Stewart, Elizabeth A.

AbstractIntroductionAdenomyosis is a benign uterine disease where endometrial glands and stroma are found within the myometrium surrounded by an area of hypertrophic myometrium. Symptomatology includes heavy menstrual bleeding and pelvic pain. The pathogenesis of adenomyosis is not known; however, animal models have shown increased uterine concentration of prolactin as a risk factor. Prolactin acts as a smooth muscle cell mitogen. If prolactin is central to adenomyosis pathogenesis, reducing uterine prolactin could be a possible medical treatment option. In this pilot study, we aim to evaluate the effect of bromocriptine, a prolactin inhibitor, on menstrual bleeding and pain in women with adenomyosis.Material and methods23 women with diffuse adenomyosis were enrolled from a university hospital in Sweden and a tertiary care center in the USA. Nineteen patients completed 6 months of treatment with vaginal bromocriptine at a dose of 5 mg daily. Participants completed validated measures at baseline, 3 and 6 months of treatment, and at 9 months (3 months after cessation of bromocriptine). Validated measures utilized included Pictorial Blood Loss Assessment Chart (PBLAC), Aberdeen Menorrhagia Clinical Outcomes Questionnaire (AMCOQ), Visual Analog Scale for pain (VAS), McGill Pain Questionnaire (MPQ), Endometriosis Health Profile (EHP‐30), Female Sexual Function Index (FSFI) and the Fibroid Symptom Quality of Life (UFS‐QOL) symptom severity and health‐related quality of life (HRQL) subscores. Scores were compared between baseline and 9 months using the Wilcoxon signed rank test.ResultsMean age of participants was 44.8 years. About 77.8% reported PBLAC scores >250 and 68.4% reported moderate to severe pain at baseline. Compared with baseline, women had lower 9‐month scores (median [interquartile range] for all) on PBLAC (baseline 349 [292‐645] vs 9‐month 233 [149‐515], P = 0.003), VAS (5.0 [4‐8.3] vs 2.5 [0‐4.5], P < 0.001), EHP Core Pain (15.9 [9.1‐50.0] vs 3.4 [2.3‐34.1], P = 0.029), EHP Core Self‐image (41.7 [16.7‐58.3] vs 25 [0‐5], P = 0.048) and Symptom Severity Score (60 [44‐72] vs 44 [25‐56], P < 0.001) and higher HRQL scores (57 [37‐63] vs 72 [51‐85], P < 0.001) following bromocriptine treatment. Other EHP core parameters and FSFI were not significantly different.ConclusionsSignificant improvement in menstrual bleeding, pain and quality of life after vaginal bromocriptine treatment suggests a novel therapeutic agent for adenomyosis.

Abstract STUDY QUESTION Can asoprisnil, a selective progesterone receptor modulator, provide clinically meaningful improvements in heavy menstrual bleeding (HMB) associated with uterine fibroids with an acceptable safety profile? SUMMARY ANSWER Uninterrupted treatment with asoprisnil for 12 months effectively controlled HMB and reduced fibroid and uterine volume with few adverse events. WHAT IS KNOWN ALREADY In a 3-month study, asoprisnil (5, 10 and 25 mg) suppressed uterine bleeding, reduced fibroid and uterine volume, and improved hematological parameters in a dose-dependent manner. STUDY DESIGN, SIZE, DURATION In two Phase 3, double-blind, randomized, placebo-controlled, multicentre studies, women received oral asoprisnil 10 mg, asoprisnil 25 mg or placebo (2:2:1) once daily for up to 12 months. PARTICIPANTS/MATERIALS, SETTING, METHODS Premenopausal women ≥18 years of age in North America with HMB associated with uterine fibroids were included (N = 907). The primary efficacy endpoint was the percentage of women who met all three predefined criteria at 12 months or the final month for patients who prematurely discontinued: (1) ≥50% reduction in monthly blood loss (MBL) by menstrual pictogram, (2) hemoglobin concentration ≥11 g/dL or an increase of ≥1 g/dL, and (3) no interventional therapy for uterine fibroids. Secondary efficacy endpoints included changes in other menstrual bleeding parameters, volume of the largest fibroids, uterine volume and health-related quality of life (HRQL). MAIN RESULTS AND THE ROLE OF CHANCE In all, 90% and 93% of women in the asoprisnil 10-mg and 25-mg groups, respectively, and 35% of women in the placebo group met the primary endpoint (P &lt; 0.001). Similar results were observed at month 6 (P &lt; 0.001). The percentage of women who achieved amenorrhea in any specified month ranged from 66–78% in the asoprisnil 10-mg group and 83–93% in the asoprisnil 25-mg group, significantly higher than with placebo (3–12%, P &lt; 0.001). Hemoglobin increased rapidly (by month 2) with asoprisnil treatment and was significantly higher versus placebo throughout treatment. The primary fibroid and uterine volumes were significantly reduced from baseline through month 12 with asoprisnil 10 mg (median changes up to −48% and −28%, respectively) and 25 mg (median changes up to −63% and −39%, respectively) versus placebo (median changes up to +16% and +13%, respectively; all P &lt; 0.001). Dose-dependent, significant improvements in HRQL (Uterine Fibroid Symptom and Quality of Life instrument) were observed with asoprisnil treatment. Asoprisnil was generally well tolerated. Endometrial biopsies indicated dose- and time-dependent decreases in proliferative patterns and increases in quiescent or minimally stimulated endometrium at month 12 of treatment. Although not statistically significantly different at month 6, mean endometrial thickness at month 12 increased by ~2 mm in both asoprisnil groups compared with placebo (P &lt; 0.01). This effect was associated with cystic changes in the endometrium on MRI and ultrasonography, which led to invasive diagnostic and therapeutic procedures in some asoprisnil-treated women. LIMITATIONS, REASONS FOR CAUTION Most study participants were black; few Asian and Hispanic women participated. The study duration may have been insufficient to fully characterize the endometrial effects. WIDER IMPLICATIONS OF THE FINDINGS Daily uninterrupted treatment with asoprisnil was highly effective in controlling menstrual bleeding, improving anemia, reducing fibroid and uterine volume, and increasing HRQL in women with HMB associated with uterine fibroids. However, this treatment led to an increase in endometrial thickness and invasive diagnostic and therapeutic procedures, with potential unknown consequences. STUDY FUNDING/COMPETING INTEREST(S) This trial was funded by AbbVie Inc. (prior sponsors: TAP Pharmaceutical Products Inc., Abbott Laboratories). E.A. Stewart was a site investigator in the Phase 2 study of asoprisnil and consulted for TAP during the design and conduct of these studies while at Harvard Medical School and Brigham and Women’s Hospital. She received support from National Institutes of Health grants HD063312, HS023418 and HD074711 and research funding, paid to Mayo Clinic for patient care costs related to an NIH-funded trial from InSightec Ltd. She consulted for AbbVie, Allergan, Bayer HealthCare AG, Gynesonics, and Welltwigs. She received royalties from UpToDate and the Med Learning Group. M.P. Diamond received research funding for the conduct of the studies paid to the institution and consulted for 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 from Bayer and ObsEva. A.R.W. Williams consulted for TAP and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr consulted for and received research funding from AbbVie. E.R. Myers consulted for AbbVie, 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 co-inventor of several patents related to asoprisnil. C. Mattia-Goldberg is a former employee of AbbVie and may own AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie and may own AbbVie stock or stock options. TRIAL REGISTRATION NUMBER NCT00152269, NCT00160381 (clinicaltrials.gov). TRIAL REGISTRATION DATE 7 September 2005; 8 September 2005. DATE OF FIRST PATIENT’S ENROLMENT 12 September 2002; 6 September 2002.

Bilateral oophorectomy in premenopausal women is a unique condition causing the abrupt and premature loss of ovarian hormones, primarily estrogen. Bilateral oophorectomy causes an alteration of several fundamental aging processes at the cellular, tissue, organ, and system levels, leading to multimorbidity, frailty, and reduced survival. However, many questions remain unanswered.

Background: Most women will experience uterine fibroids by the age of 50, yet few data exist describing the overall patient experience with fibroids. The objective of this population-based survey was to characterize symptom burden, patient awareness, and treatment decision-making for fibroids, including a comparison among women of varying backgrounds. Materials and Methods: Women (≥18 years) were recruited via email from GfK KnowledgePanel ® , a representative panel of US households, or identified with opt-in consumer panels. The Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QOL) questionnaire and Aberdeen Menorrhagia Severity Scale (AMSS) were included. Results: Eligible women were grouped into three cohorts: “at-risk” (symptoms suggestive of fibroids without clinical diagnosis, n = 300), “diagnosed” ( n = 871), and fibroid-related “hysterectomy” ( n = 272). Cohort and intracohort race/ethnicity and income analyses revealed differences in symptom burden, awareness/perception, and treatment history. Based on UFS-QOL scores, at-risk women reported significantly greater symptom severity and decreased health-related QOL versus diagnosed women; Hispanic women reported greater symptom severity versus white and black women. At-risk women also reported heavy menstrual bleeding and significant impact on work productivity. Among diagnosed women, 71% used pharmacologic therapy for symptom relief, and 30% underwent surgical or procedural treatment. Initial discussions with healthcare providers significantly impacted treatment outcomes; the hysterectomy cohort was most likely to first discuss hysterectomy. Conclusions: Women with fibroids or symptoms suggestive of fibroids experience significant distress that reduces QOL, particularly racial minorities and women in lower income brackets. Survey results suggest that many women are likely undiagnosed, underscoring the need for improved awareness and education.

e20092 Background: More than 5,000 premenopausal women are diagnosed (dx’d) with lung cancer annually in the United States. Improvements in treatment are contributing to a growing population of young survivors. Limited data exist regarding the risk of treatment-related amenorrhea, a surrogate for infertility and early menopause, after systemic therapies for lung cancer. Methods: Since 1997, we mailed annual surveys to patients seen at Mayo Clinic for lung cancer who consented to join a research cohort. Surveys queried menopausal status and age of menopause. Those who were dx’d under age 50, who were treated with curative intent, and who reported that they were premenopausal at the time of the cancer dx were included in this analysis. “Immediate” treatment-related menopause was defined as reporting age of menopause as the same as the age at diagnosis or 1 year (yr) older. Results: Of 182 survey respondents to date (mean time from dx to 1st survey: 26 mos, SD 24 mos, range 12-202 mos), 85 (mean age 44 yrs, SD 5, range 34-48) received chemo during the yr after diagnosis, 26 of whom also received targeted therapy during that yr. Lung cancer dx occurred 1958-2016. Platinum drugs, taxanes, and etoposide were the most common chemotherapies. 46% of chemo recipients (mean age 47, SD 2, range 41-49) experienced immediate menopause, 9% (mean age 43 yrs, SD 5, range 35-48) experienced menopause at least 2 yrs after the age of dx, and 45% (mean age 40 yrs, SD 5, range 25-48) remained pre- or peri-menopausal at their final survey (on average 3 years after dx, SD 2, range 1-10). Only 3 patients received targeted therapy alone, and the remaining 94 (mean age 42 yrs, SD 6 years) received no systemic therapy within a year of diagnosis. 15% of these 94 (mean age 45 yrs, SD 3, range 41-49) experienced immediate menopause, 16% (mean age 43 yrs, SD 4, range 36-49) experienced menopause 2+ yrs after the age of diagnosis, and 69% (mean age 41 yrs, SD 7, range 20-49) remained pre- or perimenopausal at their final survey (on average 4 yrs after dx, SD 3, range 1-10). Conclusions: Chemotherapy for lung cancer causes amenorrhea in a substantial proportion of women dx’d with lung cancer while premenopausal. Further research on fertility and menopausal symptoms after lung cancer treatment, and on differences between regimens, is warranted.

Abstract Objective: More than 5,000 premenopausal women are diagnosed with lung cancer annually in the United States. Limited data exist regarding the risk of treatment-related amenorrhea, a surrogate for infertility and early menopause, after systemic therapies for lung cancer. Methods: Premenopausal women diagnosed with lung cancer under age 50 were surveyed at diagnosis and annually thereafter about their menstrual status as a part of the Mayo Clinic Epidemiology and Genetics of Lung Cancer Research Program. Types of lung cancer-directed treatments were recorded, and frequencies of self-reported menopause at each survey were calculated. Results: A cohort of 182 premenopausal women were included in this study, with average age at lung cancer diagnosis 43 years (SD 6). Among the 85 patients who received chemotherapy, 64% self-reported that they had become menopausal within a year of diagnosis. Platinum salts were universally included in these chemotherapy regimens, and the majority of these women also received taxanes within 1 year of diagnosis. Only 15% of the 94 patients who did not receive systemic therapy within 1 year of diagnosis experienced self-reported menopause. Three patients received targeted therapy alone, two of whom remained premenopausal at the final qualifying survey, completed a median of 3 years after diagnosis. Conclusions: Chemotherapy for lung cancer patients appears to increase risk of early loss of menses in survivors.

INTRODUCTION: Bimanual pelvic examination is often performed for symptoms related to uterine fibroids (UF). We evaluated the clinical utility of this exam at the time of UF diagnosis in a community setting. METHODS: Retrospective sample of women diagnosed with UF between 2006 and 2010 in the Rochester Epidemiology Project, a population-based records-linkage system. Cohort includes a sample of women who had a pelvic examination within 12 months of UF diagnosis (n=141). Abnormal pelvic exam was defined as abnormal uterine size or shape, or any adnexal mass or fullness recorded by healthcare provider. We examined clinical and imaging characteristics using chi-squared for categorical and t tests for continuous data. Data reported as percentage or mean ± standard deviation. Volumes of the uterus and largest fibroid were calculated using the prolate ellipsoid formula. RESULTS: Women with UF and a normal pelvic exam (n=73) were younger than women with abnormal exam (n=68) (44.7±7.1 vs 46.9±5.4 years, P=.05), and had a higher BMI (29.4 ± 6.5 vs 26.6 ± 5.0 kg/m2, P=.007). Women with abnormal exam had significantly larger uterine volumes (226.0 ± 151.8 vs 150.9 ± 97.9 cm³, P=.005) and fibroid volumes (61.1±81.1 vs 19.9±52.8 cm³, P=.005). Abnormal examination was more frequently documented by gynecology providers (57.4%) than other providers (42.7%, P=.04). Fibroid symptoms were not associated with abnormal examination. CONCLUSION: Fifty-two percent of women with fibroids had a normal bimanual examination. Thus, a high suspicion of fibroids should prompt imaging. Lower BMI and larger uterine and fibroid dimensions increase fibroid diagnosis on pelvic examination.

Abstract Objective: The aim of the study was to determine the long-term risk of cardiovascular disease and metabolic conditions in women undergoing hysterectomy with bilateral ovarian conservation compared with age-matched referent women. Methods: Using the Rochester Epidemiology Project records-linkage system, we identified 2,094 women who underwent hysterectomy with ovarian conservation for benign indications 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 prior hysterectomy or any oophorectomy. These two cohorts were followed historically to identify de novo cardiovascular or metabolic diagnoses. We estimated hazard ratios (HRs) and 95% CIs using Cox proportional hazards models adjusted for 20 preexisting chronic conditions and other potential confounders. We also calculated absolute risk increases and reductions from Kaplan–Meier estimates. Results: Over a median follow-up of 21.9 years, women who underwent hysterectomy experienced increased risks of de novo hyperlipidemia (HR 1.14; 95% CI, 1.05-1.25), hypertension (HR 1.13; 95% CI, 1.03-1.25), obesity (HR 1.18; 95% CI, 1.04-1.35), cardiac arrhythmias (HR 1.17; 95% CI, 1.05-1.32), and coronary artery disease (HR 1.33; 95% CI, 1.12-1.58). Women who underwent hysterectomy at age ≤35 years had a 4.6-fold increased risk of congestive heart failure and a 2.5-fold increased risk of coronary artery disease. Conclusions: Even with ovarian conservation, hysterectomy is associated with an increased long-term risk of cardiovascular and metabolic conditions, especially in women who undergo hysterectomy at age ≤35 years. If these associations are causal, alternatives to hysterectomy should be considered to treat benign gynecologic conditions.