Benkt Högstedt

Hyperinsulinaemia as a Risk Factor for Developing Benign Prostatic Hyperplasia

Objective: To determine the validity coefficient of the total prostate gland volume as an expression of the transition zone (TZ) volume. To test the hypothesis of hyperinsulinaemia as a causal factor for the development of benign prostatic hyperplasia (BPH). Patients and Methods: Three hundred and seven consecutive patients with lower urinary tract symptoms were studied. A subgroup of 114 patients were tested with regard to the validity coefficient between the total prostate gland volume and the TZ volume. In the total material of 307 men, a BPH risk factor analysis was performed in which groups of men with the following conditions were related to the annual BPH growth rate: men without or with metabolic disease; men with different components of the metabolic syndrome, and men with low or high fasting plasma insulin values. The prostate gland volume and the TZ volume were determined using ultrasound. The presence of non–insulin–dependent diabetes mellitus (NIDDM) and treated hypertension was obtained from the patients’ medical records. Data on blood pressure, waist and hip measurement, body height and weight were collected and body mass index and waist/hip ratio were calculated. Blood samples were drawn from fasting patients to determine the insulin and HDL–cholesterol values. Results: In the subgroup of men subjected to measurement of both the total prostate gland volume and the TZ volume, the correlation coefficient between total prostate gland volume and the TZ volume was r.s. =0.97 (p<0.0001) which, thus, constituted the validity coefficient. The median annual BPH growth rate in the total group was 1.03 ml/year. The median annual BPH growth rate was faster in men with metabolic disease (p<0.0001), NIDDM (p<0.0001), treated hypertension (p<0.0001), obesity (p<0.0001) and dyslipidaemia (p<0.0001) than in men without metabolic disease. Moreover, the annual BPH growth rate correlated positively with the diastolic blood pressure (r.s. = 0.27; p<0.001), the BMI (r.s. = 0.22; p<0.001) and four other expressions of obesity, and negatively with the HDL–cholesterol level (r.s. = –0.15; p<0.001). The median annual BPH growth rate was faster in men with a high than in men with a low fasting plasma insulin level (p = 0.019). When the patients were divided into quartiles, the median annual BPH growth rate increased statistically significantly with increasing fasting plasma insulin levels. The fasting plasma insulin values correlated with the annual BPH growth rates (p = 0.009). When performing a multivariate analysis using the total prostate gland volume as dependent variable, fasting plasma insulin (p = 0.001) and age (p<0.001) became statistically significant. Conclusion: The results of the present report suggest that the total prostate gland volume constitutes a valid expression of BPH. The findings support the hypothesis that hyperinsulinaemia is causally related to the development of BPH and generate the hypothesis of an increased sympathetic nerve activity in men with BPH.

Clinical, anthropometric, metabolic and insulin profile of men with fast annual growth rates of benign prostatic hyperplasia.

The purpose of this study was to test the hypothesis of a causal relationship between high insulin levels and the development of benign prostatic hyperplasia (BPH) and to determine the clinical, anthropometric, metabolic and insulin profile in men with fast-growing BPH compared with men with slow-growing BPH. The present study was designed as a risk factor analysis of BPH in which the estimated annual BPH growth rate was related to components of the metabolic syndrome. Two hundred and fifty patients referred to the Urological Section, Department of Surgery, Central Hospital, Varberg, Sweden, with lower urinary tract symptoms with or without manifestations of the metabolic syndrome were consecutively included. The prevalences of atherosclerotic disease manifestations, non-insulin-dependent diabetes mellitus (NIDDM) and treated hypertension were obtained. Data on blood pressure, waist and hip measurement, body height and weight were collected and body mass index (BMI) and waist/hip ratio (WHR) were calculated. Blood samples were drawn from fasting patients to determine insulin, total cholesterol, triglycerides, HDL and LDL cholesterol, uric acid, alanine aminotransferase (ALAT) and prostate-specific antigen (PSA). The prostate gland volume was determined using ultrasound. The median annual BPH growth rate was 1.04 ml/year. Men with fast-growing BPH had a higher prevalence of NIDDM (p = 0.023) and treated hypertension (p = 0.049). These patients were also taller (p=0.004) and more obese as measured by body weight (p<0.001), BMI (p=0.026), waist measurement (p <0.001), hip measurement (p = 0.006) and WHR (p=0.029). Moreover, they had elevated fasting plasma insulin levels (p = 0.018) and lower HDL cholesterol levels (p = 0.021) than men with slow-growing BPH. The annual BPH growth rate correlated positively with diastolic blood pressure (rs = 0.14; p = 0.009), BMI (rs = 0.24; p < 0.001) and four other expressions of obesity and fasting plasma insulin level (rs = 0.18; p = 0.008), and negatively with the HDL cholesterol level (rs = -0.22; p = 0.001). In conclusion, the data suggest that NIDDM, hypertension, tallness, obesity, high insulin and low HDL cholesterol levels constitute risk factors for the development of BPH. The results also suggest that BPH is a component of the metabolic syndrome and that BPH patients may share the same metabolic abnormality of a defective insulin-mediated glucose uptake and secondary hyperinsulinaemia, as patients with the metabolic syndrome. The findings support the hypothesis of a causal relationship between high insulin levels and the development of BPH, and give rise to a hypothesis of increased sympathetic nerve activity in men with BPH.

Clinical, haemodynamic, anthropometric, metabolic and insulin profile of men with high-stage and high-grade clinical prostate cancer

Aims: Previous studies have shown that non‐insulin‐dependent diabetes mellitus (NIDDM), hypertension, atherosclerotic disease manifestations, tallness, obesity, dyslipidaemia, hyperuricaemia, hyperinsulinaemia and high alanine aminotransferase (ALAT) levels are risk factors for development of benign prostatic hyperplasia (BPH). This indicates that BPH is a component of the metabolic syndrome. In a subsequent study, we found that there was an association between the BPH growth rate and the development of clinical prostate cancer. These findings generated a hypothesis that clinical prostate cancer also was a component of the metabolic syndrome. In the present study, this hypothesis was tested on 299 patients with recently diagnosed clinical prostate cancer. If this hypothesis is true, patients with clinical prostate cancer of high stage and grade would have a larger prostate gland volume, a faster BPH growth rate and a more pronounced clinical, haemodynamic, anthropometric, metabolic and insulin profile than patients with clinical prostate cancer of low stage and grade have. Methods: Two hundred and ninety‐nine patients in whom clinical prostate cancer was diagnosed were consecutively included. The prevalence of NIDDM, treated hypertension and atherosclerotic manifestations was provided by the respective patients medical history. Body length, body weight, waist measurement, hip measurement and blood pressure were determined. Body mass index (BMI) and waist/hip ratio (WHR) were calculated. Blood samples were drawn to determine triglycerides, total cholesterol, high‐density lipoprotein (HDL)‐cholesterol, low‐density lipoprotein (LDL)‐cholesterol, uric acid, ALAT and the fasting plasma insulin level. The prostate gland volume was measured using transrectal ultrasound. The annual BPH growth rate was calculated. The prostate cancer diagnosis was established. Results: Patients with clinical prostate cancer, prostate‐specific antigen (PSA) < 50 ng/ml, stage T3, had a bigger prostate gland volume (p < 0.001), a faster BPH growth rate (p < 0.001), were more obese, as measured by body weight (p = 0.062), BMI (p = 0.003), waist measurement (p = 0.011) and hip measurement (p = 0.051) and showed a higher systolic blood pressure (p < 0.070) than patients with T2 clinical prostate cancer. When patients with clinical prostate cancer, PSA >50 ng/ml, were included at the comparison, T3 tumour patients showed a higher prevalence of treated hypertension (p = 0.026) than patients with T2 tumours. Patients with clinical prostate cancer, PSA <50 ng/ml, G3, had a greater prostate gland volume (p = 0.004), a faster BPH growth rate (p = 0.005) and were more obese as determined by waist measurement (p = 0.044) and WHR (p = 0.073). Moreover, subjects with a G3 tumour were more dyslipidaemic, as shown by a higher triglyceride level (p = 0.019) and a lower HDL‐cholesterol level (p = 0.005), and were more hyperuricaemic (p = 0.023), showed a higher plasma insulin level ( p = 0.019) and a higher ALAT level (p = 0.061) than those with a G1 tumour. When patients with clinical prostate cancer, PSA >50 ng/ml, were included at the comparison, G3 patients had a greater prostate gland volume (p = 0.002) and a faster BPH growth rate (p = 0.003) than patients with G1 tumours. Conclusions: The results of the present study suggest that the prostate gland volume, the BPH growth rate, hypertension, obesity, dyslipidaemia, hyperuricaemia, hyperinsulinaemia and high ALAT levels are risk factors for the development of clinical prostate cancer. Thus, our results support the hypothesis that clinical prostate cancer is a component of the metabolic syndrome. Patients with clinical prostate cancer may have the same metabolic abnormality of a defective insulin‐stimulated glucose uptake and secondary hyperinsulinaemia as patients with the metabolic syndrome. Our data also support the hypothesis that hyperinsulinaemia is a promoter of clinical prostate cancer.

Cancer predictive value of cytogenetic markers used in occupational health surveillance programs: a report from an ongoing study by the European Study Group on Cytogenetic Biomarkers and Health

The cytogenetic endpoints in peripheral blood lymphocytes: chromosomal aberrations (CA), sister chromatid exchange (SCE) and micronuclei (MN) are established biomarkers of exposure for mutagens or carcinogens in the work environment. However, it is not clear whether these biomarkers also may serve as biomarkers for genotoxic effects which will result in an enhanced cancer risk. In order to assess this problem, Nordic and Italian cohorts were established, and preliminary results from these two studies indicated a predictive value of CA frequency for cancer risk, whereas no such associations were observed for SCE or MN. A collaborative study between the Nordic and Italian research groups, will enable a more thorough evaluation of the cancer predictivity of the cytogenetic endpoints. We here report on the establishment of a joint data base comprising 5271 subjects, examined 1965-1988 for at least one cytogenetic biomarker. Totally, 3540 subjects had been examined for CA, 2702 for SCE and 1496 for MN. These cohorts have been followed-up with respect to subsequent cancer mortality or cancer incidence, and the expected values have been calculated from rates derived from the general populations in each country. Stratified cohort analyses will be performed with respect to the levels of the cytogenetic biomarkers. The importance of potential effect modifiers such as gender, age at test, and time since test, will be evaluated using Poisson regression models. The remaining two potential effect modifiers, occupational exposures and smoking, will be assessed in a case-referent study within the study base.

Sister chromatid exchanges and structural chromosome aberrations in relation to age and sex

SummarySister chromatid exchanges (SCE) and structural chromosome aberrations were analyzed in peripheral blood lymphocytes of 100 individuals, and correlated to age and sex. No correlation was found between the frequency of SCE and age, but older individuals had significantly more structural aberrations than younger. Females had significantly more SCE as well as structural chromosome aberrations than males. The positive correlations of SCE and structural aberrations to age and sex were also significant when these factors, as well as smoking habits, were taken into consideration in an analysis of covariance.

A Nordic data base on somatic chromosome damage in humans

Analyses of cytogenetic damage--chromosome aberrations (CA), micronuclei (MN), and sister-chromatid exchange (SCE)--are used to assess genotoxic exposure, on the supposition that higher levels of chromosome damage in peripheral lymphocytes reflect increased cancer risk. We attempt to test this hypothesis prospectively, by relating levels of cytogenetic damage to subsequent cancer morbidity in a cohort comprising 3190 subjects. All these subjects have been analyzed previously (1970-1988) for CA, MN, and/or SCE in studies of occupational and environmental exposure. The present paper describes the data base and assesses how the potential confounders smoking habits, sex, and age influence CA, MN, and SCE levels. Ten Nordic laboratories contributed data. In the present analyses, these data were treated separately to avoid the effects of interlaboratory differences. Point estimates from multiple regression analyses indicate that smoking may increase CA frequencies by up to 10-20% and SCE means by 5-8%, but that it has no effect on MN frequencies. Women had higher CA, MN, and SCE levels than men, but the sex effect was generally smaller than the effect of smoking. Age was positively associated with cytogenetic damage. Compared to the sex effect, the effect of a 10-year age increase was similar on CA, but less, 1-3%, on SCE. The amount of variation explained by the potential confounders taken together was generally low, often less than 20%. Thus, other still unknown factors must be the major sources of CA, MN, and SCE variability.

Mechanism of benzene toxicity. Effects of benzene and benzene metabolites on bone marrow cellularity, number of granulopoietic stem cells and frequency of micronuclei in mice

The effects of benzene and benzene metabolites *hydroquinone and catechol) on bone marrow cellularity, number of granulopoietic stem cells and on the frequency of micronuclei in polychromatic erythrocytes were investigated in mice. The dose-effect curve for benzene revealed that there was a threshold dose (approx. 100 mg benzene/kg body wt./day injected subcutaneously on 6 consecutive days) above which severe toxicity occurred in all three parameters. Also hydroquinone gave rise to adverse effects in the parameters studied, but the sequence of occurrence was different from that observed with benzene. These data are interpreted to indicate that hydroquinone is a hemotoxic metabolite of benzene in mice in vivo, but that other metabolites, or benzene itself, also probably contribute to the toxicity. Catechol gave no effects. However, due to acute effects like tremor and convulsions only rather low doses could be tested. Simultaneous administration of toluene dramatically reduced the toxicity of benzene, but gave only a small reduction of the hydroquinone-induced effects.

A reduced capacity for unscheduled DNA synthesis in lymphocytes from individuals exposed to propylene oxide and ethylene oxide

Propylene oxide (PO) has been produced commercially since 1925. The main uses of PO are (1) as intermediates in the synthesis of polyurethane foams and polyester resins (via propylene glycol), and (2) as a fumigant for sterilizing plastic medical equipment and foodstuffs (IARC, Vol. 11, 1976). PO has (a) rate constants for chemical reactivity with water and other nucleophils, (b) mutagenicity, and (c) estimates of risk to man, all similar to those observed for ethylene oxide (EO). (For detailed review, see Ehrenberg and Hussain, 1981.) Both PO and EO are carcinogenic in mammals, and EO has also been implicated as a human carcinogen (Hogstedt et at., 1979a, b). Recently we have shown that exposure, both in vivo and in vitro, of an individuals lymphocytes to EO inhibited unscheduled DNA synthesis (UDS), a step in the enzymatic repair of DNA lesions (Pero et al., 1981). Here we report a verification of these earlier results of EO exposure, and further extend our results to include another closely related epoxide, PO, which we have now found also caused inhibition of UDS after occupational exposure. According to our knowledge, this is the first report of the genotoxic effects of PO in man.

Gasoline pump mechanics had increased frequencies and sizes of micronuclei in lymphocytes stimulated by pokeweed mitogen

Fifteen gasoline pump mechanics and 15 controls were investigated with the lymphocyte micronucleus assay and also with differential count of leukocytes in the peripheral blood. The lymphocytes were stimulated with phytohemagglutinin and pokeweed mitogen in parallel cultures. The pump mechanics had increased frequencies and sizes of micronuclei in the pokeweed mitogen-stimulated cultures but not in those stimulated with phytohemagglutinin. The difference in effect between the 2 mitogens is probably due to an increased sensitivity of the B-lymphocytes to mutagens. The leukocyte count was significantly higher in the gasoline-exposed group. The effect of the occupational exposure was probably caused by the benzene content of the gasoline. The time-weighted average for 8 h was around 1 mg/m3 of benzene, but there were peak levels of 20 mg/m3.

Calculated Fast-growing Benign Prostatic Hyperplasia A Risk Factor for Developing Clinical Prostate Cancer

Objective: Whether there is an association between the development of benign prostatic hyperplasia (BPH) and clinical prostate cancer is controversial. The present report tests the hypothesis of an association between BPH growth and the development of clinical prostate cancer by examining stage, grade and PSA-level in men with recently discovered clinical prostate cancer with slow or fast-growing BPH. If the hypothesis is true, men with fast-growing BPH would have a more advanced clinical prostate cancer. Material and Methods: Two hundred and twenty patients in whom a clinical prostate cancer was diagnosed were consecutively included. The prevalence of atherosclerotic disease, non-insulin-dependent diabetes mellitus (NIDDM) or treated hypertension was provided by the respective patients medical history. Tallness, body weight, waist measurement, hip measurement and blood pressure were determined. The body mass index (BMI) and waist/hip ratio (WHR) were calculated. Blood samples were drawn to determine triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol, uric acid, ALAT and the fasting plasma insulin level. The prostate gland volume was measured using transrectal ultrasound. The annual BPH growth rate was calculated, assuming that the total prostate gland volume was 20 mL at the patient age of forty. The prostate cancer diagnosis was established using the technique of transrectal ultrasound-guided automatic needle biopsy of the prostate. Results: Men with clinical prostate cancer, PSA <50 ng/mL, and with fast-growing BPH had a higher systolic ( p = 0.009) and diastolic ( p = 0.020) blood pressure, were taller ( p < 0.001) and more obese, as determined by body weight ( p < 0.001), BMI ( p = 0.005), waist measurement ( p < 0.001) and hip measurement ( p = 0.003). They also had a higher fasting plasma insulin level ( p = 0.014) and a lower HDL-cholesterol level ( p = 0.067) than men with slow-growing BPH. Moreover, men with clinical prostate cancer, PSA <50 ng/mL, and fast-growing BPH had more pronounced clinical prostate cancer, as measured by grade ( p = 0.029) and PSA-level ( p = 0.016), than men with slow-growing BPH. In the total material, including men with clinical prostate cancer, PSA S 50 ng/mL, men with fast-growing BPH also had a higher prevalence of NIDDM ( p = 0.039) and a borderline statistical significance for higher stage ( p = 0.09) than men with slow-growing BPH. The BPH growth rate was significantly associated with the clinical prostate cancer grade ( p = 0.018) and PSA-level ( p = 0.002) but not with the clinical cancer stage in a multivariate statistical analysis. Conclusions: This report confirms findings in previous studies that fast-growing BPH is a risk factor for NIDDM, hypertension, tallness, obesity, dyslipidaemia and hyperinsulinaemia. The present report extends this list of risk factors to include atherosclerotic disease manifestations, hyperuricaemia and higher ALAT levels. The study suggests that fast-growing BPH is a risk factor for developing clinical prostate cancer and, thus, supports the hypothesis of an association between the development of BPH and clinical prostate cancer. The study generates the hypothesis that clinical prostate cancer is a component of the metabolic syndrome and that insulin is a promoter of clinical prostate cancer.