Premature or early bilateral oophorectomy: a 2021 update.

In this invited review, we discuss some unresolved and controversial issues concerning premature (<40 years) or early (40-45 years) bilateral oophorectomy. First, we clarify the terminology. Second, we summarize the long-term harmful consequences of bilateral oophorectomy. Third, we discuss the restrictive indications for bilateral oophorectomy in premenopausal women to prevent ovarian cancer that are justified by the current scientific evidence. Fourth, we explain the importance of estrogen replacement therapy when bilateral oophorectomy is performed. Hormone replacement therapy is indicated after bilateral oophorectomy until the age of expected natural menopause like in premature or early primary ovarian insufficiency. Fifth, we discuss the relationship between adverse childhood experiences, adverse adult experiences, mental health, gynecologic symptoms and bilateral oophorectomy. The acceptance and popularity of bilateral oophorectomy over several decades, and its persistence even in the absence of supporting scientific evidence, suggest that non-medical factors related to sex, gender, reproduction, cultural beliefs and socioeconomic structure are involved. We discuss some of these non-medical factors and the need for more research in this area.

A 12-month extension study to evaluate the safety and efficacy of asoprisnil in women with heavy menstrual bleeding and uterine fibroids.

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 INTERESTS: 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.

Safety and efficacy of the selective progesterone receptor modulator asoprisnil for heavy menstrual bleeding with uterine fibroids: pooled analysis of two 12-month, placebo-controlled, randomized trials.

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 < 0.001). Similar results were observed at month 6 (P < 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 < 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 < 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 < 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.

Academic advocacy in public health: Disciplinary 'duty' or political 'propaganda'?

The role of 'advocacy' within public health attracts considerable debate but is rarely the subject of empirical research. This paper reviews the available literature and presents data from qualitative research (interviews and focus groups conducted in the UK in 2011-2013) involving 147 professionals (working in academia, the public sector, the third sector and policy settings) concerned with public health in the UK. It seeks to address the following questions: (i) What is public health advocacy and how does it relate to research?; (ii) What role (if any) do professionals concerned with public health feel researchers ought to play in advocacy?; and (iii) For those researchers who do engage in advocacy, what are the risks and challenges and to what extent can these be managed/mitigated? In answering these questions, we argue that two deeply contrasting conceptualisations of 'advocacy' exist within public health, the most dominant of which ('representational') centres on strategies for 'selling' public health goals to decision-makers and the wider public. This contrasts with an alternative (less widely employed) conceptualisation of advocacy as 'facilitational'. This approach focuses on working with communities whose voices are often unheard/ignored in policy to enable their views to contribute to debates. We argue that these divergent ways of thinking about advocacy speak to a more fundamental challenge regarding the role of the public in research, policy and practice and the activities that connect these various strands of public health research.

Limited impact of awareness-raising campaigns on hepatitis C testing practices among general practitioners.

The global hepatitis strategy calls for increased effort to diagnose those infected, with a target of 90% diagnosed by 2030. Scotland's Action Plan on Hepatitis C included awareness-raising campaigns, undertaken during 2008-2011, to promote testing by general practitioners. We examined hepatitis C virus (HCV) testing practice among general practitioners before and following these campaigns. Scottish general practitioners were surveyed, using Dillman's method, in 2007 and 2013; response rates were 69% and 60%, respectively. Most respondents offer testing when presented with a risk history (86% in 2007, 88% in 2013) but only one-fifth actively sought out risk factors (19% in 2007, 21% in 2013). Testing was reportedly always/almost always/usually offered to people who inject drugs (84% in 2007, 87% in 2013). Significant improvements in the offer of testing were reported in patients with abnormal LFTs (41% in 2007, 65% in 2013, P<.001) and who had received medical/dental treatment in high prevalence countries (14% in 2007, 24% in 2013, P=.001). In 2013, 25% of respondents had undertaken HCV-related continued professional development. This group was significantly more likely to actively seek out risk factors (P=.009) but only significantly more likely to offer a test to patients who had received medical/dental treatment in high prevalence countries (P=.001). Our findings suggest that government-led awareness raising campaigns have limited impact on general practitioners' testing practices. If the majority of the HCV-infected population are to be diagnosed, practitioner-based or physician-centred interventions should be considered alongside educational initiatives targeted at professionals.

Epidemiology of uterine fibroids: a systematic review.

BACKGROUND: Uterine fibroids (UFs) are the most common neoplasm affecting women that can cause significant morbidity and may adversely impact fertility. OBJECTIVES: To examine UF epidemiology and to evaluate the relative strengths of putative risk factors. SEARCH STRATEGY: MEDLINE and Embase were searched for studies published in English between January 1995 and April 2015. SELECTION CRITERIA: Publications reporting relevant data from registries and other observational studies with over 1000 patients and single-centre studies with over 100 patients were selected. DATA COLLECTION AND ANALYSIS: Data on UF incidence, prevalence and associated risk factors were extracted from 60 publications. MAIN RESULTS: Wide ranges were reported in both UF incidence (217-3745 cases per 100 000 women-years) and prevalence (4.5-68.6%), depending on study populations and diagnostic methods. Black race was the only factor that was recurrently reported to increase UF risk, by two-threefold compared with white race. Eleven other factors affected UF risk to a magnitude similar to or greater than race. Age, premenopausal state, hypertension, family history, time since last birth, and food additive and soybean milk consumption increased UF risk; use of oral contraceptives or the injectable contraceptive depot medroxyprogesterone acetate, smoking in women with low body mass index and parity reduced UF risk. CONCLUSIONS: We identified 12 risk factors that play an important role in UF epidemiology. The UF risk factor with the strongest evidence is black race. High-quality prospective observational data are needed to improve our understanding of UF epidemiology, and thus its aetiology and optimal management. TWEETABLE ABSTRACT: Uterine fibroids occur in about 70% of women. Black race and 11 other factors affect uterine fibroid risk.

Medical therapies for heavy menstrual bleeding in women with uterine fibroids: a retrospective analysis of a large commercially insured population in the USA.

OBJECTIVES: To report patterns and patient characteristics associated with initiation of and persistence with medical therapies for uterine fibroid-related heavy menstrual bleeding. DESIGN: Retrospective cohort study. SETTING: US commercial insurance claims database. POPULATION: 41 561 women aged 18-54 years with uterine fibroids and heavy menstrual bleeding who initiated medical therapies from January 2000 through December 2013. METHOD: Multinomial logistic regression was used to assess patient characteristics associated with initiation and persistence. Cox proportional hazards regression was used on propensity score-matched cohorts to examine change from index medication. MAIN OUTCOMES MEASURES: Initiation of and persistence with four first-line medical therapies: short- and long-acting reversible contraceptive steroids, leuprolide acetate, and tranexamic acid. RESULTS: Most women (79.4%) took short-acting reversible contraceptive steroids as first-line therapy (index medication), whereas 9.5%, 8.5%, and 2.7% used long-acting reversible contraceptive steroids, leuprolide acetate, and tranexamic acid, respectively. During follow-up, 16 594 women (39.9%) switched to nonindex medication (18.4%) or procedural treatment (81.6%). In comparison with women taking short-acting steroids, those receiving long-acting steroids were less likely to switch [hazard ratio (HR) 0.84, 95% CI 0.79-0.91], whereas women taking leuprolide acetate (HR 2.44, 95% CI 2.27-2.62) or tranexamic acid (HR 1.44, 95% CI 1.26-1.65) were more likely to switch. Older age, emergency department visits, anaemia, and inflammatory disease diagnoses at baseline were associated with increased probability of discontinuing the index medication or switching to another therapy. CONCLUSIONS: Women with uterine fibroid-related heavy menstrual bleeding were more likely to persist with their initial therapy of long-acting reversible contraceptive steroid compared with other medical options. TWEETABLE ABSTRACT: 80% women with fibroid-related heavy menstrual bleeding use SARC, but LARC users are more persistent.

Dexamethasone reverses the effects of high glucose on human retinal endothelial cell permeability and proliferation in vitro.

Diabetic macular oedema (DMO), a leading cause of preventable visual loss in the working population, is caused by an increase in microvascular endothelial cell permeability, and its prevalence is on the increase in parallel with the rising worldwide prevalence of diabetes. It is known that retinal vascular leakage in DMO is contributed to by VEGF upregulation as well as non-VEGF dependent inflammatory pathways, and the potential use of anti-inflammatory agents such as the glucocorticoids, including dexamethasone are being extensively studied. However, the mechanisms of action of dexamethasone in DMO reduction are not fully understood. Using human primary retinal endothelial cells (REC) the in vitro effect of dexamethasone in modulating the proliferation, permeability and gene expression of key tight and adheren junction components, and the expression of angiopoietins (Ang) 1 and 2 in high (25 mM) glucose conditions were investigated. High glucose decreased REC proliferation, an effect that was reversed by dexamethasone. High glucose conditions significantly increased REC permeability and decreased claudin-5, occludin and JAM-A gene expression; dexamethasone was effective in partially reversing these changes, restoring EC permeability to the normal or near normal state. High glucose levels resulted in reduction of Ang1 secretion, although Ang2 levels were consistently high. DEX increased Ang1 and decreased Ang2, indicating that the balance of Ang1/Ang2 may be important in determining functional changes in REC under high glucose conditions.

A review of therapies for diabetic macular oedema and rationale for combination therapy.

Diabetic macular oedema (DMO) is responsible for significant visual impairment in diabetic patients. The primary cause of DMO is fluid leakage resulting from increased vascular permeability through contributory anatomical and biochemical changes. These include endothelial cell (EC) death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx. The molecular changes include increased reactive oxygen species, pro-inflammatory changes: advanced glycation end products, intracellular adhesion molecule-1, Complement 5-9 deposition and cytokines, which result in increased paracellular permeability, tight junction disruption, and increased transcellular permeability. Laser photocoagulation has been the mainstay of treatment until recently when pharmacological treatments were introduced. The current treatments for DMO target reducing vascular leak in the macula once it has occurred, they do not attempt to treat the underlying pathology. These pharmacological treatments are aimed at antagonising vascular endothelial growth factor (VEGF) or non-VEGF inflammatory pathways, and include intravitreal injections of anti-VEGFs (ranibizumab, aflibercept or bevacizumab) or steroids (fluocinolone, dexamethasone or triamcinolone) as single therapies. The available evidence suggests that each individual treatment modality in DMO does not result in a completely dry macula in most cases. The ideal treatment for DMO should improve vision and improve morphological changes in the macular (eg, reduce macular oedema) for a significant duration, reduced adverse events, reduced treatment burden and costs, and be well tolerated by patients. This review evaluates the individual treatments available as monotherapies, and discusses the rationale and potential for combination therapy in DMO. A comprehensive review of clinical trials related to DMO and their outcomes was completed. Where phase III randomised control trials were available, these were referenced, if not available, phase II trials have been included.

The effect of hyperglycaemia on permeability and the expression of junctional complex molecules in human retinal and choroidal endothelial cells.

Diabetic retinopathy is the leading cause of preventable blindness in the working population and its prevalence continues to increase as the worldwide prevalence of diabetes grows. Diabetic choroidopathy is less well studied and occurs in the late stages of diabetic eye disease. The main cause of visual loss in diabetic eye disease is diabetic macular oedema caused by an increase in microvascular endothelial permeability. Endothelial cell permeability is influenced by multiple factors which have not been fully elucidated, particularly in human models. In addition, the gene and protein expression between retinal and choroidal endothelial cells, even in humans, has been shown to be heterogeneous. The aim of this project was to determine, in vitro, the effect of high glucose (25 mM) on human paracellular permeability in retinal and choroidal endothelial cells. The expression of selected tight junction molecules (Occludin, Claudin-5, JAM-A and JAM-C) and adheren junction (VE-Cadherin) molecules was also compared between retinal and choroidal endothelial cells and with high glucose. High glucose conditions significantly increased the permeability in both retinal and choroidal endothelial cells monolayers although the increase was higher in retinal endothelial cells. Under normal glucose culture conditions microarray analysis determined that occludin and claudin-5 gene expression was higher in retinal endothelial cells than choroidal endothelial cells, and western blotting indicated that claudin-5 protein expression was also higher in retinal endothelial cells whilst JAM-A, and C and VE-Cadherin levels were similar. In retinal endothelial cells exposed to high glucose claudin-5, occludin and JAM-A was found to be reduced, whereas the expression of VE-Cadherin and JAM-C was unchanged when evaluated with western blotting, immunofluorescence and qPCR. None of the proteins were significantly decreased by high glucose in choroidal endothelial cells. The increase in retinal endothelial cell permeability is likely caused by a decrease in selective tight junction protein expression, leading to increased paracellular permeability. This may indicate differences in junctional molecule regulation of permeability in retinal compared to choroidal endothelial cells.

Adenomyosis: Epidemiology, Risk Factors, Clinical Phenotype and Surgical and Interventional Alternatives to Hysterectomy.

Adenomyosis is an important clinical challenge in gynecology and healthcare economics; in its fully developed form, hysterectomy is often used to treat it in premenopausal and perimenopausal women. Symptoms of adenomyosis typically include menorrhagia, pelvic pain and dysmenorrhea. Moreover, adenomyosis and leiomyomas commonly coexist in the same uterus, and differentiating the symptoms for each pathological process can be problematic. Although it has been recognized for over a century, reliable epidemiological studies on this condition are limited, because only postoperative diagnoses were possible in the past. Minimally invasive surgical techniques (endometrial ablation/resection, myometrial excision/reduction, myometrial electrocoagulation, uterine artery ligation) have had limited success in the treatment of adenomyosis, and the reported data for these procedures have been obtained from case reports or small case series with only short follow-up times. However, newer techniques including uterine artery embolization (UAE) and magnetic resonance imaging guided focused ultrasound (MRgFUS) show promise in treating adenomyosis. The data is strongest for UAE; these studies have the largest patient cohorts. However, none of the UAE studies were randomized or controlled. Thus, despite the clinical importance of adenomyosis, there is little evidence on which to base treatment decisions. The objective of this review is to summarize the epidemiology, risk factors, clinical phenotype and to evaluate the accrued experience with surgical and interventional alternatives to hysterectomy.

Magnetic resonance-guided focused ultrasound (MRgFUS) compared with abdominal hysterectomy for treatment of uterine leiomyomas.

OBJECTIVES: To compare women undergoing magnetic resonance-guided focused ultrasound (MRgFUS) to a group of contemporaneously recruited women undergoing total abdominal hysterectomy. Patient demographics, safety parameters, quality of life outcomes and disability measures are reported. METHODS: One hundred and nine women were recruited in seven centers for MRgFUS treatment and 83 women who underwent abdominal hysterectomy were recruited in seven separate centers to provide contemporaneous assessment of safety. The adverse-event profile and disability parameters were prospectively assessed. Patients were also screened at baseline and at 1, 3 and 6 months using the SF-36 health survey questionnaire. RESULTS: There were no life-threatening adverse events in either group. Overall, the number of significant clinical complications and adverse events was lower in women in the MRgFUS group compared to women undergoing hysterectomy. MRgFUS was associated with significantly faster recovery, including resumption of usual activities. At 6 months of follow-up, there were four (4%) treatment failures in the MRgFUS arm. Regarding SF-36 subscale scores, at 6 months there was improvement in all SF-36 subscales for both treatment groups. However, most of the SF-36 subscale scores were significantly better at this stage in the hysterectomy group than in the MRgFUS group. Women undergoing MRgFUS had steady improvement in all parameters throughout the 6-month follow-up period, despite the fact that they continued to have myomatous uteri and menstruation, which at baseline had given them significant symptomatology. CONCLUSIONS: The results of this study show that MRgFUS treatment of uterine leiomyomas leads to clinical improvement with fewer significant clinical complications and adverse events compared to hysterectomy at 6 months' follow-up.

Gonadotropins and the uterus: is there a gonad-independent pathway?

In the gonads, LH and hCG act via the same receptor to stimulate the production of progesterone in the luteal phase of the menstrual cycle and in early pregnancy. There are numerous reports that these two hormones can have direct actions on the uterus in addition to their indirect actions via stimulation of ovarian steroid hormones. However, unlike the situation in the gonads, various uterine tissues have been shown to respond to the related hormones FSH and TSH or the alpha-subunit common to these hormones. These additional actions cannot be mediated by the gonadal LH/hCG receptor. There have also been a series of reports that the uterus contains LH/hCG receptors. Attempts to characterize the molecular structure of these receptors have been difficult; thus, the possibility of a variant receptor cannot be excluded. The possibility also exists of a nonhomologous receptor, which would explain the differences in ligand specificity in uterine tissues. I will review the evidence regarding gonadotropin action in nongonadal tissues, primarily the uterus. In addition, the data regarding receptors will be reviewed. Finally, the clinical areas informed by this information will be explored.

Adenomyosis demonstrates increased expression of the basic fibroblast growth factor receptor/ligand system compared with autologous endometrium.

OBJECTIVES: Basic fibroblast growth factor (bFGF) is an angiogenic growth factor present in human endometrium and myometrium. Women with leiomyoma-related abnormal uterine bleeding have local dysregulation of bFGF and its type 1 receptor (FGF-R). This study was designed to evaluate if adenomyosis expresses bFGF and FGF-R, and if present, to compare bFGF and FGF-R expression in adenomyosis and autologous endometrium. DESIGN: Menopausal uteri containing endometrium and adenomyosis were analyzed using immunohistochemistry with monoclonal antibodies specific for bFGF, FGF-R, and proliferating cell nuclear antigen (PCNA), a marker of cellular proliferation. The expression and intensity of staining for bFGF, FGF-R, and PCNA were evaluated in the glandular epithelium and stroma of adenomyosis and endometrium. RESULTS: Glandular epithelial staining was significantly greater in adenomyosis compared with autologous endometrium for bFGF and FGF-R. Stromal staining for bFGF and PCNA was significantly increased in adenomyosis compared with autologous endometrium. CONCLUSIONS: Upregulation of the bFGF receptor/ligand system and increased cellular proliferation in adenomyosis may contribute to the pathogenesis of abnormal uterine bleeding associated with adenomyosis.

Uterine fibroids.

Uterine leiomyomas (fibroids or myomas), benign tumours of the human uterus, are the single most common indication for hysterectomy. They are clinically apparent in up to 25% of women and cause significant morbidity, including prolonged or heavy menstrual bleeding, pelvic pressure or pain, and, in rare cases, reproductive dysfunction. Thus, both the economic cost and the effect on quality of life are substantial. Surgery has been the mainstay of fibroid treatment, and various minimally invasive procedures have been developed in addition to hysterectomy and abdominal myomectomy. Formation of new leiomyomas after these conservative therapies remains a substantial problem. Although medications that manipulate concentrations of steroid hormones are effective, side-effects limit long-term use. A better approach may be manipulation of the steroid-hormone environment with specific hormone antagonists. There has been little evidence-based evaluation of therapy. New research into the basic biology of these neoplasms may add new treatment options for the future as the role of growth factors and genetic mutations in these tumours are better understood.

A high-resolution radiation hybrid map of the human genome draft sequence.

We have constructed a physical map of the human genome by using a panel of 90 whole-genome radiation hybrids (the TNG panel) in conjunction with 40,322 sequence-tagged sites (STSs) derived from random genomic sequences as well as expressed sequences. Of 36,678 STSs on the TNG radiation hybrid map, only 3604 (9.8%) were absent from the unassembled draft sequence of the human genome. Of 20,030 STSs ordered on the TNG map as well as the assembled human genome draft sequence and the Celera assembled human genome sequence, 36% of the STSs had a discrepant order between the working draft sequence and the Celera sequence. The TNG map order was identical to one of the two sequence orders in 60% of these discrepant cases.

The comparative constitution of twinship: strategies and paradoxes.

In both traditional and modern societies, twinship, as an unusual mode of reproduction, involves difficulties for social systems in maintaining consistent classification systems. It is proposed that the most prevalent response to twinship involves various 'strategies of normalisation' to defuse and contain the potential disruption. This proposition is illustrated and analysed in relation to ethnographic maternal drawn mainly (but not exclusively) from African communities in the twentieth century. Following a discussion of twin infanticide as the most extreme of the normalising strategies, the article concludes by identifying a number of paradoxes in the social construction of twinship.