Wulf H. Utian

Executive summary: stages of reproductive aging workshop (STRAW)

A select group of investigators attended a structured workshop, the Stages of Reproductive Aging Workshop (STRAW), at Park City, Utah, USA, in July 2001, which addressed the need in women for a staging system as well as the confusing nomenclature for the reproductive years.

Postmenopausal hormone therapy: An endocrine society scientific statement

OBJECTIVE Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement. EVIDENCE Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence. CONSENSUS PROCESS A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors. CONCLUSIONS The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Womens Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate

OBJECTIVE To evaluate the efficacy of lower doses of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for relieving vasomotor symptoms and vaginal atrophy. DESIGN A randomized, double-blind, placebo-controlled trial (the Womens Health, Osteoporosis, Progestin, Estrogen study). SETTING Study centers across the United States. PATIENT(S) Two thousand, six hundred, seventy-three healthy, postmenopausal women with an intact uterus, including an efficacy-evaluable population (n = 241 at baseline). INTERVENTION(S) Patients received for 1 year (13 cycles; in milligrams per day) CEE, 0.625; CEE, 0.625 and MPA, 2.5; CEE, 0.45; CEE, 0.45 and MPA, 2.5; CEE, 0.45 and MPA, 1.5; CEE, 0.3; CEE, 0.3 and MPA, 1.5; or placebo. MAIN OUTCOME MEASURE(S) Number and severity of hot flushes and Papanicolaou smear with vaginal maturation index (VMI) to assess vaginal atrophy. RESULT(S) In the efficacy-evaluable population, reduction in vasomotor symptoms was similar with CEE of 0.625 mg/d and MPA of 2.5 mg/d (the most commonly prescribed doses) and all lower combination doses. CEE of 0.625 mg/d alleviated hot flushes more effectively than the lower doses of CEE alone. VMI improved in all active treatment groups. CONCLUSION(S) Lower doses of CEE plus MPA relieve vasomotor symptoms and vaginal atrophy as effectively as commonly prescribed doses.

Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: A comprehensive review

Many women experience vasomotor symptoms at or around the time of menopause. Hot flushes and night sweats are considered primary menopausal symptoms that may also be associated with sleep and mood disturbances, as well as decreased cognitive function. All of these symptoms may lead to social impairment and work-related difficulties that significantly decrease overall quality of life. Hot flushes have shown a great deal of variability in their frequency and severity in women. In some women, hot flushes persist for several months; in others, they may last for more than 10 years. Traditionally vasomotor symptoms were reported to begin 5 to 10 years prior to the cessation of the final menstrual cycle, corresponding with the initial decline in circulating gonadal hormones; however, night sweats in particular most often begin in perimenopause. The pathogenesis of hot flushes has not yet been fully elucidated, but the circuitry involving estrogen and neurotransmitters, norepinephrine and serotonin specifically, are hypothesized to play a major role in the altered homeostatic thermoregulatory mechanisms underlying these events.Menopause-associated vasomotor symptoms are associated with significant direct and indirect costs. Overall costs of traditional pharmacotherapy or complementary and alternative medicine modalities, including over-the-counter treatments and dietary supplements, for managing menopause-related vasomotor symptoms are substantial and include initial and follow-up physician visits and telephone calls. Additional costs include laboratory testing, management of adverse events, loss of productivity at work, and personal and miscellaneous costs. Pharmacoeconomic analyses, including those that consider risks identified by the Womens Health Initiative, generally support the cost-effectiveness of hormonal therapy for menopause-associated vasomotor symptoms, which have been the mainstay for the management of these symptoms for more than 50 years. However, because many women now want to avoid hormone therapy, there is a need for additional targeted therapies, validated by results from controlled clinical trials that are safe, efficacious, cost-effective, and well tolerated by symptomatic menopausal women.

Stages of Reproductive Aging Workshop (STRAW)

A select group of clinicians and investigators met recently for the express purpose of developing a staging system for female reproductive aging. The group also addressed the confusing and redundant nomenclature that is commonly used to describe the late reproductive years. A summary and recommendations are presented.

Executive summary: Stages of Reproductive Aging Workshop (STRAW)

A select group of investigators attended a structured workshop, the Stages of Reproductive Aging Workshop (STRAW), at Park City, Utah, USA, in July 2001, which addressed the need in women for a staging system as well as the confusing nomenclature for the reproductive years.

Relief of vasomotor symptoms with the tissue-selective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial

Objective: The aim of this study was to assess the safety and efficacy of bazedoxifene (BZA)/conjugated estrogens (CE) treating moderate to severe vasomotor symptoms in the Selective Estrogen Menopause and Response to Therapy 2 trial. Methods: This was an outpatient, multicenter, double-blind, randomized, placebo-controlled, phase 3 study conducted in the United States. Healthy postmenopausal women (N = 332; aged 40-65 y) with moderate to severe hot flushes (≥7/d or 50/wk) were randomized to BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, or placebo once daily for 12 weeks. Changes from baseline in the average daily number of moderate and severe hot flushes and daily severity score were assessed at weeks 4 and 12; adverse events were recorded. Results: BZA/CE significantly reduced the number and severity of hot flushes at weeks 4 and 12 (P < 0.001). At week 12, BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg reduced hot flushes from baseline by 74% (10.3 hot flushes [baseline] vs 2.8 [week 12]) and 80% (10.4 vs 2.4), respectively, compared with 51% (10.5 vs 5.4) for placebo. More participants at week 12 had at least a 75% decrease in hot flushes with BZA 20 mg/CE 0.45 mg (61%) and BZA 20 mg/CE 0.625 mg (73%) versus placebo (27%; P < 0.001). The safety profile was similar between BZA/CE and placebo, and no unexpected safety findings were reported. Conclusions: BZA 20 mg paired with CE 0.45 or 0.625 mg is effective, with short-term safety, for treating vasomotor symptoms in postmenopausal women.

The Utian Quality of Life (UQOL) Scale: Development and validation of an instrument to quantify quality of life through and beyond menopause

ObjectiveQuality of life (QOL) is an outcome variable requiring measurement in clinical care or pivotal regulatory trial research. Current menopause QOL measures are mostly life phase or disease symptom inventories or scores. Believing that QOL should refer more to “sense of well-being,” we have developed the Utian QOL scale (UQOL) that is strongly based on perception of sense of well-being as distinct from menopausal symptoms. DesignA pool of items sampling various aspects of well-being was developed. Peri- and postmenopausal women (n = 327) responded to the items, and their responses were subjected to a factor analysis. Four factors emerged, each representing a QOL domain. The resulting 23-item instrument was validated in a geographically and socioeconomically diverse sample of peri- and postmenopausal women using the Short Form-36, an established, frequently used QOL inventory. QOL domains were subjected to confirmatory factor analyses, formal item analysis was completed, and the measure was assessed for reliability and validity, including a second sample of women (n = 270). ResultsWomen (n = 597; mean age, 52.9 years) from 12 communities across the United States completed the measure. The UQOL seems to reflect four components of QOL: occupational QOL, health QOL, emotional QOL, and sexual QOL. The questionnaire and scoring system are presented. ConclusionWe are reporting on the process of validating an instrument for quantifying sense of well-being in a perimenopausal population. Substantial reliability and validity estimates for the scale and its subscales support the UQOL as a valuable new tool for use in clinical research and practice.

Effective Treatment of Vaginal Atrophy With an Ultra-Low-Dose Estradiol Vaginal Tablet

OBJECTIVE: To evaluate the efficacy of ultra–low-dose 10-microgram 17&bgr;-estradiol (E2) vaginal tablets for treatment of vaginal atrophy. METHODS: Postmenopausal women (N=309) were randomly assigned to 10-microgram E2 or placebo vaginal tablets for 52 weeks in a multicenter, double-blind study. Primary efficacy endpoints included change from baseline to week 12 in vaginal cytology, vaginal pH, and most bothersome urogenital symptoms score. Grading of vaginal health was a secondary efficacy assessment. Safety assessments included endometrial biopsy, physical and gynecologic examinations, and recording adverse events. RESULTS: At week 12, the change from baseline for 10 micrograms E2 compared with placebo demonstrated significant improvement in vaginal Maturation Index (proportion of parabasal cells: –37% compared with –9%; superficial cells: 13% compared with 4%; intermediate cells: 24% compared with 5%; P<.001 for each), Maturation Value (25.0 compared with 6.5, P<.001), grading of vaginal health (–0.91 compared with –0.51, P<.001), vaginal pH grade (–1.3 compared with –0.4, P<.001), and most bothersome symptoms score (–1.23 compared with –0.87, P=.003). For each component of vaginal Maturation Index, vaginal Maturation Value, grading of vaginal health, and vaginal pH, treatment effects were statistically different from placebo after 2 weeks of treatment. For most bothersome symptoms, treatment effect became apparent after 4 weeks and reached statistical significance at week 8 of therapy. All treatment effects were statistically significant at week 52. There were no major safety findings regarding physical, gynecologic, or laboratory assessments. CONCLUSION: After 12 weeks of treatment, an ultra–low-dose 10-microgram E2 vaginal tablet, compared with placebo, demonstrated significant improvement for the primary endpoints: vaginal cytology and pH and most bothersome urogenital symptoms score. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00108849 LEVEL OF EVIDENCE: I

Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients

Abstract Objective: Our purpose was to evaluate the efficacy and safety of 3 dosages of Esclim, delivering 0.025 mg, 0.050 mg, or 0.100 mg 17β-estradiol per 24 hours, in the treatment of moderate to severe vasomotor symptoms. Study Design: In this double-blind, placebo-controlled, parallel-group, multicenter trial, 196 highly symptomatic menopausal women received 12 weeks of continuous unopposed treatment with 1 of the 3 dosages of Esclim or a matching placebo patch. Results: The reduction in frequency of moderate to severe vasomotor symptoms was statistically significant compared with placebo ( P Conclusion: All 3 dosages of Esclim were effective in the treatment of vasomotor symptoms. The efficacy and safety of Esclim 25 indicate a good risk-benefit ratio. (Am J Obstet Gynecol 1999;181:71-9.)