Infertility is a common problem in the United States. Technological advances have made therapy for infertility quite effective. However, all of the assisted reproductive techniques require the use of gonadotropins (whether recombinant or derived from menopausal urine) to induce ovulation. Serious complications of these therapies include multiple pregnancy, ovarian hyperstimulation syndrome (OHSS), and premature delivery (even in singletons). These complications exact a huge toll upon the physical, emotional and financial status of these couples, and place a major strain on the health care resources of our entire society. Our hypothesis is that the hypersecretion of luteal products (such as VEGF, renin and IL-6) caused by multiple corpora lutea is responsible for the development of OHSS. We also hypothesize that the hypersecretion of luteal products such as relaxin causes much of the prematurity associated with gonadotropin use. We have presented data that hyperrelaxinemia (in pregnancies conceived after the use of gonadotropins) correlates with prematurity. We have also demonstrated relaxin receptors in the human cervix, and that relaxin stimulates proMMP-1 and proMMP-3 expression as well as inhibiting TIMP-1 production, all effects which can contribute to increased collagen breakdown and cervical ripening. We plan to develop a method of superovulation which should result in luteal regression, which in turn should eliminate OHSS and decrease the risk of prematurity. This could have the secondary effect of making multiple pregnancies safer. hLH, with a much shorter half-life, will be substituted for hCG as the ovulatory stimulus. Pretreatment with a GnRH-agonist will eliminate endogenous LH secretion. The lack of continued luteotrophic stimulus will allow luteolysis. The endometrium will be maintained with exogenous estradiol and progesterone as is done in oocyte donation cycles. We will then test the hypothesis that this novel protocol, by preventing the hypersecretion of luteal products in gonadotropin-induced pregnancies, will result in safer infertility therapy.
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