Treatment with doxycycline does not decrease unscheduled bleeding in continuous oral contraceptive users

CONTRACEPTION SPECIAL INTEREST GROUP O-134 Tuesday, October 20, 2009 4:15 PM TREATMENT WITH DOXYCYCLINE DOES NOT DECREASE UNSCHEDULED BLEEDING IN CONTINUOUS ORAL CONTRACEPTIVE USERS. B. Kaneshiro, A. Edelman, K. Morgan, M. Nichols, J. Jensen. Department of Obstetrics and Gynecology, University of Hawaii, Honolulu, HI; Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR. OBJECTIVE: Matrix metalloproteinases (MMPs) are known to play a role in uterine bleeding. The objective of this study was to determine whether doxycycline, an MMP inhibitor, will decrease unscheduled bleeding associated with initiation of a continuous oral contraceptive pill. DESIGN: This was a randomized, placebo controlled, double blind study that was conducted over four 28 day cycles (112 days of hormonally active pills). MATERIALS AND METHODS: All women took the same oral contraceptive (20mcg ethinyl estradiol/90mcg levonorgestrel) administered in a continuous fashion, without a placebo week. Women were randomized to doxycycline 100 mg orally twice a day for 5 days or placebo taken at the onset of each bleeding/spotting episode. After the first 84 days, bleeding was observed on the oral contraceptive alone for 28 days. The number of bleeding/spotting days for the first 84, last 28, and all 112 days of the trial were compared using a Mann Whitney U test. The length of bleeding and amenorrheic episodes was also compared. Our sample was calculated to detect a difference of 9 days over 84 days with 80% power and a significance of p¼0.05. RESULTS: Administration of doxycycline at the time of bleeding did not result in a reduction in the median bleeding/spotting days in the first 84 days [doxycycline 18.0 (SD 19.3), placebo 12.0 (SD 18.4), p¼ 0.46], last 28 days [doxycycline 4.0 (SD 9.16), placebo 4.0 (SD 9.48), p¼0.98] or all 112 days [doxycycline 24.0 (SD 27.38), placebo 17.0 (SD 26.3), p¼0.47]. There was no difference in the median length of the longest bleeding/spotting episode [doxycycline 3.0 (SD 14.3), placebo 7.0 (SD 11.3), p¼0.64)] or the longest amenorrheic episode [doxycycline 29.0 (SD 21.6), placebo 33.5 (SD 24.8), p ¼ 0.16]. CONCLUSIONS: Despite initial studies which suggested that doxycycline could treat unscheduled bleeding, this randomized trial shows that this MMP inhibitor does not decrease unscheduled bleeding associated with initiation of a continuous oral contraceptive. Supported by: Family Planning Fellowship, Wyeth.

O-135 Tuesday, October 20, 2009 4:30 PM LEVONORGESTREL EFFECT ON VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) AND B-FIBROBLAST GROWTH FACTOR (B-FGF) IN SERUM, AND UTERINE FLUID, AND ENDOMETRIAL VEGF. D. F. Archer, S. Zhao, Y. Zhao, C. Choksuchat, F. Stanczyk. Obstetrics and Gynecology, Clinical Research Center, Eastern Virginia Medical School, Norfolk, VA; Epidemiology and Biostatistics Core, Graduate Program of Public Health, Eastern Virginia Medical School, Norfolk, VA; Obstetrics and Gynecology, Prince of Songla Medical School, Hat-Yai, Songkla, Thailand; Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA. OBJECTIVE: To determine the effects of levonorgestrel (LNG) on VEGF and bFGF in serum and uterine fluid and endometrial VEGF. VEGF and bFGF are involved in endometrial angiogenesis. LNG-subcutaneous implant (LNG-SI) users have altered vascularity by hysteroscopy. DESIGN: Randomized double-blind clinical trial in women using a LNGSI who were randomized to doxycycline or placebo. MATERIALS AND METHODS: 44 women between 18-40 years with regular menstrual cycles had a LNG-SI inserted and were then randomization to oral doxycycline (DOX) 20mg or placebo (PL) twice a day. Serum LNG levels were quantified by radioimmunoassay, serum and uterine fluid levels of VEGF and bFGF were estimated using enzyme-linked immunosorbent assays and endometrial VEGF levels were assessed by immunohistochemistry (IHC). RESULTS: Serum LNG levels were significantly higher at 1 month compared to 6 months following LNG-SI insertion (p¼0.003) (see Table 1). VEGF levels in serum were unchanged from baseline and between treatment groups. VEGF in uterine wash increased in the PL group at 1 month compared to baseline and higher than the levels found in the DOX group

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Abstracts

(p¼0.012). VEGF IHC intensity at 6 months following insertion increased in the PL compared to DOX (p¼0.02). The bFGF PL level in uterine wash increased at 6 months compared to 1 month (p¼ 0.043) Table 1. The bFGF level in the DOX group at 6 months was less compared to the PL group (p¼ 0.02).

VEGF, bFGF, and LNG Levels in Serum and Uterine Wash

Serum Serum Uterine Uterine

LNG pg/mL VEGF pg/mL Dox PL VEGF pg/mL Dox PL bFGF pg/mL Dox PL

Baseline

1

2

67.8 70.9 19.6 23.6 275.2 247.8

763.3 74.0 66.4 14.7 49.2 201.4 172.9

640.7 74.7 69.8 8.4 22.1 157.7 482.7

CONCLUSIONS: LNG increased VEGF and bFGF levels in the uterine wash while DOX inhibited VEGF and bFGF in uterine wash and VEGF in endometrial tissue. DOX may play a role in angiogenesis by inhibiting endometrial angiogenic factors induced by LNG. Supported by: The study supported by Grants NIH R01 HD43175-01 and Jones Institute Foundation 572822. O-136 Tuesday, October 20, 2009 4:45 PM COMBINED ORAL CONTRACEPTIVES AND BODY WEIGHT: DO ORAL CONTRACEPTIVES CAUSE WEIGHT GAIN? A PRIMATE MODEL. A. B. Edelman, J. T. Jensen, M. Bulechowsky, J. Cameron. Department of Obstetrics & Gynecology, Oregon Health & Science University (OHSU), Portland, OR; Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR. OBJECTIVE: To determine if oral contraceptive (OC) use effects body weight, composition, and metabolic rate in female rhesus macques and if this effect differs depending on the baseline weight. DESIGN: Prospective cohort study MATERIALS AND METHODS: Reproductive-age female monkeys of normal (n ¼ 5, mean weight ¼ 5.76 kg) and obese (n ¼ 5, mean weight ¼ 8.11 kg) weight were followed for 12 weeks to document baseline weight and metabolic stability, and then placed on 24 weeks of OC dosed to achieve equivalent human serum levels for a 30 mcg ethinyl estradiol/150 mcg levornorgestrel preparation. Monkeys were monitored for changes in body weight, activity levels (triaxial Actical accelerometer), food/caloric intake, body composition (DEXA), and metabolic biomarkers (24 hour metabolic rate and plasma samples). RESULTS: All monkeys completed the study protocol with no adverse events. No significant changes in study outcomes were found for the entire group except an increase in metabolic rate (p < 0.01). The obese group was found to have several changes with OC use including a decrease in weight (-0.7 kg, p < 0.01), a decrease in % body fat (-12%, p ¼ 0.02) with no change in % lean muscle mass, and a decreasing trend in metabolic rate (p ¼ 0.08). No changes were seen in food intake or activity level with OC use in either BMI-based group. CONCLUSIONS: Overall, OC use appears to increase 24 hour metabolic rates in female monkeys which in turn appears to differentially affect weight and % body fat depending on baseline weight. Supported by: Grant funding from the Society of Family Planning. O-137 Tuesday, October 20, 2009 5:00 PM REPEAT USE OF THE LNG-IUS: RESULTS OF A EUROPEAN MULTICENTER PROSPECTIVE STUDY. O. Heikinheimo, K. Gemzell-Danielsson, P. Inki, M. Kunz, L. Boubli, M. O’Flynn. Dept Ob&Gyn, University of Helsinki, Helsinki, Finland; WHO-center/Karolinska Sjukhuset, Stockholm, Sweden; Bayer Schering Pharma AG/Global Medical Affairs Women´s Health, Berlin, Germany; Bayer Schering Pharma AG/Global Clinical Statistics, Berlin, Germany; Hoˆpital Nord, Marseille, France; The Practice, Cork, Mallow, Ireland. OBJECTIVE: Levonorgestrel-releasing intrauterine system (LNG-IUS) is increasingly used for contraception, treatment of heavy menstrual bleeding

Vol. 92., No. 3, Supplement, September 2009