Glenn D. Braunstein

Transdermal Testosterone Treatment in Women with Impaired Sexual Function after Oophorectomy

BACKGROUND The ovaries provide approximately half the circulating testosterone in premenopausal women. After bilateral oophorectomy, many women report impaired sexual functioning despite estrogen replacement. We evaluated the effects of transdermal testosterone in women who had impaired sexual function after surgically induced menopause. METHODS Seventy-five women, 31 to 56 years old, who had undergone oophorectomy and hysterectomy received conjugated equine estrogens (at least 0.625 mg per day orally) and, in random order, placebo, 150 microg of testosterone, and 300 microg of testosterone per day transdermally for 12 weeks each. Outcome measures included scores on the Brief Index of Sexual Functioning for Women, the Psychological General Well-Being Index, and a sexual-function diary completed over the telephone. RESULTS The mean (+/-SD) serum free testosterone concentration increased from 1.2+/-0.8 pg per milliliter (4.2+/-2.8 pmol per liter) during placebo treatment to 3.9+/-2.4 pg per milliliter (13.5+/-8.3 pmol per liter) and 5.9+/-4.8 pg per milliliter (20.5+/-16.6 pmol per liter) during treatment with 150 and 300 microg of testosterone per day, respectively (normal range, 1.3 to 6.8 pg per milliliter [4.5 to 23.6 pmol per liter]). Despite an appreciable placebo response, the higher testosterone dose resulted in further increases in scores for frequency of sexual activity and pleasure-orgasm in the Brief index of Sexual Functioning for Women (P=0.03 for both comparisons with placebo). At the higher dose the percentages of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased two to three times from base line. The positive-well-being, depressed-mood, and composite scores of the Psychological General Well-Being Index also improved at the higher dose (P=0.04, P=0.03, and P=0.04, respectively, for the comparison with placebo), but the scores on the telephone-based diary did not increase significantly. CONCLUSIONS In women who have undergone oophorectomy and hysterectomy, transdermal testosterone improves sexual function and psychological well-being.

A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone

Abstract With antiserum to the β-subunit of human chorionic gonadotropin (HCG), we have developed a radioimmunoassay which selectively measures HCG in samples containing both human pituitary luteinizing hormone (HLH) and HCG. High HLH levels observed in samples obtained at the midcycle peak or from castrate patients do not cause significant inhibition in the specific HCG radioimmunoassay. The sensitivity of the assay is sufficient for distinguishing HCG from follicular and luteal phase HLH levels. This specific HCG radioimmunoassay is ideal for following serum HCG levels in patients under going chemotherapy for HCG-secreting tumors as well as for follow-up of patients after termination of molar pregnancies. In addition, the sensitivity of the assay will permit earlier diagnosis of pregnancy which, in turn, would permit earlier therapeutic intervention if desired.

Management of the clinically inapparent adrenal mass ("incidentaloma").

The adrenals are triangular glands that sit atop each kidney. They influence or regulate the bodys metabolism, salt and water balance, and response to stress by secreting various hormones. Based on autopsy studies, adrenal masses are among the most common tumors in humans. At autopsy, an adrenal mass is found in at least 3% of persons older than age 50 years. Most adrenal masses cause no health problems. A small proportion, however, can lead to many serious hormonal diseases; approximately 1 of every 4000 adrenal tumors is malignant. Clinically inapparent adrenal masses are discovered inadvertently during diagnostic testing or treatment for other clinical conditions that are not related to suspicion of adrenal disease; thus, they are commonly known as incidentalomas. The definition of incidentaloma excludes patients undergoing imaging procedures as part of staging and work-up for cancer. Improvements in abdominal imaging techniques and technologies have increased detection of adrenal incidentalomas. Increasing clinical and scientific interest is reflected in a 20-fold increase in publications about this condition over the past three decades. When detected, clinically inapparent adrenal masses raise challenging questions for physicians and their patients. Diagnostic evaluation determines whether the lesion is hormonally active or nonfunctioning and whether it is malignant or benign. The test results will influence whether the mass is removed surgically or treated nonsurgically. Because the prevalence of these masses increases with age, appropriate management of adrenal tumors will be a growing challenge in our aging society. Over the past three decades, new information has become available regarding the epidemiology, biology, screening, treatment, and follow-up of adrenal tumors. For example, recent refinements in the field of minimally invasive surgery have made laparoscopic adrenalectomy a more frequently used method for removing adrenal masses. Recent reports suggest that up to 20% of patients with adrenal incidentaloma have some form of subclinical hormonal dysfunction and may represent a population at higher risk for metabolic disorders and cardiovascular disease. It is important to determine whether groups of patients with subclinical disease benefit from treatment. The psychological effect of the patients knowing that he or she harbors an adrenal incidentaloma, an incompletely understood clinical problem, merits investigation. A 2.5-day National Institutes of Health (NIH) state-of-the-science conference, Management of the Clinically Inapparent Adrenal Mass (Incidentaloma), was convened on 46 February 2002 to explore and assess the current knowledge regarding adrenal incidentalomas, so that health care providers and the general public can make informed decisions about this important public health issue. After 1.5 days of expert presentations and questions and public discussion by members of the panel and the audience of interested attendees on incidental adrenal masses, an independent, nonfederal panel weighed the evidence and drafted a statement that was presented on the third day of the conference. Expert presentations and the panels statement addressed the following questions: 1) What are the causes, prevalence, and natural history of clinically inapparent adrenal masses? 2) Based on available scientific evidence, what is the appropriate evaluation of a clinically inapparent adrenal mass? 3) What criteria should guide the decision on surgical versus nonsurgical management of these masses? 4) If surgery is indicated, what is the appropriate procedure? 5) What is the appropriate follow-up for patients for each management approach? and 6) What additional research is needed to guide practice? The panels draft statement was posted on the NIH Consensus Program Web site (consensus.nih.gov) on 6 February 2002. The primary sponsors of this meeting were the National Institute of Child Health and Human Development and the NIH Office of Medical Applications of Research. Cosponsors included the National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases. 1. What are the Causes, Prevalence, and Natural History of Clinically Inapparent Adrenal Masses? Clinically inapparent adrenal masses are detected incidentally with imaging studies conducted for other reasons. They may be clinically important because some are caused by adrenal cortical carcinomas (estimated prevalence, 4 to 12 per million), which have a high mortality rate. The other clinical concern is hormone overproduction from pheochromocytomas, aldosteronomas, and subclinical hypercortisolism, which may be associated with morbidity if untreated. Prevalence of Clinically Inapparent Adrenal Masses In autopsy series, the prevalence of clinically inapparent adrenal masses is about 2.1%. Because of increased use of noninvasive high-resolution imaging technology, clinically inapparent adrenal masses are being recognized more often. Estimates range from 0.1% for general health screening with ultrasonography to 0.42% among patients evaluated for nonendocrinologic symptoms to 4.3% among patients who have a previous diagnosis of cancer. In addition to source of data (autopsy versus clinical series) and reasons for imaging (cancer work-up, nonendocrinologic symptoms, and general health screening), the prevalence of clinically inapparent adrenal masses varies with age. The prevalence of clinically inapparent adrenal masses detected at autopsy is less than 1% for patients younger than 30 years of age and increases to 7% in patients 70 years of age or older. Many of these lesions detected at autopsy are very small. More patients with clinically inapparent adrenal masses are women. This probably reflects the sex distribution of the population undergoing imaging procedures. Autopsy studies or general health examinations show no evidence of difference in prevalence between men and women. There is insufficient information to determine whether the prevalence of clinically inapparent adrenal masses differs by the initial diagnostic test. Causes of Clinically Inapparent Adrenal Masses Clinically inapparent adrenal masses can be benign or malignant. These include adenomas, pheochromocytomas, myelolipomas, ganglioneuromas, adrenal cysts, hematomas, adrenal cortical carcinomas, metastases from other cancers, and other rare entities. The distributions of the pathologic origins of clinically inapparent adrenal masses vary with several clinically important factors, including cancer history and mass size. Three fourths of clinically inapparent adrenal masses among patients with cancer are metastatic lesions. In contrast, two thirds of clinically inapparent adrenal masses in populations with no history of cancer are benign tumors. Prevalence of primary adrenal cortical carcinoma is clearly related to the size of the tumor. Adrenal cortical carcinoma accounts for 2% of tumors that are 4 cm or less, 6% of tumors that are 4.1 to 6 cm, and 25% of tumors that are greater than 6 cm. Among unselected patients and those with nonendocrinologic symptoms, clinically inapparent adrenal masses are most often nonfunctioning tumors (approximately 70%). Approximately 5% to 10% of patients being evaluated for nonendocrinologic symptoms have subclinical hypercortisolism (sometimes called subclinical Cushing syndrome). The percentage of patients with subclinical hypercortisolism depends on the testing methods and cortisol levels achieved after dexamethasone suppression. The distribution of clinically inapparent adrenal masses derived from surgical series will overestimate the prevalence of adrenal cortical carcinoma, since suspicion of adrenal cortical carcinoma is an indication for surgery. Moreover, the reported frequency of adrenal cortical carcinomas is derived from highly selected patient populations and does not reflect the prevalence rates seen in population-based studies. The age and sex of the patient do not seem to help predict the presence of adrenal cortical carcinoma. Distribution estimates from autopsy studies are not biased by surgical indications but may not reflect the risk for adrenal cortical carcinoma among the subset of people undergoing abdominal imaging studies. A precise estimate of the risk for adrenal cortical carcinoma that could guide clinical decision making may not be possible. Almost all the reported large studies used imaging equipment that is now considered obsolete. The use of contemporary equipment may increase the prevalence of detected clinically inapparent adrenal masses and enhance our ability to differentiate adrenal cortical carcinomas from adenomas. In addition, the literature comprises mainly small, retrospective studies with variable definitions of clinically inapparent adrenal masses, which cause variation in the relative proportions of adrenal pathologic classifications. Natural History of Clinically Inapparent Adrenal Masses The observed natural history of clinically inapparent adrenal masses varies, depending on the composition of the study sample and the size and pathologic classification of the adrenal mass. Patients with or without a previous cancer diagnosis found to have adrenal gland metastatic lesions will have a clinical course defined by the stage, grade, and site of the primary tumor. Usually, large clinically inapparent adrenal masses (>6 cm) are treated surgically. Approximately 25% of masses greater than 6 cm in diameter are adrenal cortical carcinomas, and these patients have poor clinical outcomes. Most studies report less than 50% 5-year overall survival for adrenal cortical carcinoma, and several report less than 50% 2-year overall survival. Inconclusive evidence suggests that adrenalectomy at stage 1 or 2 may improve the survival rate. Follow-up of patients with nonfunctioning adrenal masses suggests that 5% to 25% of masses increase in size by at least 1 cm. The threshold for clinically significant

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.

Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health--National Heart, Lung, and Blood Institute sponsored Women's Ischemia Syndrome Evaluation.

BACKGROUND Women with polycystic ovary syndrome (PCOS) have a greater clustering of cardiac risk factors. However, the link between PCOS and cardiovascular (CV) disease is incompletely described. OBJECTIVE The aim of this analysis was to evaluate the risk of CV events in 390 postmenopausal women enrolled in the National Institutes of Health-National Heart, Lung, and Blood Institute (NIH-NHLBI) sponsored Womens Ischemia Syndrome Evaluation (WISE) study according to clinical features of PCOS. METHODS A total of 104 women had clinical features of PCOS defined by a premenopausal history of irregular menses and current biochemical evidence of hyperandrogenemia. Hyperandrogenemia was defined as the top quartile of androstenedione (> or = 701 pg/ml), testosterone (> or = 30.9 ng/dl), or free testosterone (> or = 4.5 pg/ml). Cox proportional hazard model was fit to estimate CV death or myocardial infarction (n = 55). RESULTS Women with clinical features of PCOS were more often diabetic (P < 0.0001), obese (P = 0.005), had the metabolic syndrome (P < 0.0001), and had more angiographic coronary artery disease (CAD) (P = 0.04) compared to women without clinical features of PCOS. Cumulative 5-yr CV event-free survival was 78.9% for women with clinical features of PCOS (n = 104) vs. 88.7% for women without clinical features of PCOS (n = 286) (P = 0.006). PCOS remained a significant predictor (P < 0.01) in prognostic models including diabetes, waist circumference, hypertension, and angiographic CAD as covariates. CONCLUSION Among postmenopausal women evaluated for suspected ischemia, clinical features of PCOS are associated with more angiographic CAD and worsening CV event-free survival. Identification of postmenopausal women with clinical features of PCOS may provide an opportunity for risk factor intervention for the prevention of CAD and CV events.

Testosterone for Low Libido in Postmenopausal Women Not Taking Estrogen

BACKGROUND The efficacy and safety of testosterone treatment for hypoactive sexual desire disorder in postmenopausal women not receiving estrogen therapy are unknown. METHODS We conducted a double-blind, placebo-controlled, 52-week trial in which 814 women with hypoactive sexual desire disorder were randomly assigned to receive a patch delivering 150 or 300 microg of testosterone per day or placebo. Efficacy was measured to week 24; safety was evaluated over a period of 52 weeks, with a subgroup of participants followed for an additional year. The primary end point was the change from baseline to week 24 in the 4-week frequency of satisfying sexual episodes. RESULTS At 24 weeks, the increase in the 4-week frequency of satisfying sexual episodes was significantly greater in the group receiving 300 microg of testosterone per day than in the placebo group (an increase of 2.1 episodes vs. 0.7, P<0.001) but not in the group receiving 150 microg per day (1.2 episodes, P=0.11). As compared with placebo, both doses of testosterone were associated with significant increases in desire (300 microg per day, P<0.001; 150 microg per day, P=0.04) and decreases in distress (300 microg per day, P<0.001; 150 microg per day, P=0.04). The rate of androgenic adverse events - primarily unwanted hair growth - was higher in the group receiving 300 microg of testosterone per day than in the placebo group (30.0% vs. 23.1%). Breast cancer was diagnosed in four women who received testosterone (as compared with none who received placebo); one of the four received the diagnosis in the first 4 months of the study period, and one, in retrospect, had symptoms before undergoing randomization. CONCLUSIONS In postmenopausal women not receiving estrogen therapy, treatment with a patch delivering 300 microg of testosterone per day resulted in a modest but meaningful improvement in sexual function. The long-term effects of testosterone, including effects on the breast, remain uncertain. (ClinicalTrials.gov number, NCT00131495.)

Serum human chorionic gonadotropin levels throughout normal pregnancy.

Human chorionic gonadotropin (hCG) levels were measured in the sera of 443 pregnant women by the beta-hCG radioimmunoassay in order to determine if the third-trimester secondary peak in hCG levels observed by less specific immunoassays was due to cross-reacting substances. hCG was detected as early as six days after presumed conception and peaked between 56 and 68 days, with a nadir at 18 weeks. No secondary rise in hCG levels was demonstrated, indicating that the nonspecific hCG immunoassays give spuriously high values for hCG during the last trimester of pregnancy.

Hypoestrogenemia of hypothalamic origin and Coronary artery disease in Premenopausal women: A report from the NHLBI-sponsored WISE study

OBJECTIVES We sought to evaluate hypoestrogenemia of hypothalamic origin and its association with angiographic coronary artery disease (CAD) in premenopausal women. BACKGROUND Coronary artery disease in premenopausal women appears to have a particularly poor prognosis. Primate animal data suggest that premenopausal CAD is strongly determined by psychosocial stress-induced central disruption of ovulatory cycling and resulting hypoestrogenemia. METHODS We assessed reproductive hormone blood levels and angiographic CAD using core laboratories in 95 premenopausal women with coronary risk factors who were enrolled in the National Heart, Lung, and Blood Institute-sponsored Womens Ischemia Syndrome Evaluation and were undergoing coronary angiography for evaluation for suspected ischemia. RESULTS Premenopausal women with angiographic CAD (n = 13) had significantly lower estradiol, bioavailable estradiol, and follicle-stimulating hormone (FSH) (all p < 0.05) than women without angiographic CAD (n = 82), even after controlling for age. Hypoestrogenemia of hypothalamic origin, defined as estradiol <184 pmol/l (50 pg/ml), FSH <10 IU/l, and luteinizing hormone <10 IU/l, was significantly more prevalent among the women with CAD than those without CAD (9/13 [69%] vs. 24/82 [29%], respectively, p = 0.01). Hypoestrogenemia of hypothalamic origin was the most powerful predictor of angiographic CAD in a multivariate model (odds ratio [OR] 7.4 [confidence interval (CI) 1.7 to 33.3], p = 0.008). Anxiolytic/sedative/hypnotic and antidepressant medication use were independent predictors of hypoestrogenemia of hypothalamic origin in a multivariate model (OR 4.6 [CI 1.3 to 15.7], p = 0.02, OR 0.10 [CI 0.01 to 0.92], p = 0.04, respectively). CONCLUSIONS Among premenopausal women undergoing coronary angiography for suspected myocardial ischemia, disruption of ovulatory cycling characterized by hypoestrogenemia of hypothalamic origin appears to be associated with angiographic CAD.

Meta-Analysis: Angiotensin-Receptor Blockers in Chronic Heart Failure and High-Risk Acute Myocardial Infarction

Angiotensin-receptor blockers (ARBs) were first introduced into the marketplace in the early 1990s and have been used to treat various conditions, including hypertension and heart failure (1). Angiotensin-receptor blockers reduce afterload and increase cardiac output in heart failure (2, 3), similar to the mechanism of action seen with angiotensin-converting enzyme (ACE) inhibitors, while also reversing left ventricular remodeling (4). The benefits of ACE inhibitors might also be partly attributed to prevention of the formation of inflammatory cytokines by angiotensin II (5-7). A study has suggested that ARBs could share similar anti-inflammatory properties (6). The American College of Cardiology/American Heart Association (ACC/AHA) (8) and the Heart Failure Society of America (HFSA) (9) recommend that ACE inhibitors be preferred over ARBs for patients with heart failure and left ventricular systolic dysfunction but state that ARBs may be considered for patients who are intolerant of ACE inhibitors. Furthermore, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) (10) and the Centers for Medicare & Medicaid Services (CMS) (11) have defined quality indicators for patients with heart failure and acute myocardial infarction (MI), which currently include administering ACE inhibitors as first-line therapy for patients with an ejection fraction less than 0.40. Neither JCAHO nor the CMS has defined quality indicators for ARB administration, and they have not recognized ARB therapy as an acceptable reason for not administering ACE inhibitors. This may have occurred partly because of the inconclusive and conflicting nature of the data in previously published randomized, controlled trials about the effect of ARBs on death and hospitalizations. A 2000 systematic review by Flather and colleagues (12) showed that ACE inhibitors result in lower mortality and heart failure hospitalizations as compared with placebo in patients with heart failure and left ventricular systolic dysfunction. However, a 2002 meta-analysis by Jong and colleagues (13) included randomized, controlled trials published up to May 2001 and showed no statistically significant difference in mortality or heart failure hospitalization rates between ARBs and placebo in patients with heart failure and left ventricular systolic dysfunction. Since May 2001, the largest series of randomized, controlled trials evaluating ARBs in chronic heart failure, Candesartan in Heart FailureAssessment of Reduction in Mortality and Morbidity (CHARM) (14-17), has been published. In the CHARM-Alternative trial (15), patients who were intolerant of ACE inhibitors were randomly assigned to candesartan or placebo. The results showed that candesartan was associated with a statistically significant reduction in heart failure hospitalization but only a nonstatistically significant reduction in all-cause mortality. Data from randomized, controlled trials evaluating ARBs and ACE inhibitors in patients with high-risk acute MI (defined as acute MI complicated by heart failure) have also been recently published in the Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) (18) and Valsartan in Acute Myocardial Infarction (VALIANT) trial (19). Researchers have recommended that meta-analyses be continually updated as new and relevant randomized, controlled trials are published since meta-analyses may quickly become outdated (20, 21). The objective of this meta-analysis is to incorporate data from recently published randomized, controlled trials into the pool of evidence and to determine whether recently published research affects the statistical significance of efficacy outcomes for the use of ARBs in chronic heart failure and high-risk acute MI. Methods Data Sources We reviewed the medical literature to identify studies evaluating the efficacy of ARBs in patients with chronic heart failure and high-risk acute MI. We searched for articles from the following medical bibliographic databases: Cochrane Central Register of Controlled Trials (third quarter 2003), Cochrane Database of Systematic Reviews (third quarter 2003), Cumulative Index to Nursing and Allied Health Literature (1982 to November week 1 2003), Database of Abstracts of Reviews of Effects (third quarter 2003), HealthSTAR (1975 to October 2003), and MEDLINE (1966 to present). The search included terms related to heart failure and acute MI (cardiac failure, cardiac insufficiency, congestive heart failure, coronary disease, heart failure, and myocardial infarction) that were combined with terms related to ARBs (angiotensin receptors, candesartan, elisartan, embusartan, eprosartan, forasartan, irbesartan, losartan, olmesartan, saprisartan, tasosartan, telmisartan, valsartan, and zolasartan) using Boolean operators and syntax that were appropriate for each database. We also manually searched references from selected clinical trials and review articles. Finally, we reviewed abstracts from the 2002 and 2003 conference proceedings of the ACC, AHA, Canadian Cardiovascular Society (CCS), European Society of Cardiology (ESC), and HFSA. Study Selection We followed a written protocol with explicit article selection criteria. We rejected articles at the title and abstract stage if they were not randomized, controlled trials; were not written in English; did not address patients with chronic heart failure or high-risk acute MI; did not compare ARBs versus an appropriate control group (ARBs vs. placebo, ARBs vs. ACE inhibitors, or ARB plus ACE inhibitor combinations vs. ACE inhibitors alone); or did not enroll human participants. We subjected the full text of remaining articles to the same criteria and rejected them if all-cause mortality and heart failure hospitalization outcomes were not reported or the follow-up duration was less than 4 weeks. Data Extraction Two reviewers used a standardized form to independently extract information on study design, sample characteristics, sample size, intervention strategies, outcome measures, and other study characteristics from included randomized, controlled trials. We assessed the methodologic quality of randomized, controlled trials by using a scoring system developed by Jadad and colleagues (22). We obtained raw data, when available, for all-cause mortality and heart failure hospitalization outcomes from intention-to-treat analyses. Heart failure hospitalization was defined as the number of patients with 1 or more postrandomization admissions for heart failure, for complications from treatment of heart failure, or for management of comorbid conditions associated with heart failure. For studies in which patients were randomly assigned to 1 of several dosage groups of the same study medication, we pooled outcomes from those groups for the analysis. We resolved discrepancies through discussion and consensus opinion or by contacting the corresponding author of the original clinical trial. Statistical Analysis We calculated values for agreement by using the methods described by Fleiss (23). We calculated an odds ratio for each study outcome to allow for pooling of similar outcomes. For studies in which 1 of the randomization groups had no events, we used a continuity correction factor (that is, adding 0.5 to each cell) to avoid dividing by 0 (23). We reported results as the pooled odds ratio with 95% CIs. We calculated pooled odds ratios and 95% CIs for random-effects models on the basis of the methods of DerSimonian and Laird (24), and we used the MantelHaenszel (25) method for fixed-effects models. We used a chi-square test to assess heterogeneity. We sorted data into 3 main comparison groups: ARBs versus placebo, ARBs versus ACE inhibitors, and ARB and ACE inhibitor combinations versus ACE inhibitors alone (including comparisons of ARBs vs. placebo for studies in which patients received ACE inhibitors in both groups). We performed sensitivity analyses for each group to determine how the prespecification of end points influenced results. In the presence of statistical heterogeneity, defined as a chi-square test P value less than 0.10, we analyzed the data by using random-effects models. Otherwise, we used fixed-effects models. The P value threshold for statistical significance was set at 0.05 for effect sizes. We performed statistical calculations by using Stata, version 8.1 (Stata Corp., College Station, Texas), and RevMan, version 4.2.6 (The Cochrane Collaboration, Oxford, United Kingdom). We generated a funnel plot (by using Excel 2000 [Microsoft Corp., Redmond, Washington]) of randomized, controlled trials with estimable odds ratios for all-cause mortality in chronic heart failure to assess the presence of publication bias. We plotted the inverse of the standard error of the natural logarithm of the odds ratio against the natural logarithm of the odds ratio. Role of the Funding Source The funding source had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Data Synthesis Included Studies Figure 1 presents an article flow diagram. From the initial search of all medical bibliographic databases, we identified 1603 articles. After we excluded duplicates, 1158 unique records remained. On the basis of prespecified exclusion criteria, we rejected 1074 articles during title and abstract review. The value from the title and abstract review was 0.76. We rejected another 62 articles during the full-text review, yielding a total of 22 articles. We excluded 1 study (26) from the pooled analysis because we could not reconcile the distribution of patient deaths across study groups despite communication with the corresponding author. A manual search of relevant articles revealed 2 additional phase III randomized, controlled trials (27) whose raw data were presented in a meta-analysis, as well as the VALIANT study (19), which was published on the day of our search. Our search of abstracts f

First-trimester chorionic gonadotropin measurements as an aid in the diagnosis of early pregnancy disorders.

Abstract In order to evaluate the usefulness of serial human chorionic gonadotropin (hCG) levels as a first-trimester placental function test, we prospectively collected 685 serum samples from 256 women during the first 100 days of gestation. Dating of the samples was based upon the thermal shift in the basal body temperature (BBT). Human chorionic gonadotropin was measured by use of a sensitive and relatively specific radioimmunoassay, and the results were correlated with the outcome of pregnancy. The 90 per cent tolerance limits for normal serum hCG levels were established by measurements made on 489 samples obtained from 187 pregnancies. A pregnancy was judged to be abnormal if two or more serum samples collected at two-week intervals showed hCG levels above or below the 90 per cent tolerance limits 14 or more days after the BBT shift. Using this criterion, 1.6 per cent of normal pregnancies, 57.6 per cent of pregnancies which terminated in a spontaneous first- or second-trimester abortion, 100 per cent of ectopic pregnancies, and 60 per cent of pregnancies complicated by multiple gestations showed abnormal first-trimester serum hCG levels. The predictive value of serial hCG measurements was further demonstrated by a second prospective study in 28 patients for whom the outcome of the pregnancy was predicted based upon the normal range. All of the normal pregnancies were correctly identified, while 88.9 per cent of the pregnancies resulting in spontaneous abortions and all of the ectopic pregnancies were correctly predicted to be abnormal. These results indicate that the majority of patients with ectopic pregnancies or those whose pregnancies are destined to terminate in a first- or second-trimester spontaneous abortion will have abnormally low serum hCG levels. We conclude that serial first-trimester serum hCG determinations are useful for distinguishing between normal and abnormal trophoblastic function.