Stewart, Elizabeth A.

AbstractThere is no approved medical therapy for adenomyosis and limited evidence to guide treatments in part due to the complexity of nonhistologic diagnosis and the prevalence of concomitant gynecologic conditions. Most available evidence focuses on the treatment of heavy menstrual bleeding, painful menses, and pelvic pain. Data evaluating fertility outcomes, sexual function, and quality of life following treatment are lacking. Additionally, there is no disease-specific measure of quality of life for adenomyosis. The levonorgestrel-releasing intrauterine system appears to be the most effective first-line therapy based on efficacy compared with oral agents, maintenance of steady-state hormonal levels, and contraceptive benefit. In areas where it is marketed, the progestin dienogest appears superior to combined oral contraceptives. Long-acting gonadotropin-releasing hormone agonists are effective and should be considered second-line therapy but are limited by hypogonadal effects. Additional data regarding oral gonadotropin-releasing hormone antagonists are required. While aromatase inhibitors demonstrate improvement in heavy menstrual bleeding and pelvic pain, further research is needed to determine their role in the management of adenomyosis. Progesterone receptor modulators may have a role for this disease if released again to market with appropriate safety parameters. Finally, modulation of prolactin and/or oxytocin may provide novel nonsteroidal treatment options.

Abstract Antimullerian hormone (AMH) is a promising biomarker for ovarian reserve. In this study, we assessed AMH before and 1 year after initiation of adjuvant chemotherapy on National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology B-47 in female participants aged 42 years and younger (median age = 39 years). At baseline, median AMH was 1.2 ng/mL; 13 (4.7%) values were less than 0.1 ng/mL (the threshold for detectable levels, in the perimenopause and menopause range), and 57 values (20.6%) were less than 0.5 ng/mL. At 1 year, 215 (77.6%) were less than 0.1 ng/mL, and 264 (95.3%) were less than 0.5 ng/mL. Postchemotherapy menses were reported by 46.2% of participants. Multivariable logistic regression found that the odds of having postchemotherapy menses increased with younger age, higher body mass index, and higher prechemotherapy AMH, but not by trastuzumab administration or by the choice of chemotherapy (doxorubicin-cyclophosphamide followed by paclitaxel vs docetaxel-cyclophosphamide). We conclude that higher prechemotherapy AMH predicts a lower risk of chemotherapy-induced amenorrhea and that AMH 1 year after chemotherapy initiation is not informative in this setting because it is likely to be very low.

INTRODUCTION: Currently, pain (menstrual and non-menstrual), is poorly studied in women with uterine fibroids (UF). Relugolix combination therapy (Relugolix-CT; once-daily relugolix 40 mg, estradiol 1.0 mg, and norethindrone acetate 0.5 mg) significantly improved UF-associated heavy menstrual bleeding in the two LIBERTY randomized phase 3 trials. METHODS: In the LIBERTY 1 and 2 Institutional Review Board-approved studies, a key secondary endpoint was the proportion of women with no/minimal pain (maximal pain score ≤1 on the 0–10 numerical rating scale [NRS] during the last 35 days of treatment) in the pain-evaluable population (women with maximum pain NRS ≥4 during the 35 days prior to randomization). Pain was also evaluated on menstrual bleeding and on non-menstrual days during the last 35 days of treatment. Treatment comparisons were performed in both studies and the pooled dataset using the Cochran–Mantel–Haenszel test stratified by baseline menstrual blood loss volume. RESULTS: After 24 weeks of treatment, a significantly greater proportion of pain-evaluable patients in the Relugolix-CT groups (43.1% and 47.1% in LIBERTY 1 and 2, respectively) had no/minimum UF-associated pain during the last 35 days of treatment compared with placebo (10.1% and 17.1%, respectively; P<.0001). The proportions of women with no/minimum dysmenorrhea and non-menstrual pain were significantly higher with Relugolix-CT (pooled data: 65.0% and 44.6%, respectively) vs placebo (19.3% and 21.6%, respectively). CONCLUSION: Over 24 weeks, once-daily Relugolix-CT reduced UF-associated pain, with a more pronounced effect on menstrual vs non-menstrual pain. Thus, Relugolix-CT improved two common symptoms (menstrual bleeding and pain) associated with UF.

Abstract Objective: We studied eight mental health conditions diagnosed before bilateral oophorectomy performed for nonmalignant indications. Methods: We identified 1,653 premenopausal women who underwent bilateral oophorectomy for a nonmalignant indication in Olmsted County, Minnesota, during a 20-year period (1988-2007). Each woman was matched by age (±1 year) to one population-based control who had not undergone bilateral oophorectomy before the index date (age range: 21-49 years). Both cases and controls were identified using the records-linkage system of the Rochester Epidemiology Project (REP http://www.rochesterproject.org). For eight mental health conditions, we calculated odds ratios (ORs) and their 95% confidence intervals (95% CIs) adjusted for race, education, and income using conditional logistic regression. Results: Pre-existing mood disorders, anxiety disorders, and somatoform disorders were associated with increased risk of bilateral oophorectomy in overall analyses. These associations were also significant in women ≤45 years of age at index date. Personality disorders were associated with increased risk only in overall analyses and adjustment disorders only in women 46 to 49 years of age. Some of the associations were significantly different across strata by age at index date and by indication. There was also a linear trend of increasing adjusted ORs from 1.55 (95% CI 1.31-1.83) for one mental health condition to 2.19 (95% CI 1.40-3.41) for three or more conditions (trend P < 0.001). Conclusions: We identified several mental health conditions that were associated with bilateral oophorectomy for nonmalignant indications. Awareness of these associations may guide women and physicians in future decision-making and limit unindicated bilateral oophorectomies. Video Summary: http://links.lww.com/MENO/A458.

Abstract Objective: The aim of this research was to study the long-term risk of de novo mental health conditions in women who underwent hysterectomy with bilateral ovarian conservation compared with age-matched referent women. Methods: Using the Rochester Epidemiology Project records-linkage system, we identified a historical cohort of 2,094 women who underwent hysterectomy with ovarian conservation for benign indications at age ≥18 years and with an index date between 1980 and 2002 in Olmsted County, Minnesota. Each woman was age-matched (±1 y) to a referent woman residing in the same county who had not undergone hysterectomy or any oophorectomy before the index date. These two cohorts were followed historically to identify de novo mental health conditions. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) using Cox proportional hazards models adjusted for 20 preexisting chronic conditions and other potential confounders. We also calculated absolute risk increases (ARIs) and reductions (ARRs) at 30 years of follow-up. Results: Over a median follow-up of 21.9 years, women who underwent hysterectomy at any age experienced increased risks of de novo depression (adjusted HR 1.26; 95% CI, 1.12-1.41; ARI 6.6%) and anxiety (adjusted HR 1.22; 95% CI, 1.08-1.38; ARI 4.7%). The association for depression increased significantly with younger age at hysterectomy, but did not vary significantly by indication. Interactions were not significant for anxiety. Conclusions: Hysterectomy, even with ovarian conservation, is associated with an increased long-term risk of de novo depression and anxiety, especially when performed in women who are younger. Video Summary: http://links.lww.com/MENO/A465.

Abstract STUDY QUESTION What is the safety and efficacy profile during long-term (12–24 months) uninterrupted treatment with the selective progesterone receptor modulator asoprisnil, 10 and 25 mg in women with heavy menstrual bleeding (HMB) associated with uterine fibroids? SUMMARY ANSWER Uninterrupted treatment with asoprisnil should be avoided due to endometrial safety concerns and unknown potential long-term consequences. WHAT IS KNOWN ALREADY Asoprisnil was well tolerated in shorter-term studies and effectively suppressed HMB and reduced fibroid volume. STUDY DESIGN, SIZE, DURATION Women with uterine fibroids who had previously received placebo (n = 87) or asoprisnil 10 mg (n = 221) or 25 mg (n = 215) for 12 months in two double-blind studies entered this randomized uncontrolled extension study and received up to 12 additional months of treatment followed by 6 months of post-treatment follow-up. Women who previously received placebo were re-randomized to either asoprisnil 10 or 25 mg for the extension study. This report focuses on the 436 women who received asoprisnil in the double-blind studies and this extension study. Results for women who previously received placebo in the double-blind studies are not described. PARTICIPANTS/MATERIALS, SETTING, METHODS Women ≥18 years of age who completed a 12-month, double-blind, placebo-controlled study, had estradiol levels indicating that they were not menopausal and had no endometrial hyperplasia or other significant endometrial pathology were eligible. The safety endpoints were focused on endometrial assessments. The composite primary efficacy endpoint was the proportion of women who demonstrated a response to treatment by meeting all three of the following criteria at the final month for participants who prematurely discontinued or at month 12 for those who completed the study: a reduction from initial baseline to final visit of ≥50% in the menstrual pictogram score, hemoglobin concentration ≥11 g/dl or an increase of ≥1 g/dl from initial baseline at the final visit, and no surgical or invasive intervention for uterine fibroids. Other efficacy endpoints included rates for amenorrhea and suppression of bleeding, changes in fibroid and uterine volume and changes in hematologic parameters. No statistical tests were planned or performed for this uncontrolled study. MAIN RESULTS AND ROLE OF CHANCE Imaging studies revealed a progressive increase in endometrial thickness and cystic changes that frequently prompted invasive diagnostic procedures. Endometrial biopsy results were consistent with antiproliferative effects of asoprisnil. Two cases of endometrial cancer were diagnosed. At the final month of this extension study (total duration of uninterrupted treatment up to 24 months), the primary efficacy endpoint was achieved in 86 and 92% of women in the asoprisnil 10- and 25-mg groups, respectively. During each month of treatment, amenorrhea was observed in the majority of women (up to 77 and 94% at 10 and 25 mg, respectively). There was a progressive, dose-dependent decrease in the volume of the primary fibroid with asoprisnil 10 and 25 mg (−55.7 and −75.2% median decrease, respectively, from baseline [i.e. the beginning of the placebo-controlled study] to month 12 [cumulative months 12–24] of this extension study). These effects were associated with improvements in quality of life measures. LIMITATIONS, REASONS FOR CAUTION This study was uncontrolled, which limits the interpretation of safety and efficacy findings. The study also had multiple protocol amendments with the addition of diagnostic procedures and, because no active comparator was included, the potential place of asoprisnil in comparison to therapies such as GnRH agonists and surgery cannot be determined. WIDER IMPLICATIONS OF THE FINDINGS Long-term, uninterrupted treatment with asoprisnil leads to prominent cystic endometrial changes that are consistent with the ‘late progesterone receptor modulator’ effects, which prompted invasive diagnostic procedures, although treatment efficacy is maintained. Although endometrial cancers were uncommon during both treatment and follow-up, these findings raise concerns regarding endometrial safety during uninterrupted long-term treatment with asoprisnil. This study shows that uninterrupted treatment with asoprisnil should be avoided due to safety concerns and unknown potential long-term consequences. STUDY FUNDING/COMPETING INTEREST(S) AbbVie Inc. (prior sponsor, TAP Pharmaceutical Products Inc.) sponsored the study and contributed to the design and conduct of the study, data management, data analysis, interpretation of the data and the preparation and approval of the manuscript. Financial support for medical writing and editorial assistance was provided by AbbVie Inc. M. P. Diamond received research funding for the conduct of the study paid to the institution and is a consultant to AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution for Bayer and ObsEva. E. A. Stewart participated as a site investigator in the phase 2 study of asoprisnil and served as a consultant to TAP Pharmaceuticals during the time of design and conduct of the studies while on the faculty of Harvard Medical School and Brigham and Women’s Hospital, Boston, MA. In the last 3 years, she has received support from National Institutes of Health grants HD063312, HS023418 and HD074711. She has served as a consultant for AbbVie Inc., Allergan, Bayer HealthCare AG and Myovant for consulting related to uterine leiomyoma and to Welltwigs for consulting related to infertility. She has received royalties from UpToDate and the Med Learning Group. A.R.W. Williams has acted as a consultant for TAP Pharmaceutical Products Inc. and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr has served as consultant and received research funding from AbbVie Inc. and Synteract (Medicines360). E.R. Myers has served as consultant for AbbVie Inc., Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was a co-inventor of several patents related to asoprisnil. C. Mattia-Goldberg is a former employee of AbbVie Inc. and owns AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie Inc. and own AbbVie stock or stock options. TRIAL REGISTRATION NUMBER NCT00156195 at clinicaltrials.gov.