ABNORMAL UTERINE BLEEDING Randomized Data Shed Light on AUB Associated with Fibroids, Adenomyosis, and the Use of Progestins

UPDATE

ABNORMAL UTERINE BLEEDING Randomized data shed light on AUB associated with fibroids, adenomyosis, and the use of progestins

›› Malcolm G. Munro, MD Dr. Munro is Professor of Obstetrics and Gynecology at the David Geffen School of Medicine at UCLA and Director of Gynecologic Services at Kaiser Permanente, Los Angeles Medical Center, in Los Angeles, California.

Dr. Munro reports that he is a consultant to Bayer HealthCare.

s recently defined by the International • Coagulopathy AFederation of Gynecology and Obstet- • Ovulatory disorders rics (FIGO)—and endorsed by the American • Endometrial dysfunction College of Obstetricians and Gynecologists— • Iatrogenic the term “abnormal uterine bleeding” (AUB) • Not otherwise classified. IN THIS ARTICLE now describes any departure from normal A given individual may be found to have one menstrual bleeding.1 To determine the most or more of these features, but not all of the Consider the appropriate intervention for this widespread features may contribute to the AUB. To facili- levonorgestrel- problem, FIGO proposed that clinicians con- tate their use, these nine causes are more releasing sider potential contributors to the clinical commonly identified using the acronym intrauterine system problem by investigating and categorizing PALM-COEIN. for AUB related to patients according to the following system: In this article, I focus on three of these adenomyosis • Polyp categories, presenting recent data on AUB • Adenomyosis associated with leiomyomata (AUB-L) or ade- page 30 • Leiomyoma nomyosis (AUB-A), and AUB of an iatrogenic • Malignancy and hyperplasia nature (AUB-I). For AUB associated with the use of progestins, concomitant AUB-L: Satisfaction rates are similar doxycycline may be of benefit 5 years after fibroid treatment by page 31 surgery or uterine artery embolization

Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine omen who undergo uterine artery artery embolization for symptomatic uterine fibroids. Wembolization (UAE) for the treatment of Cochrane Database Syst Rev. 2012;5:CD005073. symptomatic uterine fibroids are just as satis- doi:10.1002/14651858.CD005073.pub3. fied with the outcome as women treated with hysterectomy or myomectomy, according to

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this 2012 review from the Cochrane Database. WHAT THIS EVIDENCE MEANS Gupta and colleagues found similar FOR PRACTICE patient-satisfaction rates at 5 years (odds ratio [OR] 0.9; 95% confidence interval [CI], This review demonstrates that women are 0.45–1.8), although women undergoing UAE satisfied with outcomes five years after were more likely to require additional inter- UAE and that ovarian failure is not more ventions within 2 years (56 additional inter- common after UAE than after surgery. ventions per 1,000 women for surgery vs Although the available evidence dem- 250 per 1,000 women for UAE; OR, 5.64). onstrates that pregnancy following UAE is possible, women requiring a surgical procedure for AUB-L who are uncertain Details and general findings about their childbearing plans or who are Gupta and colleagues selected randomized, hoping to conceive should be encouraged controlled trials comparing UAE with surgery: to select myomectomy as their interven- • three trials of UAE versus abdominal hys- tion of choice. terectomy (n = 291) • one trial of UAE versus hysterectomy or myomectomy (the specific surgery was • Pregnancy was less likely after UAE determined by patient preference) (n = 157) than after myomectomy. In the trial • one trial of UAE versus myomectomy comparing UAE with myomectomy, in women desiring future childbearing 26 women later tried to conceive after UAE (n = 121). versus 40 after myomectomy. Significantly In these trials, UAE was bilateral and involved fewer women became pregnant after UAE the use of permanent embolic material. (OR, 0.29; 95% CI, 0.10–0.85). Among the findings: • Costs were lower with UAE, as assessed Bleeding outcomes were not by measuring the duration of the proce- measured Compared with dure, length of hospitalization, and time to Strengths of this systematic review are its hysterectomy and resumption of normal activities. inclusion of high-quality, randomized, con- myomectomy, UAE • Ovarian-failure rates were comparable trolled trials and its assessment of ovarian- costs were lower between women in the UAE and surgery failure rates. However, a major weakness is and postprocedure groups. Ovarian function was assessed by the fact that its design does not allow for dis- ovarian-failure rates measuring follicle-stimulating hormone crete evaluation of bleeding outcomes. Nor (FSH), although FSH thresholds varied in can its findings be broken down by the type were comparable some of the studies. of leiomyoma being treated.

AUB-A: For adenomyosis-associated AUB, consider the LNG-IUS as an alternative to hysterectomy

Ozdegirmenci O, Kayikcioglu F, Akgul MA, et al. Com- n a small randomized, controlled trial of the parison of levonorgestrel intrauterine system versus Ilevonorgestrel-releasing intrauterine sys- hysterectomy on efficacy and quality of life in patients tem (LNG-IUS; Mirena) versus hysterectomy with adenomyosis. Fertil Steril. 2011;95(2):497–502. for adenomyosis-associated AUB, women allocated to the LNG-IUS experienced a

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reduction in bleeding and comparable gains WHAT THIS EVIDENCE MEANS FOR PRACTICE in hemoglobin values during the first year The relationship of adenomyosis to gynecologic symptoms, including of use. Both the LNG-IUS and hysterectomy heavy menstrual bleeding and dysmenorrhea, needs further study. improved health-related quality of life, but However, this trial confirmed that transvaginal ultrasound is helpful the LNG-IUS was associated with superior in the nonsurgical diagnosis of adenomyosis and suggests that the improvements in measures of psychological LNG-IUS may be as effective at 1 year as hysterectomy for the treat- and social functioning. ment of adenomyosis-associated heavy menstrual bleeding (AUB-A). Clinicians who perform office-based ultrasound to assess AUB Details and general findings of should familiarize themselves with the criteria for ultrasonic diagno- the trial sis of adenomyosis. These criteria include the presence of hetero- Eighty-six women were enrolled in the trial geneous myometrial echogenicity, a loss of clarity of the endo- after exclusion of endometrial pathology as myometrial interface, typically radially oriented linear striations, the a cause of their heavy menstrual bleeding appearance of myometrial cysts, and an overall globular enlarged and after transvaginal ultrasound and mag- uterus characterized by asymmetric thickening of the myometrium.2 In patients with heavy menstrual bleeding who have these find- netic resonance imaging findings were con- ings, particularly if there is coexistent dysmenorrhea and uterine sistent with the diagnosis of adenomyosis. tenderness, it behooves the clinician to consider the LNG-IUS as Participants then were randomly assigned first-line therapy, especially for women who wish to preserve fertil- to undergo hysterectomy or insertion of an ity, but also for women for whom fertility is not an issue. LNG-IUS (43 women in each group). At base- There is some evidence that the therapeutic effect of the line, the mean (SD) age was 44.28 (4.36) years LNG-IUS containing 20 µg of levonorgestrel may start to fade at 2 among women in the LNG-IUS group versus 3 or 3 years, a possibility that should be shared with patients. Other 46.38 (3.76) years among women undergoing features, such as cavity size, thickness of the myometrium, and the hysterectomy (P = .032), a statistical differ- coexistence of clinically relevant leiomyomas, have not been evalu- ence that I suspect is not clinically significant. ated but may have an impact on the clinical response. Menstrual bleeding, hemoglobin levels, and quality of life were assessed prior

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30 OBG Management | March 2014 | Vol. 26 No. 3 obgmanagement.com to insertion or surgery, and again at 6- and myosis, six women (18.8%) had myomas, 12-month follow-up. Eleven women in the three women (9.4%) had both adenomyo- hysterectomy group were lost to follow-up. sis and a myoma, and two women (6.2%) General findings of the trial include: had a normal uterus. Serum hemoglobin • Women in the LNG-IUS group had a levels increased from a median of roughly mean reduction in the volume of men- 10.5 g/dL at the time of treatment to strual bleeding—as measured by the num- 13 g/dL at 6 months and slightly higher at ber of pads used—from two pads to one 12 months. (There were no statistically sig- pad at 6 months, remaining at that level nificant differences in hemoglobin values until 12 months. Serum hemoglobin lev- between the LNG-IUS and hysterectomy els increased from a median of just over groups at any point in the study.) Quality of 11 g/dL at the time of insertion to 13 g/dL at life improved in three of the five domains 6 months and slightly higher at 12 months. In assessed (physical and both environmental the five self-reported quality-of-life domains domains). assessed (physical, psychological, social, Although 11 women were lost to fol- environmental, and a national environmen- low-up, this trial appeared to have an ade- tal domain), women using the LNG-IUS quate sample size to examine the selected demonstrated improvement in all five. outcomes, and the population was well • Women in the hysterectomy group defined. were treated using an abdominal surgi- Two weaknesses were the limited fol- cal approach, with one patient experi- low-up (only 12 months) and the use of encing postoperative wound infection quality-of-life measures designed for a Turk- that required secondary suture. Postop- ish population (the trial was conducted in erative pathologic analysis found that Turkey), which may or may not be fully appli- 21 of these women (65.6%) had adeno- cable to a US population.

In women with adenomyosis- related AUB, there were no significant differences in AUB-I: Low-dose doxycycline reduces hemoglobin values between the time to amenorrhea in users those treated with hysterectomy and of continuous oral contraceptives those given an LNG-IUS

Kaneshiro B, Edelman A, Carlson NE, Nichols M, ulation of matrix metalloprotineases (MMPs), Forbes MM, Jensen J. A randomized controlled trial Kaneshiro and colleagues conducted a ran- of subantimicrobial-dose doxycycline to prevent un- domized, controlled trial of doxycycline (an scheduled bleeding with continuous oral contraceptive MMP inhibitor) versus placebo among users pill use. Contraception. 2012;85(4):351–358. of continuous OCs. The addition of doxycycline to the OC regimen did not significantly reduce unscheduled bleeding during the first nscheduled bleeding is the most com- 84 days of use, but it did shorten the time Umon complaint among women who required to achieve amenorrhea (mean of use continuous combination oral con- 61.7 days for doxycycline vs 85.2 days for pla- traceptives (OCs). Because unscheduled cebo; standard error [SE], 7.7 vs 6.7, respec- bleeding has been correlated with the upreg- tively; P = .03).

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WHAT THIS EVIDENCE MEANS FOR PRACTICE randomly assigned to receive one of the following for 84 days in addition to the OC: This trial increases our insight into AUB associated with the use of • doxycycline 40 mg daily (controlled-release progestins and suggests that concomitant doxycycline may reduce Oracea), a subantimicrobial dose unscheduled bleeding and spotting in women using continuous • placebo. combination OCs. The trial was of adequate sample size for the pri- After 84 days, doxycycline was discontinued, mary outcomes, lending credence to its findings, although longer- and participants were observed for an addi- term data would be helpful. tional 28 days on the OC regimen alone for I have included this trial for two reasons: the documentation of bleeding patterns. • It offers useful information regarding the mechanisms and poten- General findings: tial prevention or reduction of AUB-I in users of continuous com- • The number of bleeding and spotting days bined estrogen-progestin contraception. decreased in both groups over the course • Doxycycline is one of the agents covered in a Cochrane review of high-quality research into AUB-I in women using progestin- of the study. only products, including injectables, implantables, intrauter- • During the first 84 days of the trial, bleed- ine systems, and oral agents.4 Estrogens have been shown to ing and spotting occurred among a median have some value in reducing breakthrough bleeding associated of 11 and 17 women in the doxycycline and with depot medroxyprogesterone acetate, and individual use of placebo groups, respectively, and bleed- tranexamic acid or doxycycline has shown value in terminating an ing alone (without spotting) occurred in a episode of breakthrough bleeding in women using progestin-only median 3 and 4 women in the doxycycline contraceptives. and placebo groups, respectively. • During the 28-day observation period, Details and general findings of the trial bleeding and spotting occurred among a Participants (n = 65) were healthy women median of 0 and 6 women in the doxycy- aged 18 to 45 years who had no contraindica- cline and placebo groups, respectively. tions to continuous use of combination OCs. Bleeding alone (without spotting) was Prior to enrollment, they all had used cyclic absent in both groups. combination contraception (pill, patch, or • Women in the doxycycline group were sig- ring) without unscheduled bleeding, thereby nificantly less likely to report side effects avoiding the “transition bleeding” that often such as headache, depressed mood, and occurs when continuous OCs are initiated. abdominal cramping. However, they were All women in the trial were started on more likely to prefer continuous OCs with- continuous OCs (20 µg ethinyl estradiol out doxycycline, compared with women with 100 µg levonorgestrel; Aviane) and then receiving placebo (16.1% vs 10.7%).

References 1. Munro MG, Critchley HO, Broder MS, Fraser IS; FIGO 2010;89(11):1374–1384. Working Group on Menstrual Disorders. The FIGO classifi- 3. Cho S, Nam A, Kim H, et al. Clinical effects of the levonorg- cation for causes of abnormal bleeding in the reproductive estrel-releasing intrauterine device in patients with adeno- years. Fertil Steril. 2011;95(7):2204–2208. myosis. Am J Obstet Gynecol. 2008;198(4):373.e1–e7. 2. Champaneria R, Abedin P, Daniels J, Balogun M, Khan 4. Abdel-Aleem H, d’Arcangues C, Vogelsong KM, Gaf- KS. Ultrasound scan and magnetic resonance imag- field ML, Gulmezoglu AM. Treatment of vaginal bleeding ing for the diagnosis of adenomyosis: Systematic review irregularities induced by progestin-only contraceptives. comparing test accuracy. Acta Obstet Gynecol Scand. Cochrane Database Syst Rev. 2013;10:CD003449.

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