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High levels of circulating testosterone are not associated with increased prostate cancer risk: A pooled prospective study

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High levels of circulating testosterone are not associated with increased prostate cancer risk: A pooled prospective study

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Abstract

Androgens stimulate prostate cancer in vitro and in vivo. However, evidence from epidemiologic studies of an association between circulating levels of androgens and prostate cancer risk has been inconsistent. We investigated the association of serum levels of testosterone, the principal androgen in circulation, and sex hormone-binding globulin (SHBG) with risk in a case-control study nested in cohorts in Finland, Norway and Sweden of 708 men who were diagnosed with prostate cancer after blood collection and among 2,242 men who were not. In conditional logistic regression analyses, modest but significant decreases in risk were seen for increasing levels of total testosterone down to odds ratio for top vs. bottom quintile of 0.80 (95% CI = 0.59-1.06; p(trend) = 0.05); for SHBG, the corresponding odds ratio was 0.76 (95% CI = 0.57-1.01; p(trend) = 0.07). For free testosterone, calculated from total testosterone and SHBG, a bell-shaped risk pattern was seen with a decrease in odds ratio for top vs. bottom quintile of 0.82 (95% CI = 0.60-1.14; p(trend) = 0.44). No support was found for the hypothesis that high levels of circulating androgens within a physiologic range stimulate development and growth of prostate cancer.

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... Thirty-one observational studies were identified that investigated the association of endogenous total testosterone with risk of PCa (aggressive and non-aggressive) . Twenty studies (25,26,(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49), out of the 31, were prospective and previously analyzed in a meta-analysis to determine association of continuous (5 nmol/L increment) endogenous total testosterone with risk of PCa ( Figure 1 and Table 1) (50). The remaining 11 studies/analyses (25,(27)(28)(29)(30)(31)(32)(33), which some may be repeated because they reported findings for both aggressive and non-aggressive PCa in opposite directions (25,26), were a combination of prospective and retrospective studies that focused on the association of continuous total testosterone (per 1 unit increment) with PCa. ...
... In this section, we identified 25 studies/analyses that investigated endogenous total testosterone in categorical format high vs. low levels ( Figure 2 and Table 2) (25)(26)(27)(28)30,38,41,46,(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61). This was a combination of prospective, retrospective, nested-control studies and one meta-analysis of two nested-control studies (52). ...
... Eight out of 25 studies/analyses reported an increasedrisk of PCa for men with high levels of testosterone compared to low [Figure 2(numbers 1-4, 10, 12, 14, 19)](25,26,38,46,(51)(52)(53)59), but only four were statistically significant (numbers 1-4)(46,(51)(52)(53). The remaining 17 studies/analyses showed a decreased-risk of PCa after comparing high vs. low levels of testosterone [Figure 2(numbers5-9,11, 13, 15, 16, 17, 18, 19 and 20-25) andTable 2](25)(26)(27)(28)30,38,41,(54)(55)(56)(57)(58)(59)(60)(61), but only 11 were statistically significant [Figure 2(numbers[6][7][8][9]13,16,17,18,20,21,25) and ...
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For more than 70 years, the contention that high levels of testosterone or that the use of testosterone therapy (TTh) increases the development and progression of prostate cancer (PCa) has been widely accepted and practiced. Yet, the increasing and emerging evidence on testosterone research seems to challenge that contention. To review literature on the associations of endogenous and exogenous testosterone with decreased-, increased-, or null-risk of PCa, and to further evaluate only those studies that reported magnitude of associations from multivariable modeling as it minimizes confounding effects. We conducted a literature search to identify studies that investigated the association of endogenous total testosterone [continuous (per 1 unit increment and 5 nmol/L increment) and categorical (high vs. low)] and use of TTh with PCa events [1990-2016]. Emphasis was given to studies/analyses that reported magnitude of associations [odds ratio (OR), relative risk (RR) and hazard ratios (HRs)] from multivariable analyses to determine risk of PCa and their statistical significance. Most identified studies/analyses included observational and randomized placebo-controlled trials. This review was organized in three parts: (I) association of endogenous total testosterone (per 1 unit increment and 5 nmol/L increment) with PCa; (II) relationship of endogenous total testosterone (categorical high vs. low) with PCa; and (III) association of use of TTh with PCa in meta-analyses of randomized placebo-controlled trials. The first part included 31 observational studies [20 prospective (per 5 nmol/L increment) and 11 prospective and retrospective cohort studies (per 1 unit increment)]. None of the 20 prospective studies found a significant association between total testosterone (5 nmol/L increment) and increased- or decreased-risk of PCa. Two out of the 11 studies/analyses showed a significant decreased-risk of PCa for total testosterone per 1 unit increment, but also two other studies showed a significant increased-risk of PCa. Remaining studies reported null-risks values. Second part: eight of out of 25 studies reported an increased-risk of PCa for men with high levels of testosterone compared to low, but only four were statistically significant. However, 17 studies showed a decreased-risk of PCa after comparing high vs. low levels of testosterone, but 11 studies/analyses were statistically significant. Third part: two meta-analyses of randomized placebo-controlled trials (n=8 and n=11, each) that investigated use of TTh with PCa reported not significant decreased-risks of PCa. The contention that high levels of testosterone or that the use of TTh increases the risk of PCa doesn't seem to be supported from the literature. Yet, we still need a study with the adequate power, follow-up data, epidemiological, pathological and clinical data that can support the safety and beneficial effects of high levels of endogenous testosterone or use of TTh in the natural history of PCa and in men's health.
... Two studies provided data on testosterone levels to the EHPCCG, but did not publish these data independently and could not be included in the present work [30,31]. Data from the Janus databank were used twice in the pooled analysis, but the two datasets were independent and were considered as two separate studies [32,33]. Stattin et al. [32] published data from three cohorts, and risk estimates were included separately. ...
... Data from the Janus databank were used twice in the pooled analysis, but the two datasets were independent and were considered as two separate studies [32,33]. Stattin et al. [32] published data from three cohorts, and risk estimates were included separately. Studies included in the meta-analysis included 5 623 prostate cancer cases and 14 604 controls. ...
... Studies included in the meta-analysis included 5 623 prostate cancer cases and 14 604 controls. The mean follow-up was 10 years (Table 1 [ [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]). ...
Article
Objective: To review and quantify the association between endogenous and exogenous testosterone and prostate specific antigen (PSA) and prostate cancer. Methods: Literature searches were performed following the PRISMA guidelines. Prospective cohort studies that reported data on the associations between endogenous testosterone and prostate cancer, and placebo controlled randomised trials of testosterone replacement therapy (TRT) that reported data on PSA and/or prostate cancer cases were retained. Meta-analyses were performed using random-effects models with tests for publication bias and heterogeneity. Results: Twenty estimates were included in a meta-analysis which produced a summary relative risk of prostate cancer for an increase of 5 nmol/L of testosterone of 0.99 (95% CI (0.96, 1.02)) without heterogeneity (I² = 0%). Based on 26 trials, the overall difference in PSA levels following onset of use of TRT was 0.10 ng/mL (-0.28, 0.48). Results were similar when conducting heterogeneity analyses by mode of administration, region, age at baseline, baseline testosterone, trial duration, type of patients and type of testosterone replacement therapy. The summary relative risk of prostate cancer as an adverse effect from 11 TRT trials was 0.87 (0.30; 2.50). Results were consistent across studies. Conclusions: Prostate cancer appears to be unrelated to endogenous testosterone levels. Testosterone replacement therapy for symptomatic hypogonadism does not appear to increase PSA levels nor the risk of prostate cancer development. The current data are reassuring although some care is essential until multiple studies with longer follow-up are available. This article is protected by copyright. All rights reserved.
... Cependant, leur rôle dans la carcinogénèse prostatique n'a pas été établi à ce jour. Les études épidémiologiques révèlent en effet un rôle controversé des androgènes dans la survenue des cancers de la prostate, comme le montrent les revues de la littérature publiées sur cette relation (Hsing 1996;Hsing et al. 2008;Platz and Giovannucci 2004), certaines études n'observant pas d'association entre la concentration d'androgènes et le cancer de la prostate (Dorgan et al. 1998;Eaton et al. 1999;Severi et al. 2006;Stattin et al. 2004), d'autres observant une association positive avec une concentration élevée (Shaneyfelt et al. 2000;Travis et al. 2007) et certaines observant une association inverse entre la concentration de testostérone et le risque de cancer de la prostate (Chen et al. 2003;Stattin et al. 2004). De plus, des concentrations plus faibles de testostérone entraîneraient la croissance de tumeurs plus agressives (Platz et al. 2005;San Francisco et al. 2014;Watts et al. 2018 (Hsing and Devesa 2001;Luo et al. 2004;Maskarinec and Noh 2004;McCracken et al. 2007;Miller et al. 2008;Shimizu et al. 1991;Yu et al. 1991). ...
... Cependant, leur rôle dans la carcinogénèse prostatique n'a pas été établi à ce jour. Les études épidémiologiques révèlent en effet un rôle controversé des androgènes dans la survenue des cancers de la prostate, comme le montrent les revues de la littérature publiées sur cette relation (Hsing 1996;Hsing et al. 2008;Platz and Giovannucci 2004), certaines études n'observant pas d'association entre la concentration d'androgènes et le cancer de la prostate (Dorgan et al. 1998;Eaton et al. 1999;Severi et al. 2006;Stattin et al. 2004), d'autres observant une association positive avec une concentration élevée (Shaneyfelt et al. 2000;Travis et al. 2007) et certaines observant une association inverse entre la concentration de testostérone et le risque de cancer de la prostate (Chen et al. 2003;Stattin et al. 2004). De plus, des concentrations plus faibles de testostérone entraîneraient la croissance de tumeurs plus agressives (Platz et al. 2005;San Francisco et al. 2014;Watts et al. 2018 (Hsing and Devesa 2001;Luo et al. 2004;Maskarinec and Noh 2004;McCracken et al. 2007;Miller et al. 2008;Shimizu et al. 1991;Yu et al. 1991). ...
Thesis
L’obésité, le diabète ainsi que le syndrome métabolique ont été associés à la survenue de plusieurs cancers. Néanmoins, le rôle de ces facteurs dans la survenue du cancer de la prostate est encore largement discuté. En effet, de nombreuses études ont montré des résultats divergents quant au rôle de l’obésité mesurée par l’indice de masse corporelle (IMC) et le cancer de la prostate, même si certaines études ont mis en évidence un rôle de l’obésité pour les cancers de la prostate agressifs. En revanche, des associations positives ont été rapportées avec le tour de taille ou le rapport taille/hanche, indicateurs reflétant plus spécifiquement une obésité abdominale. Dans les facteurs métaboliques, le diabète a été associé négativement au cancer de la prostate alors que le syndrome métabolique était associé positivement au cancer de la prostate. Dans ce contexte, nous avons étudié le rôle des facteurs anthropométriques et métaboliques dans le risque de cancer de la prostate à partir des données de l’étude cas-témoins EPICAP, incluant 819 cas et 879 témoins. Un questionnaire standardisé a permis de recueillir des informations détaillées sur l’historique du poids au cours de la vie ainsi que les antécédents personnels de maladies métaboliques. Des mesures anthropométriques ont été réalisées par des infirmières de recherche clinique au moment de l’entretien en face à face. Nous n’avons pas observé d’association entre l’IMC et le cancer de la prostate quelle que soit l'agressivité du cancer. En revanche, nous avons mis en évidence une augmentation du risque chez les hommes ayant une obésité abdominale, association plus prononcée pour les cancers agressifs. L’étude des trajectoires de poids au cours de la vie a montré que le surpoids ou l’obésité au cours de la vie étaient associé au cancer de la prostate agressif. Malgré une absence d’association entre le diabète et le cancer de la prostate, une association inverse significative a été observée avec la durée du diabète. Nous n’avons pas mis en évidence d’association entre le syndrome métabolique et le cancer de la prostate. Nos résultats renforcent l’hypothèse d’un lien entre l’obésité abdominale et le risque de cancer de la prostate, particulièrement pour les cancers agressifs. Ces résultats pourraient contribuer à l’identification de nouveaux facteurs de risque modifiables pour le cancer de la prostate pouvant être accessibles à la prévention.
... В ходе исследований было установлено, что гипогонадизм сопровождается низкой частотой развития рака предстательной железы, однако если он все же возникает у мужчин с гипогонадизмом, то отличается более агрессивными характеристиками, в том числе более высокой суммой Глисона [79]. Терапия тестостероном не приводит к гистологическим изменениям предстательной железы или к значительному повышению содержания тестостерона и дигидротестостерона в предстательной железе [80,81]. Терапия тестостероном не повышает риск развития рака предстательной железы (уровень 2, степень B) [82,83]. ...
Article
Male hypogonadism is a condition in which the body doesn’t produce enough testosterone which results in its low serum level in combination with characteristic clinical symptoms and/or signs (see the description below) that can be observed in the patients presenting with pathological changes in testicles and/or hypophysis, such as Kleinfelter’s syndrome, and in men with idiopathic metabolic or iatrogenic disorders leading to androgen deficiency. The present recommendations does not cover the entire set of pathological conditions responsible for the development of hypogonadism (deficit of testosterone); rather, they are focused on its clinical variants that account for the majority of the cases of male hypogonadism.
... The level of circulating testosterone in men more than 45 years of age, across various ethnicities, shows a tendency to converge down as compared with vastly varied levels in men of age less than 30 years (Ellison, Bribiescas et al. 2002). Many researchers have shown that higher levels of circulating testosterone do not correlate with an increased risk of PCa (Hoffman, DeWolf et al. 2000;Stattin, Lumme et al. 2004). However, low levels of serum testosterone do have a direct correlation with progression of the disease to aggressive PCa (Kumar, Wadhwa et al. 1990;Hoffman, DeWolf et al. 2000;Schatzl, Madersbacher et al. 2001;Shin, Hwang et al. 2010). ...
... Hypertestesteronemic situation in rodents also led to increasing incidence of prostate cancer [98]. There was also a positive correlation between serum testosterone levels and risk of prostate cancer [99]. However, eighteen prospective studies, consisting of 3886 men with prostate cancer and 6438 healthy individuals, showed contrary results. ...
Article
The metabolic steroid hormones, 17β stradiol (E2) and testosterone play roles in several functions including carbohydrate, lipid and protein metabolism, cellular signaling, cell proliferation, and cancer promotion. Steroid hormones have long been characterized as cell proliferation and differentiation regulators and are closely related to the development of breast and prostate cancers. In addition, cholesterol metabolism, mainly in adipose tissue, leads to the production of steroids and cytokines, thus increasing the risk of metabolic syndrome, obesity, and ER+ breast cancer in postmenopausal women. Moreover, recent studies also show that testosterone and E2 increase the levels of key enzymes of the mevalonate pathway, which lead to post-translational prenylation and farnesylation of numerous proteins in RAS signaling in several cancers, including breast and prostate cancer. There is accumulating evidence both clinically and experimentally suggesting that changes in the metabolism of cholesterol may also have an important role in carcinogenesis. In this regard, the cells treated with mevalonate in culture showed elevated proliferation. Therefore, investigation on cholesterol as a precursor of steroid hormones has led to the identification of cholesterol metabolite effects on breast and prostate cancers. Indeed, recent evidence strongly suggests that the MVA pathway and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCOA) has a crucial regulatory role in cellular proliferation and transformation. Therefore, using mevalonate inhibitors decreases the production of several biologically active downstream products of the mevalonate pathway, including cholesterol. Although for approximately 20 years statins have been identified as anticancer agents, recent studies have sparked some controversy. Therefore, further investigation to evaluate mevalonate - dependent therapeutic agents alone and in combination with other agents is merited. The current review is an attempt to focus on the role of cholesterol as well as E2/testosterone, mevalonate pathway and its inhibitors in breast and prostate tissues during normal and pathological status.
... In further juxtaposition with the previous studies, Stattin et al. analyzed data from 3 cohorts encompassing 708 patients and observed a small but significant decrease in prostate cancer risk in men with high total testosterone levels. 42 These findings were supported by 2 subsequent prospective studies of 65 and 194 men that demonstrated a protective effect of higher total testosterone levels against prostate cancer. 4344 A prospective cohort study of 227 patients with median follow-up of 7.7 years showed that increased pretreatment serum testosterone (>11 nmol/l) correlated with a decreased risk of biochemical recurrence after radical prostatectomy. ...
Article
Introduction: The use of testosterone in men with a history of prostate cancer remains controversial in light of established findings linking androgens to prostate cancer growth. However, hypogonadism significantly affects quality of life and has negative sequelae, and the risks and benefits of testosterone therapy might be worthwhile to consider in all men, even those with a history of high-risk prostate cancer. Aim: To discuss the effects of testosterone on the prostate and the use of testosterone therapy in hypogonadal men with a history of prostate cancer. Methods: Review of the literature examining the effects of testosterone on the prostate and the efficacy and safety of exogenous testosterone in men with a history of prostate cancer. Main outcome measures: Summary of effects of exogenous and endogenous testosterone on prostate tissue in vitro and in vivo, with a focus on effects in men with a history of prostate cancer. Results: Testosterone therapy ameliorates the symptoms of hypogonadism, decreases the risk for its negative sequelae, and can significantly improve quality of life. Recent studies do not support an increased risk for de novo prostate cancer, progression of the disease, or biochemical recurrence in hypogonadal men with a history of non-high-risk prostate cancer treated with testosterone therapy. Evidence supporting the use of testosterone in the setting of high-risk prostate cancer is less clear. Conclusion: Despite the historical reluctance toward the use of testosterone therapy in men with a history of prostate cancer, modern evidence suggests that testosterone replacement is a safe and effective treatment option for hypogonadal men with non-high-risk prostate cancer. Additional work to definitively demonstrate the efficacy and safety of testosterone therapy in men with prostate cancer is needed, and persistent vigilance and surveillance of treated men remains necessary.
... The level of circulating testosterone in men more than 45 years of age, across various ethnicities, shows a tendency to converge down as compared with vastly varied levels in men of age less than 30 years [52]. Many researchers have shown that higher levels of circulating testosterone do not correlate with an increased risk of PCa [65,66]. However, low levels of serum testosterone do have a direct correlation with progression of the disease to aggressive PCa [64,65,67,68]. ...
Article
Full-text available
Age is often considered an important non-modifiable risk factor for a number of diseases, including prostate cancer. Some prominent risk factors of prostate cancer include familial history, ethnicity and age. In this review, various genetic and physiological characteristics affected due to advancing age will be analysed and correlated with their direct effect on prostate cancer.
... In 2004, Stattin et al. conducted a case-control study of 708 men with CaP and found a modest but significant decrease in CaP risk among men with higher pretreatment testosterone levels (P=0.05) (56). Two similarly designed studies also reported that men with higher testosterone levels had a lower risk of CaP (50,51). ...
Article
The use of exogenous testosterone to treat hypogonadism in the men with a history of prostate cancer (CaP) remains controversial due to fears of cancer recurrence or progression. Due to the detrimental impact of hypogonadism on patient quality of life, recent work has examined the safety of testosterone therapy (TTh) in men with a history of CaP. In this review, we evaluate the literature with regards to the safety of TTh in men with a history of CaP. TTh results in improvements in quality of life with little evidence of biochemical recurrence or progression in men with a history of CaP, or de novo cancer in unaffected men. An insufficient amount of evidence is currently available to truly demonstrate the safe use of TTh in men with low risk CaP. In men with high-risk cancer, more limited data suggest that TTh may be safe, but these findings remain inconclusive. Despite the historic avoidance of TTh in men with a history of CaP, the existing body of evidence largely supports the safe and effective use of testosterone in these men, although additional study is needed before unequivocal safety can be demonstrated.
... First, it was hypothesized that men with higher endogenous levels of testosterone would carry a greater risk of PCa. Although most of the studies [9][10][11][12][13][14] have not found a correlation of serum testosterone with future development of PCa, two studies [15,16] demonstrated a positive correlation between androgen levels and PCa, and suggested a potential implication regarding TRT and the risk of developing PCa in this situation. Subsequently, it was suggested that TRT could increase the risk of PCa; however, the rate of PCa in trials of men submitted to androgen supplementation was similar to that of the general population [17]. ...
... Aunque estos estudios no evalúan el rol del reemplazo hormonal con testosterona directamente, ellos muestran repetidamente, uniformemente y con un alto nivel de evidencia, que niveles elevados de testosterona no están asociados con un incremento del riesgo de cáncer [30], [31], [32], [33], [34]. Un comentario aparte merecen los pacientes con obesidad y cáncer de próstata. ...
Article
Full-text available
For six decades, it has been a part of the conventional medical wisdom that higher levels of testosterone increase the risk of prostate cancer. This belief is mostly derived from the well-documented regression of prostate cancer after surgical or pharmacological castration. However, there is an absence of scientific data supporting the concept that higher testosterone levels are associated with an increased risk of prostate cancer. Moreover, men with hypogonadism have substantial rates of prostate cancer in prostatic biopsies, suggesting that low testosterone has no protective effect against the development of prostate cancer. Moreover, prostate cancer rate is higher in elderly patients when hormonal levels are low. These results argue against an increased risk of prostate cancer with testosterone replacement therapy.
... Likewise, one prospective study found increased PC risk associated with high levels of testosterone and low levels of sex hormone-binding globulin (Gann et al., 1996;Parsons et al., 2005). However, results from other prospective studies have not supported these findings (Heikkila et al., 1999;Chen et al., 2003;Stattin et al., 2004), and a meta-analysis of prospective studies found no statistically significant associations between risk and levels of testosterone and its metabolites (Eaton et al., 1999). These inconsistencies may reflect discrepancies between etiologically relevant hormones in younger men and measured levels in older men's sera, as male steroid hormone levels decline with age (Ellis and Nyborg, 1999). ...
Article
Although Vietnam's massive herbicide exposure in 1960s and 1970s was clearly injurious to health, not all causal relationships have been clarified. We therefore explored associations among dioxins, steroid hormones, age and prostate cancer risk in men. We compared serum levels of dioxin, steroid hormones and prostate specific antigen (PSA) in men aged 56-81years from herbicide-exposed hotspots (n=50) with those from non-sprayed regions (n=48). Mean serum levels of dioxin congeners in the hotspot group were 1.5-11.3 times higher than the non-sprayed group depending on specific compound. Levels of testosterone, estradiol and 3β-hydroxysteroid dehydrogenase (3β-HSD) activity in the hotspot group were also significantly higher than in non-sprayed group. Estradiol levels were significantly related to levels of several specific dioxin derivatives in both group. Significant positive correlations were also found between DHT and 1234678-HpCDD or 1234678-HpCDF; and between 3β-HSD activity and 123678-HxCDD, 123478-HxCDF, 123678-HxCDF, or HxCB#169. After adjusting for age, body mass index, and tobacco use, multiple linear regressions showed levels of dihydrotestosterone (DHT), estradiol, testosterone and 3β-HSD activity were not associated with dioxins in the two groups; however, levels of DHT, testosterone and 3β-HSD activity increased significantly with age in the hotspot group. The hotspot and non-sprayed groups did not significantly differ in PSA levels. But six of the hotspot subjects had PSA levels >3ng/mL, 3 of whom were suspected to have prostate cancer (PC) after digital rectal examination. Our findings suggest that dioxin exposure can lead to increased levels of several sex steroid hormones with age. The correlation of dioxin with steroid hormone levels and prostate cancer risk should be studied further.
... Прирост МПКТ через 6 мес лечения составил 1 % в шейке бедра и 2 % в позвонках. В рандомизированном плацебо-контролируемом исследовании выявлено, что добавление 1 % геля тестостерона к проводимой терапии антидепрессантами способствовало существенно большему уменьшению баллов по Шкале депрессии Гамильтона и Шкале общего клинического впечатления (Clinical Global Impression scale), чем добавление плацебо у пациентов с плохо поддающейся терапии депрессией [10,14,20,26,27]. ...
Article
Full-text available
In a critical review of the literature current data concerning etiology, clinical features, diagnostics, treatment of late-onset hypogonadism (LOH) are given. LOH is a multidisciplinary problem, because a patient with LOH can have osteoporosis, anemia, depression, obesity, diabetes mellitus, erectile dysfunction. Sometimes it is hard to realize that all this complaints are symptoms of LOH. LOH has a negative impact on a patient,s quality of life and it,s impossible to help without androgen replacement therapy. Furthermore doctors often have doubts about testosterone replacement therapy safety because of lack of accurate information. In a convenient for medical practitioners form clinical and laboratory diagnostic criteria of LOH are presented together with formulas for conversion from one measurement unit of main sex hormones into another. Based on latest ISSAM guidelines (International Society for the Study of the Aging Male) modern treatment options of LOH are summarized, full information about available testosterone preparations (oral, transdermal, injectable) with comparative analysis of advantages and disadvantages of each is given. A full description of indications and contraindications for androgen replacement treatment is presented, also treatment regimen and medical supervision algorithm during treatment are described.
... However, the association between serum testosterone and prostate cancer growth is weak at best. Some studies have found a correlation between increased cancer growth and higher levels of serum free testosterone [58], but several independent groups have found contradicting evidence [59,60]. Indeed, in study of 168 patients, lower testosterone and estrogen levels were associated with a higher Gleason score suggesting the opposite association [47,61]. ...
... In monocytes/macrophages and dendritic cells (Mo/M /DC), TGR5 activation leads to decreases in LPS-induced Th1 cytokines like TNF-α and IL-12 [5]. Together, these functions make TGR5 an attractive target in the treatment of type 2 diabetes, where strategies to enhance GLP-1 [6] and mitigate chronic inflammation [7][8][9] are already demonstrating benefit in the clinic. While several pharmaceutical organizations have pursued TGR5 agonists, no TGR5 drug has been approved for diabetes or metabolic diseases indication. ...
... Truth might lie somewhere in between, i.e. SHBG might only have marginal effects not always reaching significance [87] or only in certain subgroups like younger men [88]. ...
Article
Sex hormone-binding globulin (SHBG) is a serum glycoprotein exhibiting the unique feature of binding sex steroids with high affinity and specificity. Its serum levels are regulated not only by androgens and estrogens but also by thyroid hormones and other metabolic factors. Several disease conditions are accompanied by altered SHBG levels such as hyper- and hypoandrogenism, thyroid disorders, pituitary diseases, liver disorders, and breast as well as prostate cancer. Additionally, several drugs and alcohol consumption influence serum concentrations of SHBG. In some cases, altered SHBG levels are a specific result of the underlying pathology. In others, they merely constitute an epiphenomenon, which still might offer the possibility of using serum measurements of SHBG as surrogate marker. This review article portrays the different disorders associated with altered SHBG levels and discusses the usefulness of SHBG as disease biomarker from a clinicians as well as from an endocrinological researchers point of view.
... P. Stattin и соавт. в 2004 г. провели исследование типа «случай-контроль» с участием 708 мужчин с РПЖ и 2242 без РПЖ и пришли к заключению, что при росте уровня общего тестостерона в физиологическом диапазоне риск развития РПЖ статистически значимо снижается [6]. G. Severi и соавт. ...
... W komórkach prostaty testosteron redukowany jest pod wpływem 5-alfa--reduktazy do dihydrotestosteronu. Receptory androgenowe wiążą zarówno testosteron, jak i dihydrotestosteron, przy czym ten ostatni ma większe powinowactwo do receptorów [6]. Ciągle badana jest rola testosteronu i dihydrotestosteronu (DHT) jako induktorów nowotworu stercza. ...
Article
Full-text available
Prostate cancer is the most commonly diagnosed cancer among men in the world and in Poland it is the second cause of death in men suffering from cancer. Recent evidence suggests that obesity is associated with prostate cancer. Increased BMI correlates with aggressive disease and with higher risk of recurrence and mortality in prostate cancer patients. Obesity can promote the progression of prostate cancer through endocrine disturbances, mainly in sex steroids, through chronic inflammation resulting in altered production of adipokines, peripheral insulin resistance with hyperinsulinemia and oxidative stress. Diagnosis of metabolic syndrome can be used in the global assessment of prognosis in patients with prostate cancer. The aim of the paper is to present current state of knowledge about connections between obesity, metabolic syndrome, sex steroids and adipokines in men with prostate cancer.
... In a longitudinal study of O200 000 European men, higher levels of circulating testosterone were found to be related with reduced risk of prostate cancer with the odds ratio for the top vs bottom quintile of 0.80 (95% ClZ0.59-1.06; Stattin et al. 2004). Similar conclusions have been made through several other retrospective and prospective studies. ...
Article
Full-text available
Androgens and androgen receptor (AR) signaling are necessary for prostate development and homeostasis. AR signaling also drives the growth of nearly all prostate cancer cells. The role of androgens and AR signaling has been well characterized in metastatic prostate cancer, where it has been shown that prostate cancer cells are exquisitely adept at maintaining functional AR signaling to drive cancer growth. As androgens and AR signaling are so intimately involved in prostate development and the proliferation of advanced prostate cancer, it stands to reason that androgens and AR are also involved in prostate cancer initiation and the early stages of cancer growth, yet little is known of this process. In this review, we summarize the current state of knowledge concerning the role of androgens and AR signaling in prostate tissue, from development to metastatic, castration-resistant prostate cancer and use that information to suggest potential roles for androgens and AR in prostate cancer initiation.
... Stattin et al. reported modest but significant decreases in CaP risk with increasing levels of total testosterone when comparing the top and bottom quintiles (OR = 0.80, 95% CI = 0.59-1.06; p(trend) = 0.05) among 708 men with CaP [34]. Subsequent studies with smaller sample sizes also reported a modest protective effect of testosterone on CaP [35,36]. ...
Article
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Purpose of review: The role of testosterone in the development of prostate cancer and the safety of testosterone therapy (TTh) after prostate cancer treatment, or in the setting of active surveillance, remains controversial. There are many concerns about using TTh in men, particularly those with a history of prostate cancer, ranging from a possible increased risk of cardiovascular disease to cancer progression or recurrence. With many prostate cancer patients living longer, and hypogonadism having significant morbidity, much care must go into the decision to treat. Here, we review the literature investigating the effects of testosterone on the prostate as well as the efficacy and safety of exogenous testosterone in men with a history of prostate cancer. Recent findings: The improvement in quality of life with TTh is well studied and understood, while the argument for significantly increased risk of cancer or other adverse effects is much less robust. Neither increased rates of prostate cancer, cancer recurrence, or cardiovascular risk have been well established. In men with high-risk prostate cancer, evidence in the setting of TTh is very limited, and TTh should be used with caution. The fears of TTh causing or worsening prostate cancer do not appear to be well supported by available data. Though more studies are needed to definitively determine the safety of TTh in men with prostate cancer, consideration should be given to treatment of hypogonadal men with a history of CaP.
... Although the development of PCa is androgen-dependent, the incidence of PCa actually increases as systemic androgen levels decline with age. Even though some studies have found a correlation between increased cancer growth and higher levels of circulating free T [22,23], suggesting that clinically low levels of free T may be protective against PCa, other independent groups have found an opposite association [24,25]. Recent studies demonstrated that low levels of free and total serum T are associated with an increased risk of high-grade PCa, being associated with aggressive PCa and predicting poor PCa-specific survival [26][27][28]. ...
Article
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Purpose: The importance of androgen receptor variants (AR-Vs) is recognized in prostate cancer. AR-Vs have been the focus of many studies. Expression of AR-Vs has been proposed as a biomarker for resistance to androgen deprivation therapy for metastatic disease. Herein, we show dynamic changes in AR-Vs expression in response to androgen modulation. Methods: The C4-2B cell line was exposed to low (10-13 M) and high (10-8 M) androgen (dihydrotestosterone, DHT) levels, with or without flutamide. mRNA and protein expression levels were assessed by qPCR and immunohistochemistry, respectively. Results: We demonstrated that high levels of DHT downregulate AR-FL and AR-Vs. Even though AR-Vs did not present ligand-binding domain, thus were not capable of binding to DHT, they present dynamic changes under androgen treatment. Treatment with flutamide alone or in association with low levels of DHT stimulates growth of prostatic cells. Conclusions: Importantly, we provide evidence that AR-Vs respond differently to androgenic modulation. These findings have implications for a better understanding of the role of AR-Vs in prostate carcinogenesis.
... In line with that, enhancing testosterone levels to a supraphysiological level results in reduced disease progression [6]. Accordingly, low dose of androgens in individuals is associated with increased PCa risk, which suggests a tumor-suppressive role by higher androgen levels [7,8]. This is further supported by ongoing clinical trials that use intermittent pharmacologic SAL that might be beneficial for a subset of PCa patients [9][10][11]. ...
Article
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The bipolar androgen therapy (BAT) to treat prostate cancer (PCa) includes cycles of supraphysiological androgen levels (SAL) under androgen-deprivation therapy (ADT). We showed previously that SAL induces cellular senescence in androgen-sensitive PCa cells and in ex vivo-treated patient PCa tumor samples. Here, we analyzed the underlying molecular pathway and reveal that SAL induces cellular senescence in both, castration-sensitive (CSPC) LNCaP and castration-resistant PCa (CRPC) C4-2 cells through the cell cycle inhibitor p15INK4b and increased phosphorylation of AKT. Treatment with the AKT inhibitor (AKTi) potently inhibited SAL-induced expression of p15INK4b and cellular senescence in both cell lines. Proximity-ligation assays (PLA) combined with high-resolution laser-scanning microscopy indicate that SAL promotes interaction of endogenous androgen receptor (AR) with AKT in the cytoplasm as well as in the nucleus detectable after three days. Transcriptome sequencing (RNA-seq) comparing the SAL-induced transcriptomes of LNCaP with C4-2 cells as well as with AKTi-treated cell transcriptomes revealed landscapes for cell senescence. Interestingly, one of the identified genes is the lncRNASAT1. SAL treatment of native patient tumor samples ex vivo upregulates lncRNASAT1. In PCa tumor tissues, lncRNASAT1 is downregulated compared with nontumor tissues of the same patients. Knockdown indicates that the lncRNASAT1 is crucial for SAL-induced cancer-cell senescence as an upstream factor for pAKT and for p15INK4b. Further, knockdown of lncRNASAT1 enhances cell proliferation by SAL, suggesting that lncRNASAT1 serves as a tumor suppressor at SAL. Interestingly, immunoprecipitation of AR detected lncRNASAT1 as an AR-interacting partner that regulates AR target-gene expression. Similarly, RNA-ChIP experiments revealed the interaction of AR with lncRNASAT1 on chromatin. Thus, we identified a novel AR-lncRNASAT1-AKT-p15INK4b signaling axis to mediate SAL-induced cellular senescence.
... были проанализированы данные по сывороточному уровню тестостерона более 2 млн европейцев и оценены риски возникновения рака простаты. Более высокий уровень циркулирующего тестостерона оказался связан с уменьшением риска возникновения заболевания [13]. ...
... Les hommes ayant un cancer de la prostate et une testostérone basse paraissent avoir un risque augmenté de cancer agressif (Gleason élevé, stades avancés) [92,93]. ...
Article
Résumé Cet article vise à présenter aux sexologues les recommandations françaises pour le diagnostic et la prise en charge du déficit en testostérone (DT). Ce sont des recommandations de bonne pratique. Elles ont été élaborées par la Société francophone de médecine sexuelle (SFMS) et le Comité d’andrologie et de médecine sexuelle (CAMS) de l’Association française d’urologie (AFU) qui ont réuni un panel d’experts. Elles ont utilisé la méthode des recommandations pour la pratique clinique (RCP). Le DT se définit comme l’association de signes et symptômes cliniques évocateurs et d’une diminution du taux de testostérone (T) dans le sang. Les troubles sexuels sont souvent les premiers signes d’appel car la T est importante pour toute la fonction sexuelle masculine (désir, excitation, plaisir et orgasme). Les symptômes les plus typiques sont : la baisse du désir sexuel, la disparition des érections nocturnes, de la fatigue, une perte de la force musculaire. Sont également fréquemment associés : un surpoids, une humeur dépressive, de l’anxiété ou de l’irritabilité. Le DT est plus fréquent chez les patients présentant certaines maladies chroniques, chez les patients ayant des antécédents andrologiques, et chez des patients traités au long cours par certaines molécules. Pour le diagnostic biologique, il est recommandé de préférer le dosage des T libre ou biodisponible, plutôt que la T totale. Le traitement du DT nécessite un bilan préalable clinique (toucher rectal, examen mammaire, testiculaire) et biologique (PSA, hématocrite). Les contre-indications au traitement par T sont peu nombreuses et les effets secondaires peu fréquents. Le traitement consiste en une supplémentation par la T au long cours et des conseils d’hygiène de vie. La surveillance du traitement se fait à 3, 6, 12 mois puis tous les ans. Elle est clinique (toucher rectal annuel) et biologique (T totale, PSA, NFS).
... However, we did not investigate the influence of androgens produced by the adrenal gland. Moreover, elevation of the hematocrit value [45] and cardiovascular risk [46] resulting from an increase in the blood testosterone level is of concern, but the increased risk of prostate cancer remains controversial [3,[47][48][49]. Furthermore, whether changes in blood testosterone levels are the cause or result of various diseases remains to be clarified. ...
Article
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Background: Testosterone signals through the androgen receptor (AR) and AR knockout mice develop obesity, suggesting a functional association between AR and leptin signaling. Furthermore, physiological blood concentrations of testosterone have been found to inhibit the development of arteriosclerosis, obesity and diabetes. However, these findings have not been verified by testosterone replacement in animal models and whether or not testosterone acts directly by activating AR to enhance leptin signaling, or indirectly by its conversion into estrogen remains unclear. Therefore, we investigated the effect of exogenously supplemented testosterone on glucose and lipid metabolism. Methods: Four-week-old male leptin receptor-knockout db/db mice were used as controls for a model of obesity retaining low testosterone. Mice were divided into sham-operated, castrated, or castrated and testosterone-supplemented groups and fed a high-fat diet (HFD) for 2 weeks from 5 weeks of age. Testosterone concentrations, blood glucose, plasma insulin levels, and intraperitoneal glucose tolerance and insulin tolerance were measured. At 7 weeks, triglyceride and glycogen content were measured in the liver and muscle. Lipid accumulation in the liver and soleus muscle was determined by immunohistochemistry with Oil Red O. Statistical analyses were performed using the Student's t-test or ANOVA where applicable. Results: Lower testosterone levels in db/db mice compared with wild type (WT) db/+ mice were associated with glucose intolerance and fatty liver. Furthermore, castrated male db/db mice at 4 weeks of age progressively developed glucose intolerance accompanying a 15% increase in liver fat. Male mice fed a HFD had lower levels of testosterone compared with those fed a normal diet. We found that exogenous testosterone replacement injected subcutaneously into castrated male db/db mice alleviated the exacerbation of fatty liver and glucose intolerance, suggesting a leptin-independent mechanism. This mechanism is most likely mediated through gonadal axis suppression in this mouse model. Conclusions: In summary, testosterone may use a novel pathway to complement leptin signaling to regulate glucose and lipid metabolism, and thus offers a new therapeutic target to treat metabolic disorders.
... 16,17 However, several others have shown that there is either no association, 18 or an inverse association between serum androgens and CaP risk. 19 Importantly, several studies have shown that low serum testosterone levels at the time of CaP diagnosis is correlated with more aggressive disease. 20,21 Along this same line of thought, several studies have implicated loss of epithelial AR in prostatic disease to increased malignancy. ...
Article
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Background Castration-resistant prostate cancer (CRPC) occurs when prostate cancer (CaP) progresses under therapy-induced castrate conditions. Several mechanisms have been proposed to explain this acquired resistance, many of which are driven by androgen receptor (AR). Recent findings, however, sub-classified CRPC by downregulation/absence of AR in certain subtypes that consequently do not respond to anti-androgen therapies. To highlight the significance of CRPC sub-classification, we reviewed the development and treatment of CRPC, AR downregulation in CRPC, and summarized recent reports on the prevalence of CRPC subtypes. Methods Using a medline-based literature search, we reviewed mechanisms of CRPC development, current treatment schemes, and assessed the prevalence of AR low/negative subtypes of CRPC. Additionally, we performed immunohistochemical staining on human CRPC specimens to quantify AR expression across CRPC subtypes. Results In the majority of cases, CRPC continues to rely on AR signaling, which can be augmented in castrate-conditions through a variety of mechanisms. However, recently low/negative AR expression patterns were identified in a significant proportion of patient samples from a multitude of independent studies. In these AR low/negative cases, we postulated that AR protein may be downregulated by (1) promoter methylation, (2) transcriptional regulation, (3) post-transcriptional regulation by microRNA or RNA-binding-proteins, or (4) post-translational ubiquitination-mediated degradation. Conclusions Here, we discussed mechanisms of CRPC development and summarized the overall prevalence of CRPC subtypes; interestingly, AR low/negative CRPC represented a considerable proportion of diagnoses. Because these subtypes cannot be effectively treated with AR-targeted therapeutics, a better understanding of AR low/negative subtypes could lead to better treatment strategies and increased survival.
... Aunque estos estudios no evalúan el rol del reemplazo hormonal con testosterona directamente, ellos muestran repetidamente, uniformemente y con un alto nivel de evidencia, que niveles elevados de testosterona no están asociados con un incremento del riesgo de cáncer [30], [31], [32], [33], [34]. Un comentario aparte merecen los pacientes con obesidad y cáncer de próstata. ...
Article
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For six decades, it has been a part of the conventional medical wisdom that higher levels of testosterone increase the risk of prostate cancer. This belief is mostly derived from the well-documented regression of prostate cancer after surgical or pharmacological castration. However, there is an absence of scientific data supporting the concept that higher testosterone levels are associated with an increased risk of prostate cancer. Moreover, men with hypogonadism have substantial rates of prostate cancer in prostatic biopsies, suggesting that low testosterone has no protective effect against the development of prostate cancer. Moreover, prostate cancer rate is higher in elderly patients when hormonal levels are low. These results argue against an increased risk of prostate cancer with testosterone replacement therapy.
... Gann et al. [20] reported raised serum testosterone levels in these diseases, Mearini et al. [16] reported reduced serum levels. Other studies reported that these hormones are not affected in these disorders [11,22]. Our findings show that levels of testosterone in CaP did not differ significantly from the level in controls, but E 2 was significantly raised compared to levels in controls and BPH. ...
Article
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Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of death as a result of cancer in men in the US and other parts of the world. There are conflicting reports on the serum levels of testosterone and 17β-estradiol (E2) in benign prostatic hyperplasia (BPH) and prostate cancer. This study was designed to evaluate the serum concentrations of these hormones in patients with these disorders. Serum levels of prostate specific antigen (PSA), total testosterone and estradiol were determined in 228 subjects comprising of 116 subjects with BPH, 62 subjects with prostate cancer (CaP) and 50 age-matched apparently healthy controls, using ELISA methods. PSA levels were significantly elevated (p < 0.05) in BPH subjects than controls, while there was no significant difference (p > 0.05) in testosterone and estradiol levels of these subjects. PSA and estradiol levels were significantly higher (p < 0.05) in CaP subjects than in controls, while there was no observed significant difference (p > 0.05) in testosterone levels. CaP subjects had significantly raised PSA, testosterone, and estradiol levels than BPH subjects. The mean molar ratio of testosterone: E2 was lowest among CaP patients (134:1) and highest among controls (166:1). Significant positive correlation between PSA and 17β-estradiol was observed in prostate disorders (BPH and CaP patients: r = 0.347; p = 0.000). Significant negative correlations between testosterone and PSA were also observed among BPH patients (r = -0.221, p = 0.049) and control subjects (r = -0.490, p = 0.000). No significant correlation existed between testosterone and PSA in CaP patients (r = 0.051, p = 0.693). Correlations between age and estradiol in both BPH and CaP were not significant (p > 0.05). This study has shown that, there was a significant increase in serum estradiol in CaP subjects, while the testosterone levels in both BPH and CaP subjects were not different from those of controls.
Article
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Objectives. Prostate-specific antigen (PSA) is the most used and validated marker of prostate cancer risk. The aim of this study was to assess PSA levels during treatment with testosteronum undecanoat in patients with type 2 diabetes (T2DM). Material and Methods. We evaluated 38 T2DM patients aged between 48 and 61 years with confirmed hypogonadism. 1000 mg testosterone undecanoate was injected intramuscular every 10 to 14 weeks. Total testosterone and PSA levels were assessed at baseline and after 6, 12, 24 months of treatment. Results. The average age was 55.03 ± 2.40 years and 3 patients (7.89%) had a family history of prostate cancer. Treatment with testosterone undecanoate generated significant changes in serum total testosterone (482.29±50.78 ng/dl vs. 246.66±51.50 ng/dl, p < 0.001) but not in serum PSA levels (2.11±.0.49 ng/ml vs. 2.09±0.47 ng/ml, p - NS). Conclusion.Testosterone replacement therapy may normalize serum androgen levels but appears to have little effect on PSA levels.
Article
Background To evaluate the individual and combined effects of enterolactone, vitamin D, free testosterone, Chlamydia trachomatis and HPV-18 on the risk of prostate cancer in a large population-based biochemical material that combined three Nordic serum sample banks. Material and methods A joint cohort of 209 000 healthy men was followed using cancer registry linkages. From this cohort altogether 699 incident cases of prostate cancer were identified. Four controls were selected by incidence density sampling and matching for country, age and date of the blood sampling. Complete data for all investigated exposures was available for 483 eligible cases and 1055 eligible controls. Multivariate regression analyses were performed to investigate the solitary and combined effects. Results The solitary effects were small. Significantly increased risk [rate ratio 1.6 (95% CI 1.0-2.5)] was found in those seronegative for C. trachomatis infection. The joint effect in risk levels of enterolactone and vitamin D was antagonistic [observed rate ratio (RR) 1.4 (1.0-2.1), expected RR 2.0 (1.0-4.1)] as well as that of HPV-18 and C. trachomatis [observed RR 1.9 (0.8-4.5), expected RR 9.9 (1.1-87.0)]. Conclusion A large follow-up study combining data from several previously investigated exposures to investigate joint effects found no evidence that exposure to two risk factors would increase the risk of prostate cancer from that expected on basis of exposure to one risk factor. If anything, the results were consistent with antagonistic interactions.
Article
Male hypogonadism is one of the most common endocrinologic syndromes. The diagnosis is based on clinical signs and symptoms plus laboratory confirmation via the measurement of low morning testosterone levels on two different occasions. Serum luteinizing hormone and follicle-stimulating hormone levels distinguish between primary (hypergonadotropic) and secondary (hypogonadotropic) hypogonadism. Hypogonadism associated with aging (andropause) may present a mixed picture, with low testosterone levels and low to low-normal gonado-tropin levels. Androgen replacement therapy in hypogonadal men has many potential benefits: improved sexual function, an enhanced sense of well-being, increased lean body mass, decreased body fat, and increased bone density. However, it also carries potential risks, including the possibility of stimulating the growth of an occult prostate cancer. The benefits of androgen therapy outweigh the risks in men with classic hypogonadism. However, for men with mild hypogonadism or andropause, the balance between benefits and risks is not always clear. Unfortunately, studies to date have included too small a number of patients and have been too short in duration to provide meaningful data on the long-term risks versus the benefits of androgen replacement therapy in these populations. Several products are currently marketed for the treatment of male hypogonadism. Weekly-to-biweekly injections of testosterone cypionate (cipionate) or testosterone enanthate (enantate) are widely used, as they are economical and generally well tolerated. However, once-daily transdermal therapies have become increasingly popular and now include both patch and gel systems. Intramuscular injection of testosterone undecanoate is an attractive new therapy that can be administered quarterly. To confirm an adequate replacement dosage, assessment of clinical responses and measurement of serum testosterone levels generally suffice. For selected men, serial measurement of bone mineral density during androgen therapy might be helpful to confirm end-organ effects. For men aged >50 years, we advocate measurement of hematocrit for detection of polycythemia and a digital rectal examination with a serum prostate-specific antigen level measurement for prostate cancer screening during the first few months of androgen therapy. Subsequently, a hematocrit should be obtained yearly or after changes in therapy, and annual prostate cancer screening can be offered to the patient after a discussion of its risks and benefits.
Article
Objective: There is controversial evidence regarding preoperative testosterone (T) levels related to poor prognosis factors after radical prostatectomy (RP). The aim of this manuscript is to determine the relationship between preoperative T levels and final pathologic report together to biochemical recurrence after RP. Materials and methods: We prospectively analysed 143 patients submitted to RP from February 2008 to June 2010 in our centre. Pretreatment T and sex hormone-binding globulin levels were determined as part of our clinical protocol. Free calculated (fT) and bioavailable (bioT) T were calculated using Vermeulen's formula. Low T levels were defined as 346 ng/dL or less. A comparative analysis with variables pTNM, positive margins, tumour burden, Gleason score, multifocality and biochemical recurrence (using both PSA>0.4 ng/dL and PSA>0.2 ng/dL as cut-off values) was performed, according to preoperative levels of T. Results: Variables Gleason score, rate and number of positive margins, tumour burden, tumour multifocality, time to biochemical recurrence and pathological stage were not related to preoperative hormonal levels. Preoperative T<346 ng/dL was not found to be related to PSA recurrence (PSA>0,4 ng/dL log-rank, P=.512), although a trend was observed when PSA>0,2 ng/dL (log-rank, P=.097). Conclusion: Preoperative T levels were not related to final pathological report or to biochemical recurrence.
Chapter
Although prostate cancer represents a major health issue in men in Western countries, being a common cause of morbidity and mortality after the age of 50, it ought to be preventable and curable. Notwithstanding, despite the most recent advances in both basic and translational research, the molecular basis of prostate cancer remains poorly understood. In particular, the mechanisms underlying development and progression of this neoplasm appear to be complex: genetic and environmental factors (notably lifestyle and diet), along with endogenous sex hormones and host immune and inflammatory response, are likely to be interconnected in the pathogenesis of the disease.
Article
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Prostate cancer (PCa) is the second-leading cause of cancer-related deaths in men. PCa cells require androgen receptor (AR) signaling for their growth and survival. Androgen deprivation therapy (ADT) is the preferred treatment for patients with locally advanced and metastatic PCa disease. Despite their initial response to androgen blockade, most patients eventually will develop metastatic castration-resistant prostate cancer (mCRPC). Bone metastases are common in men with mCRPC, occurring in 30% of patients within 2 years of castration resistance and in >90% of patients over the course of the disease. Patients with mCRPC-induced bone metastasis develop lesions throughout their skeleton; the 5-year survival rate for these patients is 47%. Bone-metastasis-induced early changes in the bone that proceed the osteoblastic response in the bone matrix are monitored and detected via modern magnetic resonance and PET/CT imaging technologies. Various treatment options, such as targeting osteolytic metastasis with bisphosphonates, prednisone, dexamethasone, denosumab, immunotherapy, external beam radiation therapy, radiopharmaceuticals, surgery, and pain medications are employed to treat prostate-cancer-induced bone metastasis and manage bone health. However, these diagnostics and treatment options are not very accurate nor efficient enough to treat bone metastases and manage bone health. In this review, we present the pathogenesis of PCa-induced bone metastasis, its deleterious impacts on vital organs, the impact of metastatic PCa on bone health, treatment interventions for bone metastasis and management of bone- and skeletal-related events, and possible current and future therapeutic options for bone management in the continuum of prostate cancer disease.
Article
Ob eine Früherkennung im hohen Alter noch empfehlenswert ist, hängt vom biologischen und nicht vom kalendarischen Lebensalter ab. Durchaus können individuelle Gesundheitsleistungen auch bei betagten Patienten angebracht sein.
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References and Tabulated Key Information on the 389 Studies (162 KB PDF)
Chapter
One of the more controversial issues over the last several years has been the use of testosterone (T) therapy (TTh) in men with prostate cancer (PCa). Many men 50 years or older suffer from ­symptoms of testosterone deficiency, including symptoms of erectile dysfunction, diminished libido, fatigue, depression, and sense of decreased vitality. TTh effectively treats these symptoms in many men, and may provide additional benefits such as increased strength, muscle mass, and bone mineral density (Table 47.1). Yet there has been a long-standing and widely held concern that higher serum T causes more rapid PCa growth. For this reason, any history of PCa has been considered an absolute contraindication to TTh, even in men with apparent cure.
Chapter
There is an increasing interest in the use of testosterone replacement therapy (TRT) for lateonset hypogonadism (LOH). Mean testosterone values can decline by as much as 50% between the ages of 25 and 75.1 This results in 20% of men being androgen-deficient by the age of 60, increasing to 40% by the age of 80 (Fig. 16.1).2 Clinically, this can lead to symptoms, including fatigue, depression, impaired memory, poor concentration, and loss of muscle mass and sexual vigor.3 TRT has been found to be of use in decreasing the severity of these symptoms;4 however, there remain considerable concerns regarding the potential long-term effect of such treatment, particularly on the prostate. Concerns about TRT on the prostate stem from knowledge that medical or surgical castration in prostate cancer patients can lead to delayed disease progression, at least initially. Therefore, it has been suggested that increasing testosterone could lead to an over-expression of prostate cancer or other prostate-related diseases such as benign prostate hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS).
Chapter
Prostate cancer presents a major health issue as it is the most common non-skin cancer in American males and the second most common cause of cancer- related death in men. The etiology of the disease appears to be multi-factorial and remains poorly understood. However, it is well established that androgens play an important role in prostate carcinogenesis. The beneficial effects of androgen deprivation on prostate cancer were first realized over 70 years ago. Today, it remains the only successful treatment option for advanced prostate cancer. In contrast, the role of androgens in prostate cancer development and progression remains controversial. Evidence from epidemiologic studies of associations with serum androgens and the risk of prostate cancer is conflicting and inconclusive. Upon closer review, the available evidence does not support the traditional assertion that high testosterone level increase the risk of developing prostate cancer or cause it to progress. This chapter reviews the mechanisms of androgen production and action on the prostate and considers the historical and recent evidence regarding the role of androgens in prostate cancer.
Chapter
Androgen and estrogen receptors and the downstream signaling pathways are pivotal to multiple biological processes, physiologically and pathologically. Androgen and estrogen receptor signaling pathways are important in developing and maintaining normal sexual and reproductive systems. Moreover, they also play a large number of roles in cardiovascular, musculoskeletal, immune, central nervous systems and oncology. Notably, associations between these two hormone receptors do exist in addition that estrogen could be synthesized from androgens. Many reports demonstrated the crosstalk between these two signaling pathways, bringing novel insights into investigating therapeutic strategies against prostate and breast cancer. This article introduces biological characteristics and clinical significance of the androgen and estrogen signaling pathways. Moreover, we also include the crosstalk between these two signaling pathways to comprehensively summarize the functional aspects of hormone receptors in cell biology.
Chapter
According to the American Cancer Society, prostate cancer is the second most common cause of cancer-related mortality for US men. A continuing research challenge is to improve diagnosis (especially the ability to detect uncommon aggressive cancers) and improve chemoprevention (through nutrition and lifestyle factors). The chapter highlights the growing importance of secondary prevention since prostate cancer is an indolent, slow growing tumor; preventing early tumor progression or eradicating early bone metastases may cure the disease. Considerations of the known etiology and biology of prostate cancer are presented as well as the strengths and limitations of current diagnostic and prognostic factors and specific interventions that have been tested. Lastly, promising avenues for secondary prevention strategies are presented based upon current knowledge.
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Introduction Sex hormones have been implicated in the etiology of a number of diseases. To better understand disease etiology and the mechanisms of disease-risk factor associations, this analysis aimed to investigate the associations of anthropometric, sociodemographic and behavioural factors with a range of circulating sex hormones and sex hormone-binding globulin. Methods Statistical analyses of individual participant data from 12,330 male controls aged 25–85 years from 25 studies involved in the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group. Analysis of variance was used to estimate geometric means adjusted for study and relevant covariates. Results Older age was associated with higher concentrations of sex hormone-binding globulin and dihydrotestosterone and lower concentrations of dehydroepiandrosterone sulfate, free testosterone, androstenedione, androstanediol glucuronide and free estradiol. Higher body mass index was associated with higher concentrations of free estradiol, androstanediol glucuronide, estradiol and estrone and lower concentrations of dihydrotestosterone, testosterone, sex hormone-binding globulin, free testosterone, androstenedione and dehydroepiandrosterone sulfate. Taller height was associated with lower concentrations of androstenedione, testosterone, free testosterone and sex hormone-binding globulin and higher concentrations of androstanediol glucuronide. Current smoking was associated with higher concentrations of androstenedione, sex hormone-binding globulin and testosterone. Alcohol consumption was associated with higher concentrations of dehydroepiandrosterone sulfate, androstenedione and androstanediol glucuronide. East Asians had lower concentrations of androstanediol glucuronide and African Americans had higher concentrations of estrogens. Education and marital status were modestly associated with a small number of hormones. Conclusion Circulating sex hormones in men are strongly associated with age and body mass index, and to a lesser extent with smoking status and alcohol consumption.
Chapter
In the contemporary scene, less than 5% of men with newly diagnosed prostate cancer (PC) have metastases at first presentation, compared to 20–25%, more than 20 years ago. Nonetheless, the use of androgen deprivation therapy (ADT) has increased over the years, suggesting that patients in Europe and United States may receive ADT in cases of lower disease burden, and not always according to evidence based indications. Nonetheless, PC remains the second most common cause of cancer death after lung cancer in American men. Thus, there is a need for more effective, specific and well tolerated agents which can provide a longer and good quality of life while avoiding the side effects related to disease and treatment morbidity.
Article
With prostate cancer not observed in eunuchs and total androgen suppression by castration an effective first-line treatment for advanced prostate cancer, the dramatic regression seen in tumour symptoms after castration, lead to the theory that high levels of circulating androgens were a risk factor for prostate cancer. This theory however, ignored the effects testosterone variations within a physiologic range could have on early tumour events and since the early 2000s, clinical evidence discounting testosterone as a linear mechanistic cause of prostate cancer growth mounted, with alternative mechanistic hypotheses such as the saturation model being proposed. Together with a growing understanding of the negative health effects and decreased quality of life in men with testosterone deficiency or hypogonadism, a paradigm shift away from testosterone as a prostate cancer inducer occurred allowing clinicians to use testosterone therapy as potential treatment for men with difficult and symptomatic hypogonadism that had been previously treated for prostate cancer. In this review we contextualise the idea of testosterone as a risk factor for prostate cancer inducement and compile the most current literature with regards to the influence of testosterone and testosterone therapy in prostate cancer.
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The European Association of Urology (EAU) Guidelines Panel on Male Infertility has prepared these Guidelines to assist urologists and healthcare professionals from related specialties in the treatment of male infertility. Urologists are usually the initial specialty responsible for assessing men when male infertility is suspected. However, infertility can be a multifactorial condition requiring multidisciplinary involvement.
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Testosterone (T) is linked with diverse characteristics of human health, yet, whether these associations reflect correlation or causation remains debated. Here, we provide a broad perspective on the role of T on complex diseases in both sexes leveraging genetic and health registry data from the UK Biobank and FinnGen (total N=625,650). We find genetically predicted T affects sex-biased and sex-specific traits, with a particularly pronounced impact on female reproductive health. We show T levels are intricately involved in metabolism, sharing many associations with sex hormone binding globulin (SHBG), but report lack of direct causality behind most of these associations. Across other disease domains, including behavior, we find little evidence for a significant contribution from normal variation in T levels. Highlighting T’s unique biology, we show T displays antagonistic effects on stroke risk and reproduction in males and females. Overall, we underscore the involvement of T in both male and female health, and the complex mechanisms linking T levels to disease risk and sex differences.
Article
Résumé Objectifs La Société francophone de médecine sexuelle (SFMS) et le Comité d’andrologie et de médecine sexuelle (CAMS) de l’Association française d’urologie (AFU) ont réuni un panel d’experts afin d’élaborer des recommandations françaises pour la prise en charge du déficit en testostérone (DT). Méthodes Revue systématique de la littérature entre 01/2000 et 07/2019. Utilisation de la méthode des recommandations pour la pratique clinique (RPC) et de la grille AGREE II. Résultats Le DT se définit comme l’association de signes et symptômes cliniques évocateurs de DT à une diminution de la testostéronémie ou de l’activité des androgènes sériques. Le diagnostic nécessite une T inférieure aux valeurs de référence de l’homme jeune sur 2 dosages successifs. Les troubles sexuels sont souvent au premier plan, et concernent l’ensemble de la fonction sexuelle masculine (désir, excitation, plaisir et orgasme). Les symptômes les plus évocateurs sont : baisse du désir sexuel, disparition des érections nocturnes, fatigue, perte de la force musculaire. Sont également fréquemment retrouvés : surpoids, humeur dépressive, anxiété, irritabilité et mal-être. Le DT est plus fréquent en cas de maladies métaboliques, cardiovasculaires, chroniques, d’antécédents andrologiques, et de traitements corticoïdes, opioïdes, antipsychotiques, anticonvulsivants, antirétroviraux, ou du cancer. La SHBG étant fréquemment anormale, nous recommandons de préférer le dosage des T libre ou biodisponible, plutôt que la T totale. Le traitement du DT nécessite un bilan préalable clinique (TR, examen mammaire) et biologique (PSA, NFS). Les contre-indications au traitement par T sont : cancer de la prostate ou du sein évolutifs, insuffisance cardiaque sévère ou évènement cardiovasculaire récent, polyglobulie, HBP compliquée, projet de paternité. Il est possible en cas de syndrome d’apnée du sommeil appareillé, antécédent psychiatrique, cardiopathie stable, cancer de la prostate en surveillance active et après un an de rémission complète d’un cancer de la prostate localisé de risque faible ou intermédiaire traité de manière curative. Il comporte une supplémentation par testostérone au long cours et des conseils d’hygiène de vie. La surveillance du traitement se fait à 3, 6, 12 mois puis tous les ans. Elle est clinique (TR annuel) et biologique (T totale, PSA, NFS), l’effet secondaire le plus fréquent étant la polyglobulie. Conclusion Ces recommandations doivent contribuer à améliorer la prise en charge du DT.
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Androgens and prostate androgen receptors (ARs) are at the root of prostate cancer (PCa); thus, surgical or chemical castration and AR blocking have been effective methods in inhibiting growth and achieving remission. Unfortunately, the remissions are not long lasting and proliferation, invasion, and metastasis inevitably reappear. When this happens, the tumor is usually refractory to antiandrogen treatment, which is not a synonym of androgen independency but of castration resistance. The discovery of abiraterone, an inhibitor of adrenal and intratumoral androgen production, and enzalutamide an AR blocker represented an important breakthrough in PCa therapy. These drugs significantly prolong survival. However, their benefits are short lived and they do not solve the problem. Further research along the path of AR and androgen inhibition is necessary for more effective treatments. The secrets of this problem are hidden somewhere in the androgen metabolism of the castration-resistant stage and in the peculiarities of AR function. Evidently, androgen metabolism changes during PCa evolution and understanding these changes will lead to the development of new drugs such as specific AR degraders and allow the repurposing of some old pharmaceuticals. Ketoconazole is the best example of a repurposed antiandrogen that has shown some positive results. Castration-resistant PCa treatments need to evolve from an androgen-centered view to an AR-centered approach.
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Prostate-specific antigen (PSA) is a member of the kallikrein gene family and is expressed exclusively in human prostatic epithelial cells. PSA protein has been an important biological marker for prostate cancers. Until now, very little was known about the regulation of PSA expression in prostatic cells. In this study, we have developed a specific oligonucleotide probe which recognizes PSA but not the human glandular kallikrein. This is crucial because both PSA and human glandular kallikrein are expressed in the prostate at relatively high levels and have high nucleotide sequence homology (greater than 82%). Utilizing a S-labeled PSA-specific probe, PSA mRNA was localized within the glandular epithelium of the prostate. Northern blot analysis detected a single 1.6-kilobase transcript in LNCaP cells, a cell line derived from a human prostate adenocarcinoma metastasis. Therefore, LNCaP cells were used to study the androgenic effects on PSA mRNA expression. A time course study demonstrated that PSA mRNA was induced by mibolerone (a nonmetabolizable synthetic androgen) and reached maximal levels after 9 h. The induction of PSA mRNA required as little as 0.3 nM mibolerone. In addition to mibolerone, PSA mRNA could be induced by the natural androgen, dihydrotestosterone, but not by the synthetic glucocorticoid, dexamethasone, or the synthetic estrogen, diethylstilbestrol. Moreover, in the presence of dihydrotestosterone, PSA mRNA was depressed by hydroxyflutamide (an antiandrogen). These results suggest strongly that the androgenic effects on PSA mRNA in LNCaP cells may be via the function of the androgen receptor.
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The length of a polymorphic CAG repeat sequence, occurring in the androgen receptor gene, is inversely correlated with transcriptional activity by the androgen receptor. Because heightened androgenic stimulation may increase risk of prostate cancer development and progression, we examined whether shorter CAG repeats in the androgen receptor gene are related to higher risk of prostate cancer. We conducted a nested case-control study of 587 newly diagnosed cases of prostate cancer detected between 1982 and 1995, and 588 controls without prostate cancer, within the Physician's Health Study. An association existed between fewer androgen receptor gene CAG repeats and higher risk of total prostate cancer [relative risk (RR) = 1.52; 95% confidence interval (CI) = 0.92-2.49; P trend = 0.04; for men with CAG repeat lengths < or = 18 relative to > or = 26 repeats]. In particular, a shorter CAG repeat sequence was associated with cancers characterized by extraprostatic extension or distant metastases (stage C or D) or high histologic grade (RR = 2.14; CI = 1.14-4.01; P trend = 0.001). This association was observed individually both for high stage (RR = 2.23) and high grade prostate cancer (RR = 1.89). Men with shorter repeats were at particularly high risk for distant metastatic and fatal prostate cancer. Variability in the CAG repeat length was not associated with low grade or low stage disease. These results demonstrate that a shorter CAG repeat sequence in the androgen receptor gene predicts higher grade and advanced stage of prostate cancer at diagnosis, and metastasis and mortality from the disease. The clinical implications of these results should be evaluated further.
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Several lines of evidence suggest that sex hormones may be involved in the etiology of prostate cancer. We conducted a prospective nested case-control study to evaluate the relationships of serum androgens and estrogens to prostate cancer using serum collected at baseline for the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The 29,133 male smokers who participated in the trial were 50-69 years old at baseline. During 5-8 years of follow-up, 246 men were diagnosed with prostate cancer, and 116 of these were randomly selected for inclusion in the current study. For each case, two controls matched on age, date of blood collection, intervention group, and study center were selected. Hormones were measured in serum by RIA using standard procedures. None of the individual androgens or estrogens was significantly related to prostate cancer. These findings were unaltered by simultaneous evaluation of serum androgen and estrogen concentrations in multivariate models. These results do not support a strong relationship of serum androgens and estrogens with prostate cancer in smokers. Within-person variation in concentrations of some hormones may have contributed to the lack of significant associations.
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To investigate from the HERITAGE Family Study database, 13 steroid hormones (androstane-3alpha, 17beta-diol glucuronide, androsterone glucuronide, cortisol, dehydroepiandrosterone (DHEA), DHEA ester (DHEAE), DHEA sulfate (DHEAS), dihydrotestosterone (DHT), estradiol, 17-hydroxyprogesterone, progesterone, pregnenolone ester, sex hormone binding globulin (SHBG) and testosterone in each sex for their relationships with age, body mass index (BMI), race and key lifestyle variables. Sample sizes varied from 676 to 750 per hormone. Incremental regression methods were used to examine the contributions of the variables to steroid hormone variability. Age was a major predictor for most steroid hormones. The greatest contribution of age was a negative relationship with DHEAS (R(2)=0.39). BMI was also associated with the variability of several steroid hormones, being the most important predictor of SHBG (R(2)=0.20) and of testosterone (R(2)=0.12) concentrations. When age and BMI were included, race still contributed significantly to the variations in cortisol (R(2)=0.02 for men and 0.04 for women), DHT (R(2)=0.02 for men and 0.03 for women), and progesterone (R(2)=0.03 for women). Nevertheless, race appeared to be less important than age and BMI. In addition, lifestyle indicators (food and nutrient intakes, smoking and physical activity) influenced steroid hormone variability. Their contributions, however, were minor in most cases once age, BMI and race had been taken into account. We conclude that age was the most important factor, followed by BMI, race and lifestyle factors in explaining steroid hormone variability.
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We present a review of the epidemiological evidence for relations of prostate cancer risk to circulating total and bioavailable androgens, to alterations in the metabolism of insulin-like growth factor-1 (IGF-1), and to anthropometric indices of longitudinal growth (body stature) and overweight. In addition, we review the physiological inter-relationships between insulin, growth hormone/IGF-1 axis, and sex steroid metabolism, as well as the associations of bioavailable sex steroid levels with overweight and obesity. A first conclusion of this review is that, taken together, epidemiological studies have provided little support for the hypothesis that prostate cancer risk is increased in men with elevated total or biovailable testosterone (T). Although one prospective study showed an increased risk in men with low plasma sex hormone-binding globulin (SHBG) and with elevated plasma T for given levels of SHBG, this was not confirmed by results from other cohort studies. A second conclusion is that overweight, which is generally associated with moderate reductions in both total and bioavailable plasma T, appears to be unrelated to any significant increase or decrease in prostate cancer risk. However, significant increases in risk have been observed for men with a taller body stature, or with elevated plasma IGF-1. IGF-1 may directly enhance prostate tumorigenesis by inhibiting apoptosis and by stimulating cell proliferation. In addition, IGF-1 downregulates the synthesis of SHBG, and enhances sex steroid synthesis. Therefore, we do not entirely rule out that due to an elevation of plasma IGF-1 levels, men at increased risk of prostate cancer also have mildly elevated plasma bioavailable T, which epidemiological studies may have failed to demonstrate because of methodological problems. Prostate Cancer and Prostatic Diseases (2000) 3, 157-172
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Prostate adenocarcinoma has the highest incidence of any malignancy and is the second leading cause of cancer‐related deaths in men in industrialized countries. The development and progression of prostate cancer are dependent on testosterone and dihydrotestosterone; the androgen receptor is the vehicle through which these androgens exert their regulation on prostate cellular proliferation and differentiation. As a result, much effort has been devoted to elucidating the role of the androgen receptor in prostate cancer. The CAG and GGN trinucleotide repeats in exon 1 of the androgen receptor gene have been linked to prostate cancer risk and progression in some studies. Also, androgen receptor gene amplification may be a mechanism of prostate cancer cell adaptation to hormonal therapy. In addition, androgen receptor somatic mutations can result in receptors that have altered binding specificity when compared with wild‐type receptors and heightened affinity for hormones other than testosterone and dihydrotestosterone. Gene amplification and somatic mutations, coupled with the fact that various growth factors have been shown to stimulate androgen receptor activity independently of androgens, may enable prostate cancer cells to grow despite testicular‐androgen ablation. Unfortunately, current medical therapy for metastatic prostate cancer is deficient, hormone‐refractory prostate cancer is a major obstacle in treatment, and, as a result, prostate cancer mortality is still significant. Further study of the function of the androgen receptor will offer a better understanding of prostate cancer pathogenesis and progression, aiding the development of more effective treatments for this disease.
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Prostate cancer is known as a disease with an extremely high prevalence relative to its clinical incidence in the population. The combination of preclinical incidence and duration that could yield this phenomenon is of tremendous interest to researchers trying to understand the natural history of the disease and to develop efficient screening strategies. In this article, the authors present estimates of the age-specific asymptomatic incidence and average preclinical duration of prostate cancer. The methodological approach is to first estimate the age-specific incidence of new (stage Al) prostate cancers using preclinical prevalence data from autopsy studies performed between 1941 and 1964 and clinical incidence data for the years 1960-1986 from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. Then, the preclinical prevalence estimates are divided by the derived preclinical incidence estimates to yield estimates of the average duration of asymptomatic disease. The estimated mean duration among white men is between 11 and 12 years and appears to be approximately 1 year shorter for blacks than for whites. Comparison of the lifetime risks of preclinical and clinical disease suggests that approximately 75% of prostate cancers will never become diagnosed if clinical incidence remains at levels observed in 1984-1986, prior to the introduction of prostate-specific antigen (PSA) screening in the population.
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Prostate-specific antigen (PSA) has revolutionized the diagnosis and management of men with prostate cancer. Significant advances have been made since the early development of immunoassays. While PSA is useful for staging and monitoring of established disease, it has shown the greatest utility in the realm of early detection realm. PSA is the most important tumor marker; its importance in evaluating men for the possibility of prostate cancer is irrefutable. Enhancing specificity is a pressing need. In this regard, the recognition of the molecular forms of free PSA and complex PSA have shown the most promise and undoubtedly will result in fewer false-positive PSA test results. The salient literature is reviewed and commentary made on the current status of PSA with particular emphasis on methods to enhance its specificity in early detection and applications. Semin. Surg. Oncol. 18:3–9, 2000. © 2000 Wiley-Liss, Inc.
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BACKGROUND It has been hypothesized that high androgen levels are determinants of prostate carcinoma.METHODS Serum concentrations of testosterone, sex hormone-binding globulin (SHBG), and androstenedione were analyzed to determine their role as predictors of prostate carcinoma in a longitudinal, population-based, nested case–control study. The serum concentrations of testosterone, SHBG, and androstenedione were determined from serum samples collected by the Finnish Mobile Clinic Health Examination Survey between 1968–1972 and stored at -20 °C. During a follow-up period of 24 years, a total of 166 prostate carcinoma cases occurred among men who originally were cancer free. Two controls (matched for age and municipality) were chosen.RESULTSThere was no association between serum testosterone, SHBG, or androstenedione concentrations and the occurrence of subsequent prostate carcinoma in the total study population or in subgroups determined based on age or body mass index. The association was not strengthened by simultaneous adjustment for the hormonal variables.CONCLUSIONS The results of the current study do not appear to corroborate the hypothesis that serum testosterone, SHBG, or androstenedione are determinants of the subsequent occurrence of prostate carcinoma. Cancer 1999;86:312–5. © 1999 American Cancer Society.
Article
Prostate specific antigen (PSA) is serine protease produced at high concentrations by normal and malignant prostatic epithelium. It is mainly secreted into seminal fluid, where it digests the gel forming after ejaculation. Only minor amounts of PSA leak out into circulation from the normal prostate, but the release of PSA is increased in prostatic disease. Thus PSA is a sensitive serum marker for prostate cancer but its specificity is limited by a high frequency of falsely elevated values in men with benign prostatic hyperplasia (BPH). Approximately two-thirds of all elevated values (>4 μg/l) in men over 50 years of age are due to BPH. In serum, most of the PSA immunoreactivity consists of a complex between PSA and α1-antichymotrypsin (PSA-ACT) whereas approximately 5–40% are free. The proportion of PSA-ACT is larger and the free fraction is smaller in prostate cancer than in benign prostatic hyperplasia (BPH). Determination of the proportion of free PSA has become widely used to improve the cancer specificity of PSA especially in men with PSA values in the `grey zone' (4–10 μg/l). PSA also occurs in complexes with other protease inhibitors and determination of these and other markers may further improve the diagnostic accuracy for prostate cancer. Interpretation of the results for many different markers is complicated, but this can be simplified by using statistical methods. The diagnostic accuracy can be further improved by using logistic regression or neural networks to estimate the combined impact of marker results and other findings like digital rectal examination (DRE), transrectal ultrasound (TRUS) and heredity.
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To test the reliability of a single plasma testosterone (T) or dihydrotestosterone (DHT) level, respectively, as a parameter of the long term hormonal milieu, plasma T and DHT levels were measured eight times, over a period of 50 weeks, in 169 middle-aged and elderly men with symptomatic benign prostatic hyperplasia, who were otherwise healthy. The results show an excellent correlation (r = 0.849) between plasma androgen levels at first sampling and the mean of the 7 samples taken subsequently over 1 yr. Of the 22 subjects with plasma testosterone levels below the lower limit of normal (10 nmol/L) at first sampling, none had an annual plasma T value greater than 13.5 nmol/L, i.e. the annual mean was also below the normal limit or in the low normal range, whereas of the 18 subjects with a T level at first sampling above 25 nmol/L (+/- 90th percentile), none had a mean plasma T level below 19.0 nmol/L (70th percentile). Similar results were obtained for DHT. When plasma testosterone levels at first sampling were subdivided into groups, with a concentration interval of 5 nmol/L from 5 to more than 25 nmol/L, multifactor analysis of variance showed no significant difference between the values within the same group at each sampling, whereas at each sampling the groups remained highly significantly (P less than 0.001) different from each other. The same applies to DHT levels when subdivided into groups with a concentration interval of 0.5 nmol/L. It is concluded that in healthy middle-aged and elderly men, single point plasma androgen measurements reflect fairly reliably the annual mean androgen level.
Article
To study the mechanism of regression of human prostatic cancer following androgen ablation, the androgen-responsive PC-82 human prostatic adenocarcinoma xenograft was used as a model system. Castration of male nude mice bearing PC-82 xenografts results in a 50% tumor regression by 2 wk following androgen ablation. This regression is due to a sequence of biochemical and morphological events that results in both the cessation of cell proliferation and activation of programmed death or apoptosis of the androgen-dependent prostatic cancer cells. Associated with this response are an enhanced expression of the transforming growth factor beta 1 gene, a potent inhibitor of cell proliferation, and testosterone-repressed prostatic message 2 (designated TRPM-2), a programmed cell death-associated gene. Fragmentation of tumor DNA into nucleosomal oligomers and histological appearance of apoptotic bodies are characteristic early events that preceded the dramatic reduction in tumor volume following androgen ablation. These results suggest that androgen-dependent human prostatic cancer cells, like normal prostatic cells, retain the ability to inhibit proliferation and to activate programmed cell death in response to androgen ablation. Clarification of the biochemical pathway involved in the activation of this programmed cell death should identify new targets of therapy for even androgen-independent human prostatic cancer.
Article
Androgens are thought to play a role in the pathogenesis of prostate cancer. We evaluated androgen levels in 3 age-matched groups of men who were part of the Baltimore Longitudinal Study of Aging: 1) 16 men with no prostatic disease by urologic history and exam (control group); 2) 20 men with a histologic diagnosis of benign prostatic hyperplasia (BPH) who had undergone simple prostatectomy; and 3) 20 men with a histologic diagnosis of prostate cancer (16 with local/regional cancer, and 4 with metastatic cancer). Luteinizing hormone (LH), total testosterone (T), and free T were measured on stored AM sera by radioimmunoassay (RIA). Free T was also calculated from the measured concentrations of total T and sex hormone binding globulin (SHBG). The median number of repeated sex steroid measurements ranged from 6-9 over a period from 7-25 years prior to the diagnosis of prostate disease. There were no significant differences in age-adjusted LH, total T, SHBG, or calculated free T levels among the groups at 0-5, 5-10, and 10-15 years before diagnosis. These data suggest that there are no measurable differences in serum testosterone levels among men who are destined to develop prostate cancer and those without the disease.
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Oral administration of finasteride, a 5 alpha-reductase inhibitor, affects intraprostatic androgens by suppressing dihydrotestosterone and increasing testosterone. This study was designed to determine the correlation of these effects of finasteride with changes in serum dihydrotestosterone, testosterone and androstanediol glucuronide. In a double blind, placebo-controlled study, 27 men with symptomatic benign prostatic hyperplasia were treated with placebo or 1 or 5 mg. per day finasteride for 6 to 8 weeks before transurethral resection of the prostate. There was no significant change in serum testosterone in any group, or in serum dihydrotestosterone or androstanediol glucuronide in the placebo group. There was a decrease in serum dihydrotestosterone by 66 +/- 4% and 70 +/- 8% (p = 0.32), and of serum androstanediol glucuronide by 78 +/- 3% and 86 +/- 3% (p = 0.012) in the 1 and 5 mg. finasteride groups, respectively. Intraprostatic dihydrotestosterone in the placebo group decreased from 18.6 +/- 1.4 nmol./kg. to 3.8 +/- 1.0 nmol./kg. and 1.7 +/- 0.7 nmol./kg. with 1 mg. and 5 mg. finasteride, respectively (p = 0.049 between 1 mg. and 5 mg. finasteride). Intraprostatic testosterone in the placebo group increased from 1.1 +/- 0.2 nmol./kg. to 7.6 +/- 1.0 nmol./kg. and 8.3 +/- 0.7 nmol./kg. with 1 mg. and 5 mg. finasteride, respectively (no significant difference between 1 mg. and 5 mg. finasteride). Serum and intraprostatic dihydrotestosterone correlated (p = 0.002). There was no correlation between intraprostatic dihydrotestosterone and serum androstanediol glucuronide. We conclude that 5 mg. of finasteride cause greater inhibition of intraprostatic 5 alpha-reductase than 1 mg. and that serum dihydrotestosterone is a better marker of intraprostatic dihydrotestosterone than androstanediol glucuronide.
Article
A population-based nested case-control study was conducted to determine the relation of prediagnostic serum levels of testosterone, dihydrotestosterone, prolactin, follicle-stimulating hormone, luteinizing hormone, estrone, and estradiol to the risk of subsequent prostate cancer. Serum specimens of study subjects were available from a blood collection campaign in Washington County, Maryland, in 1974. Serum hormone levels of 98 histologically confirmed prostate cancer cases diagnosed in the subsequent 13 years were compared to those of 98 controls who were individually matched to cases on the basis of age (within weeks), sex, and race. There were no significant differences in levels of these hormones between cases and controls, although elevated levels of luteinizing hormone and of testosterone:dihydrotestosterone ratios were associated with mild increased risks of prostate cancer.
Article
Sex steroids, particularly androgens, have been implicated in the pathogenesis of prostate cancer. Data from previous studies comparing circulating hormone levels in men with and without prostate cancer are difficult to interpret, since the studies were limited in size, hormone levels were analyzed in blood drawn after the diagnosis of cancer, nonrepresentative control subjects were used, and hormone and hormone-binding protein levels were not simultaneously adjusted. We conducted a prospective, nested case-control study to investigate whether plasma hormone and sex hormone-binding globulin (SHBG) levels in healthy men were related to the subsequent development of prostate cancer. Among participants in the Physicians' Health Study who provided plasma samples in 1982, we identified 222 men who developed prostate cancer by March 1992. Three hundred ninety control subjects, matched to the case patients on the bases of age, smoking status, and length of follow-up, were also identified. Immunoassays were used to measure the levels of total testosterone, dihydrotestosterone (DHT), 3 alpha-androstanediol glucuronide (AAG), estradiol, SHBG, and prolactin in the stored (at -82 degrees C) plasma samples. Correlations between individual hormone levels and between hormone levels and SHBG in the plasma of control subjects were assessed by use of Spearman correlation coefficients (r). Odds ratios (ORs) and 95% confidence intervals (CIs) specifying the prostate cancer risk associated with quartile levels of individual hormones, before and after adjustment for other hormones and SHBG, were calculated by use of conditional logistic regression modeling. Reported P values are two-sided. No clear associations were found between the unadjusted levels of individual hormones or SHBG and the risk of prostate cancer. However, a strong correlation was observed between the levels of testosterone and SHBG (r = .55), and weaker correlations were detected between the levels of testosterone and the levels of both estradiol (r = .28) and DHT (r = .32) (all P < .001). When hormone and SHBG levels were adjusted simultaneously, a strong trend of increasing prostate cancer risk was observed with increasing levels of plasma testosterone (ORs by quartile = 1.00, 1.41, 1.98, and 2.60 [95% CI = 1.34-5.02]; P for trend = .004), an inverse trend in risk was seen with increasing levels of SHBG (ORs by quartile = 1.00, 0.93, 0.61, and 0.46 [95% CI = 0.24-0.89]; P for trend = .01), and a non-linear inverse association was found with increasing levels of estradiol (ORs by quartile = 1.00, 0.53, 0.40, and 0.56 [95% CI = 0.32-0.98]; P for trend = .03). No associations were detected between the levels of DHT or prolactin and prostate cancer risk; for AAG, a marker of 5 alpha-reductase activity, only suggestive evidence of a positive association was found. The results were essentially unchanged when case patients diagnosed within 4 years of plasma collection, case patients diagnosed with localized (i.e., nonaggressive) disease, or control subjects with elevated prostate serum antigen levels (> 2.5 ng/mL) were excluded from the analyses. High levels of circulating testosterone and low levels of SHBG-both within normal endogenous ranges-are associated with increased risks of prostate cancer. Low levels of circulating estradiol may represent an additional risk factor. Circulating levels of DHT and AAG do not appear to be strongly related to prostate cancer risk.
Article
It is suspected that male hormones are associated with the risk of prostate cancer. To test this hypothesis, we conducted a nested case-control study in a cohort of 6860 Japanese-American men examined from 1971 to 1975. At the time of examination, a single blood specimen was obtained, and the serum was frozen. After a surveillance period of more than 20 years, 141 tissue-confirmed incident cases of prostate cancer were identified, and their stored sera and those of 141 matched controls were assayed for total testosterone, free testosterone, dihydrotestosterone, 3-alpha-androstanediol glucuronide, androsterone glucuronide, and androstenedione. Odds ratios for prostate cancer, based on quartiles of serum hormone levels, were determined using conditional logistic regression methods. The odds ratios for the highest quartiles were 1.37 (95% confidence interval, 0.73-2.55) for 3-alpha-androstanediol glucuronide and 1.24 (95% confidence interval, 0.62-2.47) for androstenedione, but none of the differences was statistically significant. The results were unremarkable for the other four hormonal measurements. In addition, the patients and controls were compared by hormonal ratios (i.e., total testosterone:dihydrotestosterone), but the results were also unremarkable. The findings of this study indicate that none of these androgens is strongly associated with prostate cancer risk.
Article
The biological mechanisms involved in androgen-dependent and -independent prostate cancer growth after castration were analyzed in the LuCaP 23.1 human prostate cancer xenograft model. Athymic mice (n = 82) bearing LuCaP 23.1 xenograft were castrated and tumors were harvested at different time points from day 0 to day 112 post castration. In each group of mice, tumor growth rate (TGR), serum PSA concentration, percentage of tumor cells incorporating bromodeoxyuridine (BUdR index), percentage of apoptotic tumor cells assessed by morphological analysis (apoptotic index), and presence of apoptosis-related DNA "ladder" were analyzed. Castration induced a significant decrease in TGR and serum PSA from day 1 to day 7, and a progressive increase in the 2 parameters from day 14 to day 112, heralding androgen-independent tumor relapse. Meanwhile the BUdR and apoptotic indexes varied as follows after castration: an increase was noted for both at day 3, a significant increase in apoptotic index with a decrease in BUdR index from day 5 to day 14, and a progressive decrease in apoptotic index while BUdR index remained at 50% of the pre-castration value from day 28 to day 112. DNA ladder was present sparsely in tumors grown in non-castrated hosts, universally present in tumors from day 1 to day 28 post castration, and frequent in tumors from day 56 to 112. Castration-induced effects in LuCaP 23.1 tumors were characterized by an increase in number of apoptotic cells and a decrease in proliferative activity. The androgen-independent tumor relapse after castration was associated with a low apoptotic index with no increase in proliferative activity.
Article
The results of recent studies suggest that a relative hypogonadism in men is associated with several established risk factors for prevalent diseases. Therefore, we determined total and free testosterone, luteinizing hormone (LH), and sex-hormone binding globulin (SHBG) in a cohort of randomly selected men (n = 659) at 67 years of age. These data were analyzed cross-sectionally in relation to blood glucose and serum insulin, which were measured while fasting and after an oral glucose tolerance test, in addition to plasma lipids and blood pressure. The data were also analyzed in relation to impaired glucose tolerance (IGT) and diabetes, which were discovered at examination or earlier diagnosis. Risk factors for the development of diabetes up to 80 years of age were analyzed with univariate and multivariate statistics. Total and free testosterone and SHBG concentrations correlated negatively with glucose and insulin values; total testosterone and SHBG, with triglycerides; and SHBG, with blood pressure (from P < 0.05 to P < 0.01). Men with IGT or newly diagnosed diabetes had higher BMI values (26.2 +/- 0.31 and 27.0 +/- 0.59 [mean +/- SE], respectively) and waist circumference (99.0 +/- 1.03 and 100.5 +/- 1.57) than nondiabetic men (BMI, 25.1 +/- 0.14; waist circumference, 95.4 +/- 0.47; P < 0.05), indicating abdominal obesity. Such men and men with previously diagnosed diabetes had, in general, lower total and free testosterone and SHBG levels, while those for LH were not different. In multivariate analyses that included BMI, waist-to-hip ratio, total and free testosterone, and SHBG, the remaining independent predictors for the development of diabetes were low total testosterone (P = 0.015) and, on the borderline, low SHBG (P = 0.053). In relation to nondiabetic men, the risk ratio for mortality, myocardial infarction, and stroke increased gradually and significantly from 1.18 to 1.68, from 1.51 to 1.78, and from 1.72 to 2.46 in men with IGT, newly diagnosed diabetes, and previously known diabetes, respectively. It was concluded that low testosterone and SHBG concentrations in elderly men are associated with established risk factors for diabetes and in established diabetes. Moreover, low testosterone levels independently predict the risk of developing diabetes. In different degrees of expression, the diabetic state predicts strongly (and gradually mortality from) myocardial infarction and stroke. It has been suggested that a relative hypogonadism might be a primary event, because other studies have shown that testosterone deficiency is followed by insulin resistance, which is ameliorated by testosterone substitution. The data suggest that the relative hypogonadism involved might be of both central and peripheral origin.
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Several immortalized and malignant adult human prostatic epithelial cell lines have recently been developed. The three most widely used carcinoma cell lines, DU-145, PC-3, and LNCaP, developed between 1977 and 1980, have greatly contributed to our present understanding of prostate cancer. Before a cell line can be accepted as having prostatic epithelial origin, some basic characteristics must be established. Expression of specific cytokeratins, but absence of desmin and factor VIII, should be first determined to establish epithelial origin. Responsiveness to androgens and expression of androgen receptor and prostate specific antigen should be examined under stringent culture conditions to establish prostatic epithelial origin. Response to growth factors and expression of their receptors facilitates further characterization of cell behavior. Cell lines immortalized by human papillomaviruses (HPVs) are of special interest because HPVs are involved in a variety of anogenital cancers and may also play a role in prostate carcinogenesis. Malignant transformation of HPV-18 immortalized cells with the ras oncogene provides cell systems for investigating the multistep process of carcinogenesis. Each cell line has some unique characteristics, whether it arose directly from a carcinoma or resulted from immortalization with simian virus 40 (SV40) or HPV or was transformed in vitro by oncogenes. Comparisons of these characteristics should facilitate elucidation of the mechanisms involved in initiation, promotion, and progression of prostate cancer. These cell lines will further serve as useful models for investigating tumor progression, invasion, metastasis, new therapeutic strategies, drug resistance, and its reversal and chemoprevention. This review will be published in three parts and will summarize cell markers necessary for characterization, as well as the characteristics and some applications of the immortalized as well as malignant adult human prostatic epithelial cell lines. Part 1 deals with cell markers and the immortalized, nontumorigenic cell lines.
Article
We report a nested case-control study of serum biomarkers of 5 alpha-reductase activity and the incidence of prostate cancer. From a cohort of more than 125,000 members of the Kaiser Permanente Medical Care Program who underwent multiphasic health examinations during 1964-1971, we selected 106 incident prostate cancer cases. A control was pair matched to each case on age, date of serum sampling, and clinic location. Serum levels of total testosterone, free testosterone, androsterone glucuronide, and 5 alpha-androstane-3 alpha,17 beta androstanediol glucuronide (3 alpha-diol G) were measured on the stored samples and scored as quartiles. Potential confounders included alcohol, smoking, and body mass index. The adjusted odds ratios and 95% confidence intervals for a one quartile score increase were 1.00 (0.75-1.34) for total testosterone, 1.14 (0.86-1.50) for free testosterone, 1.13 (0.84-1.53) for androsterone glucuronide, and 1.16 (0.86-1.56) for 3 alpha-diol G. A limitation of this study is that there are two different 5 alpha-reductase isoenzymes, only one of which is expressed in high levels within the prostate, yet both of which may affect serum biomarkers. Since the two isoenzymes are encoded on different chromosomes, variation in one would act as an independent source of measurement error in any analysis of serum biomarker effects of the other. Consequently, the odds ratios may be underestimated and the study, although negative, cannot exclude the previously hypothesized possibility that a positive relationship between intraprostatic 5 alpha-reductase activity and prostate cancer may exist. A clinical trial to test this hypothesis is under way.
Article
We tested the hypothesis that serum levels of testosterone (T), dihydrotestosterone (DHT), and the DHT metabolite 3 alpha,17 beta-androstanediol glucuronide are positively associated with the risk of prostate cancer. This nested case-control study was based on the cohort of men who donated blood to the Janus serum bank at Oslo University Hospital (Oslo, Norway) between 1973 and 1994. Cancer incidence was ascertained through linkage with the Norwegian Cancer Registry. The study included sera from 59 men who developed prostate cancer (cases) subsequent to blood donation and 180 men who were free of any diagnosed cancer (controls) in 1994 and were of similar age (+/- 1 year) and had similar blood storage time (+/- 6 months) to the cases. Neither T, DHT, nor the ratio T:DHT was associated with risk of developing prostate cancer. Compared to the bottom quartile, the odds ratio (OR) associated with the top quartile of T was 0.83 [95% confidence interval (CI), 0.36-1.93]; the OR for the top (compared to the bottom) quartile of DHT was 0.83 (95% CI, 0.36-1.94), and the equivalent OR for T:DHT was 1.31 (95% CI, 0.58-2.97). Similarly, 3 alpha,17 beta-androstanediol glucuronide showed no association with prostate cancer risk; the OR for the top (compared to the bottom) quartile was 1.10 (95% CI, 0.41-2.90). These results showed no association, positive or negative, between androgens measured in serum and the subsequent risk of developing prostate cancer.
Article
Prostate cancer is known as a disease with an extremely high prevalence relative to its clinical incidence in the population. The combination of preclinical incidence and duration that could yield this phenomenon is of tremendous interest to researchers trying to understand the natural history of the disease and to develop efficient screening strategies. In this article, the authors present estimates of the age-specific asymptomatic incidence and average preclinical duration of prostate cancer. The methodological approach is to first estimate the age-specific incidence of new (stage AI) prostate cancers using preclinical prevalence data from autopsy studies performed between 1941 and 1964 and clinical incidence data for the years 1960-1986 from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. Then, the preclinical prevalence estimates are divided by the derived preclinical incidence estimates to yield estimates of the average duration of asymptomatic disease. The estimated mean duration among white men is between 11 and 12 years and appears to be approximately 1 year shorter for blacks than for whites. Comparison of the lifetime risks of preclinical and clinical disease suggests that approximately 75% of prostate cancers will never become diagnosed if clinical incidence remains at levels observed in 1984-1986, prior to the introduction of prostate-specific antigen (PSA) screening in the population.
Article
This paper presents a quantitative review of the data from eight prospective epidemiological studies, comparing mean serum concentrations of sex hormones in men who subsequently developed prostate cancer with those in men who remained cancer free. The hormones reviewed have been postulated to be involved in the aetiology of prostate cancer: androgens and their metabolites testosterone (T), non-SHBG-bound testosterone (non-SHBG-bound T), di-hydrotestosterone (DHT), androstanediol glucuronide (A-diol-g), androstenedione (A-dione), dehydroepiandrosterone sulphate (DHEAS), sex hormone binding globulin (SHBG), the oestrogens, oestrone and oestradiol, luteinizing hormone (LH) and prolactin. The ratio of the mean hormone concentration in prostate cancer cases to that of controls (and its 95% confidence interval (CI)) was calculated for each study, and the results summarized by calculating the weighted average of the log ratios. No differences in the average concentrations of the hormones were found between prostate cancer cases and controls, with the possible exception of A-diol-g which exhibited a 5% higher mean serum concentration among cases relative to controls (ratio 1.05, 95% CI 1.00-1.11), based on 644 cases and 1048 controls. These data suggest that there are no large differences in circulating hormones between men who subsequently go on to develop prostate cancer and those who remain free of the disease. Further research is needed to substantiate the small difference found in A-diol-g concentrations between prostate cancer cases and controls.
Article
The free and nonspecifically bound plasma hormone levels generally reflect the clinical situation more accurately than total plasma hormone levels. Hence, it is important to have reliable indexes of these fractions. The apparent free testosterone (T) concentration obtained by equilibrium dialysis (AFTC) as well as the fraction of serum T not precipitated by 50% ammonium sulfate concentration (non-SHBG-T; SHBG, sex hormone-binding globulin), often referred to as bioavailable T, appear to represent reliable indexes of biologically readily available T, but are not well suited for clinical routine, being too time consuming. Several other parameters have been used without complete validation, however: direct immunoassay of free T with a labeled T analog (aFT), calculation of free T (FT) from total T and immunoassayed SHBG concentrations (iSHBG), and the free androgen index (FAI = the ratio 100T/iSHBG). In the view of substantial discrepancies in the literature concerning the free or bioavailable T levels, we compared AFTC, FT, aFT, FAI, and non-SHBG-T levels in a large number of sera with SHBG capacities varying from low, as in hirsute women, to extremely high as in hyperthyroidism. All these indexes of bioavailable T correlated significantly with the AFTC concentration; AFTC and FT values were almost identical under all conditions studied, except during pregnancy. Values for aFT, however, were only a fraction of either AFTC or FT, the fraction varying as a function of SHBG levels. Also, the FAI/AFTC ratio varied as a function of the SHBG levels, and hence, neither aFT nor FAI is a reliable index of bioavailable T. The FT value, obtained by calculation from T and SHBG as determined by immunoassay, appears to be a rapid, simple, and reliable index ofbioavailable T, comparable to AFTC and suitable for clinical routine, except in pregnancy. During pregnancy, estradiol occupies a substantial part of SHBG-binding sites, so that SHBG as determined by immunoassay overestimates the actual binding capacity, which in pregnancy sera results in calculated FT values that are lower than AFTC. The nonspecifically bound T, calculated from FT, correlated highly significantly with and was almost identical to the values of non-SHBG-T obtained by ammonium sulfate precipitation, testifying to the clinical value of FT calculated from iSHBG.
Article
Pathologic and epidemiologic data suggest that while little racial variation exists in prostate cancer prevalence ("autopsy cancer"), striking racial variation exists for the clinically diagnosed form of the disease. A review of the available literature was performed to define whether racial differences in serum androgen levels or qualitative or quantitative differences in the androgen receptor were correlated with prostate cancer incidence or severity. Black men were found to be exposed to higher circulating testosterone levels from birth to about age 35 years. Such differences were not consistently noted among older men. Significant differences also were found for dihydrotestosterone metabolites among black, white, and Asian men. Unique racial genetic polymorphisms were noted for the gene for 5 alpha-reductase type 2 among black and Asian men. Novel androgen receptor mutations recently have been described among Japanese, but not white, men with latent prostate cancer. Finally, androgen receptor gene polymorphisms leading to shorter or longer glutamine and glycine residues in the receptor protein are correlated with racial variation in the incidence and severity of prostate cancer. This same polymorphism also could explain racial variation in serum prostate-specific antigen levels. Collectively, these data strongly suggest racial differences within the androgen/androgen receptor pathway not only exist but could be one cause of clinically observed differences in the biology of prostate cancer among racial groups.
Article
The objective was to examine prospectively the association between low testosterone and sex hormone-binding globulin (SHBG) levels and the subsequent development of type 2 diabetes in men. Analyses were conducted on the cohort of the Massachusetts Male Aging Study, a population-based random sample of men aged 40-70. Of the 1,709 men enrolled in 1987-1989 (T1), 1,156 were followed up 7-10 years later (T2). Testosterone and SHBG levels at T1 were used to predict new cases of diabetes between T1 and T2. After controlling for potential confounders, diabetes at follow-up was predicted jointly and independently by lower baseline levels of free testosterone and SHBG. The odds ratio for future diabetes was 1.58 for a decrease of 1SD in free testosterone (4 ng/dl) and 1.89 for a 1SD decrease in SHBG (16 nmol/l), both significant at P < 0.02. Our prospective findings are consistent with previous, mainly cross-sectional reports, suggesting that low levels of testosterone and SHBG play some role in the development of insulin resistance and subsequent type 2 diabetes.
Article
Carcinoma of the prostate is the most frequently diagnosed malignancy and the second leading cause of death as a result of cancer in men in the United States and in many other Western countries. Notwithstanding the importance of this malignancy, little is understood about its causes. The epidemiology of prostate cancer strongly suggests that environmental factors, particularly diet and nutrition, are major determinants of risk for this disease, and evidence is mounting that there are important genetic risk factors for prostate cancer. Human prostate carcinomas are often androgen sensitive and react to hormonal therapy by temporary remission, followed by relapse to an androgen-insensitive state. These well-established features of prostate cancer strongly suggest that steroid hormones, particularly androgens, play a major role in human prostatic carcinogenesis, but the precise mechanisms by which androgens affect this process are unknown. In addition, the possible involvement of estrogenic hormones is not entirely clear. The purpose of this overview is to summarize the literature about steroid hormonal factors, androgens and estrogens, and prostate carcinogenesis. From these literature observations, a multifactorial general hypothesis of prostate carcinogenesis emerges with androgens as strong tumor promoters acting via androgen receptor-mediated mechanisms to enhance the carcinogenic activity of strong endogenous genotoxic carcinogens, such as reactive estrogen metabolites and estrogen- and prostatitis-generated reactive oxygen species and possible weak environmental carcinogens of unknown nature. In this hypothesis, all of these processes are modulated by a variety of environmental factors such as diet and by genetic determinants such as hereditary susceptibility and polymorphic genes that encode for steroid hormone receptors and enzymes involved in the metabolism and action of steroid hormones.
Article
Recent years have seen an increasing interest in the study of the aging male, with a particular interest in the problem of whether so-called rejuvenating hormones and, more spe- cifically, androgens can improve quality of life, counteract progressive skeletal muscle loss and strength, prevent falls and fractures, prolong independent living, and reduce the dependence on medical care. Almost a decade has elapsed since the first studies on androgen supplementation in elderly men were published (1, 2) and, in the view of the persisting controversies con- cerning this problem as well as the increasing public interest for rejuvenating hormones, it may be indicated to evaluate critically the clinical relevance of the relative androgen de- ficiency in elderly males, the diagnostic criteria of androgen deficiency, as well as the risks and benefits of androgen supplementation in elderly men. Male hormone replacement therapy implies, of course, that elderly men have a significant deficit in male hormone. Therefore, the first question to be answered is whether the common occurrence of the age-associated decline of testos- terone levels is inherent to the aging process and occurs also in healthy men or whether the observed decline is the con- sequence of intercurrent disease, obesity, stress, relative physical inactivity, medications, etc. After years of controversy, due to differences in the char- acteristics of the population studied and variation in the timing of blood sampling (morning or afternoon) or the frequently small number of elderly subjects studied, authors now agree that in healthy men also there is a clear, slow but continuous, age-dependent decline of testosterone (T) levels, which is more pronounced for free T (FT) than for total T, a consequence of the age-associated increase of the levels of sex hormone binding globulin (SHBG); at 75 yr of age mean total T level in the morning is about two thirds of the mean level at 20 -30 yr of age, whereas the mean FT and bioactive T (FT plus albumin bound T) level are only 40% of the mean levels in younger males. Moreover, the circadian rhythm of plasma T levels, with higher levels in the morning than in the evening, is generally lost in elderly men (3). However, wide interindividual variations exist due to genetic factors, body mass index, diet, social habits (alcohol, tobacco), and stress, and about 20% of males over 70 yr old have T levels in the upper third of males 20 - 40 yr of age (4). This is in clear distinction to the situation in postmenopausal women who all have clearly decreased estradiol levels. It is important to mention that this decrease, observed in cross-sectional stud- ies, has now been confirmed by longitudinal studies (5-9). However, the androgen deficiency in elderly men is gener- ally moderate; therefore, some authors have suggested the term partial androgen deficiency in the aging male (PADAM). Others, in analogy with the term menopause in women, use the term andropause, although distinct from women in menopause, elderly men retain their reproductive capacity. Although the decrease in (F)T levels occurs in healthy elderly men, it is evident that sequelae of intercurrent disease (10), medication, environmental, psychosocial, and socioeco- nomic factors accelerate this age-associated decrease. Re- cently, the important role of abdominal obesity in the age- associated decrease of T levels has been stressed (10 -12). Clinical significance of the age-associated decline in androgen levels in elderly men
Article
Prostate adenocarcinoma has the highest incidence of any malignancy and is the second leading cause of cancer-related deaths in men in industrialized countries. The development and progression of prostate cancer are dependent on testosterone and dihydrotestosterone; the androgen receptor is the vehicle through which these androgens exert their regulation on prostate cellular proliferation and differentiation. As a result, much effort has been devoted to elucidating the role of the androgen receptor in prostate cancer. The CAG and GGN trinucleotide repeats in exon 1 of the androgen receptor gene have been linked to prostate cancer risk and progression in some studies. Also, androgen receptor gene amplification may be a mechanism of prostate cancer cell adaptation to hormonal therapy. In addition, androgen receptor somatic mutations can result in receptors that have altered binding specificity when compared with wild-type receptors and heightened affinity for hormones other than testosterone and dihydrotestosterone. Gene amplification and somatic mutations, coupled with the fact that various growth factors have been shown to stimulate androgen receptor activity independently of androgens, may enable prostate cancer cells to grow despite testicular-androgen ablation. Unfortunately, current medical therapy for metastatic prostate cancer is deficient, hormone-refractory prostate cancer is a major obstacle in treatment, and, as a result, prostate cancer mortality is still significant. Further study of the function of the androgen receptor will offer a better understanding of prostate cancer pathogenesis and progression, aiding the development of more effective treatments for this disease.
Article
Prostate cancer is a leading cause of cancer death in men. Treatment goals for men with advanced prostate cancer include prolonging survival, preventing or delaying symptoms due to disease progression, improving and maintaining quality of life, reducing treatment related morbidity. Androgen suppression therapy is considered a mainstay of treatment for men with advanced prostate cancer. However it is not clear whether early androgen suppression for men with locally advanced disease or asymptomatic metastases improves length and quality of life compared to androgen suppression deferred until signs and symptoms of clinical progression. This systematic review assessed the efficacy and adverse effects of primary therapy with early versus deferred androgen suppression therapy in men with advanced prostate cancer. Randomized controlled trials were searched in general and specialized databases (MEDLINE, EMBASE, CancerLIT, Cochrane Library, VA Cochrane Prostate Disease register) and by reviewing bibliographies including those of the Blue Cross and Blue Shield Association Technology Evaluation Center/Evidence-based Practice Center of the Agency for Healthcare Research and Quality (BCBS/TEC-AHRQ) report No.4. All published randomized trials were eligible for inclusion provided they: randomized men with advanced prostate cancer to early versus deferred androgen suppression; reported overall, progression-free, and cancer-specific survival, and/or adverse events; did not utilize androgen suppression as adjuvant therapy to radiation treatment. An independent reviewer using a standardized form extracted information on trial characteristics, interventions, and outcomes. Results were reviewed for accuracy and discrepancies resolved by discussion. The main outcome measure for comparing effectiveness was the overall survival at 1, 2, 5 and 10 years. Progression-free survival, cancer-specific survival, complications due to disease progression and the incidence of adverse effects of treatment were also measured. Four trials involving 2,167 patients were included in this review. All of the trials were conducted prior to use of prostate specific antigen (PSA) testing. There was variability between studies regarding the treatments used and the requirements for initiation of treatments. The percent overall survival at 1, 2, 5, and 10 years for the early treatment group was 88%, 73%, 44%, and 18%. For the deferred therapy group the percent overall survival was 86%, 71%, 37%, and 12%. The pooled estimate for the difference in overall survival favored early therapy but was significant only at 10 years when few patients had survived [OR = 1.16 (95% CI: 0.90 to 1.49) at 1 year, 1.08 (95% CI: 0.89 to 1.33) at 2 years, 1.19 (95% CI: 0.95 to 1.50) at 5 years, and 1.50 (95% CI: 1.04 to 2.16) at 10 years]. The pooled estimate of prostate cancer specific survival at 2, 5, and 10 years favored early therapy though the confidence intervals were wide and the results not statistically different. The risk differences at 2, 5, and 10 years were 2.7%, 5.8%, and 4.6%. Although each study used unique definitions of progression free survival, all studies found progression free survival was consistently better in the early intervention group at all time points. Complications due to disease progression were only reported in one study but were more frequent in the deferred treatment group. Adverse events due to treatment were also only reported in one study but occurred more frequently in the early treatment group. The evidence from randomized controlled trials is limited by the variability in study design, stage of cancer and subjects enrolled, interventions utilized, definitions and reporting of outcomes and the lack of PSA testing for diagnostic and monitoring purposes. However, the available information suggests that early androgen suppression for treatment of advanced prostate cancer reduces disease progression and complications due to progression. Early androgen suppression may provide a small but statistically significant improvement in overall survival at 10 years. There was no statistically significant difference in prostate cancer specific survival but a clinically important difference could not be excluded. These outcomes need to be evaluated with the evidence suggesting higher costs and more frequent treatment related adverse effects with early therapy. Additional studies are required to evaluate more definitively the efficacy and adverse effects of early versus delayed androgen suppression in men with prostate cancer. In particular trials should evaluate patients with advanced prostate cancer diagnosed by PSA testing and men with persistent or rising PSA levels following treatment options (e.g. radical prostatectomy, radiation therapy or observation) for clinically localized disease.
Article
Enterolactone, a phytoestrogen belonging to the class of lignans, is produced by the intestinal microflora from precursors in plant foods and has been implicated in protection against cancer. We study the effect of enterolactone on the risk of a subsequent diagnosis of prostate cancer. We conducted a longitudinal, nested case-control study by linkage of 3 biobanks to the cancer registries in Finland, Norway and Sweden, respectively. Enterolactone concentrations were measured by time-resolved fluoroimmunoassay in serum from 794 men who had a diagnosis of prostate cancer at a mean follow-up time of 14.2 years after blood collection and among 2,550 control men matched within each cohort for age (+/-2 years), date of blood collection (+/-2 months) and county. The median enterolactone concentrations did not differ between case and control subjects in the full study group (8.4 nmol/L [25th-75th percentile = 4.5-15.0] vs. 8.5 nmol/L [25th-75th percentile = 4.3-15.9]), nor in the national groups. Odds ratios of prostate cancer risk estimated by conditional logistic regression for increasing concentrations of enterolactone in quartiles in the full study group were 1.00 (referent), 1.21 (95% confidence interval [CI] = 0.96-1.52), 1.16 (95% CI = 0.91-1.47) and 1.08 (95% CI = 0.83-1.39). The OR estimate for the highest vs. the lowest quartile of enterolactone in separate analyses of the Norwegian, Finnish and Swedish cohort was 1.21 (95% CI = 0.91-1.60), 1.02 (95% CI = 0.59-1.76) and 0.87 (95% CI = 0.45-1.67), respectively. No support for the hypothesis that high circulating enterolactone is protective against prostate cancer was found.