of pulsatile GnRH for patients with polycystic ovarian syndrome by a) defining the pathophysiologic factors associated with responsiveness (or lack thereof) to pulsatile GnRH and b) attempting to alter the underlying gonadotropin dynamics in patients who do not initially respond to this form of therapy by using concurrent treatment with a GnRH antagonist or pretreatment with a progestagen.
In Specific Aim #4, we will seek to determine the role of pulsatile GnRH for controlled amplification of folliculogenesis in women with unexplained infertility based on our observation that such augmented folliculogenesis is less variable in response to pulsatile GnRH than following exogenous gonadotropin administration.
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