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Unscheduled Vaginal Bleeding with Progestin-Only Contraceptive Use Rachel E

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Unscheduled Vaginal Bleeding with Progestin-Only Contraceptive Use Rachel E Expert Reviews ajog.org Unscheduled vaginal bleeding with progestin-only contraceptive use Rachel E. Zigler, MD; Colleen McNicholas, DO, MSCI rogestin-only methods of contra- P ception include progestin-only pills Nearly 20% of women using contraception are using progestin-only contraception, (POPs), depot-medroxyprogesterone ac- including progestin-only pills, depot-medroxyprogesterone acetate, subdermal etono- etate (DMPA), subdermal etonogestrel gestrel implants, and levonorgestrel intrauterine devices. This number will continue to (ENG) implants, and levonorgestrel grow with the increased provision of long-acting reversible contraception. Although intrauterine devices (LNG IUDs). Use of overall satisfaction among women using progestin-only contraception is high, dissatis- progestin-only methods is increasing, in faction and discontinuation may be associated with unscheduled bleeding and spotting. part because of growing popularity of The exact etiology of irregular bleeding associated with progestin-containing contra- long-acting reversible contraceptives ceptives is not completely understood, yet several mechanisms have been suggested. (LARC) but also because they are safe in Several therapies targeting these mechanisms have been evaluated with mixed results. womenwith other medical comorbidities. This paper will review the physiology and management of unscheduled bleeding with The LARC methods, including intra- progestin-containing contraceptives. uterine devices (IUDs) and implants are Key words: appealing for their ease of use, long-term irregular bleeding, long-acting reversible contraception, progestin-only protection, noncontraceptive benefits, contraception, unscheduled bleeding and relatively few contraindications. Despite the benefits, both LARC and shorter acting progestin methods can women who chose the LNG IUD, ENG method. A leading cause of unscheduled result in unscheduled bleeding and implant, or DMPA at least once during bleeding with initiation is thought to be spotting, which may lead to dissatisfac- their study participation. Among dis- secondary to the rapid endometrial tion and discontinuation.1 continuers, 19% of LNG IUD users, 46% thinning effects of progestins. More Unscheduled bleeding and spotting of ENG implant users, and 26% of practically, if women are going from while on active hormones is subjective DMPA users listed bleeding changes as relatively thick endometrium to rela- but has been defined in the literature as their main reason for discontinuation.3 tively thin endometrium, it is biologi- any bleeding requiring the use of a sani- Bleeding patterns are not standardized cally plausible that unscheduled tary product. Estimating the prevalence is across the different forms of progestin- bleeding/spotting will result.4 As women difficult because the literature has not only contraceptives. Bleeding patterns continue their method, sustained been consistent. A recent study evaluating can range from amenorrhea to unpre- exposure can lead to endometrial reasons for early discontinuation (within dictable timing with varying degrees of angiogenesis disruption, resulting in the 6 months of initiation) among LNG IUD flow to normal monthly menses. Un- development of a dense venous network and ENG implant users found irregular/ scheduled bleeding/spotting has been that is fragile and prone to bleeding.5 frequent bleeding was reported in 9% consistently demonstrated as a side effect Treatment of unscheduled bleeding/ and 53% of these women, respectively.2 for all progestin-only contraceptives. spotting from a progestin-containing The Contraceptive Choice Project The etiology of such bleeding is poorly contraceptive may increase accept- evaluated reasons for discontinuation in understood: over the past 35 years, 5 ability, which may increase continuation different World Health Organization rates. We will discuss different forms of workshops have attempted to investigate progestin-containing contraceptives and fi From the Department of Obstetrics and the pathogenesis. Part of the dif culty their mechanisms of action, possible Gynecology and Division of Clinical Research with identifying the predominant etiol- mechanisms for unscheduled bleeding/ and Family Planning, Washington University ogy is the multiple contributors to the spotting, and current considerations for School of Medicine in St Louis, St Louis, MO. problem. Unscheduled bleeding is likely management of this bothersome side Received Sept. 15, 2016; revised Nov. 29, influenced by type/dose of progestin, effect. 2016; accepted Dec. 7, 2016. how the progestin is delivered, duration fl The authors report no con ict of interest. of use, and specific effects to the endo- Progestin-containing contraceptive Corresponding author: Rachel E. Zigler, MD. metrium because of the mechanism of methods [email protected] action. Progestin-only pills 0002-9378/$36.00 The quantity/duration of bleeding Progestin-only pills, or POPs, are avail- ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2016.12.008 may change between the initiation of a able in the United States in 1 formula- method and continuation of that tion: norethindrone 0.35 mg tablets. MAY 2017 American Journal of Obstetrics & Gynecology 443 Downloaded for Anonymous User (n/a) at Michigan State University from ClinicalKey.com by Elsevier on September 16, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved. Expert Reviews ajog.org This pill should be taken daily at the higher serum levels of progestin, DMPA highest after placement and then slowly same time because POPs have a short will suppress ovulation via inhibition of decrease, peaking at 70 mg/d and slowly duration of action and short half-life.6 gonadotropin secretion. With decreased decreasing to 25e30 mg/d by the end of The primary mechanism of action for ovarian function, a hypoestrogenic state 3 years of use.21 the POPs is increased viscosity of cervical occurs, which will ultimately inhibit The ENG implant is associated with mucus, which inhibits sperm penetra- endometrial proliferation. Cervical mu- unpredictable alterations in a woman’s tion. Secondary mechanisms of action cous changes as well as decreased tubal bleeding pattern, from amenorrhea include the thinning of the endome- motility may also occur with DMPA.12 to recurrent, unscheduled bleeding.22 trium, decreased action of the tubal cilia, Both formulations of DMPA reach Bleeding patterns with the ENG implant and suppressed ovulation.7 their peak blood concentrations within tend to be more unpredictable than with Two hours after ingestion, POPs reach the first 3 weeks after administration. DMPA and the LNG IUD. In a previous a maximum serum level, and therefore The subcutaneous formulation persists study, 78% of women had unscheduled maximum effect, within hours. This at 0.2 ng/mL through day 91, and the bleeding in a 3 month period.23 Yet if a effect persists for approximately 20e24 intramuscular formulation persists at woman has a favorable bleeding pattern hours, when serum levels return to near 0.4 ng/mL through day 84. They both during her first 3 months after initiation, baseline, making consistently timed become undetectable between days 120 she will likely continue to have a favorable daily administration imperative.7,8 and 200.13,14 bleeding pattern. A previous study suggested that when The majority of women using DMPA Recent data suggest that women who compared with combined oral contra- experience menstrual changes as a result initially reported unfavorable bleeding ceptive (COC) users, women using POPs of the high level of progestin. During patterns ultimately had an approxi- have more frequent and longer episodes the months after the first to second mately 50% chance of improvement of bleeding as well as shorter, less pre- injection, episodes greater than 7 days with continued use.23 Furthermore, 30% dictable intervals between bleeding.9 of unscheduled bleeding/spotting are of users will be amenorrheic by 1 year of Although unscheduled bleeding is the common.15 This potentially is due to use.24,25 Bleeding pattern with the most common side effect in women endometrial instability and subsequent implant is thought to be secondary to using POPs, with approximately 40% of capillary leakage from scant uterine atrophy as well as disruption in endo- users having irregular cycles, up to 50% lining.16 The frequency/duration of metrial angiogenesis, creating a fragile of users have regular monthly menses, these episodes decreases with continued venous network.23,26 and approximately 10% report amen- use. Forty-six percent of users will be orrhea.4,7,9,10 These differences are likely amenorrheic by 1 year and 70% with Intrauterine device secondary to large variations of serum longer use.15 These rates are similar in The LNG IUD is currently marketed in 4 levels of progestin among users and daily both intramuscular and subcutaneous forms in the United States: Mirena, fluctuations in serum levels.7 formulations.16 Liletta, Kyleena, and Skyla. The mecha- Previous endometrial biopsy studies Endometrial biopsy studies show a nism for all LNG IUDs is dominated by have shown a variable/unpredictable predominance of endometrial atrophy local effects of thickened cervical mucus, endometrial response to POPs. Patterns and chronic endometritis. The latter endometrial decidualization, glandular include irregular secretory endome- most often is due to atrophy rather than atrophy, and increased glycodelin
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