ABSTRACT
Prostate cancer is a common disease in older men. Rodent models have demonstrated that an early and later-life exposure to estrogen can lead to cancerous lesions and implicated hormonal dysregulation as an avenue for developing future prostate neoplasia. This study utilizes a human fetal prostate xenograft model to study the role of estrogen in the progression of human disease. Histopathological lesions were assessed in 7-, 30-, 90-, 200-, and 400-day human prostate xenografts. Gene expression for cell cycle, tumor suppressors, and apoptosis-related genes (ie, CDKN1A, CASP9, ESR2, PTEN, and TP53) was performed for 200-day estrogen-treated xenografts. Glandular hyperplasia was observed in xenografts given both an initial and secondary exposure to estradiol in both 200- and 400-day xenografts. Persistent estrogenic effects were verified using immunohistochemical markers for cytokeratin 10, p63, and estrogen receptor α. This model provides data on the histopathological state of the human prostate following estrogenic treatment, which can be utilized in understanding the complicated pathology associated with prostatic disease and early and later-life estrogenic exposures.
Subject(s)
Disease Models, Animal , Estradiol/pharmacology , Heterografts/drug effects , Prostate/transplantation , Prostatic Neoplasms/etiology , Animals , Disease Progression , Estradiol/adverse effects , Gene Expression/drug effects , Heterografts/embryology , Heterografts/pathology , Humans , Male , Prostate/drug effects , Prostate/embryology , Prostate/metabolism , Prostatic Hyperplasia/chemically induced , Prostatic Hyperplasia/etiology , Prostatic Hyperplasia/pathology , Prostatic Neoplasms/chemically induced , Prostatic Neoplasms/pathology , Rats, Nude , Testosterone/adverse effects , Testosterone/pharmacologyABSTRACT
Prostate cancer is the most frequent non-cutaneous malignancy in men. There is strong evidence in rodents that neonatal estrogen exposure plays a role in the development of this disease. However, there is little information regarding the effects of estrogen in human fetal prostate tissue. This study explored early life estrogen exposure, with and without a secondary estrogen and testosterone treatment in a human fetal prostate xenograft model. Histopathological lesions, proliferation, and serum hormone levels were evaluated at 7, 30, 90, and 200-day time-points after xenografting. The expression of 40 key genes involved in prostatic glandular and stromal growth, cell-cycle progression, apoptosis, hormone receptors and tumor suppressors was evaluated using a custom PCR array. Epigenome-wide analysis of DNA methylation was performed on whole tissue, and laser capture-microdissection (LCM) isolated epithelial and stromal compartments of 200-day prostate xenografts. Combined initial plus secondary estrogenic exposures had the most severe tissue changes as revealed by the presence of hyperplastic glands at day 200. Gene expression changes corresponded with the cellular events in the KEGG prostate cancer pathway, indicating that initial plus secondary exposure to estrogen altered the PI3K-Akt signaling pathway, ultimately resulting in apoptosis inhibition and an increase in cell cycle progression. DNA methylation revealed that differentially methylated CpG sites significantly predominate in the stromal compartment as a result of estrogen-treatment, thereby providing new targets for future investigation. By using human fetal prostate tissue and eliminating the need for species extrapolation, this study provides novel insights into the gene expression and epigenetic effects related to prostate carcinogenesis following early life estrogen exposure.
Subject(s)
Cell Transformation, Neoplastic/metabolism , Epigenesis, Genetic , Estrogens/metabolism , Prostate/metabolism , Prostate/pathology , Animals , Biomarkers/metabolism , Cell Transformation, Neoplastic/drug effects , CpG Islands , DNA Methylation , Disease Models, Animal , Epigenesis, Genetic/drug effects , Epithelial Cells/metabolism , Epithelial Cells/pathology , Estrogens/pharmacology , Gene Expression Regulation/drug effects , Heterografts , Humans , Immunohistochemistry , Male , Mice , Mice, Nude , Phenotype , Prostate/drug effects , Prostate-Specific Antigen/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Signal Transduction/drug effectsABSTRACT
OBJECTIVE: To derive normal ranges of serum testosterone and luteinizing hormone (LH) concentrations in healthy men, and thus evaluate whether testosterone replacement therapy is prescribed inappropriately. SUBJECTS AND METHOD: The study comprised 266 healthy male volunteers (aged 18-75 years) who were defined as healthy by strict eligibility criteria. Subjects had a body mass index (BMI) of 18.6-32.2 kg/m2, smoked 0-10 cigarettes/day, and had an alcohol intake 0-40 units/week (one unit = 8 g ethanol). We measured serum testosterone and LH concentrations in the morning (08.00-09.00 hours) and evening (20.00-21.00 hours). RESULTS: Morning normal ranges of testosterone for men aged < or = 40 years were 10.07-38.76 nmol/L (2.90-11.18 microg/L), and for men age > or = 40 years, 7.41-24.13 (2.14-6.96); the respective evening normal ranges were 6.69-31.51 (1.93-9.09) and 6.46-21.93 (1.86-6.33). Both morning and evening serum testosterone declined significantly with increasing age and BMI. LH was significantly higher in the morning than in the evening, but did not vary between the age groups or with BMI. The calculated normal ranges of LH were 0.9-7.0 IU/L (morning) and 0.7-6.8 IU/L (evening). CONCLUSIONS: The lower limit of normal for serum testosterone was 3-4 nmol/L (0.86-1.15 microg/L) lower than that of published ranges. The results have important implications for the diagnosis of hypogonadism and use of testosterone replacement therapy.