Original research articleEffect of intermittent treatment with mifepristone on bleeding patterns in Norplant® implant 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.
References (38)
- et al.
Long-acting contraceptive implantsan analysis of menstrual bleeding patterns
Contraception
(1978) - et al.
Norplant consensus statement and background review
Contraception
(1998) - et al.
A randomized multicenter study comparing the efficacy and bleeding pattern of a single-rod (Implanon) and a six-capsule (Norplant) hormonal contraceptive implant
Contraception
(1999) - et al.
Vaginal bleeding disturbances and implantable contraceptives
Contraception
(2002) - et al.
Hormonal treatment for bleeding irregularities in Norplant implant users
Am J Obstet Gynecol
(1996) - et al.
Effects of the antiprogesterone RU 486 in normal women. I. Single-dose administration in the midluteal phase
Am J Obstet Gynecol
(1987) - et al.
The analysis of menstrual bleeding patternsa review
Contraception
(1988) Implantable contraceptives for womeneffectiveness, discontinuation rates, return of fertility, and outcome of pregnancies
Contraception
(2002)- et al.
Anovulation, inadequate luteal phase and poor sperm penetration in cervical mucus during prolonged use of Norplant implants
Contraception
(1985) - et al.
Treatment with Norplant subdermal implants inhibits sperm penetration through cervical mucus in vitro
Contraception
(1987)
Mechanisms that explain the contraceptive action of progestin implants for women
Contraception
Potency and pharmacokinetic of gestogens
Contraception
Pharmacokinetics and metabolism of RU486
J Steroid Biochem
Comparative progestational activity of norgestimate, levonorgestrel-oxime and levonorgestrel in the rat and binding of these compounds to the progesterone receptor
Contraception
Contraception and menstrual bleeding disturbances: a clinical overview
The performance of levonorgestrel rod and Norplant® contraceptive implantsa 5-year randomized study
Hum Reprod
Post-marketing surveillance of Norplant® contraceptive implantsI. Contraceptive efficacy and reproductive health
Contraception
A comparison of mechanisms underlying disturbances of bleeding caused by spontaneous dysfunctional uterine bleeding or hormonal contraception
Hum Reprod
A functional model for progestogen-induced breakthrough bleeding
Hum Reprod
Cited by (36)
Unscheduled vaginal bleeding with progestin-only contraceptive use
2017, American Journal of Obstetrics and GynecologyCitation Excerpt :Also, as an abortifacient, this medication is highly regulated, not available for pharmacy distribution, and requires physicians to be registered with the manufacturer. Finally, there have been concerns that an antiprogestin may alter the contraceptive efficacy of progestin-only contraception, although these concerns have not been well studied.57,58 Allergy is the main contraindication to this medication.
Mifepristone
2012, FMC Formacion Medica Continuada en Atencion PrimariaA randomized study of the effect of mifepristone alone or in conjunction with ethinyl estradiol on ovarian function in women using the etonogestrel-releasing subdermal implant, Implanon®
2011, ContraceptionCitation Excerpt :In Norplant users, a single dose of 50 mg of mifepristone was effective in stopping an episode of bleeding and possibly prolonging the duration of the next bleeding-free interval [3]. Mifepristone (100 mg) given intermittently to Norplant users was also able to reduce the total duration and number of episodes of prolonged bleeding over time compared to placebo [4]. In Norplant users, there is an increase in endometrial stromal progesterone receptor (PRA) and a reduction of PRB and estrogen receptors leading to altered angiogenesis and an endometrium constantly liable to patchy breakdown, as confirmed visually by Fraser and Hickey [5].
Selective progesterone receptor modulators in reproductive medicine: Pharmacology, clinical efficacy and safety
2011, Fertility and SterilityCitation Excerpt :Furthermore, intrauterine administration of the SPRM ZK230211 in women scheduled for hysterectomy due to menorrhagia or dysmenorrhea resulted in a reduced number of days with bleeding and spotting compared with intrauterine administration of levonorgestrel (96). Finally, women experiencing breakthrough bleeding during progestin treatment show a clear improvement in bleeding pattern following SPRM administration (112, 113). Uterine leiomyomata arise from the smooth muscle cells of the myometrium (114, 115).
Bleeding related to etonogestrel subdermal implant in a US population
2011, Contraception