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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- ac- including progestin-only pills, depot-medroxyprogesterone acetate, subdermal etono- etate (DMPA), subdermal gestrel implants, and 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 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 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 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 in 1 formula- method and continuation of that tion: norethindrone 0.35 mg tablets.

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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 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 , 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 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 A pro- trium, lack of proliferation, suppressed an infectious process.4,17 duction, which inhibits fertilization.27 proliferation, and an increase in the Ovulation suppression is not a primary number of veins and number of dilated Subdermal implant mechanism of action for the LNG IUD.28 veins at the endometrial/myometrial The implant is currently marketed in the Mirena, or LNG IUD 52/5 (mg of junction.11 The variety of histological United States as Nexplanon and contains LNG per years of Food and Drug findings further supports the difficulty in the progestin ENG. This implant is a Administration approval), releases 20 clearly identifying the etiology and 40 mm 2 mm semirigid plastic rod mg/d for 5 years. After 5 years, the release effective treatment approaches. containing 68 mg of ENG and is rate decreases slowly to 10e14 mg/d. currently approved by the Food and Recent data suggest extended efficacy to Depot medroxyprogesterone acetate Drug Administration for 3 years of use. 7 years.18,29 Depot medroxyprogesterone acetate, or Recent data suggest extended efficacy to Liletta, or LNG IUD 52/3, releases DMPA, is currently the only form of at least 5 years.18,19 As with DMPA, the 18.6 mg/d over 3 years. After 3 years, this injectable contraceptive in the United ENG implant prevents conception by rate slowly decreases to 13 mg/d. There is States. Previously, DMPA was adminis- inhibiting gonadotropin secretion to aid ongoing data collection with plans to tered in only 1 form: 150 mg per 1 mL in ovulation suppression. Secondary apply for extended approval of up to 7 given intramuscularly every 13 weeks. mechanisms include cervical mucus and years.30 Now DMPA can also be administered in tubal motility changes.20 Kyleena, or LNG 19.5/5, releases 17.5 a subcutaneous formulation (104 mg per Once placed, the implant slowly re- mg/d for 5 years. After 5 years, this rate 0.65 mL) every 13 weeks. Because of the leases etonogestrel. These rates are the slowly decreases to 7.4 mg/d.31

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Finally, Skyla, or LNG IUD 13.5/3, necessarily require intervention. For those used in similar contraceptive releases 14 mg/d for 3 years. After women in whom the bleeding changes methods. 3 years, this rate slowly decreases to are bothersome, the following questions We will review the available data for all 5 mg/d.32 may be helpful in eliciting potential investigated potential treatments. This Rates of amenorrhea differ among the causes: will include larger and more robust formulations. For LNG IUD 52/5 and studies as well as those that are smaller LNG IUD 52/3, 20% of users experience What was her bleeding pattern both and exploratory in nature. amenorrhea within 1 year and 50% before and during her current con- within 2 years.33,34 The LNG IUD 19.5/5 traceptive use? Medical therapy: has a lower rate of amenorrhea, 12%, at How many bleeding days is she having antiinflammatory the end of year 1. Data for amenorrhea per month? Nonsteroidal antiinflammatory at 2 years are not available, but rates at If she is using a non-LARC method, (NSAID) medications primarily act by 5 years are reported to be 23%.31 The such as POPs or DMPA, is she using it inhibiting , which is a LNG IUD 13.5/3 behaves differently, correctly? synthase. Given that some likely attributable to a lower dose of LNG — Is her bleeding heavy or light? women with irregular bleeding have released, causing amenorrhea in only 6% — Is she having regular/irregular been shown to have elevated levels of and 12% of users within 1 and 2 years, cycles or is the bleeding prostaglandin (PGE2 and PGF2a increase respectively.32 intermenstrual? during the secretory phase), short Up to 52% of women using any form Is she taking any other medications courses of NSAIDs could plausibly have of LNG IUD have some form of un- (ie, antiepileptic drugs, St John’s an impact on this particular mechanism scheduled bleeding.32-34 Importantly, Wort) that could interact with her (Table 1).37,38 unlike the ENG implant, data suggest contraceptive and therefore affect her Studies using mefenamic acid have that bleeding patterns experienced with bleeding? shown that it decreases bleeding days in the LNG IUD tend to improve with Are there any symptoms that are DMPA in the short term as well as both continued use and for most within associated with her bleeding (ie, pain, the short and long term in both ENG and 12 weeks of insertion.35 This likely is nausea, , breast tenderness)? LNG implant users.38,40,43 When tested due to strong endometrial suppression Does the bleeding occur at specific in women using the ENG implant in a provoked by high local LNG concentra- times (ie, after sex)? randomized controlled trial (RCT), tion within the endometrial cavity, mefenamic acid users (n ¼ 25) had fewer leading to atrophy of the glandular Examination and/or further testing bleeding episodes over 4 weeks as epithelium.35 Other changes noted are should be considered based on the in- compared with the placebo group (n ¼ extensive decidualization of endometrial dividual clinical situation. For example, 25) (10.5 days vs 16.8 days, P < .05).40 stromal cells and changes in vascular if she complains of symptoms including This study did not include subjective morphology.36 pain, vaginal discharge, and postcoital assessment of patient satisfaction of bleeding, a workup for cervicitis or resultant bleeding patterns; therefore, it Management of unscheduled endometritis may be indicated. If un- is difficult to understand the clinical bleeding scheduled bleeding is believed to be significance of 10.5 vs 16.8 bleeding days. Anticipatory counseling regarding un- secondary to progestin-only contracep- Regardless, this study did suggest that scheduled bleeding for women initiating tion, further workup is often not neces- NSAIDs may demonstrate improvement progestin-only methods is important. sary; however, a pelvic examination or in an LNG method user and thus led to Even with adequate counseling, many ultrasound may be helpful in IUD users the investigation of in LNG women may still express dissatisfaction to confirm that the device has not been IUD users. with their bleeding pattern. It is impor- expelled. In an RCT of LNG IUD users, nap- tant to remind women that unscheduled If pathology is not suspected, or has roxen users (n ¼ 42) demonstrated a bleeding is not indicative of decreased been ruled out, and the bleeding pattern 10% decrease in bleeding/spotting days efficacy of their method. Yet pregnancy is bothersome to the patient, interven- when compared with the placebo group should always be ruled out if a woman tion may be considered. Because the (n ¼ 43) (adjusted relative risk 0.90, 95% complains of an abrupt change in her etiology of unscheduled bleeding with confidence interval [CI], 0.84e0.97) bleeding pattern. progestin-only contraception is not during the active treatment period.46 A detailed description of the bleeding fully understood and potentially multi- However, these results were not sus- pattern should be elicited. It is important factorial, investigated therapies have tained beyond the 4 weeks following to distinguish between unscheduled shown mixed results. Previous studies treatment. bleeding that is bothersome to the pa- have been performed in populations of These studies suggest a short course of tient and unscheduled bleeding that is women using progestin contraceptives NSAIDs may be helpful in some women, tolerable or insignificant to the patient. not used in the United States; therefore, although interruption in bleeding may Women in the latter category do not some therapies are extrapolated from not be sustained. Although mefenamic

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(n ¼ 33) and placebo (n ¼ 31) and TABLE 1 measured clinical improvement, or Previous studies of nonsteroidal antiinflammatory medications bleeding less than 8 days or an interval of Contraceptive Medical therapy bleeding-free days greater than 20 days. DMPA Mefenamic acid 500 mg 2 times per day 5 days38 Twenty-three of the patch users (69.7%) 40 mg daily 5 days39 and 13 of the placebo users (41.9%) had clinical improvement, which was not 40 ENG implant (Implanon) Mefenamic acid 500 mg 3 times per day 5 days statistically significant (statistical anal- LNG implants (Norplanta; Jadelleb) 800 mg 3 times per day 5 days41 ysis not shown).50 Ibuprofen 800 mg 2 times per day 5 days42 Several studies have evaluated oral , and most have shown a Mefenamic acid 500 mg 2 times per day 5 days43 benefit.47-49 When compared with pla- 44 80 mg daily 10 days cebo, 93% (84 of 90) of DMPA partici- 200 mg daily 5 days45 pants randomized to 50 mg ethinyl LNG IUD Naproxen 500 mg 2 times per day 5 days46 for 14 days reported bleeding DMPA ENG LNG LNG IUD cessation vs 74% (72 of 97) receiving , depot-medroxyprogesterone acetate; , etonogestrel; , levonorgestrel; , levonorgestrel intrauterine 47 device. placebo (P < .001). a No longer available in the United States; b Available internationally but not in the United States. One study, with a relatively small Zigler. Unscheduled bleeding with progestin-only contraception. Am J Obstet Gynecol 2017. sample size (n¼26), aimed to evaluate COCs in ENG implant users. Partici- pants were randomized to 1 month of acid was tested only in DMPA and women. Exogenous estrogen may aid in COC (n ¼ 13) or placebo (n ¼ 13). implant users and naproxen in LNG IUD tissue repair and stabilization of the Although all women randomized to users, it is reasonable to try these thera- endometrial lining (Table 2). COCs reported bleeding/spotting reso- pies in other progestin-only methods. Few studies have evaluated the use of lution as opposed to 75% of placebo For many patients, naproxen is likely transdermal estrogen. The first ran- users, the study was stopped early sec- more accessible because it is less expen- domized users of the LNG IUD to a ondary to difficulty with recruitment sive and available over the counter. 0.1 mg estradiol patch (n ¼ 44) and and did not meet its predetermined Use of any NSAIDs may be contra- placebo (n ¼ 43) for the first 12 weeks of sample size.48 indicated in women with some medical IUD use. Surprisingly, the study Finally, in a 3 arm study that ran- conditions such as a history of gastro- demonstrated an increase in bleeding/ domized LNG implant users to ethinyl intestinal bleeding, renal impairment, or spotting days in women randomized to estradiol (n ¼ 33), COC (n ¼ 45), and allergy. estrogen therapy (adjusted relative risk placebo (n ¼ 46), 91%, 67%, and 15%, 1.25, P < .05).46 respectively, saw bleeding cessation Medical therapy: estrogen A second study with transdermal within 3 days of use. In this study, COC Estrogen, whether given by itself or as a estrogen randomized users of the LNG and ethinyl estradiol were significantly COC, may be an option for some implant to the 0.1 mg estradiol patch different from placebo (P < .01) and COCs showed greater improvement than ethinyl estradiol (P < .01).49 TABLE 2 Summation of these studies evaluating Previous studies of estrogen estrogen-containing interventions sug- Contraceptive Medical therapy gest that an oral method may be of benefit. Suggested regimens include oral DMPA EE 50 mg daily 14 days47 conjugated estrogen 1.25 mg or estradiol 48 ENG implant LNG 150 mg/EE 30 mg daily 4 weeks 2 mg (because ethinyl estradiol is not LNG 150 mg/EE 30 mg daily 14 days26 available as a monotherapy in the United e LNG implant (Norplant) EE 50 mg daily 20 days41,49 States) daily for 1 2 weeks or COCs for 1e3 cycles. More data are needed to m 42 EE 20 g daily 10 days know whether extended continuous LNG 250 mg/EE 50 mg daily 20 days49 regimens improve outcomes. Unfortu- Estradiol patch 0.1 mg/d 6 weeks50 nately, estrogen is contraindicated in many medical comorbidities (ie, LNG IUD Estradiol patch 0.1 mg weekly 12 weeks46 with aura, history of venous DMPA, depot-medroxyprogesterone acetate; EE, ethinyl estradiol; ENG, etonogestrel; LNG, levonorgestrel; LNG IUD, levo- intrauterine device. thromboembolism, or use over Zigler. Unscheduled bleeding with progestin-only contraception. Am J Obstet Gynecol 2017. the age of 35 years), eliminating this option for many women.

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Medical therapy: doxycycline At subantimicrobial doses, doxycycline TABLE 3 inhibits matrix-metalloproteinase (MMP) Previous studies of doxycycline activity. MMPs play an important role in Contraceptive Medical therapy tissue remodeling, and it is thought that DMPA Doxycycline 100 mg 2 times per day 5 days51 increased MMP activity within the endo- ENG implant Doxycycline 100 mg 2 times per day 5 days52,53 metrium is a cause for unscheduled DMPA, depot-medroxyprogesterone acetate; ENG, etonogestrel. bleeding (Table 3). An RCT in women using DMPA Zigler. Unscheduled bleeding with progestin-only contraception. Am J Obstet Gynecol 2017. assigned women to 100 mg of doxycy- cline daily for 5 days (n ¼ 34) or placebo (n ¼ 34) and demonstrated no benefitof In an RCT, Senthong et al demon- In summary, TXA showed benefit doxycycline when evaluating bleeding strated using 250 mg of TXA 4 times a in the DMPA trial and acutely for the cessation by day 10 (relative risk, 0.88, day (n ¼ 50) compared with placebo LNG implant but not for the LNG IUD. 95% CI, 0.64e1.21).51 Furthermore, (n ¼ 49) showed a positive effect with In the United States, TXA is available there was no significant difference in the unscheduled bleeding, both in the acute in 650 mg tablets. A common regimen number of bleeding/spotting days in the phase and at 4 weeks for DMPA users.54 used for abnormal uterine bleeding 3 months following treatment (doxycy- Specifically, bleeding cessation was seen can be extrapolated: 1300 mg 3 times a cline group with 7.28 days of bleeding in 88% of TXA users as compared with day for 5 days. Because of the mecha- and 3.77 days of spotting vs placebo 8.2% of placebo users (P < .001). At nism by which it works, TXA must be group with 7.38 days of bleeding and 4 weeks, this difference persisted, with avoided in women with a personal his- 3.66 days of spotting, both with P > 68% of TXA users continuing to have no tory of or increased risk of venous .05).51 An RCT in women using the ENG bleeding as compared with 0% of pla- thromboembolism. implant comparing doxycycline (n ¼ 45) cebo users (P < .001).54 with placebo (n ¼ 45) did, however, Yet TXA was effective only during this Medical therapy: show a statistical difference, with doxy- studied treatment phase and not long Mifepristone is an antiprogestin that cycline being superior. term when studied in the LNG implant.55 may lead to the up-regulation of estro- The primary outcome in this study In this study, during the first week, 65% gen receptors within the endometrium, was time to bleeding cessation, and of TXA users experienced bleeding thus stabilizing the endometrium subjects randomized to doxycycline cessation as compared with 35% of pla- (Table 5).20 achieved bleeding cessation more cebo users, which was statistically sig- Mifepristone has been shown to quickly, 4.8 days as compared with 7.5 nificant (P ¼ .015), but there was no decrease bleeding days in users of days.52 The authors set out to replicate statistical difference at 4 weeks after DMPA, LNG implant, and LNG IUD the study with a planned enrollment of treatment when measuring bleeding-free when used prophylactically.57-59 In an 490 subjects. Despite not being able to intervals of greater than 20 days (59% RCT of DMPA users in their first duplicate their findings, they were able to TXA vs 77% placebo, P ¼.12).55 3 months of use, women who also took enroll only 42% (n ¼ 204) of their Finally, when a trial randomized mifepristone (n ¼ 20) experienced a planned sample.52,53 women with LNG IUDs to TXA (n ¼ 63) median percentage days of breakthrough Despite inconsistent results, if endo- or placebo (n ¼ 61), they saw a decrease bleeding of 15 as compared with 36 metritis is believed to be a potential of bleeding and spotting days by a me- in women taking placebo (n ¼ 20) contributor to the etiology of an in- dian of 6 days over a period of 90 days (P ¼ .05). At 6 months, though, results dividual’s disrupted bleeding, doxycy- (P ¼.049). This significance was not seen were no longer significant (7 vs 18, cline 100 mg 2 times per day for 10e14 after adjusting for multiplicity.56 respectively, P ¼ .52).57 days may be worthwhile. This medica- tion has few contraindications, but we TABLE 4 must acknowledge possible side effects Previous studies of tranexamic acid including gastrointestinal symptoms and potential for antibiotic resistance. Contraceptive Medical therapy DMPA TXA 250 mg 4 times per day 5 days54 Medical therapy: tranexamic acid LNG implant TXA 500 mg 2 times per day 5 days55 Tranexamic acid (TXA) is an anti- fibrinolytic medication that has been LNG IUD TXA 500 mg 3 times per day from bleeding onset until day after bleeding cessation56 previously used for heavy menstrual DMPA, depot-medroxyprogesterone acetate; LNG, levonorgestrel; LNG IUD, levonorgestrel intrauterine device; TXA, tranexamic bleeding. It aids in decreasing clot acid. breakdown, thus decreasing bleeding Zigler. Unscheduled bleeding with progestin-only contraception. Am J Obstet Gynecol 2017. (Table 4).

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3 months may be required to establish TABLE 5 their new bleeding pattern and that for Previous studies of mifepristone many methods, problematic bleeding Contraceptive Medical therapy improves over time. DMPA Mifepristone 50 mg 1 every 14 days57 When a woman presents with irreg- fi ENG implant Mifepristone 25 mg 2 times daily 1 day53 ular bleeding, she should rst be reas- sured. If appropriate, further workup 58 LNG implant Mifepristone 100 mg daily 2 days such as ruling out infection or other DMPA, depot-medroxyprogesterone acetate; ENG, etonogestrel; LNG, levonorgestrel. pathology should be performed. In Zigler. Unscheduled bleeding with progestin-only contraception. Am J Obstet Gynecol 2017. women with an IUD, correct placement should be confirmed. If bleeding persists and the woman desires treatment, a Although the total number of in the acute period. In a recent RCT course of NSAIDs or estrogen (alone or bleeding/spotting days during a 6 month comparing tamoxifen (n ¼ 28) and as COC) may be of use. If these medi- treatment phase showed a 35% decrease placebo (n ¼ 28) in ENG implant users, cations are contraindicated or unsuc- when the mifepristone group (n ¼ 58) the investigators found that women us- cessful, other available options include was compared with the placebo group ing tamoxifen had 5 fewer bleeding/ doxycycline, TXA, mifepristone, and (n ¼ 57), in women with LNG implants spotting days than those using placebo tamoxifen, although not all may be (P < .001), this was not observed at the within a 30 day period (95% CI, e9.9 to accessible/appropriate for all patients. individual level.58 e0.05). They also experienced 15 more Doxycycline may be helpful if the patient Although this is a promising medi- continuous bleeding free days (95% CI, is believed to have endometritis, either cation in the acute phase, most studies 2.8e27.5).59 Benefit was also demon- acute or chronic. use a dose that is not available in the strated in an RCT of tamoxifen (n ¼ 50) TXA has shown some benefitina United States (available dose is 200 and placebo (n ¼ 50) in LNG implant DMPA trial and may be of clinical benefit mg). Also, as an , this users. This study demonstrated bleeding with the IUD. Mifepristone, although medication is highly regulated, not cessation was seen in 88% of the promising for acute bleeding, is not available for pharmacy distribution, tamoxifen group as compared with 68% available in the United States in the and requires physicians to be registered in the placebo group (P ¼ .016) at 3 studied dose and is otherwise difficult to with the manufacturer. Finally, there months.60 Further research with larger obtain. have been concerns that an anti- trials is needed before routine use of Finally, tamoxifen has been studied progestin may alter the contraceptive tamoxifen is undertaken. with implant use and may provide an efficacy of progestin-only contracep- increase in continuous bleeding-free tion, although these concerns have not Conclusion days. Further research is needed on all been well studied.57,58 Allergy is the Unscheduled bleeding and spotting with of these medications because many main contraindication to this progestin-only contraceptive use is of studies show mixed reviews. Thus, medication. utmost importance because it is a these medications may be helpful in a contributing cause for discontinuation, subsetofwomanbutnothelpfulin Medical therapy: tamoxifen which can leave women vulnerable to another, and treatment, as in most Tamoxifen, a selective estrogen . Prior to initia- cases, should be tailored to the indi- modulator, may work by antagonizing tion of progestin-only contraception, it vidual woman. - the angiogenic effect of estrogen is important to discuss the likelihood of 22 (Table 6). unscheduled bleeding/spotting. Setting REFERENCES Although there are not many studies, this expectation may decrease a woman’s 1. Moreau C, Cleland K, Trussel J. Contracep- tamoxifen has been noted to have a dissatisfaction. Women should also be tive discontinuation attributed to method beneficial effect in unscheduled bleeding counseled, prior to initiation, that up to dissatisfaction in the United States. Contracep- tion 2007;76:267-72. 2. Grunloh DS, Casner T, Secura GM, Peipert JF, Madden T. Characteristics associ- TABLE 6 ated with discontinuation of long-acting revers- Previous studies of tamoxifen ible contraception within the first 6 months of use. Obstet Gynecol 2013;122:1214-21. Contraceptive Medical therapy 3. 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