Search

Background: Allergic contact dermatitis (ACD) from topical medication often occurs in occluded areas, for example, with wound treatment, but also in certain body locations, such as the anogenital area., Objectives: To investigate the demographics and specific lesion location of patients with ACD from topical drugs applied onto the (peri)anal/genital area, and to identify the respective causal topical pharmaceutical products and ingredients involved., Methods: From January 2000 to December 10, 2018, 532 patients were tested with the baseline series, sometimes with additional series, and the topical medication used along with the ingredients. The relevant data were extracted from our electronic databases developed in-house., Results: Forty-four patients (9%) out of 473 patients suffering from lesions in the (peri)anal/genital area had positive patch test results to topical drug preparations and/or their ingredients, sometimes in association with cosmetics for intimate hygiene. The most frequent sensitizing active principles were local anaesthetics and corticosteroids, while wool alcohols and to a minor extent benzoic acid were the most frequent culprits among the vehicle components and preservative agents, respectively., Conclusions: The local conditions (eg, occlusion, sweating, moist) in the anogenital area may favour skin sensitization to topical medication used to treat various skin diseases., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Objectives: In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG Outcome), empagliflozin, in addition to standard of care, significantly reduced risk of cardiovascular death by 38%, hospitalization for heart failure by 35%, and incident or worsening nephropathy by 39% compared with placebo in patients with type 2 diabetes and established cardiovascular disease. Using EMPA-REG Outcome data, we assessed whether the Kidney Disease Improving Global Outcomes (KDIGO) CKD classification had an influence on the treatment effect of empagliflozin., Design, Setting, Participants, & Measurements: Patients with type 2 diabetes, established atherosclerotic cardiovascular disease, and eGFR≥30 ml/min per 1.73 m 2 at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. Post hoc , we analyzed cardiovascular and kidney outcomes, and safety, using the two-dimensional KDIGO classification framework., Results: Of 6952 patients with baseline eGFR and urinary albumin-creatinine ratio values, 47%, 29%, 15%, and 8% were classified into low, moderately increased, high, and very high KDIGO risk categories, respectively. Empagliflozin showed consistent risk reductions across KDIGO categories for cardiovascular outcomes ( P values for treatment by subgroup interactions ranged from 0.26 to 0.85) and kidney outcomes ( P values for treatment by subgroup interactions ranged from 0.16 to 0.60). In all KDIGO risk categories, placebo and empagliflozin had similar adverse event rates, the notable exception being genital infection events, which were more common with empagliflozin for each category., Conclusions: The observed effects of empagliflozin versus placebo on cardiovascular and kidney outcomes were consistent across the KDIGO risk categories, indicating that the effect of treatment benefit of empagliflozin was unaffected by baseline CKD status., Clinical Trial Registry Name and Registration Number: EMPA-REG OUTCOME, NCT01131676., (Copyright © 2020 by the American Society of Nephrology.)

Objective: To assess the efficacy and safety of the sodium-glucose cotransporter 2 inhibitor ertugliflozin across racial groups in patients with type 2 diabetes mellitus (T2DM). Methods: Pooled analysis of data from randomized, double-blind studies in the ertugliflozin phase III development program. Seven placebo- and comparator-controlled studies were used to assess safety ( N  = 4859) and three placebo-controlled studies were used to assess efficacy ( N  = 1544). Least-squares (LS) mean change from baseline was calculated for glycated hemoglobin (HbA1c), body weight and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs). Results: At Week 26, ertugliflozin provided a greater reduction in HbA1c, body weight and SBP versus placebo in all racial subgroups. The placebo-adjusted LS mean change (95% confidence interval) from baseline in HbA1c was -0.8% (-1.0, -0.7) and -1.0% (-1.1, -0.8) with ertugliflozin 5 mg and 15 mg, respectively, in the White subgroup, -0.7% (-1.2, -0.2) and -0.8% (-1.3, -0.3) in the Black subgroup, and -0.8% (-1.1, -0.5) and -1.0% (-1.3, -0.8) in the Asian subgroup. The incidences of overall AEs, serious AEs and AEs leading to discontinuation from study medication were similar between the ertugliflozin 5 mg, 15 mg and non-ertugliflozin groups within each racial subgroup. The incidence of female genital mycotic infection (GMI) was higher with ertugliflozin than non-ertugliflozin across all racial subgroups. The incidence of male GMI was higher with ertugliflozin than non-ertugliflozin in the White sub-group; however, there were few male GMI events in the non-White subgroups. Conclusions: In patients with T2DM, treatment with ertugliflozin improved HbA1c, body weight and SBP across all racial subgroups. Ertugliflozin had a generally similar safety profile across racial subgroups and was generally well tolerated. Clinicaltrials.gov identifiers: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, and NCT02226003.

Aims: The objective of the study was to quantify the association between SGLT2 inhibitors and genital mycotic infection and between SGLT2 inhibitors and urinary tract infection (UTI) within 30 days of drug initiation among older women and men., Materials and Methods: This was a retrospective cohort study using linked administrative databases of women and men with diabetes, aged 66 years or older, in Ontario, Canada. We compared the incidence of genital mycotic infection or UTI within 30 days between new users of an SGLT2 inhibitor and of a dipeptidyl-peptidase-4 (DPP4) inhibitor., Results: We identified 21 444 incident users of SGLT2 inhibitor and 22 463 incident users of DPP4 inhibitor. Among SGLT2 inhibitor users, there were 8848 (41%) women and the mean age at index was 71.8 ± 5 (SD) years. After adjusting for propensity score, age, sex and recent UTI, there was a 2.47-fold increased risk of genital mycotic infection with incident use of SGLT2 inhibitors (adjusted hazard ratio (HR), 2.47; 95% confidence interval (CI), 2.08-2.92; P < 0.001) within 30 days compared to incident use of DPP4 inhibitors. For UTI, the adjusted HR was 0.89 (95% CI, 0.78-1.00; P = 0.05)., Conclusions: Incident use of SGLT2 inhibitors among older women and men is associated with increased risk of genital mycotic infections within 30 days; there is no associated increased risk of UTI. These findings from a real-world setting provide evidence of the potential harms of SGLT2 inhibitors., (© 2019 John Wiley & Sons Ltd.)

Objective: Sodium glucose cotransporter-2 inhibitors (SGLT2i) exert cardiorenal protection in people with diabetes. By inducing glycosuria, SGLT2i predispose to genital infections. In addition, rare occurrence of Fournier's gangrene (FG) has been reported. We aimed to investigate such association through the U.S. Food and Drug Administration (FDA) adverse event (AE) reporting system (FAERS)., Research Design and Methods: We mined the FAERS up to 2018q3 (before FDA warning about SGLT2i-associated FG) to retrieve reports including FG as an AE and SGLT2i as suspect or concomitant drugs, and calculated proportional reporting ratios (PRR)., Results: We retrieved 47 cases of FG and 17 cases of other severe AEs of the genital area associated with SGLT2i. Patients with FG were ~10 years older than those with other severe genital AEs. Overall, 77% occurred in men. Three patients were concomitantly treated with systemic immunosuppressive drugs. Increased reporting frequency emerged for SGLT2i compared with other drugs, with a PRR ranging from 5 to 10. The disproportional reporting of FG with SGLT2i remained robust and consistently significant when restricting to the period when SGLT2i were available, to reports filed for glucose-lowering medications or for drugs with the diabetes indication, and after refining the definition of FG. FG was disproportionally associated with psoriasis and with the combination of immunosuppressants and SGLT2i., Conclusions: Although causality cannot be demonstrated, SGLT2i may predispose to FG and other severe genital AEs. Since the use of SGLT2i is expected to increase significantly, clinicians should be aware of these severe, although rare, AEs and their predisposing factors., Competing Interests: Competing interests: GPF reports grants, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Boehringer-Ingelheim, personal fees from Mundipharma during the conduct of the study; grants, personal fees and non-financial support from Eli Lilly, personal fees and non-financial support from NovoNordisk, personal fees and non-financial support from Sanofi, non-financial support from Genzyme, personal fees and non-financial support from Abbott, personal fees and non-financial support from Novartis, personal fees from Merck Sharp & Dohme, outside the submitted work. AA reports grants, personal fees and non-financial support from AstraZeneca, personal fees from Boehringer-Ingelheim, personal fees from Janssen, during the conduct of the study; personal fees from Merck Sharp & Dome, personal fees and non-financial support from Novartis, personal fees from Sanofi, grants and personal fees from Mediolanum, personal fees from NovoNordisk, personal fees from Lilly, personal fees and non-financial support from Servier, personal fees from Takeda, outside the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Bullous fixed drug eruption (FDE) is a severe reaction due to drug intake and requires specific management in dermatology. The sites of predilection are the lips, trunk, genitalia, and perineal area. The aim of our study was to assess the features and outcomes of bullous FDE with genital involvement through a retrospective study of 18 years (2000-2017) conducted in the Dermatology Department of Habib Thameur Hospital. Ten patients were included in the study. The ratio of men to women was 6.4. The mean age of the patients was 46.3 years. The most frequently affected genital site in men was the glans penis. Nonsteroidal anti-inflammatory drugs were the most frequent drugs associated with genital bullous FDE, followed by paracetamol and trimethoprim-sulfamethoxazole. Residual hyperpigmentation of the genitals was not observed in our patients. Genital involvement in bullous FDE is more frequent in men.

Hormones are substances that serve as chemical communication between cells. They are unique biological molecules that affect multiple organ systems and play a key role in maintaining homoeostasis. In this role, they are usually produced from a single organ and have defined target organs. However, hormones can affect non-target organs as well. As such, biochemical and hormonal abnormalities can be associated with anatomic changes in multiple target as well as non-target organs. Hormone-related changes may take the form of an organ parenchymal abnormality, benign neoplasm, or even malignancy. Given the multifocal action of hormones, the observed imaging findings may be remote from the site of production, and may actually be multi-organ in nature. Anatomic findings related to hormone level abnormalities and/or laboratory biomarker changes may be identified with imaging. The purpose of this image-rich review is to sensitize radiologists to imaging findings in the abdomen and pelvis that may occur in the context of hormone abnormalities, focusing primarily on sex hormones and their influence on these organs.

Poisoning from pesticides is a global public health problem and accounts for nearly 300,000 deaths worldwide every year. Exposure to pesticides is inevitable; there are different modes through which humans get exposed to pesticides. The mode of exposure is an important factor as it also signifies the concentration of pesticides exposure. Pesticides are used extensively in agricultural and domestic settings. These chemicals are believed to cause many disorders in humans and wildlife. Research from past few decades has tried to answer the associated mechanism of action of pesticides in conjunction with their harmful effects. This perspective considers the past and present research in the field of pesticides and associated disorders. We have reviewed the most common diseases including cancer which are associated with pesticides. Pesticides have shown to be involved in the pathogenesis of Parkinson's and Alzheimer's diseases as well as various disorders of the respiratory and reproductive tracts. Oxidative stress caused by pesticides is an important mechanism through which many of the pesticides exert their harmful effects. Oxidative stress is known to cause DNA damage which in turn may cause malignancies and other disorders. Many pesticides have shown to modulate the gene expression at the level of non-coding RNAs, histone deacetylases, DNA methylation patterns suggesting their role in epigenetics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Natalizumab is administered for the treatment of relapsing-remitting multiple sclerosis (RR-MS) with high disease activity.Natalizumab therapy has been associated with adverse effects, such as progressive multifocal leukoencephalopathy, liver damage, nasopharyngitis, urinary tract infection, urticaria, cephalgia, dizziness, fatigue, nausea, fever, rigidity, anxiety and gastroenteritis., Objective: To describe a case of a woman with RR-MS who developed recurrent vaginitis on natalizumab administration., Methods: Case report and review of the literature., Results: The case of a 26-year-old Caucasian woman with RR-MS, who presented with recurrent vaginitis since the initiation of treatment with natalizumab, is reported. The patient had a 4-year history of RR-MS; monotherapy with natalizumab (inj. 300 mg/month) came after one year after the initial diagnosis. Since then, she had a history of persistent gynecological infections; the repeated vaginal cultures revealed a variety of underlying pathogens. The patient underwent numerous treatments with local and systematic antibiotics as well as antifungal agents. After the initiation of probiotics and local hygiene measures, recurrences resolved and the patient remains recurrence-free at one-year follow-up., Conclusions: Recurrent vaginitis should be taken into account as a possible adverse effect causing discomfort during long-term natalizumab treatment. Simple measures, such as probiotic administration and meticulous local hygiene, can provide adequate relief for such patients., (Copyright © 2018. Published by Elsevier B.V.)

Objectives: Restless genital syndrome (RGS) includes discomfort, pain, numbness, vibration, restlessness, or a burning sensation involving the vagina, perineum, pelvis, penis, and proximal portion of the lower limbs in patients. The RGS has been sometimes reported in Parkinson disease. In patients without Parkinson disease, RGS is also known as persistent genital arousal disorder (PSAS), which includes uncontrollable genital arousal, with or without orgasm or genital engorgement, unrelated to sexual desire. Although withdrawal from selective serotonin reuptake inhibitors antidepressants is reported to induce PSAS, there is no report of RGS or PSAS induced by antidepressants., Methods: We obtained the consent for the presentation and have not identified individuals for ethical reasons., Results: We first report a woman patient with depression induced RGS by milnacipran (MLN)., Conclusions: We discuss the relationship with restless legs syndrome and the difference from akathisia. It is highly possible MLN affected her RGS because she experienced RGS for the first time after the dose of MLN was increased. A limitation of this report is that we stopped MLN and administered gabapentin enacarbil immediately. We should join MLN to the list of compounds suspected of inducing RGS.

Introduction: Treatment of type 2 diabetes with sodium-glucose cotransporter 2 (SGLT2) inhibitors may result in genital fungal infections. We investigated possible risk factors for developing such infections among patients treated with the SGLT2 inhibitor dapagliflozin., Methods: The Association of British Clinical Diabetologists (ABCD) collected data on patients treated with dapagliflozin in routine clinical practice from 59 diabetes centres. We assessed possible associations of patient's age, diabetes duration, body mass index, glycated haemoglobin, renal function, patient sex, ethnicity and prior genital fungal infection, urinary tract infection, urinary incontinence or nocturia, with the occurrence of ≥1 genital fungal infection within 26 weeks of treatment., Results: 1049 out of 1116 patients (476 women, 573 men) were analysed. Baseline characteristics were, mean±SD, age 56.7±10.2years, BMI 35.5±6.9kg/m 2 and HbA 1c 9.4±1.5%. Only patient sex (13.2% women vs 3.3% men) and prior history of genital fungal infection (21.6% vs 7.3%) were found to be associated with occurrence of genital fungal infections after dapagliflozin treatment, adjusted OR 4.22 [95%CI 2.48,7.19], P<0.001 and adjusted OR 2.41 [95% CI 1.04,5.57], P=0.039, respectively., Conclusion: Women and patients with previous genital fungal infections had higher risks of developing genital fungal infections with dapagliflozin treatment., (Copyright © 2017 Primary Care Diabetes Europe. All rights reserved.)

Pyrethroids have been associated with a range of toxicological effects on various organs in animals.Recent animal studies suggest that neurodevelopmental, reproductive, and immunological effects may result following exposure to some pyrethroids at levels below those that induce overt signs of neurotoxicity. A variety of pyrethroids and their metabolites have the potential to affect the reproductive system. Dose-dependent effects on reproduction are associated with exposure across pyrethroid types. In mammals, permethrin and tetramethrin and cypermethrin have been found to be associated with adverse effects at high doses. Fenvalerate, deltamethrin, cypermethrin, caused morphometric and structural changes in the female genital organs. These pyrethroids affect ovulation, cause atresia of follicles, decrease the number of follicular cells, oocytes and corpora lutea and induce vesicular atrophy of the endometrial glands. The potential hormonal activity of pyrethroids showed that certain pyrethroids and their metabolites have multiple effects on the endocrine system. The level of steroid hormones, such as progesterone and estradiol, was inhibited. The pyrethorids may have the potential to mimic estrogens or to inhibit estrogen action. Some metabolites of pyrethroids, in particular permethrin and cypermethrin, are more likely to interact with the cellular estrogen receptors than the parent pyrethroids. Though several pyrethroids posses low toxicity, some pyrethroids, such as deltamethrin, cypermethrin, fenvalerate and bifenthrin have showed considerable toxicity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose To assess the role of participant-reported symptoms on long-term adherence to preventive therapy in the United Kingdom sample of the International Breast Cancer Intervention Study (IBIS-I). IBIS-I was a randomized controlled trial that investigated the effectiveness of tamoxifen in reducing the risk of breast cancer among women at increased risk of the disease. Participants and Methods Women were randomly assigned to tamoxifen versus placebo (20 mg/day; n = 4,279). After 456 exclusions, 3,823 women were included in this analysis. Adherence (< 4.5 years or ≥ 4.5 years) was calculated using data from six monthly clinical visits. Analyses were adjusted for age, Tyrer-Cuzick risk, smoking, use of hormone replacement therapy, menopausal status, baseline menopausal symptoms, and treatment. Results Overall, 69.7% of women were adherent for at least 4.5 years (tamoxifen: 65.2% v placebo: 74.0%; P < .001). Differences in adherence between treatment arms were observed from 12 months onward (all P < .01) and were largest at 54 months. Dropout rates were highest in the first 12 to 18 months and decreased thereafter. Women reporting nausea/vomiting were less likely to be adherent in both the tamoxifen (odds ratio [OR], 0.57; 95% CI, 0.37 to 0.86; P = .007) and placebo (OR, 0.58; 95% CI, 0.37 to 0.93; P = .023) arms. Headaches were associated with adherence only in the placebo arm (OR, 0.62; 95% CI, 0.42 to 0.91; P = .016), whereas gynecologic symptoms were significant only in the tamoxifen arm (OR, 0.77; 95% CI, 0.62 to 0.97; P = .024). Effect sizes for each symptom on adherence were not significantly different between the treatment groups ( P > .05). In both treatment arms, we observed significant trends for lower adherence with increasing severity for all symptoms ( P < .01) except headaches ( P = .054). Conclusion In the IBIS-I trial, experiencing predefined symptoms in the first 6 months reduced long-term adherence. Effects were similar between treatment arms, suggesting that women were attributing age-related symptoms to preventive therapy. Interventions were required to support symptom management.

A total of 84 healthy female mice were kept with various concentrations of sodium fluoride (F) (0, 50, 100, 150 mg F - /L in drinking water for 90 days) and were then mated with healthy male mice for 1 week to study the effect of excessive fluoride on female reproductive function, particularly in embryo implantation. The rate of pregnancy, litter size, and the birth weight of female mice were evaluated. Ultrastructural changes of uteri tissues were observed by transmission electron microscopy (TEM). The mRNA expression levels of MMP-9 and TIMP-1 were determined by quantitative real-time PCR. The protein expression levels of MMP-9 and TIMP-1 were analyzed by western blotting. Results showed a significant decrease of litter size in mice exposed to fluoride. TEM images of uteri tissue of mice that underwent a 150 mg/L F - treatment for 90 days showed a vague nucleus, reduced microvilli, increased lysosomes, a dilated endoplasmic reticulum, and a vacuolization mitochondrion when compared with the control group. Following the damage of the structure, the expression levels of MMP-9 and TIMP-1 in uteri tissues were significantly unregulated in the F 150 group. These results show that MMP-9/TIMP-1 system disturbance and changes of histological structure in uteri tissue are involved in fluoride-induced reproductive dysfunctions.

A comprehensive systematic literature review of reproductive side effects in women aged 18 to 55 years treated with opioids for 1 month or longer for chronic noncancer pain. A search of 7 databases including EMBASE and Medline was undertaken (October 2014 and a limited rerun April 2016). The search contained key words for opioids (generic and specific drug names) and side effects (generic and specific reproductive). Titles were screened using predefined criteria by a single reviewer and abstracts and full texts by 2 independent reviewers. A total of 10,684 articles were identified and 12 full texts (cohort [n = 1], case-control [n = 4], cross-sectional [n = 4], case series [n = 1], and case report [n = 2] with a maximum of 41 cases in 1 article) were included covering 3 different modes of administration: oral (n = 6), intrathecal (n = 5), and transdermal (n = 1). Amenorrhoea occurred in 23% to 71% of those receiving oral or intrathecal opioids. Decreased libido was seen in 61% to 100%. Of the 10 studies that undertook hormonal assays, only 2 studies showed a statistically significant decrease in hormone levels. This review supports the view that there is a potential relationship between the use of long-term opioids in women and reproductive side effects. The evidence is however weak and the mode of administration, duration, type, and dose of opioid might influence associations. Although hormone levels were statistically significant in only 2 studies, women exhibited clinically important symptoms (decreased libido and altered menstrual cycle). Further investigation is required with larger cohorts and analysis of different delivery methods.

Aims: To review prevalence and significance of urinary tract (UTI) and genital infections (GI) in diabetes and the effects of sodium glucose cotransporter 2 (SGLT-2) inhibitors on these complications., Data Synthesis: The prevalence of asymptomatic bacteriuria (ASB) is 2-3 times higher in diabetic than in non-diabetic women. The treatment of ASB has no impact on the development of UTIs and/or a decline in renal function. Therefore, there is no indication for screening for and/or treatment of ASB. The incidence of UTI is higher and frequently complicated in diabetic patients, particularly in those with longer duration of disease and of older age. There is no consistent evidence of an association between A1c levels, glycosuria and the risk of ASB and/or UTIs. Diabetes is a known risk factor for Candida colonization and GI, and a poor glycemic control is associated with a higher risk. While patients treated with SGLT-2 inhibitors may have a non-significant increased risk of UTI, they have a clearly increased risk of GI; most of these infections are mild, easy to treat, and the rate of recurrence is low., Conclusion: Diabetic patients are at high risk of UTIs and of GI. Only GI are associated with poor glycemic control. Although patients treated with SGLT-2 inhibitors have an increased 3-5 fold risk of GI, proper medical education can reduce this risk., (Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: Patients with type 2 diabetes mellitus (T2DM) have increased risk of adverse events (AEs; e.g. dehydration, hypoglycaemia) in hot weather. This analysis assessed the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with T2DM who live in hot climates., Methods: This post hoc analysis evaluated patients with T2DM using pooled data from four 26-week, placebo-controlled studies (N=2,313) and data from a 104-week, active-controlled study (add-on to metformin vs glimepiride; N=1,450). Changes in HbA1c, fasting plasma glucose (FPG), body weight and blood pressure (BP) were assessed in subsets of patients living in hot climates (pooled, placebo-controlled studies, n=611; active-controlled study, n=307) and those living in other climates (i.e. other climate subset; pooled, placebo-controlled studies, n=1,702; active-controlled study, n=1,143). Safety was assessed based on AE reports., Results: Canagliflozin 100 and 300 mg lowered HbA1c, FPG, body weight and BP vs placebo over 26 weeks and glimepiride over 104 weeks in the hot climate subsets. Canagliflozin was generally well tolerated in the hot climate subsets, with a higher incidence of AEs related to the mechanism of SGLT2 inhibition (i.e. genital mycotic infections). Volume depletion-related AEs were low across groups., Conclusion: Canagliflozin improved glycaemic control, lowered body weight and BP, and was generally well tolerated in patients with T2DM living in hot climates compared with placebo over 26 weeks or glimepiride over 104 weeks., Clinical Trials Registration: ClinicalTrials.gov NCT01081834, NCT01106677, NCT01106625, NCT01106690, NCT00968812., (© 2016 The Authors. International Journal of Clinical Practice published by John Wiley & Sons Ltd.)

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as canagliflozin, are used in patients with Type 2 diabetes mellitus (T2DM). In clinical studies, canagliflozin significantly reduced A1C, bodyweight and blood pressure, and was generally well tolerated with no increased risk of hypoglycemia. Most common adverse effects observed were genital mycotic infections and urinary tract infections, and increased urination. Approximately 10% of women treated with canagliflozin experienced a genital mycotic infection compared with 3% treated with placebo; those with a prior history were at greater risk. Approximately 9% of women treated with canagliflozin reported a urinary tract infection compared with 7% treated with placebo. Most adverse events were considered mild to moderate in intensity and responded to standard therapy. Treatment with canagliflozin was effective and generally well tolerated in both women (and men) with T2DM.

Context: A growing body of evidence suggests that endocrine-disrupting chemicals (EDCs) contribute to female reproductive disorders., Objective: To calculate the associated combined health care and economic costs attributable to specific EDC exposures within the European Union (EU)., Design: An expert panel evaluated evidence for probability of causation using the Intergovernmental Panel on Climate Change weight-of-evidence characterization. Exposure-response relationships and reference levels were evaluated, and biomarker data were organized from carefully identified studies from the peer-reviewed literature to represent European exposure and approximate burden of disease as it occurred in 2010. Cost-of-illness estimation used multiple peer-reviewed sources., Setting, Patients and Participants and Intervention: Cost estimation was carried out from a societal perspective, ie, including direct costs (eg, treatment costs) and indirect costs such as productivity loss., Results: The most robust EDC-related data for female reproductive disorders exist for 1) diphenyldichloroethene-attributable fibroids and 2) phthalate-attributable endometriosis in Europe. In both cases, the strength of epidemiological evidence was rated as low and the toxicological evidence as moderate, with an assigned probability of causation of 20%–39%. Across the EU, attributable cases were estimated to be 56 700 and 145 000 women, respectively, with total combined economic and health care costs potentially reaching €163 million and €1.25 billion., Conclusions: EDCs (diphenyldichloroethene and phthalates) may contribute substantially to the most common reproductive disorders in women, endometriosis and fibroids, costing nearly €1.5 billion annually. These estimates represent only EDCs for which there were sufficient epidemiologic studies and those with the highest probability of causation. These public health costs should be considered as the EU contemplates regulatory action on EDCs.

Endocrine disruptors are natural or synthetic chemical compounds which are present in the environment and which are able to interfere with hormonal regulation pathways and to induce human health deleterious effects. While their precise implication in human health and diseases is still matter of debates, it becomes likely that they have to be considered as risk factors in numerous chronic diseases: developmental and reproductive defects and hormone dependent cancers (present review), metabolic diseases (obesity and type 2 diabetes), neurodevelopmental or neurodegenerative diseases. Low doses exposure during critical windows of exposure such as foetal, perinatal and peri-pubertal periods, or chronic exposure with bioaccumulation in the adipose tissue, and possible synergic effects of several compounds ("cocktail effect") may participate to the genetic/environment interface suspected to participate to the pathophysiology of many diseases., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Aim: To investigate the efficacy and safety of ertugliflozin, in a phase II dose-ranging study, in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin., Methods: A total of 328 patients [mean T2DM duration, 6.3 years; mean glycated haemoglobin (HbA1c), 8.1%] were randomized to once-daily ertugliflozin (1, 5, 10, 25 mg), sitagliptin (100 mg) or placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in HbA1c concentration and the secondary efficacy endpoints were changes from baseline to week 12 in body weight, fasting plasma glucose (FPG) and systolic/diastolic blood pressure (SBP/DBP). Safety and tolerability were also monitored., Results: Ertugliflozin (1-25 mg/day) produced significant reductions in HbA1c concentration [placebo-corrected least-squares mean (LSM) -0.45% (1 mg) to -0.72% (25 mg); p ≤ 0.002, similar to sitagliptin (-0.76%; p = 0.0001)], FPG (LSM -1.17 to -1.90 mmol/l; p < 0.0001) and body weight (-1.15 to -2.15%; p < 0.0001). The LSM SBP decreased by -3.4 to -4.0 mmHg from baseline with ertugliflozin 5-25 mg/day. No reductions in body weight or blood pressure were observed with sitagliptin. After randomization, 2.7% of patients (9/328) withdrew because of adverse events (AEs); the frequency of AEs was evenly distributed across groups. No dose-related increase in AE frequency occurred with ertugliflozin. Hypoglycaemia was reported in 5 (1.5%) randomized participants (all in the ertugliflozin group). The frequency of urinary tract infection was 3.2% for ertugliflozin (pooled across groups), 1.8% for sitagliptin, 7.4% for placebo, and the frequency of genital fungal infections was 3.7% for ertugliflozin (pooled) versus 1.9% for placebo., Conclusion: Ertugliflozin (1-25 mg/day) improved glycaemic control, body weight and blood pressure in patients with T2DM suboptimally controlled on metformin, and was well tolerated., (© 2015 John Wiley & Sons Ltd.)

Introduction: In 2006, 528 tons of petroleum toxic waste have been released in Abidjan (Ivory Coast) during a major environmental accident. This study was aimed to describe the clinical manifestations provoked by these toxic waste., Methods: We have analysed the records of patients admitted to the university hospital of Cocody (Abidjan) following exposure to toxic waste. All the information were recorded on specific files or on notification files created by the physicians of the National Institute of Public Health, the authority charged with the supervision of this exercise. The files were completed by the physician in the course of the examination of the patient., Results: Over a period of 3-month-period, 10,598 patients were examined. The clinical manifestations affected all age groups. They were dominated by respiratory symptoms: pulmonary (74.5%) and upper respiratory (31.0%). Pulmonary symptoms included cough (48.8%), chest pain (37.9%), dyspnoea (9.5%) and a few cases of hemoptysis. Digestive symptoms mainly comprised abdominal pain (36.2%), diarrhea (23.0%), abdominal distension (19.9%) and vomiting (9.9%). The other symptoms were neurological, ophthalmic, cardiovascular and gynaecological. More than 96% of patients presented with at least two symptoms. The respiratory symptoms were significantly more frequent in patients over the age of 17 while diarrhea and vomiting were more often found in patients less than 17 years old. Chest pain was significantly more common in men while abdominal pain and vomiting predominated in women (P=0.001)., Conclusion: The clinical consequences of toxic waste exposure were varied and sometimes serious. A medium- and long-term evaluation of the subjects is required., (Copyright © 2014 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Objective: To characterize genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) using pooled data from Phase 3 studies., Research Design and Methods: Genital mycotic infections with canagliflozin 100 and 300 mg were evaluated in Population 1 (N = 2313; mean exposure [weeks]: canagliflozin, 24.3; placebo, 23.8), including patients from four placebo-controlled studies, and Population 2 (N = 9439; mean exposure [weeks]: canagliflozin, 68.1; control, 64.4), including patients from eight placebo/active-controlled studies (including older patients and those with renal impairment or high cardiovascular disease risk)., Clinical Trial Registration: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690; NCT01032629; NCT01064414; NCT01106651; NCT00968812., Main Outcome Measures: Adverse events suggestive of genital mycotic infections were recorded, with additional information collected using supplemental electronic case report forms., Results: In Population 1, genital mycotic infection incidence was higher with canagliflozin 100 and 300 mg than placebo (95% confidence intervals excluded zero) in females (10.4%, 11.4%, 3.2%) and males (4.2%, 3.7%, 0.6%). These were generally mild to moderate in intensity, none were serious, and few led to discontinuation. Most events with canagliflozin were treated with antifungal therapies, and median symptom duration following treatment initiation was similar across groups; few patients had >1 event (females, 2.3%; males, 0.9%). Findings with canagliflozin 100 and 300 mg versus control were similar in Population 2 (females: 14.7%, 13.9%, 3.1%; males: 7.3%, 9.3%, 1.6%); a low proportion of males underwent circumcision across groups. Most events with canagliflozin occurred within the first 4 months in females and first year in males; no consistent evidence of dose dependence was observed. Key limitations included lack of laboratory confirmation for most events and variable treatment methods., Conclusions: Genital mycotic infection incidences were higher with canagliflozin than control in patients with T2DM; events were generally mild to moderate in intensity and responded to standard treatments.

Aim: The efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, was evaluated in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and pioglitazone., Methods: In this randomized, double-blind, phase 3 study, patients (N = 342) received canagliflozin 100 or 300 mg during a 26-week, placebo-controlled, core period and a 26-week, active-controlled extension in which placebo-treated patients were switched to sitagliptin 100 mg. Efficacy comparisons for canagliflozin versus placebo at week 26 are reported, with no comparisons versus sitagliptin at week 52 (sitagliptin used to maintain double-blind and control for safety). Safety data are reported for canagliflozin and placebo/sitagliptin., Results: Canagliflozin 100 and 300 mg significantly lowered haemoglobin A1c (HbA1c) compared with placebo at week 26 (-0.89%, -1.03% and -0.26%; p < 0.001); reductions with canagliflozin 100 and 300 mg were maintained at week 52 (-0.92% and -1.03%). Relative to placebo, both canagliflozin doses significantly reduced body weight (-2.5 and -3.5 kg), fasting plasma glucose and systolic blood pressure (BP) at week 26 (p < 0.05 for all), with reductions maintained at week 52. Overall adverse event (AE) incidence over 52 weeks was 69.9, 76.3 and 76.5% with canagliflozin 100 and 300 mg and placebo/sitagliptin; AE-related discontinuation and serious AE rates were low. Incidences of genital mycotic infections and AEs related to osmotic diuresis and volume depletion were higher with canagliflozin than placebo/sitagliptin., Conclusion: Canagliflozin improved glycaemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM on metformin and pioglitazone over 52 weeks., (© 2014 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: Sodium glucose co-transport-2 (SGLT-2) inhibitors, a new class of glucose-lowering agents, reduce tubular glucose reabsorption, producing a reduction of blood glucose without stimulating insulin release. The aim of the present meta-analysis is the assessment of the overall efficacy and safety profile of these drugs., Methods: A meta-analysis was performed including all trials with a duration of at least 12 weeks, comparing a SGLT-2 inhibitor with a non-SGLT-2 inhibitor agent in type 2 diabetes. The principal outcome of this analysis was the effect of SGLT-2 inhibitors on HbA1c at 12, 24 and 52 weeks. Hypoglycaemia, genital and urinary infections were retrieved and combined to calculate Mantel-Haenszel odds ratio (MH-OR). Furthermore, data on body mass index (BMI), endpoint fasting plasma glucose, systolic and diastolic blood pressure, creatinine, hematocrit and lipid profile were collected., Results: Among placebo-controlled trials, HbA1c reduction at 12, 24 and 52 weeks was 0.5 [0.4; 0.6], 0.6 [0.6; 0.5] and 0.6 [0.7; 0.5]%. In placebo-controlled studies, 24-week reduction of HbA1c with SGLT-2 inhibitors was greater in trials enrolling patients with a lower mean age and duration of diabetes, and a higher baseline BMI, HbA1c and fasting glucose. In placebo-controlled trials, SGLT-2 inhibitors determined a weight loss during the first 24 weeks, which was maintained up to 52 weeks., Conclusions: SGLT-2 inhibitors are effective in the treatment of type 2 diabetes, providing additional benefits, such as weight loss, reduction of blood pressure and increase in high-density lipoprotein (HDL)-cholesterol. Apart from genital and urinary infections, rather frequent but usually mild, SGLT-2 inhibitors appear to be well tolerated., (© 2013 John Wiley & Sons Ltd.)

Aims: Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), has been shown to improve glycaemic control, stabilize insulin dosing and mitigate insulin-associated weight gain over 48 weeks in patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled despite high doses of insulin. Here the efficacy and safety of dapagliflozin therapy after a total of 104 weeks are evaluated in this population., Methods: This was a 24-week, randomized, placebo-controlled, double-blinded, multicentre trial followed by two site- and patient-blinded extension periods of 24 and 56 weeks (NCT00673231), respectively. A total of 808 patients, whose T2DM was inadequately controlled on insulin ≥30 IU/day, with or without up to two oral antidiabetic drugs, were randomly assigned to receive placebo or 2.5, 5 or 10 mg/day of dapagliflozin for 104 weeks. At 48 weeks, patients on dapagliflozin 5 mg were switched to 10 mg. Outcomes over 104 weeks included change from baseline in HbA1c, insulin dose and body weight; analyses used observed cases and included data after insulin up-titration. Adverse events (AEs) were evaluated throughout 104 weeks., Results: Five hundred and thirteen patients (63.6%) completed the study. Mean HbA1c changes from baseline at 104 weeks were -0.4% in the placebo group and -0.6 to -0.8% in the dapagliflozin groups. In the placebo group, mean insulin dose increased by 18.3 IU/day and weight increased by 1.8 kg at 104 weeks, whereas in the dapagliflozin groups, insulin dose was stable and weight decreased by 0.9-1.4 kg. AEs, including hypoglycaemia, were balanced across groups. Proportions of patients with events suggestive of genital infection and of urinary tract infection (UTI) were higher with dapagliflozin versus placebo (genital infection 7.4-14.3% vs. 3.0%; UTI 8.4-13.8% vs. 5.6%) but most occurred in the first 24 weeks and most were single episodes that responded to routine management., Conclusions: Dapagliflozin improved glycaemic control, stabilized insulin dosing and reduced weight without increasing major hypoglycaemic episodes over 104 weeks in patients whose T2DM was inadequately controlled on insulin. However, rates of genital infection and of UTI were elevated with dapagliflozin therapy., (© 2013 John Wiley & Sons Ltd.)

Purpose: Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial., Patients and Methods: Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment., Results: A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation., Conclusion: Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.

Background: Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2, may improve glycemic control with a lower dose of insulin and attenuate the associated weight gain in patients with inadequate control despite high doses of insulin., Objective: To evaluate the efficacy and safety of adding dapagliflozin therapy in patients whose type 2 diabetes mellitus is inadequately controlled with insulin with or without oral antidiabetic drugs., Design: A 24-week, randomized, placebo-controlled, multicenter trial followed by a 24-week extension period. An additional 56-week extension period is ongoing. (ClinicalTrials.gov registration number: NCT00673231), Setting: 126 centers in Europe and North America from 30 April 2008 to 19 November 2009., Patients: 808 patients with inadequately controlled type 2 diabetes mellitus receiving at least 30 U of insulin daily, with or without up to 2 oral antidiabetic drugs., Intervention: Patients were randomly assigned in a 1:1:1:1 ratio and allocated with a computer-generated scheme to receive placebo or 2.5, 5, or 10 mg of dapagliflozin, once daily, for 48 weeks., Measurements: The primary outcome was change in hemoglobin A(1c) from baseline to 24 weeks. Secondary outcomes included changes in body weight, insulin dose, and fasting plasma glucose level at 24 weeks and during the 24-week extension period. Adverse events were evaluated throughout both 24-week periods., Results: 800 patients were analyzed. After 24 weeks, mean hemoglobin A(1c) decreased by 0.79% to 0.96% with dapagliflozin compared with 0.39% with placebo (mean difference, -0.40% [95% CI, -0.54% to -0.25%] in the 2.5-mg group, -0.49% [CI, -0.65% to -0.34%] in the 5-mg group, and -0.57% [CI, -0.72% to -0.42%] in the 10-mg group). Daily insulin dose decreased by 0.63 to 1.95 U with dapagliflozin and increased by 5.65 U with placebo (mean difference, -7.60 U [CI, -10.32 to -4.87 U] in the 2.5-mg group, -6.28 U [CI, -8.99 to -3.58 U] in the 5-mg group, and -6.82 U [CI, -9.56 to -4.09 U] in the 10-mg group). Body weight decreased by 0.92 to 1.61 kg with dapagliflozin and increased by 0.43 kg with placebo (mean differences, -1.35 kg [CI, -1.90 to -0.80 kg] in the 2.5-mg group, -1.42 kg [CI, -1.97 to -0.88 kg] in the 5-mg group, and -2.04 kg [CI, -2.59 to -1.48 kg] in the 10-mg group). These effects were maintained at 48 weeks. Compared with the placebo group, patients in the pooled dapagliflozin groups had a higher rate of hypoglycemic episodes (56.6% vs. 51.8%), events suggesting genital infection (9.0% vs. 2.5%), and events suggesting urinary tract infection (9.7% vs. 5.1%)., Limitation: Insulin doses were not titrated to target, and the study was not designed to evaluate long-term safety., Conclusion: Dapagliflozin improves glycemic control, stabilizes insulin dosing, and reduces weight without increasing major hypoglycemic episodes in patients with inadequately controlled type 2 diabetes mellitus., Primary Funding Source: AstraZeneca and Bristol-Myers Squibb.

Despite concern about the harmful effects of substances contained in various plastic consumer products, little attention has focused on the more heavily exposed women working in the plastics industry. Through a review of the toxicology, industrial hygiene, and epidemiology literatures in conjunction with qualitative research, this article explores occupational exposures in producing plastics and health risks to workers, particularly women, who make up a large part of the workforce. The review demonstrates that workers are exposed to chemicals that have been identified as mammary carcinogens and endocrine disrupting chemicals, and that the work environment is heavily contaminated with dust and fumes. Consequently, plastics workers have a body burden that far exceeds that found in the general public. The nature of these exposures in the plastics industry places women at disproportionate risk, underlining the importance of gender. Measures for eliminating these exposures and the need for regulatory action are discussed.

Objective: The aim of this study was to report the gynecologic safety findings from the Generations trial, a phase 3 study of the selective estrogen receptor modulator (SERM), arzoxifene., Methods: A predefined objective of the trial was to evaluate the effects of arzoxifene on the genital tract. Gynecologic examinations were performed yearly, and further gynecologic assessment, including endometrial biopsy, was performed in a predefined subset of women and in those who developed vaginal bleeding., Results: Overall, 9,354 women were randomized (4,678 to placebo, 4,676 to arzoxifene 20 mg/d). There were 13 adjudicated cases of endometrial cancer (placebo, 4 cases; arzoxifene, 9 cases: P = 0.165) and 6 cases of endometrial hyperplasia (placebo, 2 cases; arzoxifene, 4 cases). Endometrial thickness, assessed at 24- and 36-month transvaginal ultrasounds in a subset of women, increased slightly in women assigned to arzoxifene compared with baseline and women in placebo. At the last measurement, 3 (1.7%) women assigned to placebo and 21 (10.2%) assigned to arzoxifene had an endometrial thickness greater than 5 mm (P < 0.001 for difference between treatment groups). Endometrial polyps were more common in women treated with arzoxifene (n = 37) than in women treated with placebo (n = 18; P < 0.05). Vulvular and vaginal inflammation, including mycotic infections, and vaginal discharge were reported more frequently in women treated with arzoxifene than in women treated with placebo, as were urinary tract infections., Conclusions: Gynecologic events were generally more common in women treated with arzoxifene than in women treated with placebo. The gynecologic effects of arzoxifene seem to differ from those of raloxifene, although both SERMs have a benzothiophene structure. Although all SERMs influence cells through the estrogen receptor, they need to be evaluated independently in terms of their effects on various tissues, including the genital tract.

Aromatase inhibitors (AIs) have been shown to reduce the risk of breast cancer recurrence and are widely used today as adjuvant therapy in women with early stage endocrine-responsive breast cancer. Aromatase inhibitors may be prescribed as initial hormonal therapy, sequentially following 2-3 years of tamoxifen, or as extended adjuvant therapy (following 5 years of tamoxifen). Aromatase inhibitors are generally well tolerated; however, certain side effects, particularly arthralgia/musculoskeletal symptoms and gynecologic effects, may result in poor adherence to treatment. Patients receiving adjuvant therapy with an AI should be counseled regarding possible side effects and the importance of completing treatment. Interventions to ameliorate side effects should be individualized based on symptoms, comorbid conditions, and pre-existing therapies. In addition, bone and cardiovascular health should be monitored during AI therapy. Prompt therapeutic management of common side effects associated with AIs may provide patients with the opportunity to receive the full benefit of their adjuvant hormonal treatment while minimizing toxicity.

Background: many topical products are used in the genital region. Allergic contact dermatitis (ACD) may develop from product use or due to treatment of an underlying dermatosis., Objectives: our goal was to identify the frequency of ACD and identify top allergens in the genital region., Methods: data were analyzed for 1,238 patients tested between January 1990 and December 2006. Fifteen allergens caused reactions at rates greater than 1%. Thirteen anatomic regions were assessed. Statistical analyses were by chi-square test and Fisher exact test. Adjusted level of significance due to multiple testing was α  =  .002., Results: of individuals with genital dermatitis (n  =  37; aged 24-77 years, 48.6% female), 41% (15 of 37) had at least one positive patch-test result although only 30% (11 of 37) had a final diagnosis of relevant ACD. Mean age was 46 years for males and 41 years for females. The top five allergens were balsam of Peru (10.8%), fragrance mix I (8.1%), tolu balsam (8.1%), phenylmercuric acetate (8.1%), and neomycin (5.4%). Females were more often allergic (50%) compared to males (37%); 59.5% of patients had no positive reactions., Conclusion: genital dermatitis is rare; the minority tested positively for ACD. The top five allergens were present in toiletries and cosmetics used on genital skin. The top three allergens are fragrance related, underscoring the importance of using fragrance-free products on mucosal skin.

Endocrine disruptors (EDs) are dangerous chemicals widely used daily and spread in the environment and able to impair male and female fertility by interfering with the endocrine regulation of reproductive system. Many epidemiological studies showed the role of the EDs in the pathogenesis of reproductive pathologies such as infertility, recurrent abortions, malformations and endometriosis. Personal data show a significant correlation between phthalates and bisphenols and endometriosis. Further studies are needed to assess a clear relationship between environmental exposure to ED and reproductive pathologies and to find exposure's markers for environmental pollutants in biological fluids with the aim to have useful instruments for monitoring and preserving the reproductive health of women at risk of occupational/environmental exposure to ED.

In the last decade interest has increased in the possible effects of endocrine disruptor compounds. Numerous papers have appeared as to their possible effects on humans, but definitive effects are hard to demonstrate. In the field of animal husbandry, however, the effects of the endocrine disruptors are well documented. This paper discussed the effects of the endocrine disruptors seen in animals and the possible implications for humans. The areas considered are reproductive disorders, premature udder/breast development, prolapsed oviduct/uterus, scrotal atrophy, and skewed sex ratio.

Development of the reproductive organs can be strongly affected by the hormonal environment. In the mouse, exposure to estrogens and androgens during the critical developmental period induces estrogen-independent cell proliferation and differentiation in the adult vaginal epithelium, which often results in cancerous lesions later in life. In the present study, we assessed the contributions of estrogen receptor 1 (alpha) (ESR1) to the developmental effects of the nonaromatizable androgen 5alpha-dihydrotestosterone (DHT) on female mouse vagina and external genitalia. The vagina of Esr1(-/-) mice treated neonatally with DHT showed atrophic epithelium, whereas the vaginal epithelium of Esr1(+/+) mice was stratified and keratinized even after ovariectomy. In addition, neonatal treatment with DHT led to persistent phosphorylation of ESR1 in the vaginae of 60-day-old ovariectomized mice. We infer from these data that ESR1 is obligatory for the induction and maintenance of persistent vaginal epithelial changes induced by neonatal administration of DHT. Neonatal DHT treatment also induced hypospadias in both Esr1(-/-) and Esr1(+/+) mice. In contrast, DHT-induced formation of an os penis-like large bone in the clitoris was found in Esr1(-/-) mice but not in Esr1(+/-) or Esr1(+/+) mice. These results shed light on mechanisms of the induction of developmental effects elicited by sex steroid hormones on the developing animals.

Objective: To gain a greater understanding of published safety data for candidate vaginal microbicides., Design: A systematic review of human safety trials of candidate vaginal microbicides - agents designed to protect women against HIV and other sexually transmitted infections., Methods: Trials were published in peer-reviewed journals, and publication cut-off was August week 4, 2008. Trials of nonoxynol-9 were excluded, as were trials without a control group, trials that enrolled only male participants or reported on the investigation of a product for the treatment of a genital infection., Results: Twenty-one trials of 11 products, involving 1465 women, satisfied review criteria. Most trials reported on genital epithelial findings and urogenital symptoms and a number reported a range of other local and systemic toxicity endpoints. Trials were generally of short duration (2 weeks or less) with small sample sizes. There were few findings of significant difference between women in active and control arms. Among the products assessed in more than one study, there were significantly more genital findings with intact epithelium in recipients of PRO2000 [relative risk (RR) 1.68, 95% confidence interval (CI) 1.08-2.60] and a lower incidence of bacterial vaginosis in dextrin sulphate recipients (RR 0.61, 95% CI 0.42-0.88). CIs were generally very wide, and most studies were unable to exclude differences of a substantial magnitude between treated and control women., Conclusion: Larger and longer safety studies are necessary to detect clinically important toxicities, including those that indicate a potential increase in HIV risk, and provide assurance that agents are ready for large-scale effectiveness trials.

The article presents data on the levels of reproductive system diseases morbidity among fertile age women residing in the areas adjacent to the Tadzhik aluminum plant in Surkhandaryinskaya oblast of Uzbekistan. The relationship of the reproductive system diseases morbidity and the degree of atmospheric air, soil and foodstuff pollution with unhealthy chemical ingredients discharged by the aluminum plant is demonstrated. The data on the diseases of reproductive system organs most frequently occurring in fertile age women is presented.

The Bhopal gas tragedy is undoubtedly one of the worst industrial disasters in the history of mankind resulting in mortality of 2500-6000 and debilitating over 200 000 people. Inhabitants in the township were exposed to different degrees and there are more than 500 000 registered victims that survived the tragedy. Clinical studies have shown chronic illnesses such as pulmonary fibrosis, bronchial asthma, chronic obstructive pulmonary disease (COPD), emphysema, recurrent chest infections, keratopathy and corneal opacities in exposed cohorts. Survivors continue to experience higher incidence of reported health problems including febrile illnesses, respiratory, neurologic, psychiatric and ophthalmic symptoms. In-utero exposure to methyl isocyanate in the first trimester of pregnancy caused a persistent immune system hyper-responsiveness, which was in an evident way genetically linked with the organic exposure. Recent experimental studies have provided mechanistic understanding of methyl isocyanate exposure at a molecular level. Immunotoxic implications, toxico-genomic effect, inflammatory response, elicitation of mitochondrial oxidative stress, chromosomal and microsatellite instability have been studied comprehensively in cultured mammalian cells. Besides providing a framework for understanding potential mechanisms of toxicity of a host of other exposures, these studies may also uncover unique abnormalities thereby stimulating efforts to design newer and effective diagnostic and therapeutic strategies. The authors recommend long-term monitoring of the affected area and use of appropriate methods of investigation that include well-designed cohort studies, case-control studies for rare condition, characterization of personal exposure and accident analysis to determine the possible elements of the gas cloud.

Objective: Results of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial have shown that tamoxifen is associated with a significantly higher incidence of gynecologic adverse events than anastrozole., Study Design: This was a retrospective analysis of all gynecologic adverse events and interventions conducted in patients receiving anastrozole or tamoxifen in the main ATAC trial database., Results: Women taking tamoxifen experienced significantly more gynecologic adverse events than those taking anastrozole (34.2% vs 20.5%; P < .0001) and this led to more diagnostic and/or therapeutic interventions, including an almost 4-fold increase in the number of hysterectomies (5.1% vs 1.3%; P < .0001). The majority of the gynecologic adverse events with tamoxifen occurred during the first 2.5 years., Conclusion: The lower incidence of gynecologic adverse events and interventions with anastrozole and the early occurrence of these events provide further support for using anastrozole as the initial adjuvant treatment for early hormone receptor-positive breast cancer.

Irritant and allergic contact dermatitis is commonly seen in patients complaining of itching, burning and irritation in the genital area. The aim of this retrospective study was to establish the prevalence of allergic contact dermatitis patients with genital complaints. We followed 33 patients with persistent or recurrent genital redness, itching and burning sensation. Diagnosis was made by history, clinical examination and patch testing. Patch tests were carried out according to the International Contact Dermatitis Research Group with a standard series of allergens. We also tested topical pharmaceutical products that individual patients used for treating genital symptoms and patients self intimate hygiene products. There were 11 male and 22 female patients, mean age 38 years. Thirteen (39%) patients had one or more positive allergic reactions, mainly to nickel-sulfate, thimerosal, balsam of Peru, formaldehyde and neomycin sulfate. In seven of 13 patients with positive patch test results, these reactions were considered to be relevant to their clinical condition. Three patients had positive patch test reactions to their intimate hygiene products. One patient had positive patch test reaction to latex condom. Patients with genital symptoms are at a risk of developing contact sensitivity. Patch testing is useful in the management of these patients and many can be helped by allergen avoidance.

Aromatase inhibitors are now the first choice endocrine therapy in the metastatic setting for postmenopausal women.These endocrine agents also seem likely to soon become the standard adjuvant therapy for postmenopausal patients with hormone-responsive breast cancer, either alone or in sequence with tamoxifen. In the treatment with aromatase inhibitors, the incidence of some adverse effects such as endometrial cancer, stroke or pulmonary tromboembolism treatment associated with tamoxifen is reduced. Questions remain about the long-term side-effects and safety profile of aromatase inhibitors--monitoring and handling of bone loss associated with their application are essential and are being addressed in ongoing trials. Further studies with longer follow-up are required to clarify the effects of aromatase inhibitors on lipid metabolism and cardiovascular health.