Testosterone Replacement Therapy: Effects on Blood Pressure in Hypogonadal Men.

PURPOSE: While testosterone therapy can improve the various pathologies associated with adult-onset testosterone deficiency (TD), Summary of Product Characteristics (SPC) of five testosterone preparations caution that treatment may be associated with hypertension. This paper evaluates the impact of testosterone undecanoate (TU) on blood pressure (BP) in men with adult-onset TD. MATERIALS AND METHODS: Of 737 men with adult-onset TD in an on-going, observational, prospective, cumulative registry, we studied changes in BP using non-parametric sign-rank tests at final assessment and fixed time points. We used multiple regression analysis to establish factors (baseline BP, age, change/baseline waist circumference [WC] and hematocrit [HCT] and follow-up) potentially associated with BP change in men on TU. RESULTS: TU was associated with significant reductions in systolic, diastolic BP and pulse pressure, regardless of antihypertensive therapy (at baseline or during follow-up), larger reductions were seen with concurrent antihypertensive therapy. In men never on antihypertensive agents, median changes (interquartile range [IQR]) in systolic BP, diastolic BP and pulse pressure were -12.5 (-19.0, -8.0), -8.0 (-14.0, -3.0), and -6.0 (-10.0, -1.0) mmHg, respectively at final assessment, with only baseline BP values inversely associated with these changes (HCT and WC were not significantly associated). In men not on TU, systolic BP, diastolic BP, and pulse pressure significantly increased. In the TU treated men only 1 of the 152 men (not on antihypertensive agents at baseline) were started on antihypertensives during follow-up. In contrast 33 of the 202 men on antihypertensives (at baseline or follow-up) had the antihypertensive agent discontinued by the end of the follow-up. CONCLUSIONS: TU was associated with lowering of BP during follow-up irrespective of antihypertensive therapy, with greater reductions in men with higher baseline BP. In the context of SPC warnings, our long-term data provide reassurance on the effect of TU on BP.

Testosterone replacement therapy: association with mortality in high-risk patient subgroups.

OBJECTIVES: We describe studies determining the association between testosterone therapy (TTh) and mortality. MATERIALS & METHODS: We used a registry database of 737 men with adult-onset testosterone deficiency defined as presenting with low serum total testosterone (TT) levels ≤12.1 nmol/L and associated symptoms over a near 10-year follow-up. We compared associations between testosterone undecanoate (TU), cardio-metabolic risk factors and mortality using non-parametric statistics followed by separate Cox regression models to determine if any association between TU and morality was independent of age and cardio-metabolic risk factors. Finally, the association between TU and mortality was studied in men stratified by cardio-metabolic risk. RESULTS: During a median follow-up interquartile range (IQR) of 114 (84-132) months, 94 of the 737 men died. TU (ref: non-treatment) was associated with mortality; hazard ratio = 0.23, 95% confidence intervals = 0.14-0.40. Cox's regression models showed the above association to be independent of baseline age, waist circumference, hemoglobin A1c, lipids, blood pressure, smoking, and type 2 diabetes. These variables remained associated with mortality. We finally stratified the men by the high-risk baseline variables and established that the association between mortality and TU was only evident in men at higher risk. A possible explanation could lie with the "law of initial value," where greater improvements are evident following treatment in patients with worse baseline values. CONCLUSIONS: This study with long follow-up confirms that TTh is associated with lower mortality in men with adult-onset TD. This association was evident only in men with greater cardio-metabolic risk factors who demonstrated greater benefit.

Testosterone replacement therapy: Pre-treatment sex hormone-binding globulin levels and age may identify clinical subgroups.

BACKGROUND: Testosterone replacement therapy (TRT) improves health in some but not all men with type 2 diabetes (T2DM) and adult-onset testosterone deficiency (TD). Such heterogeneity is compatible with the concept of patient subgroups that respond differently to therapy. OBJECTIVES: Use baseline SHBG and age to identify putative subgroups that demonstrate different responses in variables such as waist circumference and HbA1c following TRT. MATERIALS AND METHODS: A randomized double-blind trial approach was used to recruit and randomize men with T2DM and adult-onset TD into placebo and TRT-treated groups. Multiple regression was used to study differences between groups. RESULTS: Baseline SHBG and change in SHBG (∆SHBG) were inversely related in the TRT group. Both median values of SHBG and age mediated the effect of TRT on ∆SHBG depending on whether baseline values were ≤ or>median (28.1 nmol/L, 63 years, respectively). In men with both SHBG ≤ 28.1 nmol/L and age ≤ 63 years (subgroup 1), TRT was positively associated with ∆SHBG (c = 4.67, 95%CI 1.17-8.16, P = .010) while in those with SHBG > 28.1 nmol/L and age > 63.1 years (subgroup 4) the association was inverse (c = -7.07, 95%CI -11.64 to -2.49, P = .003). The association between TRT and change (∆) in waist circumference, HbA1c and International Index of Erectile Function (IIEF) score differed between subgroups; in subgroup 4 but not subgroup 1, the therapy was significantly associated with ∆waist circumference, ∆HbA1c and ∆IIEF. DISCUSSION: Though the mechanism remains unclear, our finding of different responses to TRT in terms of change in waist circumference, HbA1c and IIEF score supports the concept of subgroups in men with T2DM and adult-onset TD. CONCLUSION: Our approach may provide a basis for identifying men who will or will not derive benefit from TRT though a larger study is required.

Long-Term Testosterone Therapy in Type 2 Diabetes Is Associated with Decreasing Waist Circumference and Improving Erectile Function.

PURPOSE: To describe the 4-year metabolic follow-up results from the BLAST study. MATERIALS AND METHODS: Baseline hemoglobin A1c (HbA1c), weight, and waist circumference (WC) data were recorded in 185 men recruited for the BLAST randomised controlled trial (RCT) and erectile function (EF) scores were also available in an additional 48 men screened for the RCT. Intra/inter-group associations between these parameters and testosterone replacement therapy (TRT) were assessed at 1) end of the RCT (30 weeks), 2) open-label phase (82 weeks), and 3) final assessment via non-parametric statistics. RESULTS: Improvement in HbA1c and weight at the end of the RCT and open-label phase in men on TRT was not maintained long-term. The convergence in HbA1c could have been due to incentivised care with HbA1c targets. Interestingly those on TRT at final assessment required fewer anti-diabetic agents. The weight increase in routine care may have been due to changes in diabetes medication or an increase in lean muscle mass. WC continued to decrease in men on TRT indicating possible reduction in visceral fat. Improvement in EF scores continued with long-term TRT, this was abolished when TRT was discontinued. CONCLUSIONS: This study hints at benefits in glycaemic control, weight and WC, and long-term RCTs studying mechanisms of benefit and clinical outcomes are necessary. Our results also show that EF scores continued to improve with long-term TRT, even beyond the 6 months that we previously reported in the BLAST RCT.

Sex Hormone Binding Globulin: A Review of its Interactions With Testosterone and Age, and its Impact on Mortality in Men With Type 2 Diabetes.

INTRODUCTION: The age-related fall in male testosterone levels can have clinical consequences. The concentration of serum-free testosterone, the putative bioactive moiety, is mediated by carrier proteins, especially SHBG. AIM: The aim of this study was to consider the nature of hormone binding to carriers with new insights into determining calculated free testosterone levels and review how SHBG and testosterone influence age-related mortality. METHODS: Where possible, we focused on recent literature describing binding of testosterone to carrier proteins or, associations among age, SHBG, testosterone, and mortality. We then used logistic regression to study the impact of SHBG and total testosterone on age-related mortality in men with type 2 diabetes mellitus (T2DM). MAIN OUTCOME MEASURES: The association between mortality and age and SHBG and/or total testosterone was determined in a cohort of 364 men with T2DM leading to a graphical display of the impact of SHBG/testosterone levels on age-related mortality. RESULTS: Low total testosterone and high SHBG are independently associated with increased all-cause mortality. Our analyses support these findings showing that men with T2DM and a combination of total testosterone <12 nmol/L and SHBG >35nmol/L (odds ratio [OR]: 3.05; 95% CI: 1.43-6.53; P = .004) demonstrated an increased risk of mortality, independent of age (OR: 1.08; 95% CI: 1.06-1.11; P < .001). We graphically demonstrated that the risk combination altered the relationship between age and mortality. CONCLUSION: Until free testosterone is precisely, accurately, and conveniently measured, calculated values may provide useful even if somewhat inaccurate estimates. We also suggest that SHBG and testosterone assays are standardized to allow establishment of diagnostic and treatment thresholds. Although it is possible that the association in men with T2DM, among the combination of SHBG and total testosterone and age-related mortality is driven by free hormone levels, it is so far, unproven. Sudarshan Ramachandran, Geoffrey I. Hackett, Richard C. Strange, et al. Sex Hormone Binding Globulin: A Review of its Interactions With Testosterone and Age, and its Impact on Mortality in Men With Type 2 Diabetes. Sex Med Rev 2019;7:669-678.

Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics.

INTRODUCTION: Clinical guidelines indicate that hematocrit should be monitored during testosterone replacement therapy (TTh), with action taken if a level of 0.54 is exceeded. AIM: To consider the extent of changes in hematocrit and putative effects on viscosity, blood flow, and mortality rates after TTh. METHODS: We focused on literature describing benefits and possible pitfalls of TTh, including increased hematocrit. We used data from the BLAST RCT to determine change in hematocrit after 30 weeks of TTh and describe a clinical case showing the need for monitoring. We consider the validity of the current hematocrit cutoff value at which TTh may be modified. Ways in which hematocrit alters blood flow in the micro- and macro-vasculature are also considered. MAIN OUTCOME MEASURES: The following measures were assessed: (i) change in hematocrit, (ii) corresponding actions taken in clinical practice, and (iii) possible blood flow changes following change in hematocrit. RESULTS: Analysis of data from the BLAST RCT showed a significant increase in mean hematocrit of 0.01, the increase greater in men with lower baseline values. Although 0 of 61 men given TTh breached the suggested cutoff of 0.54 after 30 weeks, a clinical case demonstrates the need to monitor hematocrit. An association between hematocrit and morbidity and mortality appears likely but not proven and may be evident only in patient subgroups. The consequences of an increased hematocrit may be mediated by alterations in blood viscosity, oxygen delivery, and flow. Their relative impact may vary in different vascular beds. CONCLUSIONS: TTh can effect an increased hematocrit via poorly understood mechanisms and may have harmful effects on blood flow that differ in patient subgroups. At present, there appears no scientific basis for using a hematocrit of 0.54 to modify TTh; other values may be more appropriate in particular patient groups. König CS, Balabani S, Hackett GI, et al. Testosterone Therapy: An Assessment of the Clinical Consequences of Changes in Hematocrit and Blood Flow Characteristics. Sex Med Rev 2019;7:650-660.

Long-term testosterone therapy in type 2 diabetes is associated with reduced mortality without improvement in conventional cardiovascular risk factors.

OBJECTIVES: To further characterize the beneficial impact of testosterone replacement therapy (TRT) on the association between mortality and hypogonadism (HG) in men with type 2 diabetes (T2DM), by determining, firstly, if changes in cardiovascular disease (CVD) risk factors after TRT play a role, secondly, whether the reduction in mortality is lost when TRT is discontinued and, finally, the presence of subgroups where benefit may be greater. MATERIALS AND METHODS: We studied 857 men with T2DM, screened for the BLAST randomized controlled trial, over 3.8 years of follow-up. The men were stratified first by testosterone levels: group 1: total testosterone (TT) >12 nmol/L and free testosterone (FT) >0.25 nmol/L; Group 2: TT ≤12 nmol/L or FT ≤0.25 nmol/L. Group 2 was further stratified into those not on TRT (Group 2a) and those on TRT (Group 2b). Group 2b was further stratified by whether TRT was discontinued (Group 2b1) or not (Group 2b2). The principal outcome, mortality, was studied using Cox regression. RESULTS: We found that TRT was not associated with improvements in CVD risk factors. CVD risk factors (baseline and changes during follow-up) were not associated with mortality. Men in Group 1 and Group 2b were found to have lower mortality (reference: Group 2a), even with CVD risk factors included in the regression models. Mortality was lower in men in Group 2b1 (6.2%) and Group 2b2 (0%) compared with those in Group 2a (16.9%). The lower mortality associated with Group 1 and Group 2b was observed primarily in older (>64.6 years) and less overweight (≤93.8 kg) men. CONCLUSIONS: The benefits associated with normal testosterone levels and TRT (even after discontinuation) do not appear to be related to improvements in the CVD risk factors studied. In view of TRT having greater impact in men of lower weight, better outcomes may be achieved with concurrent TRT and weight reduction programmes.

Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes.

AIM: To determine how statins, testosterone (T) replacement therapy (TRT) and phosphodiesterase 5-inhibitors (PDE5I) influence age related mortality in diabetic men. METHODS: We studied 857 diabetic men screened for the BLAST study, stratifying them (mean follow-up = 3.8 years) into: (1) Normal T levels/untreated (total T > 12 nmol/L and free T > 0.25 nmol/L), Low T/untreated and Low T/treated; (2) PDE5I/untreated and PDE5I/treated; and (3) statin/untreated and statin/treated groups. The relationship between age and mortality, alone and with T/TRT, statin and PDE5I treatment was studied using logistic regression. Mortality probability and 95%CI were calculated from the above models for each individual. RESULTS: Age was associated with mortality (logistic regression, OR = 1.10, 95%CI: 1.08-1.13, P < 0.001). With all factors included, age (OR = 1.08, 95%CI: 1.06-1.11, P < 0.001), Low T/treated (OR = 0.38, 95%CI: 0.15-0.92, P = 0.033), PDE5I/treated (OR = 0.17, 95%CI: 0.053-0.56, P = 0.004) and statin/treated (OR = 0.59, 95%CI: 0.36-0.97, P = 0.038) were associated with lower mortality. Age related mortality was as described by Gompertz, r2 = 0.881 when Ln (mortality) was plotted against age. The probability of mortality and 95%CI (from logistic regression) of individuals, treated/untreated with the drugs, alone and in combination was plotted against age. Overlap of 95%CI lines was evident with statins and TRT. No overlap was evident with PDE5I alone and with statins and TRT, this suggesting a change in the relationship between age and mortality. CONCLUSION: We show that statins, PDE5I and TRT reduce mortality in diabetes. PDE5I, alone and with the other treatments significantly alter age related mortality in diabetic men.

A study in high-risk, maximally pretreated patients to determine the potential use of PCSK9 inhibitors at various thresholds of total and LDL cholesterol levels.

PURPOSE OF THE STUDY: Statins and ezetimibe reduce low-density lipoprotein cholesterol (LDL-c) and cardiovascular disease (CVD) risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower LDL-c by 50%-70% and might be useful in refractory patients. The National Institute for Health and Care Excellence (NICE) technology appraisal guidance (TAG) recommends use of these drugs in secondary prevention and familial hypercholesterolaemia (FH) at differing LDL-c thresholds. We have estimated the proportion of patients in whom this third-line drug might be useful. STUDY DESIGN: We used data from a lipid-lowering audit programme to study 72 with FH and/or CVD of 271 patients referred over 12 months who failed to achieve target total cholesterol (TC) and LDL-c levels. All 72 patients were treated with ezetimibe, and 69 cases also received statins. We used LDL-c thresholds 1.5-5.5 mmol/L to estimate how many of these refractory patients could benefit from PCSK9 inhibitors. RESULTS: In 72 patients, TC and LDL-c targets were not met by 64 and 53 patients, respectively. We judged using the NICE TAG that only one patient (1.4% ezetimibe requiring and 0.4% total referrals) required a PCSK9 inhibitor. CONCLUSIONS: We determined that the proportion of patients eligible for a PCSK9 inhibitor at various TC and LDL-c levels is modest. This may reflect the use of all available statins in UK lipid clinics often at non-daily frequency. We suggest that cost-effective use of PCSK9 inhibitors requires prescribing being restricted to clinicians working in specialised lipid clinics.

Use of fibrates in the metabolic syndrome: A review.

The use of fibrates in the treatment of dyslipidaemia has changed significantly over recent years. Their role appeared clear at the start of this century. The Helsinki Heart Study and Veterans Affairs High-Density Cholesterol Intervention Trial suggested significant benefit, especially in patients with atherogenic dyslipidaemia. However, this clarity disintegrated following the negative outcomes reported by the Bezafibrate Infarction Prevention, Fenofibrate Intervention and Event Lowering in Diabetes and Action to Control Cardiovascular Risk in Diabetes randomised controlled trials. In this review we discuss these and other relevant trials and consider patient subgroups such as those with the metabolic syndrome and those needing treatment to prevent the microvascular complications associated with diabetes in whom fibrates may be useful. We also discuss observations from our group that may provide some explanation for the varying outcomes reported in large trials. The actions of fibrates in patients who are also on statins are interesting and appear to differ from those in patients not on statins. Understanding this is key as statins are the primary lipid lowering agents and likely to occupy that position for the foreseeable future. We also present other features of fibrate treatment we have observed in our clinical practice; changes in creatinine, liver function tests and the paradoxical high density lipoprotein reduction. Our purpose is to provide enough data for the reader to make objective decisions in their own clinical practice regarding fibrate use.

Metabolic syndrome: A review of the role of vitamin D in mediating susceptibility and outcome.

Despite the well-recognised role of vitamin D in a wide range of physiological processes, hypovitaminosis is common worldwide (prevalence 30%-50%) presumably arising from inadequate exposure to ultraviolet radiation and insufficient consumption. While generally not at the very low levels associated with rickets, hypovitaminosis D has been implicated in various very different, pathophysiological processes. These include putative effects on the pathogenesis of neoplastic change, inflammatory and demyelinating conditions, cardiovascular disease (CVD) and diabetes. This review focuses on the association between hypovitaminosis D and the metabolic syndrome as well as its component characteristics which are central obesity, glucose homeostasis, insulin resistance, hypertension and atherogenic dyslipidaemia. We also consider the effects of hypovitaminosis D on outcomes associated with the metabolic syndrome such as CVD, diabetes and non-alcoholic fatty liver disease. We structure this review into 3 distinct sections; the metabolic syndrome, vitamin D biochemistry and the putative association between hypovitaminosis D, the metabolic syndrome and cardiovascular risk.

Associations between onset age and disability in multiple sclerosis patients studied using MSSS and a progression model.

BACKGROUND: While many factors have been examined, male gender and older age at multiple sclerosis onset are among few variables consistently associated with increased disability. Interestingly, the association between onset age and disability may not be linear with some data suggesting a faster rate of accumulation of disability in patients aged more than 30 years at onset. OBJECTIVE: Explore the relationship between onset age and disability. METHODS: We studied 500 MS patients grouped by cut-offs in onset age. Disability was assessed using Multiple Sclerosis Severity Scale (MSSS) and, a model based on time to reach an Extended Disability Severity Score (EDSS) (progression model). Data were analyzed using linear and logistic regression. RESULTS: The association between disability (assessed by both MSSS and the progression model) and onset age was different in patients whose MS onset occurred after an age band of 30-35 years. Before this age range, changing age was not associated with changes in disability while during and after this age range, disability was increased. CONCLUSION: We found a significant change in the relationship between disability and onset age after about 31 years supporting the idea that while onset age does not define a sharp cut-off, it can help define subgroups of patients with differing rates of accumulation of disability.

Progression of disability in multiple sclerosis: A study of factors influencing median time to reach an EDSS value.

BACKGROUND: The extended disability severity scale (EDSS) is clinically useful in assessing disability in multiple sclerosis (MS) patients. It is also being used in studies to determine how genes and environment influence disability. However, since it has a complex relationship with functional scores and mobility and is strongly determined by disease duration its use can be limiting. OBJECTIVE: Study associations of variables with progression described by time from disease onset until EDSS. METHODS: We used a variable based on below/above median time from MS onset to reach a single EDSS value to define slow or fast progression. We compared patient categorization using this variable and MSSS, and in 533 patients (EDSS 1-8) and 242 of these patients with EDSS1-4, studied associations with skin type, gender, ultraviolet radiation and MC1R Asp294His. RESULTS: Classifying patients into quartiles of slow/fast progression showed mean MSSS increased with faster progression (p<0.001). For EDSS 1-8: MSSS, late onset age and childhood sunburning were associated with fast and MC1R CG/GG(294) with slow progression. Combinations of skin type (1/2 or 3/4) with childhood weekend exposure (< or ≥median) or sunburning (yes/no) were not associated with progression. However, in patients with EDSS1-4, relative to other combinations, those with no sunburning history and types 1/2 demonstrated slow progression (odds ratio=0.15, 95% CI=0.04, 0.57). CONCLUSION: This method, though a pilot, allows study of associations of variables with EDSS. It is based on local patients and could substitute for MSSS. In patients with EDSS1-4 but not 1-8, skin type 1/2 with no history of childhood sunburning was associated with slow progression. This is compatible with the view that disability develops through a first stage dependent on inflammation.

The Multiple Sclerosis Severity Score: associations with MC1R single nucleotide polymorphisms and host response to ultraviolet radiation.

BACKGROUND: Multiple sclerosis outcome may be influenced by ultraviolet radiation and vitamin D synthesis, suggesting skin type and genes determining this phenotype are candidates for disability. However, though associations between melanocortin 1 receptor (MC1R) single nucleotide polymorphisms and disability are reported, some data are incompatible with their expected influence on skin type. OBJECTIVE: Determine which MC1R single nucleotide polymorphisms affect disability and establish if ultraviolet radiation modifies such associations. METHODS: We studied using linear regression in 525 cases, associations of the Multiple Sclerosis Severity Score (MSSS) with skin type, gender, ultraviolet radiation exposure and six MC1R single nucleotide polymorphisms (rs1805005, rs1805006, rs2228479, rs1805007, rs1805008, rs1805009). RESULTS: CG(294) with GG(294) genotypes (rs1805009) (coefficient = -1.44, 95% CI -2.30, -0.59, mean MSSS +/- SD = 4.33 +/- 2.87) and AC(84) (rs1805006) (coefficient = 1.62, 95% CI 0.17, 3.06, mean MSSS = 7.62 +/- 2.43) were associated with MSSS. Associations with Asp294His were found in those with skin types 1/2 and 3/4, and cases stratified by ultraviolet radiation exposure. However, they were seen only in cases with a history of childhood sunburn and not in those without sunburn. We found no significant associations between exposure parameters and MSSS. CONCLUSIONS: Multiple sclerosis outcome is influenced by interactions between host response to ultraviolet radiation and MC1R single nucleotide polymorphisms. The influence of the single nucleotide polymorphisms appears distinct from their association with skin type.

Patients with both basal and squamous cell carcinomas are at a lower risk of further basal cell carcinomas than patients with only a basal cell carcinoma.

BACKGROUND: The rate of development of further basal cell carcinoma (BCC) after first presentation is highly variable. The mechanisms that determine this phenotypic difference are unclear. OBJECTIVE: We assessed the risks of developing a subsequent BCC in patients who developed a BCC and a squamous cell carcinoma (SCC) and compared them with patients who developed a BCC only. METHODS: In all, 1040 patients who developed BCC only were compared with 140 patients who developed BCC and SCC to see whether the latter group included a high proportion of risk phenotypes (eg, male sex and fair skin). We then compared the number of BCCs developing per year in the two groups (174 BCC only and 71 BCC/SCC) during a 5-year period after initial BCC presentation. RESULTS: The BCC/SCC group demonstrated a significantly lower BCC/year rate than BCC only group. The rate of development of further BCC during 5-year follow-up was lower in the BCC/SCC group because a smaller number of patients developed subsequent BCC and not because the same proportion of patients developed lesions but in smaller numbers. After 5 years of follow-up, 51.1% of BCC and 74.6% of BCC/SCC cases were free from a subsequent BCC. Logistic regression analysis corrected for age at initial presentation confirmed that patients with BCC/SCC were less likely to develop a further BCC during the 5 years after initial presentation (P = .001, odds ratio = 0.31, 95% confidence interval 0.15-0.63). LIMITATIONS: Because of the large patient group and long study follow-up from the date of the index BCC or SCC, not all data were obtained. Where this is the case, the number of patients for whom the information is available is provided. CONCLUSIONS: Patients who develop a BCC are similar to patients who develop both a BCC and SCC, confirming the overlap of causative factors. Patients who develop both a BCC and SCC are less likely to develop BCCs compared with patients who develop BCC only.

Meta-analysis and pooled analysis of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers: a HuGE-GSEC review.

The association of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers was assessed through a meta-analysis of published case-control studies and a pooled analysis of both published and unpublished case-control studies from the Genetic Susceptibility to Environmental Carcinogens database (http://www.upci.upmc.edu/research/ccps/ccontrol/index.html ). Thirty publications used in the meta-analysis included a total of 7783 subjects (3177 cases and 4606 controls); 21 datasets, 9397 subjects (3130 cases and 6267 controls) were included in the pooled analysis. The GSTM1 deletion was 2-fold more likely to occur in African American and African cases than controls (odds ratio: 1.7, 95% confidence interval: 0.9-3.3), although this was not observed among whites (odds ratio: 1.0, 95% confidence interval: 0.9-1.1). The meta-analysis and pooled analysis showed a significant association between oral and pharyngeal cancer and the CYP1A1 MspI homozygous variant (meta-ORm2/m2: 1.9, 95% confidence interval: 1.4-2.7; Pooled ORm2m2: 2.0, 95% confidence interval: 1.3-3.1; ORm1m2 or [infi]m2m2: 1.3, 95% confidence interval: 1.1-1.6). The association was present for the CYP1A1 (exon 7) polymorphism (ORVal/Val: 2.2, 95% confidence interval: 1.1-4.5) in ever smokers. A joint effect was observed for GSTM1 homozygous deletion and the CYP1A1 m1m2 variant on cancer risk. Our findings suggest that tobacco use and genetic factors play a significant role in oral and pharyngeal cancer.

Associations between timing of exposure to ultraviolet radiation, T-stage and survival in prostate cancer.

BACKGROUND: Exposure to ultraviolet radiation (UVR) has been inversely associated with prostate cancer risk. We determined if skin type and UVR exposure are linked with parameters of prostate cancer outcome. METHODS: We used a questionnaire to determine UVR exposure parameters and skin type in 553 men with prostate cancer and, using logistic regression and survival analysis, studied their association with T-stage, Gleason score, and survival after starting hormone manipulation therapy. RESULTS: UVR exposures 10, 20, and 30 years before diagnosis were inversely associated with T-stage. The odds ratio (OR) for UVR exposure 10 years before diagnosis was lowest (OR=0.69, 95% CI=0.56-0.86). ORs were lower in men with skin types I/II than III/IV. Skin types I/II were associated with longer survival after commencing hormone therapy (hazard ratio=0.62, 95% CI=0.40-0.95). CONCLUSIONS: Our finding that UVR exposure is beneficial is compatible with accumulating data showing sunlight has a protective effect on disease phenotype.

Vitamin D and oestrogen receptor polymorphisms in developmental dysplasia of the hip and primary protrusio acetabuli--a preliminary study.

We investigated the association of developmental dysplasia of the hip (DDH) and primary protrusion acetabuli (PPA) with Vitamin D receptor polymorphisms Taq I and Fok I and oestrogen receptor polymorphisms Pvu II and Xba I. 45 patients with DDH and 20 patients with PPA were included in the study. Healthy controls (n = 101) aged 18-60 years were recruited from the same geographical area. The control subjects had a normal acetabular morphology based on a recent pelvic radiograph performed for an unrelated cause. DNA was obtained from all the subjects from peripheral blood. Genotype frequencies were compared in the three groups. The relationship between the genotype and morphology of the hip joint, severity of the disease, age at onset of disease and gender were examined. The oestrogen receptor Xba I wild-type genotype (XX, compared with Xx and xx combined) was more common in the DDH group (55.8%) than controls (37.9%), though this just failed to achieve statistical significance (p = 0.053, odds ratio = 2.1, 95% CI = 0.9-4.6). In the DDH group, homozygosity for the mutant Taq I Vitamin D receptor t allele was associated with higher acetabular index (Mann-Whitney U-test, p = 0.03). Pvu II pp oestrogen receptor genotype was associated with low centre edge angle (p = 0.07). This study suggests a possible correlation between gene polymorphism in the oestrogen and vitamin D receptors and susceptibility to, and severity of DDH. The Taq I vitamin D receptor polymorphisms may be associated with abnormal acetabular morphology leading to DDH while the Xba I oestrogen receptor XX genotype may be associated with increased risk of developing DDH. No such correlations were found in the group with PPA.

Differential effects of glutathione S-transferase pi (GSTP1) haplotypes on cell proliferation and apoptosis.

Expression of the glutathione S-transferase, GSTP1, is associated with phase 1 detoxification of the products of oxidative stress. Recently, GSTP1 expression has been implicated in the regulation of cell proliferation and apoptosis through direct interaction with the c-Jun N-terminal kinase, (JNK). GSTP1 is polymorphic and allelic variants have been associated with disease susceptibility and clinical outcome. However, the influence of GSTP1 alleles on proliferation and apoptosis has not been studied previously. To investigate this, we have examined the effects of inducible expression of wild-type GSTP1*A and mutant GSTP1*C haplotypes on cell proliferation and apoptosis in NIH3T3 fibroblasts. Cells expressing GSTP1*A displayed increased doubling times and a delayed G1-S phase transition compared with cells expressing GSTP1*C. Both GSTP1*A and GSTP1*C haplotypes protected cells from undergoing apoptosis when exposed to oxidative stress. However, analysis of JNK status revealed that only GSTP1*C expression led to a reduction in JNK activity compared with GSTP1*A-expressing cells and non-induced cells. We further examined the effect of GSTP1 alleles on colony-forming efficiency (CFE) in soft agar following exposure to oxidative stress and found that GSTP1*A-expressing clones had increased CFE compared with non-induced and GSTP1*C-expressing clones. Our data suggest that GSTP1 alleles have differential effects on proliferation and apoptosis; GSTP1*A reduces cellular proliferation and protects against apoptosis through a JNK-independent mechanism. In contrast, GSTP1*C does not influence cellular proliferation but protects cells from apoptosis through JNK-mediated mechanisms.