Levonorgestrel-Releasing Intrauterine System Improves Menorrhagia-Related Quality of Life in Patients with Symptomatic Adenomyosis.

Levonorgestrel-releasing intrauterine system (LNG-IUS) relieves dysmenorrhea and heavy menstrual bleeding (HMB) in adenomyosis. However, its efficacy on health-related quality of life (HR-QOL) in patients with symptomatic adenomyosis remains unclear. The menorrhagia multi-attribute scale (MMAS), which measures HR-QOL improvement through the treatment of HMB, has never been used for evaluating menorrhagia-specific HR-QOL in patients with symptomatic adenomyosis. Hence, this study aimed to investigate the efficacy of LNG-IUS in improving menorrhagia-specific HR-QOL in these patients using the MMAS. The participants were diagnosed by magnetic resonance imaging. We also assessed the relationships between menorrhagia-specific HR-QOL, blood hemoglobin levels, and the degree of dysmenorrhea before and during LNG-IUS treatment. The LNG-IUS treatment improved the menorrhagia-specific HR-QOL more effectively in incipient type adenomyosis than in advanced type adenomyosis. The efficacy of LNG-IUS treatment on dysmenorrhea evaluated by the visual analog scale score tended to be better in the incipient type than in the advanced type. By the treatment of LNG-IUS, the blood hemoglobin level was not improved in the advanced type but in the incipient type. Furthermore, dysmenorrhea and HMB-related anemia were associated with HR-QOL impairment, and LNG-IUS treatment may improve the HR-QOL by relieving the symptoms. In conclusion, the effectiveness of LNG-IUS on HR-QOL is decreased by advanced adenomyosis. Thus, magnetic resonance imaging use should be reinforced to predict LNG-IUS efficacy in improving the HR-QOL of patients with adenomyosis.

Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.

Uterine Fibroids, or leiomyomata, affect millions of women world-wide, with a high incidence of 75% within women of reproductive age. In ~30% of patients, uterine fibroids cause menorrhagia, or heavy menstrual bleeding, and more than half of the patients experience symptoms such as heavy menstrual bleeding, pelvic pain, or infertility. Treatment is symptomatic with limited options including hysterectomy as the most radical solution. The genetic foundations of uterine fibroid growth have been traced to somatic driver mutations (MED12, HMGA2, FH -/-, and COL4A5-A6). These also lead to downstream expression of angiogenic factors including IGF-1 and IGF-2, as opposed to the VEGF-driven mechanism found in the angiogenesis of hypoxic tumors. The resulting vasculature supplying the fibroid with nutrients and oxygen is highly irregular. Of particular interest is the formation of a pseudocapsule around intramural fibroids, a unique structure within tumor angiogenesis. These aberrations in vascular architecture and network could explain the heavy menstrual bleeding observed. However, other theories have been proposed such as venous trunks, or venous lakes caused by the blocking of normal blood flow by uterine fibroids, or the increased local action of vasoactive growth factors. Here, we review and discuss the evidence for the various hypotheses proposed.

Low dose dexamethasone as treatment for women with heavy menstrual bleeding: A response-adaptive randomised placebo-controlled dose-finding parallel group trial (DexFEM).

BACKGROUND: The symptom of heavy menstrual bleeding (HMB) diminishes quality-of-life for many mid-age women and imposes substantial societal burden. We investigated our hypothesis that HMB reflects impaired endometrial vasoconstriction due to endometrial glucocorticoid deficiency. Does reversing this deficiency, by short-term luteal-phase treatment with exogenous glucocorticoid (dexamethasone), ameliorate HMB? METHODS: In our Bayesian response-adaptive parallel-group placebo-controlled randomised trial, five pre-planned interim analyses used primary outcome data to adjust randomisation probabilities to favour doses providing most dose-response information. Participants with HMB, recruited from Lothian (Scotland) NHS clinics and via community invitations/advertisements, were aged over 18 years; reported regular 21-42 day menstrual cycles; and had measured menstrual blood loss (MBL) averaging ≥ 50 mL over two screening periods. Identically encapsulated placebo, or one of six Dexamethasone doses (0·2 mg, 0·4 mg, 0·5 mg, 0·6 mg, 0·75 mg, 0·9 mg), were taken orally twice-daily over five days in the mid-luteal phase of three menstrual cycles. Participants, investigators, and those measuring outcomes were masked to group assignment. Primary outcome, change in average MBL from screening to 'treatment', was analysed by allocated treatment, for all with data. TRIAL REGISTRATION: ClinicalTrials.gov NCT01769820; EudractCT 2012-003,405-98 FINDINGS: Recruitment lasted 29/01/2014 to 25/09/2017; 176 were screened, 107 randomised and 97 provided primary outcome data (n = 24,5,9,21,8,14,16 in the seven arms, placebo to 1·8 mg total daily active dose). In Bayesian normal dynamic linear modelling, 1·8 mg dexamethasone daily showed a 25 mL greater reduction in MBL from screening, than placebo (95% credible interval 1 to 49 mL), and probability 0·98 of benefit over placebo. Adverse events were reported by 75% (58/77) receiving dexamethasone, 58% (15/26) taking placebo. Three serious adverse events occurred, two during screening, one in a placebo participant. No woman withdrew due to adverse effects. INTERPRETATION: Our adaptive trial in HMB showed that dexamethasone 1·8 mg daily reduced menstrual blood loss. The role of dexamethasone in HMB management deserves further investigation. FUNDING: UK MRC DCS/DPFS grant MR/J003611/1.

Comparison of two levonorgestrel-releasing intrauterine systems for the treatment of heavy menstrual bleeding: a randomised, controlled, phase 3 trial.

PURPOSE: To evaluate the levonorgestrel-releasing intrauterine system Donasert® (also known as Levosert®) compared with the reference product Mirena® for the alleviation of heavy menstrual bleeding (HMB). MATERIALS AND METHODS: A phase 3 multicentre, non-inferiority, active-controlled study in non-menopausal women with HMB (menstrual blood loss [MBL] ≥ 80 mL) as the primary symptom randomised to either Donasert® or Mirena® and followed for 6 months. MBL was evaluated using a validated, modified version of the Wyatt pictogram. RESULTS: Overall, 312 were randomised (158 to Donasert® and 154 to Mirena®). The mean (standard deviation) absolute change in MBL from baseline to 6 months in the per-protocol population (N = 300) was -130 (71.8) mL and -127 (67.3) mL in the Donasert® and Mirena® groups, respectively; non-inferiority of Donasert® was confirmed (p-value <0.0001). Successful treatment of HMB (MBL <80 mL) and a decrease to ≤50% of baseline MBL was achieved in 139/154 (90.3%) and 126/146 (86.3%) participants in the Donasert® and Mirena® groups, respectively and the between-treatment difference was non-significant. Most adverse events were mild in severity. Only two device expulsions occurred in the study and there were no uterine perforations. CONCLUSIONS: Donasert® has equivalent efficacy and safety during the first 6 months foralleviation of HMB compared to the reference device, Mirena®. TRIAL REGISTRATION NUMBER: 348 (Clinical Trials Registry of the Ministry of Health of the Russian Federation, http://grls.rosminzdrav.ru/default.aspx).

90 YEARS OF PROGESTERONE: Selective progesterone receptor modulators in gynaecological therapies.

Abnormal uterine bleeding (AUB) is a chronic, debilitating and common condition affecting one in four women of reproductive age. Current treatments (conservative, medical and surgical) may be unsuitable, poorly tolerated or may result in loss of fertility. Selective progesterone receptor modulators (SPRMs) influence progesterone-regulated pathways, a hormone critical to female reproductive health and disease; therefore, SPRMs hold great potential in fulfilling an unmet need in managing gynaecological disorders. SPRMs in current clinical use include RU486 (mifepristone), which is licensed for pregnancy interruption, and CDB-2914 (ulipristal acetate), licensed for managing AUB in women with leiomyomas and in a higher dose as an emergency contraceptive. In this article, we explore the clinical journey of SPRMs and the need for further interrogation of this class of drugs with the ultimate goal of improving women's quality of life.

Potentially effective therapy of heavy menstrual bleeding with an oestradiol-nomegestrol acetate oral contraceptive: a pilot study.

BACKGROUND: Heavy menstrual bleeding (HMB) exceeding 80 mL per cycle leads to considerable adverse impact on a woman's iron metabolism, incidence of iron deficiency and anaemia, as well as her functioning in society. The objective of the study is to determine the potential efficacy of a Monophasic oestradiol-17ß-nomegestrol acetate (E2/Nomac) combined oral contraceptive pill on measured menstrual blood loss as a pilot study in 12 women with objectively demonstrated HMB (>80 mL per cycle). The pilot study aimed to recruit 20 women. METHOD: Consented women completed the HMB questionnaire. The blood was taken for haemoglobin, transferrin, iron saturation, TIBC, serum iron and ferritin. Women were given verbal and written detailed instructions for MBL collection for three control cycles and four treatment cycles. RESULTS: Forty-three women were enrolled, but 31 were ineligible and withdrawn (mainly for failure to meet eligibility criteria). Twelve women entered the treatment phase and commenced the E2/nomegestrol acetate (NOMAC) 24/4 combined pill treatment on the first day of their fourth cycle. All women with complete MBL measurements had >50% reduction in MBL on treatment (exact 95% confidence interval for proportion with MBL reduction >50%: 69 to 100%). The mean percent reduction in MBL between pretreatment and during treatment was 76.9%, and the median was 79% with a range of 53.7 to 100%. CONCLUSIONS: This pilot study indicates that the E2/NOMAC COC will provide a useful potential option for treating HMB in women with FIGO classification AUB-E (primary endometrial causes) but requires a larger placebo-controlled study for confirmation.

Combined Endometrial Ablation and Levonorgestrel Intrauterine System Use in Women With Dysmenorrhea and Heavy Menstrual Bleeding: Novel Approach for Challenging Cases.

STUDY OBJECTIVE: To evaluate the feasibility and impact of levonorgestrel intrauterine system (LNG-IUS) on treatment failure after endometrial ablation (EA) in women with heavy menstrual bleeding (HMB) and dysmenorrhea at 4 years. DESIGN: Cohort study (Canadian Task Force II-2). SETTING: An academic institution in the upper Midwest. PATIENTS: All women with HMB and dysmenorrhea who underwent EA with combined placement of LNG-IUS (EA/LNG-IUS cohort, 23 women) after 2005 and an historic reference group from women who had EA alone (EA cohort, 65 women) from 1998 through the end of 2005. INTERVENTION: Radiofrequency EA, thermal balloon ablation, and LNG-IUS. MEASUREMENTS AND MAIN RESULTS: The primary outcome was treatment failure defined as persistent pain, bleeding, and hysterectomy after EA at 4 years. The combined treatment failure outcome was documented in 2 patients (8.7%) in the EA/LNG-IUS group and 19 patients (29.2%) in the EA group with an unadjusted OR of .23 (95% CI, .05-1.08). After adjusting for known risk factors of failure, the adjusted OR was .19 (95% CI, .26-.88). None of the women who underwent EA/LNG-IUS had hysterectomy for treatment failure compared with 16 (24%) in the EA group (p = .009); postablation pelvic pain was documented in 1 woman (4.3%) in the EA/LNG-IUS group compared with 8 women (12.3%) in the EA group (p = .24). One woman in the EA/LNG-IUS group (4.3%) presented with persistent bleeding compared with 15 (23.1%) in the EA group (p = .059). Office removal of the intrauterine device was performed in 4 women with no complications. CONCLUSION: LNG-IUS insertion at the time of EA is feasible and can provide added benefit after EA in women with dysmenorrhea and HMB.

Comparison of levonorgestrel-releasing intrauterine device with oral progestins in heavy menstrual bleeding (HMB) cases with uterine leiomyoma (LNG-IUD and oral progestin usage in myoma uteri).

OBJECTIVE: To compare the effectiveness and acceptability of LNG-IUD with oral progesterone (norethisterone acetate; NETA) in achieving a reduction in volume of the myomas, hemoglobin levels, satisfaction of the women. METHODS: This study includes randomized 30 women treated by LNG-IUD and randomized 30 women treated by oral norethisterone (NETA). All these participants in the study have received medical treatment and had been registered as patients in Istanbul Medeniyet University Göztepe Education and Research Hospital. Leiomyoma volumes and hemoglobin levels have been determined. In the third and sixth months, these measurements have been done again. We examined the adverse effects and the treatment continuity. For the statistical analysis of the findings NCSS [Number Cruncher Statistical System] 2007 & PASS 2008 program; student t, Mann Whitney U, Paired Samples t, Wilcoxon Signed Ranks, Ki-Kare, Fisher's Exact Ki-Kare tests have been used. RESULTS: After six months treatment, the reduction of bleeding determined by Visual Bleeding Score (VBS) in LNG-IUD group is 80% and in oral norethisteron group is 56%; in both groups leiomyoma volumes and hemoglobin levels were significantly high. CONCLUSION: LNG-IUD is a good alternative treatment to the oral progesterone in long term minimizing the hysterectomy for myoma uteri because of the good patient tolerance and easy usage.