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Biomedical subjects

A W Meikle

Publications and source records attributed to A W Meikle.

At least 55 records · Page 3Linked to original sources
PubMed1990

Nicotine and cotinine inhibit steroidogenesis in mouse Leydig cells.

Cigarette smoking alters plasma testosterone concentrations in men. The objectives of this study were to determine if nicotine and cotinine, two alkaloid products of cigarettes, affect luteinizing hormone(LH)-stimulated steroidogenesis in isolated adult mouse Leydig cells. Leydig cells from adult Swiss-Webster mice were isolated by linear density gradient and incubated (95% O2, 5% CO2) in minimum essential medium at 37 C for 3 hours with LH (10 ng) and with or without nicotine or cotinine (10(-5)-10(-7) M). Both nicotine and cotinine produced dose response inhibition (P less than 0.05) of LH-stimulated testosterone production (50-70%). The addition of 8-bromo-3',5'-cyclic monophosphate (cAMP, 500 uM) stimulated steroidogenesis comparable to LH in the absence of the alkaloids, but both nicotine and cotinine significantly (P less than 0.05) reduced testosterone production in response to cAMP, suggesting that the alkaloids inhibit testosterone production in response to LH distal to the formation of cAMP. In MEM without calcium, LH-stimulated testosterone synthesis was decreased, and neither nicotine nor cotinine significantly affected steroidogenesis. The addition of a calcium ionophore in MEM with normal calcium content enhanced (P less than 0.05) the inhibitory effects of nicotine and cotinine on LH-responsive steroidogenesis. A calcium channel blocking agent, verapamil, at 10uM significantly (P less than 0.05) reversed the inhibition of LH-stimulated testosterone production produced by both alkaloids when incubated in the medium with a normal calcium concentration. These results suggest that nicotine and cotinine either affect intracellular calcium content or block the effects of calcium on steroidogenesis in mouse Leydig cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1990

Effects of a fat-containing meal on sex hormones in men.

The effect of a fat-containing meal on plasma sex steroid concentrations was investigated in normal men. After an overnight fast on two separate occasions, subjects ingested a liquid meal containing either a nonnutritive sweetener (control), or isocaloric meals of mixed calorie sources with either high-fat content or mixed carbohydrate and protein with minimal fat. The order of the meals was alternated. Blood samples were collected at 15-minute intervals and pooled each hour. Sampling began at 7:00 AM and the test meal was ingested at 8:00 AM. Sex steroids, including estrone, estradiol, testosterone, and dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG) capacity, free testosterone concentration, and luteinizing hormone (LH) were determined by either specific radioimmunoassay or dialysis. The fat-containing meal, but not the nonnutritive or mixed carbohydrate and protein meal, resulted in a significant (P less than .01) reduction in total and free testosterone. Estrogens and luteinizing hormone were unaffected by either meal. This is the first documentation, to our knowledge, of the acute effect of a fat-containing meal on sex steroid concentrations in blood. Our observations suggest that a fat-containing meal reduces testosterone concentrations without affecting luteinizing hormone. This might indicate that fatty acids modulate testosterone production by the testes.

Adult↗
PubMed1990

Epidemiology of prostate cancer.

Available epidemiologic data do not allow targeting of specific populations for prostate cancer screening or early detection programs. Although certain strong factors have been identified (age, race, location), none sufficiently defines high-risk groups in whom recommendations should differ from those of other age-matched patients. Certainly, a strong familial tendency has been identified, but the relative contribution of genetic and environmental factors in these patients remains unclear. Some hypotheses on the pathogenesis of prostate cancer are possible based on the available data. Genetic factors appear to be permissive, as are hormonal influences, which are partially regulated by genetics. Environmental factors appear to be promotional in genetically susceptible men. Dietary fat may also be an important promotional factor in genetically susceptible men. Dietary factors appear to exert some influence by modulating sex hormone concentration. Several factors demand more investigation and understanding of the epidemiology of prostate cancer. The relative frequency of the disease and the increasing death rate from prostate cancer are of concern. The similarities in the incidence of latent prostate cancer among various groups with strong differences in the rate of clinically apparent disease raise significant issues regarding potential lifestyle or environmental promotional factors. Further understanding of the pathogenesis of prostate cancer may allow a refinement and definition of programs for prevention and early detection of the disease.

Adult↗
PubMed1989

Augmented pituitary corticotropin response to a threshold dosage of human corticotropin-releasing hormone in depressives pretreated with metyrapone.

We studied pituitary corticotropin response to exogenous corticotropin-releasing hormone infusion and attempted to control for the confounding effect of variable serum cortisol levels between depressed and control subjects. If metyrapone was given during the time of day when hypothalamic pituitary adrenal activity was otherwise low, the relative increase in the corticotropin concentration was small. Pituitary response to exogenous corticotropin-releasing hormone can be defined under conditions in which the amount of glucocorticoid-mediated negative feedback present at the level of the pituitary gland is equal in all subjects. When the ambient cortisol level was equalized (and suppressed) in all subjects at the time of study with a threshold dosage of corticotropin-releasing hormone, we found an augmented response to corticotropin-releasing hormone in depressives. This raises the possibility that either increased pituitary sensitivity to corticotropin-releasing hormone or an increased intracellular pool of corticotropin is available for release in subjects with major depressive illness.

Adrenocorticotropic Hormone↗
PubMed1989

Relationship between body mass index, cigarette smoking, and plasma sex steroids in normal male twins.

Smoking has been observed to affect plasma sex hormones and body mass index. The relationship between smoking, body mass index, and plasma concentration of sex hormones was studied in normal adult male twins. The analyses were performed for between 150 and 159 twin pairs for whom hormonal data were available on both twins. With bivariate analysis, neither body mass index nor smoking affected estrone, luteinizing hormone, follicle-stimulating hormone, ratio of testosterone to estradiol, or ratio of testosterone to dihydrotestosterone. Body mass index significantly (P less than 0.05) affected sex hormone binding globulin, whereas smoking had no effect. The plasma contents of testosterone and dihydrotestosterone and the luteinizing hormone/testosterone ratio were affected by both body mass index and smoking, although, after allowing for body mass, smoking was less significant (0.05 less than P less than 0.10). A path model was formulated to examine the relationship of body mass and sex steroid levels. Our results suggest that body mass index affects sex steroids, since common environmental factors do not account for the strength of the relationship. The bivariate analysis suggests that the smoking effect on sex hormones (except perhaps for dihydrotestosterone) is secondary to an effect on body mass index.

Adult↗
PubMed1989

Estradiol and testosterone metabolism and production in men with prostatic cancer.

We recently observed a familial influence on the plasma concentration of sex-steroids and the metabolic clearance in men with prostatic cancer. We have now determined, by isotope dilution techniques, the blood estradiol and testosterone production and clearance rates in men with prostatic cancer and in unrelated controls. Thirty-eight men had a diagnosis of prostatic cancer before the age of 63, and 22 controls matched for age were randomly selected from the general population. None of the patients or controls had received endocrine therapy. The plasma content of testosterone, dihydrotestosterone, estrone, estradiol, 3 alpha-androstanediol glucuronide, dehydroepiandrosterone sulfate, sex-hormone binding globulin, apparent free testosterone concentration, follicle stimulating hormone and luteinizing hormone were not significantly different between the groups. The metabolic clearance and production rates of testosterone were significantly (P = 0.008 and P = 0.013, respectively) higher in patients [447 +/- 26 L/day/body surface area(m2) and 2.21 +/- 0.17 mg/day/m2, n = 38] than in controls [346 +/- 20 L/day/m2 and 1.70 +/- 0.11 mg/day/m2, n = 22]. The PR and MCR of estradiol were not significantly different between patients with prostatic cancer (n = 19) and controls (n = 12). These results indicate that men with prostatic cancer have elevated clearance and production rates of testosterone without an alteration of estradiol production or clearance.

Androgens↗
PubMed1989

Nonesterified fatty acids modulate steroidogenesis in mouse Leydig cells.

The effects of nonesterified fatty acids (NEFA) in modulating testosterone synthesis stimulated by luteinizing hormone (LH, 10 ng/sample) were investigated in isolated adult mouse Leydig cells. LH-stimulated testosterone production was inhibited by triglycerides (0-500 mg/dl, 50 mg/dl, 94% of the control and 500 mg/dl, 40%) and by a mixture of NEFA (100 microM, 70% of control, 200 microM, 54%, and greater than 200 microM, less than 50%). Oleic acid was a more potent inhibitor than linoleic, stearic, or palmitic acids. 8-Bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP, 5 mM) stimulated testosterone production comparable to LH but failed to reverse the inhibition of steroidogenesis produced by the NEFA. The inhibition produced by NEFA was dependent on extracellular Ca2+; and a Ca2+ channel antagonist, verapamil (10 microM), enhanced the inhibition of chylomicrons and fatty acids. 22(R)-hydroxycholesterol (10 microM) reversed the inhibition produced by NEFA. The inhibitory effects of NEFA were reversible by removal of the fatty acids. The results indicate that NEFA are potent modulators of testosterone synthesis in Leydig cells stimulated with either LH, cAMP, or intracellular Ca2+. NEFA inhibit steroidogenesis at one of the steps preceding conversion of cholesterol to pregnenolone.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1988

The effect of nutritional factors on sex hormone levels in male twins.

Dietary intake has been hypothesized as being associated with several hormonally related cancers including prostate, breast, ovarian, and endometrial cancer. Because diet may affect hormones directly, it is logical to examine the effects of dietary factors on hormone production and levels. Therefore, a set of 72 male MZ and 83 male DZ twin pairs was ascertained from the Utah birth certificates. A quantitative food frequency questionnaire was administered and blood samples were drawn for hormonal assays. Heritability estimates for hormonal levels were calculated indicating a range from no heritability for sex hormone binding globulin (SHBG), estrone, and testosterone glucuronide to 70% for androstanediol glucuronide and luteinizing hormone. To examine nutritional factors, the difference in hormone and SHBG levels between each MZ twin and his co-twin were correlated with the difference in nutrient intake. Weight and obesity were significantly correlated with plasma testosterone and follicle stimulating hormone. Fat intake showed a significant association with testosterone. Androstanediol glucuronide, a steroid that reflects tissue formation of dihydrotestosterone, was inversely correlated with caloric intake, theobromine and caffeine. Testosterone glucuronide exhibited significant correlations with calories and vitamin A. This study suggests that dietary intake affects plasma sex-steroid levels in men.

Diet↗
PubMed1988

Lifestyle and blood pressure levels in male twins in Utah.

Healthy male monozygotic (MZ) and dizygotic (DZ) twin pairs (MZ pairs = 77; DZ pairs = 88) were studied to assess the effect of dietary intake, physical activity, physical fitness, body mass index (BMI), sum of the triceps and subscapular skinfold measurements, alcohol and caffeine consumption, and smoking patterns on blood pressure. Data on physical activity, detailed dietary intake, medical history, and demographics were obtained from a questionnaire. A bicycle ergometer was used to estimate level of fitness; other medical information was ascertained from physical examination. After normalizing the study variables, intraclass correlations for BMI and the sum of the triceps and subscapular skinfold measurements were higher in MZ than in DZ twin pairs (BMI: MZ r = 0.76, DZ r = 0.48; skinfolds: MZ r = 0.73, DZ r = 0.28), as were VO2max(MZ r = 0.63, DZ r = 0.25) and post-bike heart rate (MZ r = 0.69, DZ r = 0.19). Both systolic (SBP) and diastolic blood pressure (DBP) had high heritability estimates (SBP = 0.60, and DBP = 0.66). Using factor analysis, four major lifestyle factors were identified and categorized as: 1) dietary intake; 2) a factor heavily weighted by cigarette smoking, alcohol and caffeine consumption; 3) fatness; 4) physical activity and physical fitness. Adjustment for these factors did not alter heritability estimates for either SBP or DBP.

Blood Pressure↗
PubMed1988

Heritability of variation of plasma cortisol levels.

Heritability of the variation of the plasma concentrations of total and unbound cortisol, cortisol binding globulin (CBG), and dehydroepiandrosterone sulfate (DHEA-S) was investigated in 20 monozygotic (MZ) and 20 dizygotic (DZ) male twin pairs. Three plasma samples collected between 8 AM and 9:30 AM were pooled for the assays. Heritability was calculated from the intraclass correlation [2(rMZ - rDZ)]. The mean age, total and unbound cortisol, CBG, and DHEA-S were not significantly different between the MZ and DZ groups of twins. The heritability index for variability of the plasma content of steroids was 45.4% (p less than .05) for total cortisol, 50.6% (P less than .05) for unbound plasma cortisol, 57.8% (P less than .05) for DHEA-S, and 32.4% (P greater than .05) for CBG. The data were analyzed by factor analysis, and heritability estimates were corrected for factors including age, smoking, drinking, exercise, and degree of obesity. These factors did not account for the variation in hormone values in twin pairs. Factor analysis of the three quantitative measurements, cortisol, percent free cortisol, and DHEA-S, provides no evidence for shared factors. The correlation coefficients between age and CBG and total and unbound plasma cortisol concentrations were insignificant. The correlation coefficient between total plasma cortisol levels and CBG was 0.57, which indicates that CBG accounts for 32% of the variation of plasma cortisol concentrations. The results suggest that genetic factors have a decided influence on the variation of the concentration of cortisol of DHEA-S in normal adult men.

Age Factors↗
PubMed1988

Nicotine and cotinine effects on 3 alpha hydroxysteroid dehydrogenase in canine prostate.

We have recently observed that cigarette smoking affects plasma androgen concentrations. The effects of nicotine and cotinine, two products of cigarette smoking, on testosterone metabolism were determined. The activity of delta 4 steroid 5 alpha-reductase, which converts testosterone to 5 alpha-dihydrotestosterone (DHT) was measured in isolated dog prostate nuclei using testosterone (0-200 nM) as substrate and NADPH as cofactor. Activity of 3 alpha-hydroxysteroid dehydrogenase (HSD), which converts DHT to 3 alpha-androstanediol (3 alpha-diol) and is a reversible enzyme, was measured in isolated dog prostate microsomes with DHT (0-20 microM) as substrate and NADPH as cofactor. When microsomal fractions were incubated for 1 hour with and without nicotine (0-50 microM) and cotinine (0-100 microM), enzyme activity of HSD was significantly suppressed (p less than 0.001). The Vmax was not affected significantly (p greater than 0.60) and Km increased with increasing concentrations of nicotine and cotinine (p less than 0.05). Both nicotine and cotinine are competitive inhibitors of HSD in dog prostate microsomes with Ki's of 61 and 89 microM, respectively. The apparent 5 alpha-reductase activity was unaffected by nicotine and cotinine. The inhibitors produced a marked effect on activity of HSD when used in concentrations achieved in humans who smoke cigarettes. The results suggest that nicotine and cotinine are competitive inhibitors of the HSD, an important enzyme involved in the metabolism of DHT and produce an accumulation of DHT. These products of cigarette smoking could alter androgen action in tissue such as skin and prostate.

3-Hydroxysteroid Dehydrogenases↗
PubMed1988

Hereditary and environmental influences on the variation of thyroid hormones in normal male twins.

Heritability of the variation of the plasma total and unbound T4 (free T4), T3, T4-binding globulin (TBG), and TSH concentrations was investigated in 15 monozygotic and 15 dizygotic male twin pairs. The variability in plasma of total (58%) and free T4 (72%) concentrations was significantly less (P less than 0.01) in the twin pairs than in unrelated men. Half of the variability of T3 (P less than 0.05), TBG (P less than 0.05), and TSH (P less than 0.05) was affected by influences shared by the twin pairs in both monozygotic and dizygotic twin pairs. The heritability index for variability of the plasma total T4 and free T4 was greater than 28% (P less than 0.05), and it was 25% or less for T3 and TBG. Variation in TBG accounted for less than 20% (P less than 0.001) of the variation in thyroid hormone concentrations. The results indicate that familial factors, which are affected by genetic and/or environmental factors, influence the variation of plasma TBG, TSH, T4, free T4, and T3 concentrations among normal men. Genetic factors influenced the variation in plasma T4 and free T4 levels.

Humans↗
PubMed1988

Quantitating genetic and nongenetic factors influencing androgen production and clearance rates in men.

Both hereditary and nonhereditary factors have a decided influence on plasma sex steroid concentrations in men. We studied the relative contributions of genetic and nongenetic factors on the production rate (PR) and MCR of testosterone and dihydrotestosterone (DHT) and their conversion ratios to other metabolites in monozygotic (MZ; n = 22) and dizygotic (DZ; n = 24) male twins. Zygosity was determined by measurement of 10 blood proteins and enzymes. The kinetic studies were conducted with isotope dilution techniques. The genetic effect was determined from the equation: 2[rMZ - rDZ], where r is intraclass correlation. A heritability of over 40% was found for the PRs of DHT/body surface area and of testosterone/body surface area. Nongenetic factors accounted for 50% or more of the variation of the conversion ratios for testosterone/3 alpha-androstanediol and DHT/3 alpha-androstanediol. The results suggest that genetic factors markedly influence the PRs of testosterone and DHT, suggesting that the PR of these potent androgens is under genetic control despite the decided influence of environmental factors on their clearance.

Adult↗
PubMed1987

Production, clearance, and metabolism of testosterone in men with prostatic cancer.

It was previously unknown whether the production and metabolism of testosterone was altered in men with prostatic cancer. We recently observed a familial influence on the plasma concentration of sex steroids in men with the cancer. We have now determined, by isotope dilution techniques, the blood testosterone production and clearance rates and testosterone metabolism to potent androgen metabolites in men with prostatic cancer, their brothers, and unrelated controls. Nineteen men had a diagnosis of prostatic cancer before age 63 (probands), 23 were brothers of these index cases, and nine controls matched for age were selected randomly from the general population. None had received endocrine therapy. The plasma content of testosterone, dihydrotestosterone, sex hormone binding globulin, apparent free testosterone concentration, follicle-stimulating hormone, and luteinizing hormone were not significantly different between the groups. The metabolic clearance rate of testosterone was significantly (P = .04) higher in probands (458 liters/day/body surface area, median) than in controls (306 liters/day/body surface area). The conversion ratios of both testosterone (1.8%) and dihydrotestosterone (16.9%) to 3 alpha-androstanediol were significantly greater (P = .04 and P = .004, respectively) in probands than in controls (0.95%, 7.8%). These results indicate that men with prostatic cancer have elevated clearance rates of testosterone and an increased conversion ratio of testosterone to its potent 5 alpha-reduced metabolites.

Age Factors↗
PubMed1986

Quantitating genetic and nongenetic factors that determine plasma sex steroid variation in normal male twins.

We have observed that familial factors have a decided influence on the plasma content of sex steroids in men both in the general population and in men of families with prostatic cancer. The contribution of genetic and nongenetic familial factors on the variation of plasma sex steroid content and action has now been investigated in 75 pairs of normal male monozygotic (MZ) twins and 88 pairs of dizygotic (DZ) twins. Zygosity was determined by measuring ten blood proteins and enzymes. The mean plasma values for testosterone (T), dihydrotestosterone (DHT), estradiol (E2), estrone (E1), and 3 alpha-androstanediol glucuronide (3 alpha-diol G), free T, LH, FSH, SHBG, age, and degree of adiposity were all similar between the groups of twins. Familial factors (P less than 0.01) accounted for 50% or more of the variation in plasma hormone levels in MZ twins (3 alpha-diol G, 84%; T/DHT, 70%; T, 63%; E1, 63%; free T, 61%; E2, 57%; DHT, 56%; LH, 55%; and FSH, 54%) except for SHBG, which was 30%. The familial influence was greater in MZ twins than in DZ twins for all measurements except for SHBG. The heritability of the variation of hormone levels in plasma was determined from the equation: 2[rMZ(intraclass correlation) - rDZ]. Genes regulate 25% to 76% of the total variation of plasma content of the hormones except for DHT (12%) and SHBG (less than 1%). Genetic regulation of tissue DHT formation was suggested by observing a 48% genetic effect on the plasma content of 3 alpha-diol G.(ABSTRACT TRUNCATED AT 250 WORDS)

Dihydrotestosterone↗
PubMed1986

Effect of short- and long-term dexamethasone on 3 alpha-androstanediol glucuronide in hirsute women.

The role of glucocorticoid therapy in regulating plasma 3 alpha-androstanediol glucuronide (3 alpha-diol G) content, a marker of androgen action, in hirsute women was unclear. A pulse injection of adrenocorticotropic hormone (0.5 U) following 1 mg of dexamethasone (DEX) at midnight significantly increased the plasma level of cortisol (P less than 0.01), 17-hydroxyprogesterone (17-OHP, P less than 0.01) in 17 hirsute women, but it had an insignificant effect on delta 4-androstenedione (delta 4A), testosterone, dehydroepiandrosterone sulfate (DHEA-S), and 3 alpha-diol G. Human chorionic gonadotropin administered for 3 days produced a significant (P less than 0.01) increase only in 17-OHP. DEX administered as a single dose in the late evening failed to affect the plasma levels of these four androgens when measured at 8:00 A.M. In contrast, when the glucocorticoid was given each evening for over 2 months, plasma delta 4A, DHEA-S, and 3 alpha-diol G were suppressed (P less than 0.001) substantially, as compared with baseline values in 12 hirsute women, 7 with polycystic ovary disease and 5 with idiopathic hirsutism. These observations indicate that chronic glucocorticoid therapy suppresses androgen action in hirsute women.

17-alpha-Hydroxyprogesterone↗
PubMed1985

Familial factors affecting prostatic cancer risk and plasma sex-steroid levels.

Whether familial factors affect the frequency of prostatic cancer and the plasma content of sex-steroids was investigated. Brothers (n = 257) of probands (n = 150) diagnosed with prostatic cancer before age 62 years had a fourfold higher risk for developing the disease than men in the general population in the State of Utah and their brothers-in-law (n = 202). Familial factors markedly affected the plasma content of sex steroids (testosterone, dihydrotestosterone, the ratio of testosterone to DHT, sex-hormone binding globulin, and the free fraction of testosterone) in nonendocrinologically treated probands and their brothers and sons and in normal men in the general populations. Index cases and their brothers and sons had a significantly lower mean plasma testosterone content than controls of comparable age. Preliminary data suggest that the metabolic clearance rate of testosterone and the conversion ratio of testosterone to estradiol are relatively high in probands. The observations indicate that familial factors are potent risk factors for the development of prostatic cancer. They also suggest that plasma androgen values in families with prostatic cancer cluster in the lower range of normal and that plasma sex-steroid content is more similar in each brothers with or without prostatic cancer than among nonbrothers.

Adult↗