Review articleVaginal bleeding disturbances and implantable contraceptives
Introduction
Modern implantable contraceptives provide women with safe, long-acting fertility control that is rapidly reversible when the device is removed. Currently available devices release progestogens over 1–5 years and act at a number of different levels to effectively prevent conception. Levonorgestrel (LNG) contraceptive implants act mainly by changing the quality of cervical mucus and inhibiting normal sperm penetration [1]. Abnormal endometrial development will prevent implantation, should fertilization occur. Ovulation and luteal function may also be affected [2], although these effects may vary between women and in the same user over time.
The first progestin-only contraceptive implant placed on the market was Norplant, a multiunit system releasing LNG. Innovations have only recently led to a wider choice, with new implants that offer easier insertion and removal and other advantages depending on the type of progestogen. Jadelle is similar to Norplant, but consists of only two, rather than six, Silastic rods to simplify insertion and removal; nevertheless, LNG serum levels are identical, and performance is the same for both systems. The currently available single implant systems are Implanon, which releases etonogestrel over 3 years; Nestorone implants for breastfeeding and nonbreastfeeding women lasting up to 2 years; and Uniplant, which is effective for 1 year and releases nomegestrol acetate [3].
Disturbances of vaginal bleeding patterns are almost inevitable in users of modern contraceptive implants, and there are no devices that can guarantee regular bleeding or even amenorrhea. These bleeding disturbances are not known to threaten the health of implant users, although they may lead to further investigations to rule out cervical or even endometrial pathology. Their major significance is the degree to which bleeding disturbances are disliked by women, leading to rejection or discontinuation of these methods (as discussed in a separate article in this issue).
Recent advances in understanding of the mechanisms of this irregular bleeding will be discussed. These are mostly drawn from studies of LNG-releasing systems. In addition, the efficacy of current therapies and the potential for future therapies based on direct interruption of these mechanism as well as future directions for research will be mentioned.
Section snippets
Vaginal bleeding patterns
In the great majority of Norplant users, vaginal bleeding pattern disturbances are most common in the initial months of use and tend to diminish over time [4]. This progressive improvement reflects the decrease in release rate of LNG, which allows the return of ovulatory-like cycles. During the first year, most women experience a pattern characterized by prolonged bleeding occurring at irregular intervals, whereas a quarter of users have regular bleeding, and about 10% experience at least 3
Vaginal bleeding patterns and ovulatory function
A number of studies were carried out in implant users to investigate the relationship between vaginal bleeding patterns and ovarian function, endometrial thickness, and LNG serum levels. In longitudinal studies, it was found that women who had similar hormonal environments could experience very different bleeding patterns; for example, low estradiol levels and the absence of luteal activity could be associated with amenorrhea, frequent bleeding, or prolonged bleeding patterns [12], [13], [14].
Vaginal blood loss
There are limited data available on the amount of vaginal blood loss experienced during implant contraceptive use. In one study [22] of 13 Norplant users, blood loss was measured during a control cycle and during the whole first, sixth, and twelfth months of implant use. Although the mean number of bleeding days during the treatment cycles was significantly greater than in the control cycle, the mean blood loss of 24–31 mL was similar during the four periods of observation.
In a study [23]
Implications of vaginal bleeding patterns
Regular patterns of vaginal bleeding are central to beliefs concerning fertility, absence of pregnancy, and reproductive health for women from many cultures. In addition, for some women the presence of irregular or unpredictable bleeding is a barrier to social, sexual, and cultural activities and, hence, represents a major disruption to their lives. Because irregular bleeding may also be a feature of infection of the genital tract, and (rarely) of malignancy, this symptom may also prompt
Mechanisms underlying menstrual bleeding disturbances
Because endometrial vascular and epithelial breakdown must occur before vaginal bleeding is seen, the focus of recent investigations into implant-related irregular bleeding has focused on endometrial blood vessels and the local control of their growth, breakdown, and repair.
Hysteroscopic observations have suggested that endometrial bleeding is focal following exposure to both low and high dose progestogens [38], [39]. There is insufficient information about the pattern of vessel breakdown in
Reduced vascular structural integrity
Based largely on primate endometrial explant studies, normal menstrual bleeding is thought to arise primarily from the spiral arterioles and to be controlled initially by vasoconstriction [40]. In contrast, hysteroscopic and immunohistochemical studies have suggested that BTB arises from small capillaries and veins on the endometrial surface [38], [41], [42]. These small vessels are composed only of endothelial cells and their surrounding basement membrane and pericytes, and there is evidence
Changes in endometrial hemostasis
Constriction of the endometrial spiral arterioles is thought to be an essential early mechanism of menstrual hemostasis [40]. Spiral arteriole development is suppressed by progestogens [52], and the bleeding arising from other vessels may result in compromised hemostasis and, hence, prolonged bleeding. In addition, the powerful vasoconstrictor molecules endothelins (ET) are reduced in progestogen users [53], and the ET metabolizing enzyme neutral endopeptidase is increased [54]. Reduced ET
Sequence of events leading to BTB
BTB is likely to arise as the final point in a complex and multi-factorial process that may be activated by exposure to exogenous sex steroids, particularly progestogens.
Fig. 1 represents a possible mechanism for the onset of BTB in low-dose progestogen users. However, there is still relatively little good data to support these mechanisms, and much of this is speculative. Also, clinical trials have been based on users of particular progestogens, particularly LNG in the Norplant system, and it
The management of BTB
To date, efforts to prevent or limit BTB in women using sex steroids have largely been unsuccessful. However, these interventions have mostly been empiric, and the improved understanding of the underlying mechanisms of BTB opens the possibility of directed therapies to reduce vascular fragility. Supplemental estrogens have been given to women using progestogen-only contraceptives to try to improve bleeding patterns. However, there is no evidence that estrogens improve bleeding patterns beyond
Increasing vascular stability
In other organ systems, such as the human retina, loss of vascular stability is associated with oxidative stress and the release of free radicals [85]. At a molecular level, this vascular fragility is associated with reduced integrity of endothelial cell tight junctions and vascular basement membrane competence and clinically leads to vascular breakdown and retinal bleeding [86]. Flavonoids, part of the vitamin B complex, have been shown in controlled trials to increase peripheral capillary
Conclusions
Contraceptive implant systems containing progestogens are almost inevitably associated with disruptions in menstrual bleeding patterns. In many cases this amounts to bleeding that is frequent and/or prolonged. Evidence from studies of all available systems suggests that menstrual disturbance is one of the most common reasons for discontinuation of these methods. This is particularly unfortunate because many implant users are women who have been unable to find other suitable methods and may now
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Cited by (36)
Implanon as a contraceptive choice for teenage mothers: a comparison of contraceptive choices, acceptability and repeat pregnancy
2010, ContraceptionCitation Excerpt :The side effects of contraception are an important reason for discontinuation. We found similar side effects in this population to those seen with Norplant [15,36] and confirmed the findings of larger studies that abnormal bleeding is a main reason for discontinuation of long-acting progesterone-only contraceptives [23,37]. However, in general, the acceptability of Implanon was high in this population.
Efficacy of mifepristone in reducing intermenstrual vaginal bleeding in users of the levonorgestrel intrauterine system
2010, International Journal of Gynecology and ObstetricsCitation Excerpt :Intermenstrual bleeding has been reported in 71.4% of Indian women using the LNG-IUS within the first 3 months of insertion [1]. The cause of the irregular bleeding has is to be elucidated, although recent evidence suggests that “an increase in endometrial vascular fragility of superficial endometrial vasculature might precipitate vessel breakdown,” [4] and breakthrough bleeding may occur with associated progesterone-only treatment [4]. Owing to poor compliance caused by irregular bleeding problems, a variety of treatments have been used to minimize irregular bleeding in progestogen-only users.
Implanon: A Review of the Literature With Recommendations for Clinical Management
2009, Journal of Midwifery and Women's HealthCitation Excerpt :Neither this publication or the Urbancsek meta-analysis15 offer conclusions about the relationship between Implanon and the SAEs. Bleeding disturbances are common with progestin-only contraceptives23 and are the leading side effect and reason for early discontinuation in Implanon users.8–10,24 Cumulative rates for discontinuation for bleeding disturbances range from 8%9 to 21%.24
Tamoxifen treatment of bleeding irregularities associated with Norplant use
2005, ContraceptionMenstrual irregularity and compliance in contraception: Comparison between oral contraceptives and etonogestrel contraceptive implant
2004, International Congress Series