Surgical and chemical castration induce differential histological response in prostate lobes of Mongolian gerbil

The present study describes the short-term alterations in the prostate ventral and dorsal lobe of the adult Mongolian gerbil, in response to two different androgen suppression approaches. Groups (n = 6) of 16-week-old gerbils were maintained intact or subjected, either to the bilateral surgical castration I week previously or to daily subcutaneous injections of Flutamide (10 mg/kg body weight) for 7 days. The main microscopic features of both prostate lobes in these groups were compared using conventional paraffin tissue sections, measurements of acinar epithelial height and stereological data of main gland components (acini, collagen fibers and fibromuscular stroma). Marked alterations were observed in the basement membrane of the ventral lobe after both surgical and chemical castration, such as an increase in thickness and collagen staining. A low degree of epithelial atrophy was detected in the dorsal lobe following both androgen suppression approaches in comparison with that found in the ventral lobe, indicating that this lobe is not so responsive to testosterone ablation induced by castration or Flutamide treatment, at least insofar as secretory activity is concerned. However, the dorsal lobe exhibited marked stromal modification, such as an increase in collagen fibers following castration and an increase in fibromuscular stroma following Flutamide-treatment. Thus, the histological and quantitative data indicates a differential short-term response of the prostate dorsal lobe to surgical castration and Flutamide therapy, suggesting the existence of lobe-specific mechanisms for stromal remodeling. (c) 2006 Elsevier Ltd. All rights reserved.

CHEMICAL SYMPATHECTOMY BLOCKS ANDROGEN BIOSYNTHESIS DURING PREPUBERTY

Twenty-one-day old male Wistar rats were injected subcutaneously with guanethidine (GUA) at doses of 5 and 10 mg kg(-1) day(-1) for 20 days. Animals were sacrificed by decapitation during the prepubertal (41 days of age) and early-pubertal (51 days of age) periods of sexual development. The testes were collected, frozen in liquid N-2 and stored at -70 degrees C until determination of testicular progesterone (P): androstenedione (A) and testosterone (T). Higher levels of P (2.18 +/- 0.24 ng/g. control = 1.24 +/- 0.16 ng/g) associated with decreased levels of androgens (A = 0.26 +/- 0.06 ng/g and T = 2.05 +/- 0.19 ng/g; control = 1.86 +/- 0.76 ng/g and 8.48 +/- 1.16 ng/g, respectively) were observed in 10 mg GUA-treated rats of prepubertal age, while only P levels (3.12 +/- 0.51 ng/g control = 1.73 +/- 0.27 ng/g) were increased in rats of early pubertal age. It is important to note that in 41-day old male rats both 5 and 10 mg were effective in decreasing testicular concentration of testosterone. These results suggest that the sympathetic innervation of the testis is involved in the modulation of androgen biosynthesis, acting through a selective step in the steroid biochemical pathway during the pubertal process and that under the conditions employed the blockage in androgen biosynthesis in the prepubertal stage of sexual maturation is dependent on the dose of GUA.

Role of androgenic deprivation on the contractile response to norepinephrine in vas deferens isolated from rats submitted to swimming-stress

The effects of androgenic deprivation induced by castration on the norepinephrine contractile response of vas deferens from rats, which have been submitted to acute swimming-stress were determined. Acute swimming-stress led to subsensitivity to norepinephrine in vas deferens excised from intact rats. Similarly, castration also induced subsensitivity to norepinephrine, but no further subsensitivity occurred in organs from castrated rats submitted to acute stress. The results indicate a different response to norepinephrine in terms of relative responsiveness ratio, when vas deferens was excised from castrated rats or castrated rats submitted to acute stress. It is suggested that androgenic steroids modulate the recovery of homeostasis in rat vas deferens during acute stress, and that this effect may involve mechanisms that affect both the sensitivity of adrenergic receptors and the system of neuronal uptake of catecholamines.

Subcutaneous and testicular metastasis from prostatic adenocarcinoma with neuroendocrine differentiation

The pathological finding of testicular metastasis in cases of disseminated prostatic adenocarcinoma is rare, but was more frequently reported in the past, when bilateral castration was performed more often. The existence of skin and subcutaneous metastasis adds a worse prognosis, because generally it is sign of advanced disease with an average survival time of less than one year. The synchronous occurrence of such metastasis has not been described previously, neither their association to neuroendocrine differentiation. The presence of such differentiation of prostatic adenocarcinoma represents a very unfavorable prognostic factor, as suggested in recent literature. Herein, we discuss the case of a 53 year old man, who presented with macroscopic hematuria and frequency associated to several painless subcutaneous nodules in left axilla and shoulder, as well as in the lower abdominal wall. The right testis was painful, endured and on rectal examination, the prostate was diffusely enlarged. Serum PSA was elevated, reaching 1760 ng/ml and prostatic biopsy disclosed a Gleason 10 prostatic adenocarcinoma with neuroendocrine differentiation. The same pathological pattern was detected in the right testis and in all subcutaneous nodules, documented by positive staining of chromogranin, a marker of neuroendocrine cells. He was submitted to a prostate tunnelization and maximal androgen blockade plus adjuvant chemotherapy, nevertheless, he died 5 months latter.

Análise da expressão de proteínas da via de sinalização de insulina em próstata de ratos tratados com dexametasona

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Caracterização do infiltrado inflamatório e avaliação dos marcadores de prognóstico Ki-67, p53, receptor de estrógeno e progesterona no tumor mamário maligno de cadelas

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Androgen therapy reverses injuries caused by ethanol consumption in the prostate: testosterone as a possible target to ethanol-related disorders

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Perinatal exposure to androgen excess and the effects on the rat uterine estradiol responsiveness

Androgen exposure during sexual development induces alterations in steroidal target tissues. The objective of this study was to evaluate the uterine responsiveness to estradiol after perinatal androgenization. Pregnant Wistar rats were exposed to corn oil or testosterone propionate at 0.05, 0.1, or 0.2 mg/kg from gestational day 12 until postnatal day 21. Female offspring was challenged with estradiol (E2 ) after weaning (0.4 mg/kg) and at adulthood (10 or 100 µg/day), when the pituitary response was also evaluated. At adulthood, control and 0.05 mg/kg groups presented a uterine weight increment when exposed to 100 µg/day of E2 , 0.1 mg/kg group only responded to 10 µg/day of E2 , and the 0.2 mg/kg group showed increased uterine weight at both doses. The pituitary weight was similarly increased after estradiol stimulation in all experimental groups. In conclusion, testosterone propionate exposure induced an abnormal stimulation of uterine tissue growth by estrogen stimulus without affecting pituitary response. More studies are needed to clarify whether these alterations are capable of impairing the reproductive capacity of the female tract. © 2015 Wiley Periodicals, Inc. Environ Toxicol, 2015.

Impact of Glucocorticoid Receptor Gene Polymorphisms on the Metabolic Profile of Adult Patients with the Classical Form of 21-Hydroxylase Deficiency

Background: CAH patients have an increased risk of cardiovascular disease, and it remains unknown if lifelong glucocorticoid (GC) treatment is a contributing factor. In the general population, glucocorticoid receptor gene (NR3C1) polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of CAH patients. Methodology: Sixty-eight adult patients (34SV/34SW) with a mean age of 28.4 +/- 9 years received dexamethasone (mean 0.27 +/- 0.11 mg/day) to obtain normal androgen levels. SW patients also received fludrocortisone (50 mu g/day). Metabolic syndrome (MetS) was defined by the NCEP ATPIII criteria and obesity by BMI >= 30 kg/m(2). NR3C1 alleles were genotyped, and association analyses with phenotype were carried out with Chi-square, t-test and regression analysis. Results: Obesity and MetS were observed in 23.5% and 7.3% of patients, respectively, and were not correlated with GC doses and treatment duration. BMI was positively correlated with blood pressure (BP), triglycerides (TG), LDL-c levels and HOMA-IR and inversely correlated with HDL-c levels. BclI and A3669G variants were found in 26.4% and 9.6% of alleles, respectively. Heterozygotes for the BclI polymorphism presented with higher BMI (29 kg/m(2) +/- 5.3 vs. 26 kg/m(2) +/- 5.3, respectively) and waist circumference (89 cm +/- 12.7 vs. 81 cm +/- 13, respectively) compared to wild-type subjects. Hypertension was found in 12% of patients and heterozygotes for the BclI polymorphism presented higher systolic BP than wild type subjects. Low HDL-c and high TG levels were identified in 30% and 10% of patients, respectively, and were not associated with the NR3C1 polymorphisms. A3669G carriers and non-carriers did not differ. Conclusion: In addition to GC therapy, the BclI GR variant might play an important role in obesity susceptibility in CAH patients. Genotyping of GR polymorphisms could result in the identification of a subgroup at risk patients, allowing for the establishment of personalized treatment and the avoidance of long-term adverse consequences.

Differential expression of toll-like receptor mRNAs in recurrent aphthous ulceration

BACKGROUND: Toll-like receptors (TLR) are membrane proteins that recognize conserved molecules derived from bacterial, viral, fungal or host tissues. They are responsible for promoting the production of cytokines and chemokines, increasing the expression of costimulatory molecules and influencing the T Helper response (Th) toward either a Th1 or Th2 profile, thereby modulating the regulatory T cell response and controlling the integrity of the epithelial barrier. The key factors responsible for increased susceptibility to recurrent aphthous ulceration (RAU) are unclear, and because TLRs are involved in both immune regulation and control of the epithelial barrier, a deficiency in TLR activity is likely to cause increased susceptibility. METHODS: We investigated the gene expression of TLRs one through 10 in tissue samples and peripheral blood mononuclear cells (PBMC) of RAU patients in comparison to healthy controls using real-time quantitative reverse transcription PCR. RESULTS: The analysis of mRNA expression levels in oral lesion showed significant (P < 0.01) overexpression of the TLR2(similar to 6-fold) gene and decreased expression of the TLR3 (similar to 5-fold) and TLR5 (similar to 6-fold) genes in comparison with healthy oral mucosa. The analysis of mRNA expression in PBMC indicated a down-regulation of TLR5 gene expression in the cells from RAU patients (P < 0.05; similar to 2-fold). CONCLUSION: Our results support the hypothesis that a subset of RAU patients has fewer TLR expression that have been tentatively implicated in antiinflammatory effects. This derangement of TLR gene expression may cause an overlay exuberant inflammation reaction in situations where normal individuals are resistant. J Oral Pathol Med (2012) 41: 8085

High-Fat Diet Obesity Associated With Insulin Resistance Increases Cell Proliferation, Estrogen Receptor, and PI3K Proteins in Rat Ventral Prostate

In this study, we evaluated the effects of obesity and insulin resistance induced by a high-fat diet on prostate morphophysiology, focusing on cell proliferation, expression of androgen (AR) and estrogen receptors (ER) and proteins of the insulin signaling pathway. Adult male Wistar rats were fed a high-fat diet (20% fat) for 15 weeks, whereas control animals received a balanced diet (4% fat). Both groups were then divided and treated for 2 weeks with 1 mg/kg body weight/day of the aromatase inhibitor letrozole or vehicle only. The ventral prostate was analyzed with immunohistochemical, histopathological, stereological, and Western blotting methods. Obese rats showed insulin resistance, hyperinsulinemia, and reduced plasma testosterone levels. The incidence of prostatic intraepithelial neoplasia (PIN) was 2.7 times higher in obese rats and affected 0.4% of the gland compared with 0.1% PIN areas found in control rats. Obesity doubled cell proliferation in both prostate epithelium and stroma. AR content decreased in the prostate of obese rats and estrogen receptor beta (ER beta) increased in this group. Protein levels of insulin receptor substrate 1 and protein kinase B diminished in the obese group, whereas phosphatidylinositol 3-kinase (PI3K) increased significantly. Most structural changes observed in the prostate of obese rats normalized after letrozole treatment, except for increased stromal cell proliferation and ER beta expression, which might be associated with insulin resistance. This experimental model of obesity and insulin resistance induced by a high-fat diet increases cell proliferation in rat prostate. Such alterations are associated with decreased levels of AR and increased ER beta and PI3K proteins. This change can facilitate the establishment of proliferative lesions in rat prostate.

Effects of neonatal castration and androgenization on sexual dimorphism in bone, leptin and corticosterone secretion

This study investigated the role of neonatal sex steroids in rats on sexual dimorphism in bone, as well as on leptin and corticosterone concentrations throughout the lifespan. Castration of males and androgenization of females were used as models to investigate the role of sex steroids shortly after birth. Newborn Wistar rats were divided into four groups, two male groups and two female groups. Male pups were cryoanesthetized and submitted to castration or sham-operation procedures within 24 h after birth. Female pups received a subcutaneous dose of testosterone propionate (100 mu g) or vehicle. Rats were euthanized at 20, 40, or 120 postnatal days. Body weight was also measured at 20, 40, and 120 days of age, and blood samples and femurs were collected. The length and thickness of the femurs were measured and the areal bone mineral density (areal BMD) was determined by dual-energy X-ray absorptiometry (DEXA). Biomechanical three-point bending testing was used to evaluate bone breaking strength, energy to fracture, and extrinsic stiffness. Blood samples were submitted to a biochemical assay to estimate calcium, phosphorus, alkaline phosphatase, leptin, and corticosterone levels. Weight gain, areal BMD and bone biomechanical properties increased rapidly with respect to age in all groups. In control animals, skeletal sexual dimorphism, leptin concentration, and dimorphic corticosterone concentration patterns were evident after puberty. However, androgen treatment induced changes in growth, areal BMD, and bone mass properties in neonatal animals. In addition, neonatally-castrated males had bone development and mechanical properties similar to those of control females. These results suggest that the exposure to neonatal androgens may represent at least one covariate that mediates dimorphic variation in leptin and corticosterone secretions. The study indicates that manipulation of the androgen environment during the critical period of sexual differentiation of the brain causes long-lasting changes in bone development, as well as serum leptin and corticosterone concentrations. In addition, this study provides useful models for the investigation of bone disorders induced by hypothalamic hypogonadism. (C) 2011 Elsevier Inc. All rights reserved.