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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
5U10HD038999-04
Application #
6637950
Study Section
Special Emphasis Panel (ZHD1-DRG-D (05))
Program Officer
Parrott, Estella C
Project Start
2000-06-30
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
4
Fiscal Year
2003
Total Cost
$310,074
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Legro, Richard S; Chen, Gang; Kunselman, Allen R et al. (2014) Smoking in infertile women with polycystic ovary syndrome: baseline validation of self-report and effects on phenotype. Hum Reprod 29:2680-6
Roth, Lauren W; Huang, Hao; Legro, Richard S et al. (2012) Altering hirsutism through ovulation induction in women with polycystic ovary syndrome. Obstet Gynecol 119:1151-6
Diamond, Michael P; Kruger, Michael; Santoro, Nanette et al. (2012) Endometrial shedding effect on conception and live birth in women with polycystic ovary syndrome. Obstet Gynecol 119:902-8
Jones, Michelle R; Chua, Angela K; Mengesha, Emebet A et al. (2012) Metabolic and cardiovascular genes in polycystic ovary syndrome: a candidate-wide association study (CWAS). Steroids 77:317-22
Aubuchon, Mira; Kunselman, Allen R; Schlaff, William D et al. (2011) Metformin and/or clomiphene do not adversely affect liver or renal function in women with polycystic ovary syndrome. J Clin Endocrinol Metab 96:E1645-9
Pagidas, Kelly; Carson, Sandra A; McGovern, Peter G et al. (2010) Intercourse compliance, ovulation, and treatment success in the National Institute of Child Health and Human Development-Reproductive Medicine Network's Pregnancy in Polycystic Ovary Syndrome (PPCOS) Trial. Fertil Steril 94:1444-6
Legro, Richard S; Schlaff, William D; Diamond, Michael P et al. (2010) Total testosterone assays in women with polycystic ovary syndrome: precision and correlation with hirsutism. J Clin Endocrinol Metab 95:5305-13
Pagidas, Kelly; Carson, Sandra A; McGovern, Peter G et al. (2010) Body mass index and intercourse compliance. Fertil Steril 94:1447-50
Rausch, Mary E; Legro, Richard S; Barnhart, Huiman X et al. (2009) Predictors of pregnancy in women with polycystic ovary syndrome. J Clin Endocrinol Metab 94:3458-66
Legro, Richard S; Barnhart, Huiman X; Schlaff, William D et al. (2008) Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. J Clin Endocrinol Metab 93:792-800

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