Antibiotic prophylaxis for elective hysterectomy.

BACKGROUND: Elective hysterectomy is commonly performed for benign gynaecological conditions. Hysterectomy can be performed abdominally, laparoscopically, or vaginally, with or without laparoscopic assistance. Antibiotic prophylaxis consists of administration of antibiotics to reduce the rate of postoperative infection, which otherwise affects 40%-50% of women after vaginal hysterectomy, and more than 20% after abdominal hysterectomy. No Cochrane review has systematically assessed evidence on this topic. OBJECTIVES: To determine the effectiveness and safety of antibiotic prophylaxis in women undergoing elective hysterectomy. SEARCH METHODS: We searched electronic databases to November 2016 (including the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Studies (CRSO), MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as clinical trials registers, conference abstracts, and reference lists of relevant articles. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing use of antibiotics versus placebo or other antibiotics as prophylaxis in women undergoing elective hysterectomy. DATA COLLECTION AND ANALYSIS: We used Cochrane standard methodological procedures. MAIN RESULTS: We included in this review 37 RCTs, which performed 20 comparisons of various antibiotics versus placebo and versus one another (6079 women). The quality of the evidence ranged from very low to moderate. The main limitations of study findings were risk of bias due to poor reporting of methods, imprecision due to small samples and low event rates, and inadequate reporting of adverse effects. Any antibiotic versus placebo Vaginal hysterectomyModerate-quality evidence shows that women who received antibiotic prophylaxis had fewer total postoperative infections (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.19 to 0.40; five RCTs, N = 610; I2 = 85%), less urinary tract infection (UTI) (RR 0.58, 95% CI 0.43 to 0.77; eight RCTs, N = 1790; I2 = 44%), fewer pelvic infections (RR 0.28, 95% CI 0.20 to 0.39; 11 RCTs, N = 2010; I2 = 57%), and fewer postoperative fevers (RR 0.43, 95% CI 0.34 to 0.54; nine RCTs, N = 1879; I2 = 48%) than women who did not receive such prophylaxis. This suggests that antibiotic prophylaxis reduces the average risk of postoperative infection from about 34% to 7% to 14%. Whether this treatment has led to differences in rates of other serious infection remains unclear (RR 0.20, 95% CI 0.01 to 4.10; one RCT, N = 146; very low-quality evidence).Data were insufficient for comparison of adverse effects. Abdominal hysterectomyWomen who received antibiotic prophylaxis of any class had fewer total postoperative infections (RR 0.16, 95% CI 0.06 to 0.38; one RCT, N = 345; low-quality evidence), abdominal wound infections (RR 0.64, 95% CI 0.45 to 0.92; 11 RCTs, N = 2434; I2 = 0%; moderate-quality evidence), UTIs (RR 0.39, 95% CI 0.29 to 0.51; 11 RCTs, N = 2547; I2 = 26%; moderate-quality evidence), pelvic infections (RR 0.50, 95% CI 0.35 to 0.71; 11 RCTs, N = 1883; I2 = 11%; moderate-quality evidence), and postoperative fevers (RR 0.60, 95% CI 0.51 to 0.70; 11 RCTs, N = 2581; I2 = 51%; moderate-quality evidence) than women who did not receive prophylaxis, suggesting that antibiotic prophylaxis reduces the average risk of postoperative infection from about 16% to 1% to 6%. Whether this treatment has led to differences in rates of other serious infection remains unclear (RR 0.44, 95% CI 0.12 to 1.69; two RCTs, N = 476; I2 = 29%; very low-quality evidence).It is unclear whether rates of adverse effects differed between groups (RR 1.80, 95% CI 0.62 to 5.18; two RCTs, N = 430; I2 = 0%; very low-quality evidence). Head-to-head comparisons between antibiotics Vaginal hysterectomyWe identified four comparisons: cephalosporin versus penicillin (two RCTs, N = 470), cephalosporin versus tetracycline (one RCT, N = 51), antiprotozoal versus lincosamide (one RCT, N = 80), and cephalosporin versus antiprotozoal (one RCT, N = 78). Data show no evidence of differences between groups for any of the primary outcomes, except that fewer cases of total postoperative infection and postoperative fever were reported in women who received cephalosporin than in those who received antiprotozoal.Only one comparison (cephalosporin vs penicillin; two RCTs, N = 451) yielded data on adverse effects and showed no differences between groups. Abdominal hysterectomyWe identified only one comparison: cephalosporin versus penicillin (N = 220). Data show no evidence of differences between groups for any of the primary outcomes. Adverse effects were not reported. Combined antibiotics versus single antibiotics Vaginal hysterectomyWe identified three comparisons: cephalosporin plus antiprotozoal versus cephalosporin (one RCT, N = 78), cephalosporin plus antiprotozoal versus antiprotozoal (one RCT, N = 78), and penicillin plus antiprotozoal versus penicillin (one RCT, N = 230). Data were unavailable for most outcomes, including adverse effects. We found no evidence of differences between groups, except that fewer women receiving cephalosporin with antiprotozoal received a diagnosis of total postoperative infection, UTI, or postoperative fever compared with women receiving antiprotozoal. Abdominal hysterectomyWe identified one comparison (penicillin plus antiprotozoal vs penicillin only; one RCT, N = 230). Whether differences between groups occurred was unclear. Adverse effects were not reported. Comparison of cephalosporins in different regimensSingle small trials addressed dose comparisons and provided no data for most outcomes, including adverse effects. Whether differences between groups occurred was unclear. No trials compared route of administration.The quality of evidence for all head-to-head and dose comparisons was very low owing to very serious imprecision and serious risk of bias related to poor reporting of methods. AUTHORS' CONCLUSIONS: Antibiotic prophylaxis appears to be effective in preventing postoperative infection in women undergoing elective vaginal or abdominal hysterectomy, regardless of the dose regimen. However, evidence is insufficient to show whether use of prophylactic antibiotics influences rates of adverse effects. Similarly, evidence is insufficient to show which (if any) individual antibiotic, dose regimen, or route of administration is safest and most effective. The most recent studies included in this review were 14 years old at the time of our search. Thus findings from included studies may not reflect current practice in perioperative and postoperative care and may not show locoregional antimicrobial resistance patterns.

Recommendations for data monitoring committees from the Clinical Trials Transformation Initiative.

Background/aims Use of data monitoring committees to oversee clinical trials was first proposed nearly 50 years ago. Since then, data monitoring committee use in clinical trials has increased and evolved. Nonetheless, there are no well-defined criteria for determining the need for a data monitoring committee, and considerable variability exists in data monitoring committee composition and conduct. To understand and describe the role and function of data monitoring committees, and establish best practices for data monitoring committee trial oversight, the Clinical Trials Transformation Initiative-a public-private partnership to improve clinical trials-launched a multi-stakeholder project. Methods The data monitoring committee project team included 16 individuals charged with (1) clarifying the purpose of data monitoring committees, (2) identifying best practices for independent data monitoring committee conduct, (3) describing effective communication practices, and (4) developing strategies for training data monitoring committee members. Evidence gathering included a survey, a series of focus group discussions, and a 2-day expert meeting aimed at achieving consensus opinions that form the foundation of our data monitoring committee recommendations. Results We define the role of the data monitoring committee as an advisor to the research sponsor on whether to continue, modify, or terminate a trial based on periodic assessment of trial data. Data monitoring committees should remain independent from the sponsor and be composed of members with no relevant conflicts of interest. Representation on a data monitoring committee generally should include at least one clinician with expertise in the therapeutic area being studied, a biostatistician, and a designated chairperson who has experience with clinical trials and data monitoring. Data monitoring committee meetings are held periodically to evaluate the unmasked data from ongoing trials, but the content and conduct of meetings may vary depending on specific goals or topics for deliberation. To guide data monitoring committee conduct and communication plans, a charter consistent with the protocol's research design and statistical analysis plan should be developed and agreed upon by the sponsor and the data monitoring committee prior to patient enrollment. We recommend concise and flexible charters that explain roles, responsibilities, operational issues, and how data monitoring committee recommendations are generated and communicated. The demand for data monitoring committee members appears to exceed the current pool of qualified individuals. To prepare a new generation of trained data monitoring committee members, we encourage a combination of didactic educational programs, practical experience, and skill development through apprenticeships and mentoring by experienced data monitoring committee members. Conclusion Our recommendations address data monitoring committee use, conduct, communication practices, and member preparation and training. Furthermore recommendations form the foundation for ongoing efforts to improve clinical trial oversight and enhance the safety and integrity of clinical research. These recommendations serve as a call to action for implementation of best practices that benefit study participants, study sponsors, and society.

Data monitoring committees: Promoting best practices to address emerging challenges.

BACKGROUND AND PURPOSE: Data monitoring committees are responsible for safeguarding the interests of study participants and assuring the integrity and credibility of clinical trials. The independence of data monitoring committees from sponsors and investigators is essential in achieving this mission. Creative approaches are needed to address ongoing and emerging challenges that potentially threaten data monitoring committees' independence and effectiveness. METHODS: An expert panel of representatives from academia, industry and government sponsors, and regulatory agencies discussed these challenges and proposed best practices and operating principles for effective functioning of contemporary data monitoring committees. RESULTS AND CONCLUSIONS: Prospective data monitoring committee members need better training. Options could include didactic instruction as well as apprenticeships to provide real-world experience. Data monitoring committee members should be protected against legal liability arising from their service. While avoiding breaches in confidentiality of interim data remains a high priority, data monitoring committees should have access to unblinded efficacy and safety data throughout the trial to enable informed judgments about risks and benefits. Because overly rigid procedures can compromise their independence, data monitoring committees should have the flexibility necessary to best fulfill their responsibilities. Data monitoring committee charters should articulate principles that guide the data monitoring committee process rather than list a rigid set of requirements. Data monitoring committees should develop their recommendations by consensus rather than through voting processes. The format for the meetings of the data monitoring committee should maintain the committee's independence and clearly establish the leadership of the data monitoring committee chair. The independent statistical group at the Statistical Data Analysis Center should have sufficient depth of knowledge about the study at hand and experience with trials in general to ensure that the data monitoring committee has access to timely, reliable, and readily interpretable insights about emerging evidence in the clinical trial. Contracts engaging data monitoring committee members for industry-sponsored trials should have language customized to the unique responsibilities of data monitoring committee members rather than use language appropriate to consultants for product development. Regulatory scientists would benefit from experiencing data monitoring committee service that does not conflict with their regulatory responsibilities.

Effects of SLC22A1 Polymorphisms on Metformin-Induced Reductions in Adiposity and Metformin Pharmacokinetics in Obese Children With Insulin Resistance.

Steady-state population pharmacokinetics of a noncommercial immediate-release metformin (hydrochloride) drug product were characterized in 28 severely obese children with insulin resistance. The concentration-time profiles with double peaks were well described by a 1-compartment model with 2 absorption sites. Mean population apparent clearance (CL/F) was 68.1 L/h, and mean apparent volume of distribution (V/F) was 28.8 L. Body weight was a covariate of CL/F and V/F. Estimated glomerular filtration rate was a significant covariate of CL/F (P < .001). SLC22A1 genotype did not significantly affect metformin pharmacokinetics. The response to 6 months of metformin treatment (HbA1c , homeostasis model assessment for insulin resistance, fasting insulin, and glucose changes) did not differ between SLC22A1 wild-type subjects and carriers of presumably low-activity SLC22A1 alleles. However, SLC22A1 variant carriers had smaller reductions in percentage of total trunk fat after metformin therapy, although the percentage reduction in trunk fat was small. The median % change in trunk fat was -2.20% (-9.00% to 0.900%) and -1.20% (-2.40% to 7.30%) for the SLC22A1 wild-type subjects and variant carriers, respectively. Future study is needed to evaluate the effects of SLC22A1 polymorphisms on metformin-mediated weight reduction in obese children.

Understanding the functions and operations of data monitoring committees: Survey and focus group findings.

BACKGROUND: The use of data monitoring committees in the conduct of clinical trials has increased and evolved, but there is a lack of published information on when data monitoring committees are needed and utilized, the acceptable range of data monitoring committee practices, and appropriate qualifications of data monitoring committee members. METHODS: To gain a better understanding of data monitoring committee operations and areas for improvement, the Clinical Trials Transformation Initiative conducted a survey and set of focus groups. A total of 143 respondents completed the online survey: 76 data monitoring committee members, 52 sponsors involved with organization of data monitoring committees, and 15 statistical data analysis center representatives. There were 42 focus group participants, including data monitoring committee members; patients and/or patient advocate data monitoring committee members; institutional review board and US Food and Drug Administration representatives; industry, government, and non-profit sponsors; and statistical data analysis center representatives. RESULTS: Participants indicated that the primary responsibility of a data monitoring committee is to be an independent advisory body representing the interests of trial participants by assessing the risk and benefit ratio in ongoing trials. They noted that data monitoring committees must have access to unmasked data in order to perform this role. No clear consensus emerged regarding specific criteria for requiring a data monitoring committee for a given trial, and some participants felt data monitoring committees may be overused. Respondents offered suggestions for the data monitoring committee charter and communications with sponsors, institutional review boards, and regulators. Overall, data monitoring committee members reported that they are able to function independently and their recommendations are almost always accepted by the sponsor. Participants indicated that there are no standards or guidelines pertaining to qualifications of data monitoring committee members. Furthermore, only 8% (6/72) of data monitoring committee member survey respondents received any formal training, and 94% (68/72) were not aware of any training programs. CONCLUSION: Findings from the survey and focus groups provide a better understanding of contemporary data monitoring committee operations and insights regarding challenges and best practices. Overall, it was clear that increased training will be needed to prepare the next generation of qualified data monitoring committee members to meet the growing demand. These findings can be used by Clinical Trials Transformation Initiative and others to develop recommendations and tools to improve data monitoring committee operations and the overall quality of trial oversight.

A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that crosses the blood-brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7 alleles. METHODS: Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, double-blind, placebo-controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period. RESULTS: No safety issues were identified in this study. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 ± 8.4% on placebo to 6.1 ± 5.5% on simvastatin (P < 0.005); we observed a trend toward decreased cerebrospinal fluid dehydrocholesterol concentrations. A significant improvement (P = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist-C when subjects were taking simvastatin. CONCLUSION: This article reports what is, to our knowledge, the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin seems to be relatively safe in patients with SLOS, improves the serum dehydrocholesterol-to-total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS.Genet Med 19 3, 297-305.

Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement.

CONTEXT: Women with primary ovarian insufficiency have significantly lower serum estradiol and T levels compared with regularly menstruating women. They also have significantly reduced bone mineral density (BMD). OBJECTIVE: The objective of the study was to evaluate the efficacy of hormone replacement in maintaining BMD in these young women. DESIGN AND SETTING: This was a randomized, double-blind, single-center, placebo-controlled clinical trial at the National Institutes of Health clinical center (Bethesda, Maryland). PARTICIPANTS: Young women with primary ovarian insufficiency participated in the study. INTERVENTIONS: We compared the effect of estradiol and progestin replacement (n = 72) vs estradiol, progestin, and T replacement (n = 73) on BMD. We also compared findings with a contemporaneous control group of normal women (n = 70). All patients received transdermal estradiol (100 µg/d) plus oral medroxyprogesterone acetate 10 mg/d (12 d/mo) for a 3-month run-in period before being randomized in a double-blinded fashion to the addition of transdermal T (150 µg/d) or placebo. MAIN OUTCOME MEASURE: Change in BMD at the femoral neck was measured by dual-energy x-ray absorptiometry. RESULTS: At screening, patients had significantly lower femoral neck BMD compared with control women (0.77 vs 0.81 g/cm(2), P = .001) and did not differ in body mass index, age at menarche, or education level. Normal control women lost femoral neck BMD over the study period, whereas patients on estradiol and progestin therapy gained BMD; and at the end of the study period, femoral neck BMD of patients on estradiol and progestin therapy did not differ from that of control women (0.80 g/cm(2) in both groups, P = .9). The addition of T showed no further benefit (percentage change in BMD 3.9 vs 2.4, respectively, P = .9). Nonetheless, using a repeated-measures model, the T group achieved a mean BMD in the femoral neck 0.015 g/cm(2) higher than the placebo group at 3 years (95% confidence interval -0.005 to 0.034, P = .13). Similar findings were observed in the lumbar spine BMD as well. CONCLUSION: Long-term physiological transdermal estradiol replacement in combination with oral medroxyprogesterone acetate restores mean femoral neck BMD to normal in young women with spontaneous 46,XX primary ovarian insufficiency. However, the addition of physiological transdermal T replacement did not provide additional benefit.

Effects of physiologic testosterone therapy on quality of life, self-esteem, and mood in women with primary ovarian insufficiency.

OBJECTIVE: Women with primary ovarian insufficiency (POI) display low androgen levels, which could contribute to mood and behavioral symptoms observed in this condition. We examined the effects of physiologic testosterone therapy added to standard estrogen/progestin therapy on quality of life, self-esteem, and mood in women with POI. METHODS: One hundred twenty-eight women with 46,XX spontaneous POI participated in a 12-month randomized, placebo-controlled, parallel-design investigation of the efficacy of testosterone augmentation of estrogen/progestin therapy. Quality of life, self-esteem, and mood symptoms were evaluated with standardized rating scales and a structured clinical interview. Differences in outcome measures between the testosterone and placebo treatments were analyzed by Wilcoxon rank sum tests. RESULTS: No differences in baseline characteristics, including serum hormone levels (P > 0.05), were found. Baseline mean (SD) Center for Epidemiologic Studies Depression Scale scores were 10.7 (8.6) and 9.2 (7.8) for testosterone and placebo, respectively (P = 0.35). After 12 months of treatment, measures of quality of life, self-esteem, and mood symptoms did not differ between treatment groups. Serum testosterone levels achieved physiologic levels in the testosterone group and were significantly higher compared with placebo (P < 0.001). Baseline testosterone levels were not associated with either adverse or beneficial clinical effects. CONCLUSIONS: A 150-µg testosterone patch achieves physiologic hormone levels in women with POI. Our findings suggest that augmentation of standard estrogen/progestin therapy with physiologic testosterone therapy in young women with POI neither aggravates nor improves baseline reports of quality of life or self-esteem and had minimal effects on mood. Other mechanisms might play a role in the altered mood accompanying this disorder.

Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial.

OBJECTIVE: Metformin can decrease adiposity and ameliorate obesity-related comorbid conditions, including abnormalities in glucose homeostasis in adolescents, but there are few data evaluating the efficacy of metformin among younger children. Our objective was to determine whether metformin treatment causes weight loss and improves obesity-related comorbidities in obese children, who are insulin-resistant. RESEARCH DESIGN AND METHODS: This study was a randomized double-blind placebo-controlled trial consisting of 100 severely obese (mean BMI 34.6 ± 6.6 kg/m(2)) insulin-resistant children aged 6-12 years, randomized to 1,000 mg metformin (n = 53) or placebo (n = 47) twice daily for 6 months, followed by open-label metformin treatment for 6 months. All children and their parents participated in a monthly dietitian-administered weight-reduction program. RESULTS: Eighty-five percent completed the 6-month randomized phase. Children prescribed metformin had significantly greater decreases in BMI (difference -1.09 kg/m(2), CI -1.87 to -0.31, P = 0.006), body weight (difference -3.38 kg, CI -5.2 to -1.57, P < 0.001), BMI Z score (difference between metformin and placebo groups -0.07, CI -0.12 to -0.01, P = 0.02), and fat mass (difference -1.40 kg, CI -2.74 to -0.06, P = 0.04). Fasting plasma glucose (P = 0.007) and homeostasis model assessment (HOMA) insulin resistance index (P = 0.006) also improved more in metformin-treated children than in placebo-treated children. Gastrointestinal symptoms were significantly more prevalent in metformin-treated children, which limited maximal tolerated dosage in 17%. During the 6-month open-label phase, children treated previously with placebo decreased their BMI Z score; those treated continuously with metformin did not significantly change BMI Z score further. CONCLUSIONS: Metformin had modest but favorable effects on body weight, body composition, and glucose homeostasis in obese insulin-resistant children participating in a low-intensity weight-reduction program.

Effect of the insulin sensitizers metformin and pioglitazone on endothelial function in young women with polycystic ovary syndrome: a prospective randomized study.

OBJECTIVE: To compare the effect of two different insulin sensitizers, metformin and pioglitazone, on endothelial function in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective randomized study. SETTING: University Hospital endocrinology outpatient clinic. PATIENT(S): Young women with PCOS (aged 23.3±4.9 years). INTERVENTION(S): Patients were assigned randomly to no treatment (n=14), metformin 850 mg two times per day (n=15), and pioglitazone 30 mg daily (n=14) for 6 months. Healthy age- and body mass index-matched women served as controls (n=14). MAIN OUTCOME MEASURE(S): Brachial artery flow-mediated dilation was studied at baseline and 6 months. RESULT(S): Women with PCOS had higher insulin resistance and hyperandrogenism indices and lower flow-mediated dilation compared with controls. The three groups of women with PCOS did not differ at baseline. No differences were observed at follow-up in women who received no treatment. Metformin and pioglitazone improved flow-mediated dilation to a similar extent, restoring it to normal values at 6 months. Both insulin sensitizers induced favorable changes in insulin resistance and hyperandrogenism indices in women with PCOS. Independent predictors of flow-mediated dilation improvement at 6 months were treatment with insulin sensitizers and reduction in insulin resistance. CONCLUSION(S): In young women with PCOS, treatment with metformin or pioglitazone for 6 months induces a similar beneficial effect on endothelial function; this may be partially attributed to an improvement in insulin resistance. Further research is needed to investigate whether treatment with insulin sensitizers in women with PCOS also reduces cardiovascular risk.

Depression in women with spontaneous 46, XX primary ovarian insufficiency.

CONTEXT: A high prevalence of depressive symptoms is observed in women with primary ovarian insufficiency (POI) compared with women in whom the menopause is normally timed. Indeed, studies suggest that depression and/or its pharmacological treatment contribute to the onset of POI. OBJECTIVES: We characterize the prevalence of psychiatric disorders and the timing of onset of clinically significant depression relative to both the diagnosis of POI and the onset of menstrual irregularity in women with POI. DESIGN AND SETTING: We conducted a cross-sectional clinic-based study at the National Institutes of Health Clinical Research Center. PATIENTS: A total of 174 women with spontaneous 46, XX POI and 100 women with Turner syndrome participated in the study. MAIN OUTCOME MEASURES: The structured clinical interview for DSM-IV was performed. RESULTS: Lifetime histories of depression in POI exceeded rates of depression reported in women with Turner syndrome and community-based samples of women (P < 0.001). The onset of depression frequently preceded the diagnosis of POI but occurred after the onset of menstrual irregularity. Analyses standardizing the periods of risk for depression showed that similar numbers of depressions occurred before and after these events. CONCLUSIONS: POI is associated with an increased lifetime risk for major depression. Attention to the presence of depression in POI should become an important part of the care for these women. The onset of depression frequently occurs after signs of altered ovarian function but before the diagnosis of POI. Thus, in some women the association between POI and depression suggests an overlapping pathophysiology rather than a causal relationship.

Acute effects of betahistine hydrochloride on food intake and appetite in obese women: a randomized, placebo-controlled trial.

BACKGROUND: Central nervous system histaminergic tone is thought to play a role in appetite regulation. In animal models, histamine receptor 1 (HRH1) agonists and histamine receptor 3 (HRH3) antagonists decrease food intake. OBJECTIVE: The objective of this study was to examine the acute effects of betahistine hydrochloride (an HRH1 agonist and HRH3 antagonist) on food intakes and appetites. DESIGN: The study was a proof-of-concept, randomized, double-blinded, placebo-controlled, dose-ranging study performed to examine the effects of betahistine in women with class I or II obesity [body mass index (BMI; in kg/m²) of 30-39.99]. After a 24-h placebo run-in period, subjects received a placebo (n = 19) or 48 (n = 19), 96 (n = 17), or 144 (n = 21) mg betahistine/d for 24 h. Treatment was followed by a buffet test meal to assess energy intake. Hunger, satiety, and desire to eat were measured after consuming the meal by using visual analog scales. Data were analyzed by using regression models with the assumption that there would be an increasing effect of betahistine doses. Analyses were adjusted for age, log fat and lean mass, food preferences, and intake during a buffet test meal obtained during the placebo run-in period. RESULTS: Of the 79 obese women (mean ± SD age: 42 ± 11 y; BMI: 35 ± 3) enrolled in the study, 76 women completed the study. The betahistine dose did not significantly change intakes from those observed during the run-in period of the buffet test meal (P = 0.78). Hunger, fullness, and desire to eat (all P > 0.62) similarly showed no differences according to the betahistine dose. CONCLUSIONS: Betahistine did not produce an effect on food intakes or appetites. More potent histaminergic modulators may be required to elucidate the possible role of histaminergic pathways in human obesity. This trial was registered at clinicaltrials.gov as NCT00459992.

Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot flushes.

CONTEXT: The effect of early menopause on indices of vascular function has been little studied. OBJECTIVE: The objective of the study was to investigate the effect of early menopause on indices of subclinical atherosclerosis and identify predictors of those indices in early menopausal women. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study that included 120 early menopausal women (age range 42-55 yr, <3 yr in menopause) recruited from the menopause outpatient clinic of an academic hospital and 24 age-matched premenopausal women. MAIN OUTCOME MEASURES: Brachial artery flow-mediated dilation (FMD) and common carotid intima-media thickness (IMT) were studied. Estrogen receptor (ER)-alpha (rs2234693 T-->C and rs9340799 A-->G) and ERbeta (rs4986938 A-->G) polymorphisms were studied in menopausal women. RESULTS: FMD was significantly lower in early menopausal women compared with controls (5.43 +/- 2.53 vs. 8.74 +/- 3.17%, P < 0.001), whereas IMT did not differ between groups (P > 0.8). Severity of hot flushes was the most important independent predictor for FMD (P < 0.001) in menopausal women. Women with moderate/severe/very severe hot flushes had impaired FMD in contrast to women with no/mild hot flushes or controls. Women with no/mild hot flushes did not differ compared with controls. Age and systolic blood pressure were the main determinants of IMT (both P = 0.004). ER polymorphisms were not associated with vascular parameters. CONCLUSIONS: Impairment of endothelial function is present in the early menopausal years, whereas carotid IMT is not affected. Severity of hot flushes is the main determinant of endothelial dysfunction in early menopausal women. The studied ER polymorphisms do not offer important information on vascular health in early menopause.

A prospective evaluation of antral follicle function in women with 46,XX spontaneous primary ovarian insufficiency.

OBJECTIVE: To assess ovarian follicle function in women with 46,XX spontaneous primary ovarian insufficiency. DESIGN: Case-control with nested prospective cohort. SETTING: Clinical Research Center, National Institutes of Health. PATIENT(S): Women with primary ovarian insufficiency without estrogen replacement for 2 weeks (N = 97) and regularly menstruating control women (N = 42). INTERVENTION(S): Single injection of 300 IU hrFSH. MAIN OUTCOME MEASURE(S): Change in serum estradiol at 24 hours. RESULT(S): Antral follicles ≥3 mm were detected in 73% (69/95) of patients; both serum estradiol and progesterone levels correlated significantly with maximum follicle diameter in these women. Patients with a maximum follicle diameter ≥8 mm had significantly higher serum estradiol and progesterone levels and significantly lower FSH and LH levels compared with patients without such follicles. In controls estradiol levels increased significantly after FSH administration, but in patients this was not the case despite the presence of an antral follicle ≥8 mm. CONCLUSION(S): Most women with 46,XX spontaneous primary ovarian insufficiency have antral follicles detectable by ultrasound, suggesting that down-regulation of FSH receptors is not the predominant mechanism of follicle dysfunction. Evidence of progesterone secretion by antral follicles ≥8 mm in these patients is consistent with prior histologic evidence that follicle luteinization is the predominant mechanism of follicle dysfunction in this condition. Prospective controlled investigation designed to improve ovulatory function and fertility in these women is indicated.

Cardiovascular effects of endogenous estrogen and hormone therapy.

The incidence of cardiovascular disease is low in healthy premenopausal women and increases with age especially after the menopause; this difference has been attributed to the loss of endogenous estrogen. Atherosclerosis is a chronic inflammatory condition of the vascular wall that may result in an acute clinical event by inducing plaque rupture/erosion leading to thrombosis. A growing body of evidence suggests that the spectrum of the effects of estrogen on vascular pathophysiology is complex and may depend largely on the state of vascular pathology. In relatively healthy vessels, estrogen prevents the development and progression of atherosclerotic lesions, while in the presence of established atherosclerotic plaques, estrogen fails to inhibit the progression of atherosclerosis or may even trigger cardiovascular events. The mechanisms responsible for this are not yet fully elucidated. It is possible that postmenopausal estrogen/progestogen therapy may be beneficial in perimenopausal and early menopausal women prior to atherosclerotic plaque formation, but it may not prevent progression of atherosclerotic plaques and acute cardiovascular events in older women with cardiovascular risk factors or women with established atherosclerosis. Various formulations, doses and routes of hormone therapy administration as well as the genetic background of women should also be taken into account when considering the benefit-to-risk ratio of hormone therapy use.

A pharmacokinetic and pharmacodynamic study of delayed- and extended-release hydrocortisone (Chronocort) vs. conventional hydrocortisone (Cortef) in the treatment of congenital adrenal hyperplasia.

OBJECTIVE: Existing glucocorticoid treatment for congenital adrenal hyperplasia (CAH) is suboptimal and nonphysiological. We compared hormonal profiles during therapy with a new modified-release hydrocortisone (MR-HC), Chronocort, to conventional hydrocortisone (HC), Cortef, in patients with CAH. DESIGN AND PATIENTS: We conducted a Phase 2, open-label, crossover pharmacokinetic and pharmacodynamic study in 14 patients (out of whom seven were male subjects, age ranging from 17 to 55) with classic 21-hydroxylase deficiency. One week of thrice daily HC (10, 5 and 15 mg) was followed by 1 month of once daily MR-HC (30 mg at 22:00 hours). Twenty four-hour sampling of cortisol, 17-hydroxyprogesterone (17-OHP), androstenedione, and ACTH was performed at steady state. MEASUREMENTS: The primary outcome measures were 8- and 24-h area under the curve (AUC) hormones and 08:00 hours 17-OHP. RESULTS: Hydrocortisone therapy resulted in three cortisol peaks. A single cortisol peak occurred at approximately 06:00 hours on MR-HC. MR-HC resulted in significantly (P < 0.001) lower 24-h afternoon (12:00 to 20:00 hours), and night-time (20:00 to 04:00 hours) cortisol as compared with HC. From 04:00 to 12:00 hours, when physiological cortisol is highest, cortisol was higher on MR-HC than HC (P < 0.001). Patients on MR-HC had significantly (P < 0.05) higher afternoon (12:00 to 20:00 hours) 17-OHP, androstenedione and ACTH, but significantly (P = 0.025) lower 08:00 hours 17-OHP. No serious adverse events occurred. CONCLUSIONS: Modified-release hydrocortisone represents a promising new treatment for CAH. Overnight adrenal androgens were well-controlled, but rose in the afternoon with once-daily dosing suggesting that a morning dose of glucocorticoid is needed. Further studies are needed to determine the optimal dosing regimen and long-term clinical outcome.

Effects of calcium supplementation on body weight and adiposity in overweight and obese adults: a randomized trial.

BACKGROUND: Some data suggest that increasing calcium intake may help prevent weight gain. OBJECTIVE: To test the hypothesis that calcium supplementation can prevent weight gain in persons who are overweight or obese. DESIGN: Randomized, placebo-controlled trial. Randomization was computer-generated, and allocation was assigned by pharmacy personnel who prepared intervention and placebo capsules. Participants, providers, and those who assessed outcomes were blinded to study group assignment. SETTING: Single research center. PARTICIPANTS: 340 overweight (body mass index [BMI], 25 to <30 kg/m(2)) and obese (BMI > or =30 kg/m(2)) adults (mean age, 38.8 years [SD, 10.5]). INTERVENTION: Calcium carbonate (elemental calcium, 1500 mg/d) (n = 170) or placebo (n = 170) with meals for 2 years. MEASUREMENTS: Changes in body weight and fat mass (primary outcomes). RESULTS: Seventy-five percent of participants completed the trial (78% received calcium; 73% received placebo). There were no statistically or clinically significant differences between the calcium and placebo groups in change in body weight (difference, 0.02 kg [95% CI, -1.64 to 1.69 kg]; P = 0.98), BMI (difference, 0.32 kg/m(2) [CI, -0.41 to 1.02 kg/m(2)]; P = 0.39), or body fat mass (difference, 0.39 kg [CI, -1.04 to 1.92 kg]; P = 0.55). Parathyroid hormone concentrations decreased in the calcium group compared with the placebo group (difference, -0.71 pmol/L [CI, -1.28 to -0.13 pmol/L]). LIMITATION: The study took place at a research center, and its sample was mostly women. CONCLUSION: Dietary supplementation with elemental calcium, 1500 mg/d, for 2 years had no statistically or clinically significant effects on weight in overweight and obese adults. Calcium supplementation is unlikely to have clinically significant efficacy as a preventive measure against weight gain in such patients.

Bone mineral density in estrogen-deficient young women.

CONTEXT: Osteoporosis primarily affects postmenopausal women. However, young women with estrogen deficiency also are at increased risk for low bone density. OBJECTIVE: The aim of the study was to assess bone density and associated risk factors for reduced bone density in young, estrogen-deficient women using primary ovarian insufficiency (POI) as the disease model. DESIGN AND SETTING: We conducted a cross-sectional study at a tertiary care research center. PARTICIPANTS: We studied women with POI (n = 442), concurrent controls (n = 70), and matched controls from NHANES III (n = 353). PRIMARY OUTCOME MEASURE: We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry. RESULTS: Patients on average had 2-3% lower BMD at L1-L4, femoral neck, and total hip (P < 0.01 at all sites). The modifiable risk factors for BMD below the expected range for age (Z-score <-2) were: more than 1-yr delay in diagnosis of estrogen deficiency (P = 0.018), low (<32 ng/ml) vitamin D levels (P = 0.002), estrogen replacement nonadherence (P = 0.002), low calcium intake (P = 0.005), and lack of exercise (P = 0.005). As compared to Caucasians, African-American and Asian women with POI were 3.18 and 4.34 times more likely, respectively, to have Z-scores below -2 (P = < 0.0001 for both). Race was an overall risk factor, but on regression modeling, not an independent predictor of low bone density. CONCLUSIONS: Women with POI have lower bone density compared to regularly menstruating women. Compared to Caucasians, minority women with estrogen deficiency are more likely to have BMD below the expected range for age. This racial disparity appears to be related to a combined effect of several modifiable risk factors. Delay in diagnosis of POI also contributes to reduced bone density by delaying proper therapy.