Elsevier

Contraception

Volume 70, Issue 1, July 2004, Pages 47-54
Contraception

Original research article
Effect of intermittent treatment with mifepristone on bleeding patterns in Norplant® implant users

https://doi.org/10.1016/j.contraception.2004.02.009Get rights and content

Abstract

A double-blind, placebo-controlled, randomized trial, was carried out in 120 Norplant® users to evaluate the effect of mifepristone, 100 mg/day administered for 2 consecutive days every 30 days, on the vaginal bleeding pattern. Treatment was given from months 2–7 of implant use. Volunteers recorded bleeding and spotting days, during treatment and for the ensuing 6-month period. During treatment, women on mifepristone recorded the same frequency of bleeding/spotting episodes but significantly less prolonged bleeding episodes than placebo controls (mean ± SD: 11 ± 3 vs. 22 ± 23 days) and their total number of bleeding days was 35% lower than in the placebo group. After the end of mifepristone use, bleeding patterns were similar in both groups. One pregnancy occurred in the mifepristone-treated group, in month 6 of treatment, the outcome was a healthy male baby. We conclude that intermittent administration of mifepristone can offer a clinically significant improvement of the vaginal bleeding pattern in Norplant users.

Introduction

Disruption of the normal vaginal bleeding pattern is the most common unwanted side effect experienced by women who use progestin-only contraceptive methods and the most frequent reason for method discontinuation [1], [2], [3], [4], [5], [6]. Usually, this problem has no ill effects on health, however, it impairs the quality of women's lives and restricts their contraceptive options. Data indicate that in a 5-year period 20% of Norplant® users discontinued the use of the method for bleeding disturbances. The most frequently cited menstrual problems that led to discontinuation were prolonged, irregular or heavy bleeding. The least frequent was amenorrhea, which accounted for only 2% of all bleeding-related reasons for removal [4].

Several studies have been undertaken to elucidate the underlying physiopathology of breakthrough bleeding [7], [8], [9], [10], however, the mechanisms involved are still unclear.

Due to the clinical relevance of bleeding problems, some treatments have been tested for improving the bleeding pattern of progestin-only users [11], [12], [13], [14], [15], [16], [17], [18]. Administration of ethinylestradiol and combined oral contraceptives has proved to be partially successful in the management of prolonged bleeding, and are currently recommended as “modestly effective treatments” [19]. However, treatment with estrogen-containing pills may not be the first choice for women who opted for long-acting, estrogen-free methods.

Antiprogestins offer another alternative for the treatment of this condition [20], [21]. In theory, withdrawal of the exogenous progestin at regular intervals should induce cyclic endometrial shedding and bleeding, allowing resumption of synchronized endometrial growth. In the case of progestin implants, this could be achieved by monthly administration of an antiprogestin. Such treatment would be particularly useful during the first months of method use when bleeding disturbances are the worst [1], [2], [3], [4], [5]. In earlier studies on menses induction with mifepristone, during luteal phases extended by exogenous hCG, we found that repeated administration for 4 days was more effective than single administration and that 100–200 mg/day were the most effective doses [22].

The present study was designed to test if mifepristone improves the bleeding pattern of women using progestin-only methods. We evaluated the impact of monthly administration of mifepristone in comparison to a placebo on the duration and regularity of bleeding episodes during the first year of use of Norplant.

Section snippets

Study design and subjects

This was a prospective double-blind, placebo-controlled, randomized trial performed at the family-planning clinic of the Instituto Chileno de Medicina Reproductiva, Santiago, Chile, from March 1997 to October 1999. The protocol was reviewed and approved by the local Ethics Committee and World Health Organization Scientific and Ethical Review Group for Research in Human Reproduction. All participants gave their consent in writing after receiving oral and written information on Norplant, and on

Population

One-hundred and twenty women were enrolled in the study, of those 116 completed the 6 months of treatment and 115 were included in the analysis (1 subject in the placebo group was excluded because of lack of compliance with the treatment). The characteristics of women were similar in both groups, except that the mean age of women in the mifepristone-treated group was slightly but significantly higher (p = 0.03) (Table 1).

Follow-up

During the treatment period, women were recommended to use condoms as

Discussion

This study demonstrates that the administration of mifepristone every 30 days during the first 6 months of use of Norplant implants leads, from a clinical standpoint, to some improvement of the vaginal bleeding pattern. Treatment with the antiprogestin significantly reduced the incidence and duration of prolonged bleeding episodes in comparison with placebo. None of the women discontinued for bleeding problems in the mifepristone-treated group, while three women did so in the placebo group.

Acknowledgements

This study was funded by the UNDPD/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction. Roussel Uclaf, Romainville, France, provided the mifepristone and placebo tablets used in this study and Leiras, Turku, Finland, the Norplant implants. The authors are grateful to the participants in the study for their sustained collaboration, to R. Ferrera for coordinating the follow-up and to A. Zepeda for her statistical advice.

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