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Prevention of Endometrial Apoptosis: Randomized Prospective Comparison of Human Chorionic Gonadotropin Versus Progesterone Treatment in the Luteal Phase

Northern California Fertility Medical Center (L.P.L.), Roseville, California 95661; Center for Women’s Health and Reproduction (A.T.F.), Department of Obstetrics and Gynecology, University of Illinois, Chicago, Illinois 60612; Department of Obstetrics and Gynecology (M.A.F.), Division of Human Reproduction and Infertility, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Center for Women’s Health (D.G.M.), Oklahoma City, Oklahoma 73120; and Center for Women’s Medicine (B.A.L.), Greenville Hospital System, Greenville, South Carolina 29617

Address all correspondence and requests for reprints to: Bruce A. Lessey, Center for Women’s Medicine, 890 West Faris Road, Suite 470, Greenville, South Carolina 29617. E-mail: blessey{at}ghs.org.

To study control of apoptosis in human endometrium, we examined late luteal-phase endometrial biopsies obtained in the late luteal phase for evidence of apoptosis and compared the effects of exogenous human chorionic gonadotropin (hCG) and progesterone on this process. Using a controlled, prospective, and randomized study design, 12 healthy, fertile, reproductive-age women (ages 20–34 yr) with regular menstrual cycles (range, 26–32 d) were recruited. Each underwent an endometrial biopsy 12 d after a urinary LH surge in a control and treatment cycle. After biopsy in a natural cycle, subjects were randomized to receive luteal doses of either 200 mg intravaginal progesterone (d 18–27) or a single im injection of 10,000 IU of hCG (d 19) followed by repeat endometrial biopsy and collection of serum on d 26. Apoptosis was assessed by DNA laddering, localizing apoptotic bodies using immunofluorescent labeling of DNA fragments (the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method), and immunohistochemical assessment of apoptosis markers bcl-2, bcl-x, and bax. Serum progesterone levels were compared between treatment groups. Evidence of apoptosis in control cycles was significantly reduced in endometrium after both luteal-phase treatments. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling results demonstrated significantly less apoptosis in the hCG treatment group compared with controls. Immunostaining for bcl-2 was higher in hCG- and progesterone-treated cycles, whereas bax expression was decreased and bcl-x immunostaining was not different between treatments. Serum progesterone levels were highest in the hCG-treated group, although statistical significance was not reached (P = 0.08). These results demonstrate that signs of apoptosis, already apparent by d 26 of the menstrual cycle can be reduced with either hCG or progesterone treatment. The clinical utility of these findings includes a rational use of luteal-phase support for treatment of women with infertility and/or recurrent pregnancy loss.

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