In which cases should endometrial destruction be performed during an operative hysteroscopy? Clinical practice guidelines from the French College of Gynaecologists and Obstetricians (CNGOF)

To provide guidelines from the French College of Obstetricians and Gynaecologists (CNGOF), based on the best evidence available, concerning the impact of endometrial destruction on bleeding and endometrial cancer risk reduction in patients candidates for operative hysteroscopy.Recommendations were made according to AGREE II and the GRADE® (Grading of Recommendations Assessment, Development and Evaluation) systems to determine separately the quality of evidence (QE) and in the level of recommendation. In a retrospective study comparing the incidence of endometrial cancer in 4776 patients with menorrhagia treated with endometrial destruction vs 229 945 patients with a medical treatment. There was a non-significant reduced risk of developing endometrial cancer (HR, 0.45; 95% CI, 0.15-1.40; p = .17). In premenopausal women, five studies compared the incidence of endometrial cancer in patients treated with endometrial ablation/destruction (EA/D) to the incidence of endometrial cancer in a comparable population of women from national registers, all of which show reduced risk of endometrial cancer after endometrectomy. In case of menopausal metrorrhagia, the prevalence of endometrial cancer is 9%, by analogy with the results found in premenopausal patients, the combination of endometrial ablation during operative hysteroscopy seems justified. In a retrospective cohort of 177 non-menopausal patients treated with myomectomy for metrorrhagia and/or menorrhagia, a significantly better control of bleeding at 12 months was found when myomectomy was combined with endometrectomy using roller-ball (OR: 0.18 [95% Cl 0.05-0.63]; p = 0.003). In premenopausal women with heavy menstrual bleeding, when an operative hysteroscopy is performed, it is recommended to propose an endometrial ablation/destruction in order to prevent the risk of endometrial cancer, (QE3) and to prevent recurrence of bleeding (QE2). In menopausal women, it is probably recommended to also perform an endometrial ablation/destruction in case of operative hysteroscopy in order to prevent the risk of endometrial cancer (QE1).

Endometrial safety and bleeding profile of a 17ß-estradiol/progesterone oral softgel capsule (TX-001HR).

OBJECTIVE: The aim of the study was to evaluate the effect of a single-capsule 17ß-estradiol/progesterone (E2/P4), TX-001HR, on endometrial safety, to report on amenorrhea and bleeding patterns of users, and to identify predictors of amenorrhea. METHODS: The REPLENISH trial (NCT01942668) evaluated use of TX-001HR in menopausal women (40-65 y) with vasomotor symptoms (VMS) and a uterus. Women were randomized to daily E2/P4 (mg/mg: 1/100, 0.5/100, 0.5/50, or 0.25/50), or placebo for 12 months. Incidence rate of endometrial hyperplasia was calculated from endometrial biopsies conducted at screening and study completion. Women reported bleeding and spotting in daily diaries. The number of bleeding and/or spotting days and the proportion of women with no bleeding or amenorrhea were compared between treatment and placebo using the Fisher exact test. Predictors of cumulative amenorrhea were assessed by univariate analyses. RESULTS: Women (n = 1,835) who took at least one study dose comprised the safety population; 1,255 had baseline and 12-month biopsies and comprised the endometrial safety population. Incidence of endometrial hyperplasia was ≤0.36% with any dose of TX-001HR after 1 year of use (one-sided upper 95% confidence interval ≤4%). Cumulative amenorrhea (no bleeding/spotting) rates increased over time and were relatively high from cycle 1 to 13 with TX-001HR (56%-73%; placebo 79%; P < 0.05 except with 0.25/50 dose). Few vaginal bleeding adverse events (1.0%-4.6% TX-001HR vs 0.7% placebo) were reported and discontinuations due to bleeding were low (0.4%-1.4% vs 0%). Cumulative amenorrhea was significantly more frequent in older women, those further from their last menstrual period, and those with lower baseline E2 concentrations (all; P < 0.01). CONCLUSIONS: All doses of TX-001HR provided endometrial protection and were associated with an improved bleeding profile over time; older age, further last menstrual period, or lower baseline E2 may predict amenorrhea with TX-001HR.

A multicenter, double-blind, randomized trial on the bleeding profile of a drospirenone-only pill 4 mg over nine cycles in comparison with desogestrel 0.075 mg.

PURPOSE: A typical compliance problem in the use of traditional progestin-only pills is the irregular bleeding pattern and the strict daily intake. Desogestrel 75 mg has a 12-h missed-pill window; however, its poor cycle control limits a more common use. METHODS: A drospirenone (DRSP)-only pill was developed to improve the bleeding profile. SETTING: A phase III study in healthy women aged 18-45 years was performed to compare the bleeding profile and safety of a DRSP-only pill in a regime of 24 days of 4 mg of DRSP tablets followed by 4 days of placebo versus desogestrel 0.075 mg per day continuously over nine cycles. POPULATION: A total of 858 women with 6691 drospirenone and 332 women with 2487 desogestrel treatment cycles were analyzed. MAIN OUTCOME MEASURES: The primary end point was the proportion of women with unscheduled bleeding/spotting in each cycle from cycles 2 to 9 and cumulative in cycles 2-4 and cycles 7-9. RESULTS: In each cycle, up to cycle 7, the proportion of women with unscheduled bleeding was statistically significantly lower in the DRSP group than in the DSG group (p = 0.0001, Chi-square test). CONCLUSIONS: This report describes the improvement in bleeding profile of women using the new DRSP-only oral contraceptive in comparison to DSG, providing a better quality of live and adherence to the contraceptive method. EudraCT Registration Number: 2011-002396-42.

Tamoxifen for the prevention of unscheduled bleeding in new users of the levonorgestrel 52-mg intrauterine system: a randomized controlled trial.

OBJECTIVE: To determine if a course of oral tamoxifen initiated following placement of a levonorgestrel 52-mg intrauterine system (IUS) reduces bleeding/spotting days over 30 days. STUDY DESIGN: In this single-center, double-blind, placebo-controlled trial, we recruited women ages 15-45 years initiating the levonorgestrel 52-mg IUS. We randomized eligible women to tamoxifen 10 mg or placebo twice daily for 7 days starting 21 days after levonorgestrel 52-mg IUS insertion. Participants tracked bleeding/spotting days via daily electronic diaries for 30 days after starting drug treatment. We assessed participant satisfaction with their bleeding pattern and the IUS using a visual analog scale (0-100 mm). A sample size of 42 provided 80% power to detect a difference of 7 bleeding/spotting days in 30 days by two-sample t test, accounting for an expected 20% dropout rate. RESULTS: From September 2016 to January 2018, 42 women enrolled. A total of 34 women provided complete bleeding/spotting data, and 30 women provided satisfaction data. Mean bleeding/spotting days over 30 days did not differ between tamoxifen (12.0±5.8 days) and placebo users (16.8±9.0 days), p=.08. We found no significant differences in mean satisfaction with bleeding profiles (51 mm tamoxifen vs. 59 mm placebo, p=.48) or with the IUS (83 mm vs. 75 mm, p=.36) between groups. Both groups reported similar rates of adverse events, with no serious adverse events reported. CONCLUSION: A course of oral tamoxifen did not improve early breakthrough bleeding or satisfaction in new users of the levonorgestrel 52-mg IUS. IMPLICATIONS: Although tamoxifen treatment caused a trend toward modest bleeding/spotting day reduction in new levonorgestrel 52-mg IUS users, bleeding satisfaction did not improve. Future studies of tamoxifen treatment for IUS-related bleeding issues may be best targeted toward users with ongoing bleeding irregularities or lower-dose IUS products which cause more bleeding irregularities.

Gynaecological and obstetrical bleeding in Caucasian women with congenital factor XI deficiency: Results from a twenty-year, retrospective, observational study.

INTRODUCTION: Factor XI (FXI) deficiency is a mild bleeding disorder, common among Ashkenazis, that may be underestimated in Caucasians. Management of FXI deficiency in women is a challenge, due to its unpredictable bleeding tendency and the little evidence available on this issue. OBJECTIVE: To describe gynaecological/obstetrical bleeding complications and to analyze the effectiveness and safety of the antihaemorrhagic treatment among women with FXI deficiency. MATERIAL AND METHODS: A retrospective, observational study of 214 Caucasian subjects with FXI deficiency collected during 20 years (1994-2014) without clinical selection. RESULTS: We identified 95 women with FXI deficiency. Any haemorrhagic event was communicated by 26/95 (27.4%), being abnormal uterine bleeding the most frequently found (12/95, 12.6%). Nine postpartum haemorrhages were recorded from 136 deliveries (6.6%) in 57 women. Four postsurgical bleeding complications were registered among 25 gynaecological surgeries (16%) in 20 women. Abnormal uterine bleeding, postpartum and postsurgical haemorrhages were related to both a positive bleeding history and FXI:C values ≤43.5%. Prophylaxis with fresh frozen plasma, used in 12/25 (48%) gynaecological surgeries, did not prevent from postoperative bleeding in three cases, but two developed severe adverse reactions. CONCLUSION: Women with FXI deficiency, especially those with a positive history of bleeding or FXI:C ≤43.5%, are at risk of developing gynaecological/obstetrical haemorrhages, most of them mild/moderate. Systematic prophylaxis has questionable effectiveness, but might cause severe side effects.

Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control - a randomized controlled trial.

STUDY QUESTION: Does pre-treatment with a low dose of mifepristone improve irregular vaginal bleeding patterns during the initial 3 months after LNG-IUS placement? SUMMARY ANSWER: Mifepristone treatment prior to LNG-IUS insertion results in significantly lower bleeding and spotting rates but no significant reduction post insertion. WHAT IS KNOWN ALREADY: One of the leading causes of premature discontinuation of the LNG-IUS is unscheduled bleeding in the first months following its insertion. Up to now, there has been no effective treatment to prevent this side effect which reduces continuation rates for one of the most effective contraceptives. STUDY DESIGN, SIZE, DURATION: This randomized, double blinded, controlled trial was conducted between 2009 and 2015. In total, 68 women opting for a LNG-IUS were screened for eligibility, of whom 58 were randomized at a ratio of 1:1 in blocks of 10 to pre-treatment with mifepristone or a comparator. The main outcome was the rate of bleeding and spotting days reported during the first 3 months post LNG-IUS 52 mg placement. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthy women with regular and normal menstrual cycles aged 18-43 years were enrolled at a single center in a university hospital; 29 were allocated to 2 months pre-treatment with a low dose mifepristone and 29 to the comparator prior to insertion of the LNG-IUS. Women were advised to use barrier methods during the pre-treatment period. Bleeding diaries were collected for the pre-treatment period and for the first 6 months after the LNG-IUS placement. MAIN RESULTS AND THE ROLE OF CHANCE: There were no differences in demographics or baseline characteristics between the study groups. Data for analysis of the main outcome were contributed by a per protocol population of 19 women per group. There was a significant lower bleeding and spotting rate in the mifepristone group (-17.8% points, P < 0.001) after 2 months of pretreatment but after the LNG-IUS insertion no significant difference could be seen. While no pregnancies occurred prior to LNG-IUS insertion in the mifepristone group, there were three unintended pregnancies in the comparator group which emphasizes the need for a reliable contraceptive potential in any pre-treatment regiment used in clinical practice. LIMITATIONS, REASONS FOR CAUTION: The use of mifepristone prior to the LNG-IUS insertion in this trial was used as prophylaxis against unscheduled bleeding after the placement of the device. Although this side effect constitutes a major concern in a clinical setting, only a subset of women are at risk. This is the first study using pre-treatment to attempt improved bleeding control. The differences were small and the effect was short lasting but the reduced rate of bleeding and spotting observed during the first month following LNG-IUS insertion, even though not statistically significant, indicates that this approach may be further explored. The fact that there were three pregnancies in the comparator group stresses the need for any pre-treatment to also protect against unplanned pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: Modified treatment protocols of mifepristone could be used prior to the LNG-IUS insertion to investigate possible further improvement of the outcome. The effect size of the current dose used might have been more prominent in women with LNG-IUS if the treatment also continued some weeks after the placement of the device. Although the low dose of mifepristone used in this trial is not available in Europe, other progesterone receptor modulators currently available could be investigated in larger clinical trials. To avoid unintended pregnancy in the pretreatment period, the dosage used should, ideally, also be effective for contraception and the pretreatment period should be kept as short as possible. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Swedish Research Council (2012-2844, 2017-00932), Stockholm County Council and Karolinska Institutet (ALF). Conflicts of interests for K.G.D. and H.K.K. are listed at the end of the paper. The other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: EudraCT number 2009-009014-40. Regional ethical review board at Karolinska Institutet permit 2009/144-31/4. TRIAL REGISTRATION DATE: 20 July 2009. DATE OF FIRST PATIENT'S ENROLMENT: 24 November 2009.

Norethindrone acetate versus extended-cycle oral contraceptive (Seasonique®) in the treatment of endometriosis symptoms: A prospective open-label comparative study.

INTRODUCTION: This patient preference prospective study was designed to compare patients' satisfaction in women with endometriosis treated either by an extended-cycle oral contraception (OC) or by norethindrone acetate (NETA). METHODS: This patient preference prospective study included women of reproductive age with endometriosis. Patients were submitted to one of the following 12 months' treatments: Group A, continuous oral treatment with NETA (2.5 mg/day) and Group B, a 91-day extended-cycle OC (LNG/EE 150/30 mcg for 84 days and EE 10 mcg for 7 days). Patient satisfaction was the primary endpoint. RESULTS: There was no statistically significant difference in the rate of satisfied patients at 12-month follow up between the two study groups, 82.2% and 68.4% in Group A and Group B respectively (p = 0.143). At 6 and 12-months, there was a significant amelioration in the intensity of all pain in both groups. The median number of days of unscheduled bleeding during the first cycle was significantly higher in Group B compared to Group A. CONCLUSION: Both NETA and extended-cycle OC are effective in treating pain symptoms related to endometriosis. Extended-cycle OC may cause more unscheduled bleeding, but the rate of satisfaction for those who completed the treatment was similar in the two groups.

Unscheduled vaginal bleeding with progestin-only contraceptive use.

Nearly 20% of women using contraception are using progestin-only contraception, including progestin-only pills, depot-medroxyprogesterone acetate, subdermal etonogestrel implants, and levonorgestrel intrauterine devices. This number will continue to grow with the increased provision of long-acting reversible contraception. Although overall satisfaction among women using progestin-only contraception is high, dissatisfaction and discontinuation may be associated with unscheduled bleeding and spotting. The exact etiology of irregular bleeding associated with progestin-containing contraceptives is not completely understood, yet several mechanisms have been suggested. Several therapies targeting these mechanisms have been evaluated with mixed results. This paper will review the physiology and management of unscheduled bleeding with progestin-containing contraceptives.

The HysNiche trial: hysteroscopic resection of uterine caesarean scar defect (niche) in patients with abnormal bleeding, a randomised controlled trial.

BACKGROUND: A caesarean section (CS) can cause a defect or disruption of the myometrium at the site of the uterine scar, called a niche. In recent years, an association between a niche and postmenstrual spotting after a CS has been demonstrated. Hysteroscopic resection of these niches is thought to reduce spotting and menstrual pain. However, there are no randomised trials assessing the effectiveness of a hysteroscopic niche resection. METHODS/DESIGN: We planned a multicentre randomised trial comparing hysteroscopic niche resection to no intervention. We study women with postmenstrual spotting after a CS and a niche with a residual myometrium of at least 3 mm during sonohysterography. After informed consent is obtained, eligible women will be randomly allocated to hysteroscopic resection of the niche or expectant management for 6 months. The primary outcome is the number of days with postmenstrual spotting during one menstrual cycle 6 months after randomisation. Secondary outcomes are menstrual characteristics, menstruation related pain and experienced discomfort due to spotting or menstrual pain, quality of life, patient satisfaction, sexual function, urological symptoms, medical consultations, medication use, complications, lost productivity and medical costs. Measurements will be performed at baseline and at 3 and 6 months after randomisation. A cost-effectiveness analysis will be performed from a societal perspective at 6 months after randomisation. DISCUSSION: This trial will provide insight in the (cost)effectiveness of hysteroscopic resection of a niche versus expectant management in women who have postmenstrual spotting and a niche with sufficient residual myometrium to perform a hysteroscopic niche resection. TRIAL REGISTRATION: Dutch Trial Register NTR3269 . Registered 1 February 2012. ZonMw Grant number 80-82305-97-12030.

Serum estradiol level during withdrawal bleeding as a predictive factor for intermittent ovarian function in women with primary ovarian insufficiency.

The objective of this study was to assess the potential predictive factors for follicle growth, ovulation, and pregnancy rate in patients with primary ovarian insufficiency/premature ovarian failure (POI/POF). We enrolled 25 POI patients with desired fertility who were treated and monitored for a minimum of 7 months between the years of 2000-2009 into this retrospective study. The clinical, endocrinologic, chromosomal, and autoimmunologic parameters of these patients were collected. Furthermore, hormonal backgrounds on each of 620 treatment cycles were investigated. The main outcome measures were follicle growth, ovulation, and pregnancy rate. Four of 25 patients (16%) conceived while being monitored and undergoing treatment. Follicle growth, ovulation, and pregnancy rate were not significantly different as a function of parity, iatrogenic history (e.g., chemotherapy), age of disease onset, serum estradiol (E(2))/follicle stimulating hormone (FSH) level at the time of diagnosis, chromosomal abnormality, and positive autoantibody titer. The serum E2 levels on days 1-5 of withdrawal bleeding (Day 1-5 E(2)) were significantly higher in the cycles with successful follicle growth and ovulation than unsuccessful cycles (P<0.05). Receiver-operator characteristic curve analysis revealed the cut-off value of the Day 1-5 E(2) to be 15.5 pg/mL, and an area under the curve (AUC) value of 0.674 for follicle growth and 0.752 for ovulation. The results suggest that cycles with a Day 1-5 E(2)≥15.5 pg/mL have a higher rate of follicle growth and ovulation in patients with POI.

Randomized comparison of bleeding patterns in women using a combined contraceptive vaginal ring or a low-dose combined oral contraceptive on a menstrually signaled regimen.

OBJECTIVES: To compare bleeding patterns for 12 months continuous use of a contraceptive ring [contraceptive vaginal ring (CVR)] and pill [combined oral contraceptive (COC)] on a menstrually signaled regimen and the effectiveness of 4 days "treatment withdrawal" to stop bleeding. STUDY DESIGN: Women, 66 to each group, were randomized to continuous use of a CVR (15 mcg ethinyl estradiol/150 mcg etonogestrel) or a low-dose pill (20 mcg ethinyl estradiol/100 mcg levonorgestrel) for 360 days on a menstrually signaled regimen. Bleeding/spotting days, daily use of ring or pill, was recorded. Endpoint was the total number of bleeding/spotting days for each method over four 90-day reference periods (RP) plus the analysis of bleeding patterns using modified World Health Organization criteria. RESULTS: There was a reduction in the mean (±S.D.) number of bleeding/spotting days from RP1 (CVR 14.2±10; pill 16.6±10.9) to RP4 (CVR 8.8±9.6; pill 8.8±9.1). Fifteen percent of CVR and 4% COC users experienced amenorrhea or infrequent bleeding throughout the study. Amenorrhea increased over time (RP1 vs. RP4: CVR 10% vs. 21% and COC 2% vs. 30%). Compliance with the menstrually signaled regimen was poor. Ceasing hormones for 4 days stopped a bleeding episode within 5 days in the majority of episodes and many stopped spontaneously. CONCLUSION: Bleeding patterns with continuous use of the CVR and COC are similar and improve over 1 year of use. The unpredictability, but short duration, of bleeding episodes should be stressed during counseling. IMPLICATION: This information for clinicians and women about breakthrough bleeding patterns with use of a CVR or combined pill over 12 months using a menstrually signaled regimen will give women an indication of what to expect with continuous use.

Evaluation of ovarian function and metabolic factors in women affected by polycystic ovary syndrome after treatment with D-Chiro-Inositol.

PURPOSE: To evaluate the effects of D-Chiro-Inositol in women affected by polycystic ovary syndrome (PCOS). METHODS: We enrolled 48 patients, with homogeneous bio-physical characteristics, affected by PCOS and menstrual irregularities. These patients underwent treatment with 1 gr of D-Chiro-Inositol/die plus 400 mcg of Folic Acid/die orally for 6 months. We analyzed pre-treatment and post-treatment BMI, Systolic and Diastolic blood pressure, Ferriman-Gallwey score, Cremoncini score, serum LH, LH/FSH ratio, total and free testosterone, DHEA-S, Δ-4-androstenedione, SHBG, prolactin, glucose/IRI ratio, HOMA index, and resumption of regular menstrual cycles. RESULTS: We evidenced a statistically significant reduction of systolic blood pressure, Ferriman-Gallwey score, LH, LH/FSH ratio, total Testosterone, free Testosterone, ∆-4-Androstenedione, Prolactin, and HOMA Index; in the same patients, we noticed a statistically significant increase of SHBG and Glycemia/IRI ratio. Moreover, we observed statistically significant (62.5%; p < 0.05) post-treatment menstrual cycle regularization. CONCLUSIONS: D-Chiro-Inositol is effective in improving ovarian function and metabolism of patients affected by PCOS.

Comparison between effects of myo-inositol and D-chiro-inositol on ovarian function and metabolic factors in women with PCOS.

Myo-inositol and D-chiro-inositol are capable of improving the ovarian function and metabolism of polycystic ovary syndrome (PCOS) patients. The aim of this work is to compare the effects of myo-inositol and D-chiro-inositol in PCOS. We enrolled 50 patients, with homogeneous bio-physical features, affected by PCOS and menstrual irregularities, and we randomly divided them into two groups: 25 were treated with 4 g of myo-inositol/die plus 400 mcg of folic acid/die orally for six months, 25 with 1 g of D-chiro-inositol/die plus 400 mcg of folic acid/die orally for six months. We analyzed in both groups pre-treatment and post-treatment BMI, systolic and diastolic blood pressure, Ferriman-Gallwey score, Cremoncini score, serum LH, LH/FSH ratio, total and free testosterone, dehydroepiandrosterone sulfate (DHEA-S), Δ-4-androstenedione, SHBG, prolactin, glucose/immunoreactive insulin (IRI) ratio, homeostatic model assessment (HOMA) index, and the resumption of regular menstrual cycles. Both the isoforms of inositol were effective in improving ovarian function and metabolism in patients with PCOS, although myo-inositol showed the most marked effect on the metabolic profile, whereas D-chiro-inositol reduced hyperandrogenism better.

Hysteroscopic management of displaced levonorgestrel-releasing intrauterine system.

AIM: This study was designed to evaluate feasibility and effectiveness of hysteroscopic intervention in the management of symptoms related to the displaced levonorgestrel-releasing intrauterine system (LNG-IUS). MATERIAL AND METHODS: One hundred and thirteen patients with displaced LNG-IUS presenting with irregular uterine bleeding, pelvic pain or asymptomatic displacement were recruited for hysteroscopic examination. Displaced LNG-IUS was relocated by hysteroscopic intervention and the effect on symptoms and LNG-IUS position was followed. RESULTS: The displaced LNG-IUS was successfully relocated by hysteroscope in 112 (99.1%) of 113 cases. Following LNG-IUS relocation, 71 (79.8%) patients of 89 with preoperative irregular uterine bleeding had amenorrhea or vaginal spotting, and 14 of 15 (93.3%) patients with preoperative pelvic pain became asymptomatic. LNG-IUS expulsion was recorded in two patients 7 and 21 days after hysteroscopy. CONCLUSION: Displaced LNG-IUS can cause clinical symptoms (e.g. irregular bleeding, pain). Hysteroscopic relocation of displaced LNG-IUS is a feasible method in the management of these symptoms. Risk of spontaneous expulsion associated with hysteroscopy is low.

Treatment of unscheduled bleeding in women using extended- or continuous-use combined hormonal contraception: a systematic review.

BACKGROUND: Unscheduled uterine bleeding is common among women who choose extended or continuous combined hormonal contraception and may subsequently lead to method discontinuation. This systematic review evaluates the evidence on treatments for unscheduled bleeding for women using continuous or extended combined hormonal contraception. STUDY DESIGN: We searched the PubMed database for peer-reviewed articles that were published in any language from inception of the database through January 2012 and were relevant to therapeutic or prophylactic treatments for unscheduled uterine bleeding during extended or continuous combined hormonal contraception use. We used standard abstract forms and grading systems to summarize and assess the quality of the evidence. RESULTS: Four articles met the inclusion criteria. Evidence from two randomized controlled trials, both of fair quality, suggested that a short hormone-free interval of 3 or 4 days improved a current unscheduled bleeding episode. Evidence from one randomized controlled trial of fair quality suggested that oral doxycycline (100 mg twice daily) did not improve a current unscheduled bleeding episode. One good quality randomized controlled trial suggested that prophylactic treatment with a daily low dose of oral doxycycline (40 mg) caused earlier onset of amenorrhea in new extended combined oral contraceptive users. CONCLUSIONS: Limited evidence suggests that introducing a short hormone-free interval when unscheduled bleeding occurs during continuous or extended hormonal contraceptive use may reduce unscheduled bleeding days; one study suggests that twice-daily oral doxycycline initiated at the time of unscheduled bleeding is an ineffective treatment. Limited data suggest that prophylactic low-dose daily oral doxycycline may induce earlier amenorrhea among new extended combined hormonal contraceptive users.

Treatment of bleeding irregularities in women with copper-containing IUDs: a systematic review.

BACKGROUND: Bleeding irregularities, such as intermenstrual spotting or heavy or prolonged menstrual bleeding, are common among copper-containing intrauterine device (Cu-IUD) users and are one of the leading reasons for method discontinuation. This review evaluates the evidence for effective therapeutic and preventive treatments for bleeding irregularities during Cu-IUD use. STUDY DESIGN: We searched the PubMed database for peer-reviewed articles that were published in any language from inception of the database through March 2012 and were relevant to treatments for irregular bleeding during Cu-IUD use. We used standard abstract forms and grading systems to summarize and assess the quality of the evidence. RESULTS: From 1470 articles, we identified 17 articles that met our inclusion criteria. Evidence from two studies of poor quality demonstrated that antifibrinolytic agents or nonsteroidal anti-inflammatory drugs (NSAIDs) have been used for intermenstrual bleeding or spotting among a small number of Cu-IUD users with mixed results. Evidence from 10 studies of fair to poor quality suggested that some NSAIDs may significantly reduce menstrual blood loss or bleeding duration among Cu-IUD users with heavy or prolonged menstrual bleeding. Antifibrinolytic drugs or antidiuretics may also help reduce blood loss. High-dose aspirin was shown to increase blood loss among those with baseline menorrhagia. Evidence from five studies of fair to poor quality suggested that bleeding irregularities among new Cu-IUD users may be prevented with NSAIDs, although one large study of good quality suggested that prophylactic treatment with ibuprofen does not affect continuation of Cu-IUD use. Evidence from two studies of fair to poor quality suggested that antifibrinolytic agents might be helpful in preventing heavy or prolonged menstrual bleeding among new Cu-IUD users. CONCLUSIONS: Limited evidence suggests that NSAIDs may be effective treatments for bleeding irregularities associated with Cu-IUD use; antifibrinolytic agents and antidiuretics have also been studied as possible treatments in a small number of subjects, but their safety has not been well documented. NSAIDs and antifibrinolytics may also prevent bleeding irregularities among new CU-IUD users. Preventive NSAID use, however, does not impact Cu-IUD continuation.

A randomized controlled trial of subantimicrobial-dose doxycycline to prevent unscheduled bleeding with continuous oral contraceptive pill use.

BACKGROUND: Unscheduled bleeding is the main side effect of continuous oral contraceptive pills (OCPs) and has been correlated with the up-regulation of matrix metalloprotineases (MMPs). The study objective was to determine if prophylactic administration of doxycycline (an MMP inhibitor at low subantimicrobial doses) would prevent unscheduled bleeding during the initiation of a continuous OCP. STUDY DESIGN: Subjects using cyclic hormonal contraceptives (combined OCPs, patch or ring) without unscheduled bleeding were switched to continuous OCPs (20 mcg ethinyl estradiol/100 mcg levonorgestrel). They were randomized to receive daily doxycycline [sustained-release subantimicrobial dose (40 mg daily)] or placebo for the first 84 days and then observed for an additional 28 days on the continuous OCP alone. The number of bleeding/spotting days and the time in days it took to achieve amenorrhea were compared using a t test. RESULTS: Sixty-five subjects were randomized. Although the use of doxycycline did not significantly decrease the number of mean bleeding/spotting days in the first 84 days of the study [doxycycline 14.75 (SE 2.30), placebo 17.78 (2.31), p=.36], women who received doxycycline had a significantly earlier onset of amenorrhea [mean last day of bleeding/spotting doxycycline 61.7 (7.7), placebo 85.2 (6.7), p=.03]. CONCLUSION: The coadministration of subantimicrobial-dose doxycycline during initiation of continuous OCPs results in a significant reduction in the length of time needed to achieve amenorrhea.

Randomized placebo-controlled trial of CDB-2914 in new users of a levonorgestrel-releasing intrauterine system shows only short-lived amelioration of unscheduled bleeding.

BACKGROUND: The levonorgestrel-releasing intrauterine system (LNG-IUS) is a highly effective contraceptive. However, during early months of use unscheduled vaginal bleeding is common, sometimes leading to discontinuation. This study aimed to determine whether intermittent administration of progesterone receptor modulator CDB-2914 would suppress unscheduled bleeding during the first 4 months after insertion of the LNG-IUS. METHODS: CDB-2914 150 mg, in divided doses, or placebo tablets, were administered over three consecutive days starting on Days 21, 49 and 77 after LNG-IUS insertion, in a double-blind randomized controlled trial of women aged 19-49 years, newly starting use of LNG-IUS. Daily bleeding diaries were completed for 6 months, and summarized across blocks as percentage days bleeding/spotting (BS%). RESULTS: Of 69 women randomized to receive CDB-2914, and 67 placebo, 61 and 55, respectively, completed the trial. BS% decreased with time in both arms, but showed a much steeper treatment-phase gradient in the placebo arm (P < 0.0001), so that a benefit of CDB-2914 in the 28 days after first treatment (-11% points, 95% CI -19 to -2), converted to a disadvantage by 64 days after the third treatment (+10% points, 95% CI 1-18). CONCLUSIONS: The effect of CDB-2914 on BS% was initially beneficial but then by third treatment was disadvantageous. Nevertheless, only 3% (4/136) of all women discontinued LNG-IUS. These findings give insight into possible mechanisms and suggest future research directions. ISRCTN Trial no. ISRCTN58283041; EudraCT no. 2006-006511-72.

Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol for contraception and control of menstrual symptoms.

Considerable recent interest has focused on new methods of delivery of oral contraceptives that reduce or eliminate the hormone-free interval in order to improve convenience and acceptability, but maintain contraceptive efficacy, minimize side effects and reduce or eliminate the frequency of withdrawal bleeding episodes. Studies in several countries, including the US, have documented that many women would prefer to have no episodes of withdrawal bleeding when using oral contraceptives. This review focuses on a unique oral contraceptive formulation containing levonogestrel 90 microg and ethinyl estradiol 20 microg, approved for use in a continuous dosing regimen designed to eliminate withdrawal bleeding throughout the entire year.