1 Centro de Pesquisas de Doencias Materno-Infantis de Campinas (CEMICAMP), Campinas, SP, Brasil, 2 PROFAMILIA, Santo Domingo, Dominican Republic and 3 Centre for Biomedical Research, The Population Council, New York, USA
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Abstract |
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Key words: bleeding patterns/contraceptive implants/Nestorone®/oestradiol/progesterone
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Introduction |
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Nestorone® progestin, like other progestin-only contraceptives, causes altered bleeding patterns in women. The most noticeable effect is the increase in the mean number of days of bleeding and spotting in 30 day intervals, with about 25% of users having more than 10 days of bleeding and spotting in each month (Díaz et al., 1995).
Administration of exogenous oestrogen or in combination with a progestin is known to reduce bleeding in women using Norplant® implants (Díaz et al., 1990; Alvarez-Sanchez et al., 1996
; Archer et al., 1996
). The association between concentrations of endogenous oestrogen and bleeding during the use of Norplant® implants has also been established, and serves as the basis for treatment with ethinyl-oestradiol (Faúndes et al., 1991
, 1998
). The present study was undertaken to ascertain whether this association between concentrations of endogenous sex steroids and bleeding patterns exists in women who are NES implant users.
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Materials and methods |
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Two different implant dosages were assessed: a single 4 cm implant containing 80 mg NES (The Population Council, New York, USA) and two 3.0 cm implants, each containing 60 mg NES, delivering approximately 50 and 75 µg/day respectively. The duration of the study was 2 years.
A total of 40 volunteers, 20 in each dose, was recruited among the general population of the clinic. Healthy, sexually active women, with regular menstrual cycles, ages 1838 years, requiring a contraceptive method, not currently breastfeeding and who voluntarily agreed to participate, were enrolled in this study. Women were requested to maintain a daily bleeding calendar. Ten subjects were dropped from the study for bleeding disturbances or other complaints during the first months of use and another was unable to comply with the blood-sampling schedule. Consequently, only 29 subjects provided the periods of observation for this analysis.
Blood samples were taken twice a week for 6 consecutive weeks at specified time intervals (approximately months 6, 12, 18 and 24). In each sample, oestradiol and progesterone were measured using a solid-phase 125I radioimmunoassay (DPC, Los Angeles, CA, USA). Inter-assay coefficients of variation were 6.52 and 6.06% respectively. Quality control was assured both by the External Quality Assessment Scheme for Reproductive Hormones of the World Health Organization and by internal quality control with commercial sera.
The oestradiol and progesterone patterns that preceded bleeding episodes or that corresponded to periods of continuous bleeding or amenorrhoea were analysed retrospectively. Data were collected from 15 and 14 subjects in the low and high dose regimen, respectively. For this study, the data were analysed jointly, because its purpose was to test the possible association between different concentrations of endogenous hormones and bleeding, and not to compare the two systems. As more than one bleeding episode was observed in many subjects, data were obtained in a total of 125 bleeding episodes.
Bleeding periods were categorized as follows: normal length cycles (2535 days); long cycles (3690 days); episodes of amenorrhoea longer than 90 days; and short cycles (24 days or less between initiation of two consecutive bleedings). The association between the duration of bleeding (in days) and the preceding hormonal profile was separately analysed as well as the periods of continuous bleeding or spotting for 10 or more days.
Upon evaluation of the available hormonal data related to the bleeding patterns, it was possible to analyse 24 short cycles, 36 normal length cycles, 27 long cycles and nine episodes of amenorrhoea. Blood samples were collected only in the middle of an amenorrhoeic episode in four subjects, only during the last 3 weeks in three women and before and during the last 3 weeks in two. Twenty-eight episodes of prolonged bleeding were separately analysed.
Most of the episodes with amenorrhoea were observed during the first 6 months of use. Short cycles and prolonged bleeding were mostly seen during the first year, while normal length and long cycles were more evenly distributed over the 2 years of observation, although less frequently during the first 6 months of use of the implants.
Student's t-test was used to evaluate differences in duration of bleeding, and in hormonal concentrations. The correlation coefficient between oestradiol concentrations and duration of bleeding was calculated and a t-test was used to verify its significance.
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Results |
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All six episodes in which samples were taken during amenorrhoea, distant from a bleeding episode, showed oestradiol concentrations consistently below 350 pmol/l. However, two of five of the sampling periods which included the end of the amenorrhoea (last 3 weeks before initiation of bleeding), showed elevation of oestradiol >800 pmol/l before a decline that preceded bleeding. No luteal activity was observed in periods of amenorrhoea.
Oestradiol concentrations preceding menses
The hormonal patterns of women with normal length cycles with or without luteal activity, and with long cycles, were characterized by a rise and fall of oestradiol that preceded bleeding. In contrast, in women with short cycles, bleeding started without discernible change in constantly low oestradiol concentrations (Figure 1). The oestradiol profile was monophasic in long cycles or normal cycles without luteal activity and biphasic in normal length cycles with luteal activity.
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Discussion |
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The finding that the higher the oestradiol concentrations in a cycle, the longer the duration of bleeding and that the secretion of progesterone is associated with shorter duration of bleeding provides additional evidence in support of the hypothesis that, in spite of the continuous administration of NES, endogenous hormones have some influence over the endometrium and the mechanism that controls its bleeding.
The results also indicate that the relationship between endogenous sexual hormones and bleeding is not present in all cases, and that bleeding can start or stop without clear changes in the oestradiol concentrations. Persistently low oestradiol concentrations can coincide with long episodes of amenorrhoea, short cycles and periods of prolonged bleeding. Many times the initiation and the end of short cycles and bleeding episodes after amenorrhoea do not coincide with discernible changes in oestradiol concentrations. This finding of a variety of bleeding patterns with the same low concentration of oestradiol is the apparent reason why several authors have had to disregard the correlation between endogenous sex steroid secretion and bleeding patterns during prolonged use of other progestins (Darney et al., 1996; Fraser et al., 1996
).
The rise and fall of oestradiol or oestradiol and progesterone preceding menses in almost every normal length cycle, most long and some short cycles and even at the end of one third of the episodes of amenorrhoea, was consistent. These results disagree with those of Landgren et al. (1981), who did not find significant differences in bleeding pattern or number of bleeding days according to ovarian profile among women using 300 µg of norethindrone orally per day. They used a different form of analysis, however, and pooled women with persistently low and with high oestradiol plasma concentrations (Landgren et al., 1981). On the other hand, the same investigators had found that `a major drop in peripheral oestradiol concentrations was associated with withdrawal bleeding within 72 h in five subjects' using the same method. The observation that bleeding is often observed after a rise and fall of circulating oestradiol has also been described among users of long-acting injectable contraception, either norethindrone enanthate (Goebelsmann et al., 1979
) or depo-medroxyprogesterone (Bassol et al., 1984
). The latter authors also described low oestradiol concentrations during periods of amenorrhoea or spotting.
In addition, the data presented here confirm that endogenous progesterone secretion is associated with shorter duration of bleeding during use of progestogen-only contraception as has already been observed by other authors (Landgren et al., 1981, 1982
).
Comparing this study with one carried out several years ago among Norplant® implant users, the results are very similar (Faúndes et al., 1991). It would be interesting to ascertain if bleeding among users of NES implants can be controlled with oestrogen or combined oestrogenprogestogen administration, as has been described for users of Norplant® implants. In theory, based on the results presented here, it would be possible to obtain similar results.
The mechanism through which sex steroids affect endometrial bleeding is very poorly understood. Apparently, it is not necessarily accompanied by a parallel change in endometrial histology (Kim-Bjorkland, 1991; Landgren et al., 1994) or of endometrial thickness as measured by ultrasound (Olsson et al., 1990
; Shaaban et al., 1993
; Faúndes et al., 1998
). It may be more related to changes in the vascular physiology of the endometrium as suggested by others (Rogers et al., 1993
; Goodger et al., 1994
; Hickey et al., 1998
). Nonetheless, independently of the intervention of other factors and of the intimate mechanism of action, the accumulated evidence strongly suggests that female sex steroids continue to play a major role in endometrium bleeding control among women under continuous administration of low doses of contraceptive progestogens.
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Acknowledgments |
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Notes |
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References |
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Submitted on March 5, 1999; accepted on September 2, 1999.