Cigarette smoking: A review of possible associations with benign prostatic hyperplasia and prostate cancer

There are conflicting data on the effect of cigarette smoking on serum levels of the various sex hormones. Some studies suggest that cigarette smoke produces an antiestrogenic effect. Smoking may also affect the metabolism of other sex steroids such as testosterone and adrenal hormones, and thereby influence the incidence of benign and malignant growth of the prostate. Epidemiologic studies analyzing a possible association between cigarette smoking and prostate cancer are not conclusive, although some show a positive relationship. The etiology of BPH is undoubtedly multifactorial. Estrogens as well as androgens may be involved in the pathogenesis of BPH. There are several studies that indicate that cigarette smokers have a lower likelihood of requiring surgery for BPH. Growth of the prostate may not correlate with serum levels of androgens and estrogens. The local hormonal milieu of the target cells in the prostate are probably more critical than the more easily measured serum levels. This review examines the literature dealing with cigarette smoking and both BPH and prostate cancer. If there is an effect, then elucidation of the mechanism by which smoking affects the growth of the prostate may improve our understanding of BPH and prostate cancer, and may suggest preventive strategies for high risk groups. © 1993 Wiley-Liss, Inc.     

Understanding the role of estrogen in the development of benign prostatic hyperplasia

Introduction

Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate that affects ageing men. As the number of men affected by this condition will only continue to grow with the aging population, finding new strategies and new therapeutic options for its treatment is crucial. Androgenic hormones have been known to play an important role in the development of BPH and they have been a target in its medical treatment. Estrogens have also been implicated in BPH but in contrast to androgens, the functions of estrogens in the prostate are still obscure.

Effect of increasing ratio of estrogen: androgen on proliferation of normal human prostate stromal and epithelial cells, and the malignant cell line LNCaP

BACKGROUND: Changes in steroid ratios seen in the aging male are thought to promote prostate disease. The aims of this study were to compare the effects of varied ratios of steroids on growth of normal stromal and epithelial cell isolates, and the prostate cancer cell line, LNCaP. METHODS: The effect of altered steroid ratios on cell proliferation of normal stromal (PrSC) and epithelial (PrEC) prostate cells, and the malignant cell line, LNCaP, were assessed. RESULTS: Increasing the ratios of both estrogen:dihydrotestosterone (DHT) and DHT:estrogen, stimulated PrSC proliferation, with increasing estrogen:DHT having the greatest effect. LNCaP proliferation was increased significantly by both steroids, but altered ratios had no additional effect. PrEC proliferation was unaffected when cells were grown alone, despite presence of androgen receptors (AR) and estrogen receptors (ER). When grown in co-culture PrEC cell proliferation was significantly increased by treatments. CONCLUSIONS: PrSC proliferation is stimulated by an increasing ratio of estrogen:androgen. Proliferation of normal epithelial cells is stimulated as a result of an indirect action of steroids mediated by stromal cells. Malignant prostate cancer cells have an altered response in comparison.     

Effects of mepartricin (S-160) on spontaneous canine benign prostatic hyperplasia

OBJECTIVE: The effects of mepartricin (S-160) on spontaneous canine benign prostatic hyperplasia (BPH) were investigated by histological, histochemical and biochemical analysis. METHODS: Aged beagle dogs (5-9 years old) with spontaneously developed BPH were treated orally with a placebo or S-160 (5, 10 or 20 mg/kg/day) for 8 weeks. The methodology included measurement of prostatic volume by transrectal ultrasonography, qualitative evaluation of prostatic morphology, determination of plasma and intraprostatic estradiol level by radioimmunoassay and immunohistochemical detection of estrogen receptors and androgen receptors in the prostate. RESULTS: S-160 significantly reduced the prostatic volume and regressed histologically the hyperplastic grade of prostate, and also fairly decreased the plasma and intraprostatic estradiol concentration and the estrogen and androgen receptors in the prostate. CONCLUSIONS: These results suggest that the reduction of estradiol and estrogen receptors in the prostate may play a crucial role in the regression of BPH by S-160.     

Role of estrogens in human benign prostatic hyperplasia

The aging process is associated with a progressive decline of plasma testosterone levels, while estrone and estradiol remain unchanged and sex hormone binding globulin (SHBG) increases, with reduction of bioavailable testosterone in prostatic tissue with benign prostatic hyperplasia (BPH) the most important androgen is dihydrotestosterone: with its receptors it is almost uniformly distributed in the epithelial and stromal compartment and is not supranormal. Intraprostatic estrogens and their receptors are elevated and concentrated in the stroma. Androgens may act on the prostate indirectly through the production of growth factors; in human BPH no clear evidence exists on the modulatory effect of estrogens on bFGF, KGF and TGFbeta formation. A western diet, characterized by high fat consumption, predisposes men to BPH, while a diet rich in flavonoids and lignanes, containing phyto-estrogens, lowers this risk. These data suggest that in the medical treatment of BPH, antiestrogens or aromatase inhibitors may be used: however, up to now the clinical results of this treatment are not promising and the improvement of the obstructive symptoms does not exceed that of placebo. A possible explanation of this unsatisfactory result could be that the estrogen reduction secondary to the use of aromatase inhibitors is counterbalanced by the rise of androgen precursors.     

前列腺增生过程中性激素和内皮素相互关系

目的 :探讨性激素和内皮素 (ET)在前列腺增生发病过程中的相互关系。　方法 :采用给狗皮下埋置性缴素缓释硅胶囊的方法使狗前列腺产生增生样病理改变 (给药组 )。用RIA方法检测正常组、老年组和给药组狗前列腺组织中的ET的含量。　结果 :给药组产生与老年组类似的前列腺增生样病理改变 ,但和正常组相比 ,老年组前列腺组织中ET含量明显升高 (P <0 0 5 ) ,而与给药组无显著差异 (P >0 0 5 )。　结论 :性激素平衡失调能导致前列腺产生增生样病理改变。ET在前列腺增生发病过程中可能起一定的作用 ,但ET含量的升高与性激素没有明显的直接联系。     

Estrogenic action of commonly used fragrant agent citral induces prostatic hyperplasia

Summary A rat model for benign prostatic hyperplasia in man (BPH) was investigated. Citral treatment of male Copenhagen rats for 4 months via the transdermal route resulted in a marked hyperplasia of glandular epithelium and interglandular stroma in the ventral prostate. Despite the cellular hyperplasia there was not a significant increase in prostate weight. Investigations of the mechanism of action of citral showed that application of citral directly to the vagina in female, ovariectomized rats resulted in an increased proliferation of vaginal epithelium and a significant increase in the BrdUrd incorporation in vaginal epithelial cells, in short a similar effect to that of estrogen application. In an in vitro assay citral proved to inhibit estrogen binding to estrogen receptors, while no such inhibition was observed with testosterone for androgen receptors. These observations together with the estrogen implication in the BPH and the reported incidence of gynccomastia following exposure to geraniol, a precursor of citral, strongly suggest that the prostatic hyperplasia-inducing capacity of citral may be due to its estrogenic action.     

Epidermal growth factor modulates the expression of vascular endothelial growth factor in the human prostate

The growth and dissemination of tumors in the body has been associated with angiogenesis. Vascular endothelial growth factor (VEGF) is an angiogenic factor that stimulates endothelial cell growth and enhances vascular permeability. VEGF exerts its action by binding to specific cell surface receptors. Three receptors, VEGFR-1 (flt-1), VEGFR-2 (flk-1), and VEGFR-3 (flt-4) have been identified. Very little information on the coordinated expression of VEGF and its receptors in normal prostate, benign prostatic hyperplasia (BPH), and prostate carcinoma is available. Therefore, we examined the immunohistochemical localization of VEGF and its receptors in tissues derived from normal human prostate, BPH, and prostatic carcinoma. Immunostaining for VEGF was absent in the normal prostate. Epithelium lining the glands of prostate derived from patients with BPH exhibited strong immunostaining. The intensity of staining was relatively less in prostate carcinoma. It is interesting that VEGFR-1 and VEGFR-3 were strongly expressed in both stromal and epithelial tissues in normal prostate, BPH, and carcinoma. In comparison, VEGFR-2 was not localized to normal prostate and its expression in the stroma of BPH and epithelium of carcinoma was very weak. Because progression of prostate cancer is accompanied by altered expression of epidermal growth factor (EGF) and its receptor (EGFR) in malignant cells, we investigated the effect of EGF on VEGF gene expression by Northern blot analysis in 2 human prostate cancer cell lines that express EGFR. EGF greatly enhanced the expression of VEGF messenger RNA in DU145 and PC3 cell lines in a dose-dependent manner. The EGF induction of VEGF gene expression suggests a mechanism by which angiogenesis could be accelerated in BPH and prostate carcinoma.     

Hepatocellular Carcinoma and Sex Hormones

The liver is morphologically and functionally modulated by sex hormones. Long-term use of oral contraceptives and androgenic steroids can induce benign and malignant hepatocellular tumors. Hepatocellular carcinoma (HCC) is more prevalent in men than in women. The role of sex hormones and their receptors in the development of HCC was reviewed. Some HCCs may be androgen dependent but others may be estrogen or even both dependent. Further studies are mandatory in order to utilize such characteristics of HCC for an effective prophylaxis and therapy of this tumor.     

Changes in the endocrine environment of the human prostate transition zone with aging: simultaneous quantitative analysis of prostatic sex steroids and comparison with human prostatic histological composition

BACKGROUND: It is well-known that the incidence of benign prostatic hyperplasia (BPH) increases with aging. The age-dependent changes in the ratio of serum sex steroid concentrations may play a role in BPH development. To clarify the relationship between the prostatic tissue concentrations of these steroids and age, we established a precise method of simultaneous quantitative analysis for prostatic sex steroids and used this method to investigate the tissue concentrations of three major sex steroids (testosterone, dihydrotestosterone, and estradiol) in the human prostate. METHODS: The methodology for the simultaneous quantitative analysis of prostatic sex steroids was established using castrated rat prostatic tissue, coupled with internal standards, for androgen-deprived medium, and the validation of the method was examined. Human prostatic tissues were collected during surgery and immediately frozen at -70 degrees C. Using our method, the steroidal fractions were extracted, purified, and quantified. The proportions of stroma, epithelium, and glandular lumen were measured on each histological specimen, using an image analyzer. RESULTS: The validation tests showed that our method of quantitative analysis was precise and sensitive enough for the quantification of testosterone, dihydrotestosterone, and estradiol in the prostate. In humans, the prostatic dihydrotestosterone concentration decreased with age, but the concentrations of testosterone and estradiol showed no relation with age. Therefore, the ratio of estradiol to dihydrotestosterone concentration (E2/DHT) in prostate increased with age. The E2/DHT ratio showed a significant positive correlation with the proportion of stroma. CONCLUSIONS: The age-dependent decrease in prostatic dihydrotestosterone and constant estradiol concentration lead to a relatively estrogen-dominant environment compared to that at younger ages. We assume that this relatively estrogen-dominant status induces stromal proliferation by some mechanism and leads to the development of BPH.     

Low serum testosterone levels are predictive of prostate cancer

Purpose

Although hormones play fundamental roles in prostate growth, their clinical significance is not completely clear. Aims of present study were to assess whether testosterone and serum sex hormone levels are predictors of benign prostatic hyperplasia (BPH) or prostate cancer (PC) and to verify whether prostate cancer is associated with low testosterone levels, and to test association between testosterone levels and known prognostic factors in prostate cancer.

Methods

In 206 consecutive patients with benign prostatic hyperplasia or prostate cancer testosterone, follicle-stimulating hormone, luteinizing hormone and prolactin levels were tested and correlated with disease. In patients with prostate cancer, hormone levels were also correlated with known prognostic factors. Predictive value was assessed for age, prostate-specific antigen (PSA), PSA ratio, PSA density, prostate volume and serum sex hormone levels using multiple logistic regression analysis and receiver operating characteristic curves.

Results

Considering sex hormones, only testosterone levels were significantly lower in patients with prostate cancer than those with BPH; testosterone levels appear to be independent predictor of prostate cancer, enhancing predictive accuracy for BPH and PC. Testosterone levels do not seem to be associated with known clinical prognostic factors.

Conclusions

This study supports experimental findings that testosterone levels are predictor of prostate cancer and that prostate cancer is frequently associated with low testosterone levels. In the diagnostic work-up for prostate cancer, adding testosterone determination to PSA test may improve predictive accuracy.     

Cellular distribution of retinoic acid receptor-alpha in benign hyperplastic and malignant human prostates: comparison with androgen, estrogen and progesterone receptor status

OBJECTIVES: Retinoids are unique modulators of gene activity, cell growth and differentiation by binding to a series of nuclear receptors, i.e. all-trans-retinoic acid receptors (RAR) or 9-cis-retinoid receptors (RXR). In this study, the expression of RARalpha was immunohistochemically evaluated in benign, hyperplastic and malignant prostatic tissue and correlated with sex steroid receptor status. METHODS: Twenty-four cases of BPH and 139 cases of primary prostatic carcinoma were evaluated for RARalpha expression in correlation with androgen (AR), estrogen (ER) and progesterone (PGR) receptor staining, as well as with tumor grade. RESULTS: RARalpha was detected in the nuclei of epithelial cells in both BPH and prostate carcinoma cases. A modest inverse relationship with grade was present, especially for grade I and grade II tumors. AR staining was intense and a strong inverse relationship with grade was revealed. Although ER and PGR showed nuclear staining in prostatic epithelium, the overall expression for these receptors was low. When RARalpha content was compared to the nuclear AR expression, at least two-fold higher RARalpha levels were observed in AR+ grade II and grade III tumors. CONCLUSIONS: RARalpha expression can be immunohistochemically evaluated in formalin-fixed paraffin-embedded prostatic tissue. RARalpha expression is significantly elevated in AR+ moderately and poorly differentiated prostate carcinomas. Immunohistochemical determination of RARalpha content may be useful in defining the patient subsets in which retinoid-based treatment may be of clinical value.     

Serum sex hormones and measures of benign prostatic hyperplasia

BACKGROUND: Despite biologic plausibility, the associations between sex hormones and measures of benign prostatic hyperplasia (BPH) have not been consistently reported. METHODS: Subjects were randomly selected from the Olmsted County, MN population (n, 320; median age, 60.9 years) and followed biennially since 1990. In 2002, surrogate measures of BPH were assessed from an approximation of the American Urological Association Symptom Index (AUASI), Peak urinary flow rates (Q(max)), and a transrectal ultrasound assessment of prostate volume. Serum levels of prostate specific antigen (PSA), testosterone, bioavailable testosterone, and estradiol were also measured. RESULTS: Bioavailable testosterone levels declined with increasing cross-sectional age from 53.8, 50.2, to 41.2 ng/dl (P = 0.001) in men aged <60, 60-69, and >69 years, respectively, and the estradiol/bioavailable testosterone ratio increased from 0.042, 0.044, to 0.050 (P = 0.04). Among men with bioavailable testosterone above the median, estradiol levels had a dose response relationship with prostate size. Among men with bioavailable testosterone level 相似文献   

【特刊综述】骨骼两性异形中的雄激素和雌激素

骨骼是表达雄激素、雌激素受体以及类固醇代谢酶的一种内分泌组织。循环性激素的生物活性通过六种性激素结合球蛋白以及在骨组织中的局部转变来进行调节,例如,睾酮通过芳香酶转变成雌二醇,或通过5α还原酶转变成双氢睾酮。由于高分辨外周CT应用的增多,我们对造成骨骼强度性别差异的结构基础的认识在近几年有很大进步。这些对微小结构的观察是理解性激素对男性峰值骨量及对骨皮质和骨小梁之间转变的影响的基础。最近的研究利用Cre／LoxP技术使我们在整体基因敲除小鼠上机械的认识精确到性激素及其在成骨细胞、破骨细胞、骨细胞以及其它造成男性骨质疏松的细胞上的核受体的直接作用。同时,这些研究加强了这样的观点：雄激素和雌激素的缺乏通过与例如胰岛素样生长因子1、炎症、氧化应激、骨骼代谢的中枢神经系统控制、机械负荷的适应等的交互作用发挥直接和多种效应。这篇综述将总结性激素在男性骨骼自身平衡作用这个领域有关方面最近的进展。     

Prostate gland growth during development is stimulated in both male and female rat fetuses by intrauterine proximity to female fetuses

In rodents, steroid hormones are transported between adjacent fetuses, and male or female fetuses that develop in utero between female fetuses (2F males or 2F females) have higher serum levels of estradiol and lower serum levels of testosterone relative to siblings of the same sex that develop between two male fetuses (2M males or 2M females). The present study was prompted by the prior unexpected finding that as adults, 2F male mice have an enlarged prostate, and increased numbers of prostatic androgen receptors relative to 2M males. We examined prostate development in both male and female rat fetuses from different intrauterine positions using computer-assisted, 3-dimensional reconstruction of the urogenital complex. In males, this included the prostate, seminal vesicles and utricle (a remnant of the Müllerian ducts), while in females it included development of prostatic glandular buds. The mean cross-sectional area of developing prostatic epithelial buds, utricle and seminal vesicles was significantly increased in 2F male relative to 2M male fetuses. In female fetuses, prostatic bud development was significantly more likely to occur in 2F (67%) than in 2M (29%) animals. These findings suggest that the transport of a small supplement of estrogen from adjacent female fetuses enhances androgen-dependent accessory organ development. We also found that mRNAs encoding receptors for both estrogen and androgen were located in the mesenchyme of the developing male prostate. The localization of estrogen and androgen receptor mRNA in this region further suggests that the mesenchymal induction of prostatic epithelial growth involves both hormones. The cranial dorsolateral prostatic buds exhibited the greatest enlargement in 2F males. This region of the developing prostate in rats is comparable (that is the embryonic homologue) to the region exhibiting benign prostatic hyperplasia (BPH) during aging in men. We propose that the potential for pathological regrowth of the prostate during aging is imprinted by estradiol during fetal development.     

Relationship of serum sex-steroid hormones and prostate volume in African American men

BACKGROUND: Previous epidemiologic investigations of the associations of sex-steroid hormones and benign prostatic hyperplasia (BPH) have focused on predominately white populations. The objective of this study was to evaluate potential associations of body mass index (BMI), cigarette smoking, use of alcohol, and endogenous sex-steroid hormones with prostate volume in a population-based sample of African American (AA) men, ages 40-79 yr. METHODS: A total of 369 AA men without clinical evidence of prostate cancer were identified in the Flint Men's Health Study by using a population-based sampling procedure. All subjects underwent a complete urologic evaluation that included prostate volume determination by transrectal ultrasonography and serum assays for androgens and estrogens. RESULTS: After age adjustment, BMI (weight (kg)/height (m)2) was positively correlated with increasing levels of androstanediol glucuronide (AG), estradiol (E2), estrone sulfate (E1S), and the ratios of E2:total testosterone (TT) and E2:free testosterone (FT); however, increasing BMI was negatively correlated with androstenedione (AD), FT, TT, and sex hormone-binding globulin (SHBG). Multivariable regression models demonstrated that prostate volume increased with age (P < 0.001) and BMI (P = 0.02) and decreased with increasing levels of SHBG (P = 0.01). Larger prostatic volumes were also marginally associated with increasing levels of TT (P = 0.058). CONCLUSION: Circulating serum levels of SHBG and endogenous sex-steroid hormones are correlated with prostate volume and potentially impact the natural history of BPH. However, longitudinal studies are needed to demonstrate the temporal relationships of hormones and growth factors in the pathogenesis of BPH in AA men.     

Immunohistochemical evidence of the existence and localization of aromatase in human prostatic tissues.

Estrogens may be involved in normal growth of the prostate and the development of benign prostatic hyperplasia (BPH). The location of estrogen production is still unclear, and there has never been a direct evidence for the existence of the aromatase system, which converts androgens to estrogens, in the prostate. Using an avidin-biotin technique with a polyclonal anti-human placental aromatase, we demonstrated the existence of aromatase in normal prostates of young men and BPH tissue from elderly men. The staining is more pronounced in the stroma. However, positive stains were also seen in the glandular epithelium. While evidence of the existence of an enzyme system does not equal demonstration of its activity in a specific tissue site, our findings suggest that local estrogen production in the stroma and/or epithelium of the prostate may play a role in the maintenance of normal growth and development of BPH.     

Immunocytochemical localization of estrogen receptors in spontaneous and experimentally induced canine benign prostatic hyperplasia

Estrogens are believed to play a critical role in the etiology of canine benign prostatic hyperplasia (BPH); however, the mechanism has not been elucidated. To gain insight into this problem, we investigated the immunocytochemical localization of estrogen receptors (ER) in normal prostates, spontaneous BPH, and experimentally induced BPH by using a monoclonal ER antibody (H222). In all canine prostates the majority of ER was localized in nuclei of the same histological components: (1) transitional epithelium and subjacent stroma of the prostatic urethra, (2) periurethral prostatic ductal epithelium, and (3) prostatic stroma. ER content in the stroma was highest in the periurethral region of the prostate. Among the different groups of dogs, differences in ER location were seen only in the glandular epithelium. No ER was found in the glandular epithelium of normal prostates of young untreated dogs. In striking contrast, glandular epithelium of spontaneous BPH contained specific nuclear ER staining, though this staining was heterogeneous and was observed in only a minority (less than 10%) of the acinar epithelial cells. ER-positive acini in BPH were located predominantly in the periurethral region. These data demonstrate anatomical and biochemical heterogeneity of prostatic components and indicate that the estrogen sensitivity of prostatic cells is heterogeneous. If estrogen does play a role in BPH, it appears to act selectively rather than uniformly throughout the prostate. We reasoned that if glandular epithelial ER are involved in the development of spontaneous BPH, one might expect to find the same location of ER in BPH that was induced experimentally by specific types of treatment with androgens +/- estradiol. However, among hormone-treated dogs the presence of ER-positive prostatic glandular epithelium varied with the type of hormonal treatment but did not correlate with the experimental induction of glandular BPH. Some treatment groups with induced BPH had ER-positive prostatic glandular epithelial nuclei (with the same extent and pattern of ER localization as in spontaneous BPH); however, other treatment groups with induced BPH had ER-negative glandular epithelium. These data indicate either that glandular epithelial ER may not be involved in the pathogenesis of canine BPH or that there may be different types of BPH that have different etiologies. Possible mechanisms by which estrogen may affect the canine prostate are discussed in light of these new data on ER location.     

Histological localization of estrogen receptors in normal and diseased human prostates by immunocytochemistry.

The role of estrogens and estrogen receptors (ER) in the human prostate remains unresolved. In this study we have used the monoclonal ER antibody H222 to investigate the histological localization of ER in normal and diseased human prostates by immunocytochemistry. Prostate tissue was obtained from 3 young organ donors (Group I-normal prostate), from 14 prostates removed by radical prostatectomy or radical cystoprostatectomy, which had caused no or only mild obstructive symptoms (Group II-non-obstructive prostate), and from 11 prostates removed by suprapubic prostatectomy, which had caused severe obstructive symptoms due to a large benign prostatic hyperplasia (BPH) (Group III-obstructive prostate). In prostates of all groups ER were found to be in nuclei of the prostatic urethra and of the periurethral prostatic duct. In striking contrast, ER in the interglandular prostatic stroma was not as homogeneous among the different groups. We observed a low concentration of ER in the stroma of normal prostates, the highest concentration in non-malignant stroma of non-obstructive prostates, and no ER at all in stroma of obstructive prostates. Based on the immunocytochemical localization of ER in normal and diseased human prostate, our results indicate that stromal growth in obstructive BPH may not be mediated via ER. However, we cannot exclude that an increase of stromal ER concentration (as observed in non-obstructive prostates) is directly involved in induction of BPH, leading further prostate growth thereafter into an estrogen independent state.