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PubMed1989

Characterization of beta-adrenoceptors in the Syrian hamster Harderian gland: sexual differences and effects of either castration or superior cervical ganglionectomy.

Scatchard analysis of saturation isotherms of [125I]-iodopindolol was used to characterize beta-adrenoceptor density (Bmax) and affinity constant (Kd) in female and male hamster Harderian glands. Single-point experiments were also completed in intact females, intact males, and castrated or superior cervical ganglionectomized males. Scatchard analysis described a single population of binding sites with a Bmax of 292.2 +/- 45.1 fmol/mg protein (X +/- SEM, n = 6) in females and 18.2 +/- 3.0 fmol/mg protein (n = 6, P less than .001) in males. The affinity also varied significantly (P less than .05) with a Kd of 1.08 +/- 0.18 versus 0.26 + 0.05 nM (n = 6) in the Harderian gland of females and males, respectively. Single-point [125I]-IPIN (400 pM) binding values in females were 67.3 +/- 4.0, in intact males were 12.8 +/- 3.2, and in castrated males were 31.2 +/- 4.2 fmol/mg protein (n = 7-9). Superior cervical ganglionectomy induced no significant changes in receptor binding. The results indicate pronounced sexual differences in the density and affinity of beta-adrenoceptors in the hamster Harderian gland, which may be sex hormone dependent.

Animals↗
PubMed2002

Stat3 enhances the growth of LNCaP human prostate cancer cells in intact and castrated male nude mice.

BACKGROUND: Prostate cancer frequently progresses from an initial androgen dependence to androgen independence, rendering the only effective androgen ablation therapy useless. The mechanism underlying the androgen-independent progression is unknown. Stat3, a member of the family of signal transducers and activators of transcription, is activated in numerous cancers, including prostate. This study is to investigate the role of Stat3 activation in the growth of prostate cancer cells. METHODS: A constitutively active Stat3 was ectopically expressed in androgen-sensitive LNCaP prostate cancer cells and resulting stable clones expressing activated Stat3 were isolated. The effect of Stat3 activation on LNCaP cell growth in response to androgen in vitro and in vivo was examined. RESULTS: We show that the levels of activated Stat3 are associated with the progression of androgen-independent prostate cancer. Activation of Stat3 in androgen-sensitive LNCaP prostate cancer cells results in enhancement of tumor growth in both intact and castrated male nude mice and enhances androgen receptor-mediated prostate specific antigen expression. CONCLUSIONS: These findings demonstrate that intracellular signaling mediated by Stat3 can enhance the growth of androgen-sensitive human LNCaP prostate cancer cells in both intact and castrated male nude mice.

Androgens↗
PubMed2001

Why phase III trials of maximal androgen blockade versus castration in M1 prostate cancer rarely show statistically significant differences.

BACKGROUND: The meta-analysis of maximal androgen blockade (MAB) concluded that there is no survival advantage of MAB over castration alone. However, the results from the largest trials yield conflicting results. METHODS: The design and results of three trials were examined. RESULTS: Most studies were planned to detect an over-optimistic difference in survival and immature data were published. The survival curves show that statistical assumptions are not fulfilled. Excluding from the meta-analysis all trials where a negative impact of disease flare on survival could not be excluded resulted in no difference in survival between MAB and castration. CONCLUSIONS: Trials of MAB should be planned to detect differences of no more than 5-10% in median survival. The analyses should only be carried out on mature data and should take into account the possibility of a negative impact on survival due to disease flare if no anti-androgen has been given initially with an LH-RH agonist.

Androgen Antagonists↗
PubMed1989

Prevention and treatment of experimental prostate cancer in Lobund-Wistar rats. I. Effects of estradiol, dihydrotestosterone, and castration.

The Lobund-Wistar (L-W) rat is unique in its susceptibility to spontaneous and induced metastasizing prostate adenocarcinomas (PAs). A single IV inoculation of methylnitrosourea (MNU) produced PAs in 20% of L-W rats in 12 months. The combination of MNU plus two to seven slow-release implants of testosterone propionate (TP) induced PAs in 50-90% of rats respectively in an average of 11.5 months. The induction of PAs was prevented by early treatments of rats at risk with estradiol and less so with dihydrotestosterone (DHT). However, on a technical basis, the results were not significant. Treatments of MNU-inoculated rats with estradiol, with DHT, or by castration, at intermediate points in the projected latency time of tumor development, reduced significantly the incidences of PA development. Rats in which overt PAs had already developed in response to 12 months of exposure to implants of TP did not respond to treatment by estradiol, DHT, or castration. Thus there are early stage(s) in induced prostate tumorigenesis in L-W rats that are sensitive to modulating agents.

Adenocarcinoma↗
PubMed1989

Relationship between DNA fragmentation and apoptosis in the programmed cell death in the rat prostate following castration.

Previous studies have demonstrated that the rapid involution of the rat ventral prostate following castration involves the death of the androgen-dependent epithelial cells present within the gland and that this death is the result of a series of discrete biochemical steps. The degradation of genomic DNA into nucleosomal-sized fragments is an early event in this process and is catalyzed by calcium magnesium-dependent endonuclease activity. The morphologic correlation of the involution process involves a series of structural changes which are collectively referred to as apoptosis. The apoptotic process describes the earliest apparent signs of morphologic change exhibited by the dying cells through their eventual complete destruction and deletion from the tissue. The temporal relationship between these recently described biochemical events and the morphologic changes of the apoptotic process were compared in the present study, in order to test the cause versus effect nature of DNA fragmentation in the programmed death of androgen dependent prostatic cells following castration. These studies demonstrated that the early elevation of the Ca+2 Mg+2-dependent endonuclease activity and the fragmentation of DNA into nucleosomal oligomers occurs within prostatic glandular epithelial cells and probably does not involve the direct participation of extraprostatic cells which may subsequently migrate into the gland. Once the DNA is initially cleaved into the nucleosomal oligomers, the subsequent participation of lysosomal enzymes act in a less restricted fashion to degrade both the nucleosomal DNA as well as the cytoplasmic elements and the cell becomes morphologically apoptotic. As the elevations in Ca+2 Mg+2-dependent endonuclease activity and DNA fragmentation are initiated at a time well before the cell is morphologically dead, as defined by apoptosis, these changes in DNA metabolism must not be the consequences of cell death but instead are early causal events in an active process of programmed cell death.

Animals↗
PubMed1990

Effect of the steroidal androgen receptor antagonist Win 49,596 on steroid-induced benign prostatic hyperplasia in the castrate beagle dog.

The effects of the steroidal androgen receptor antagonist Win 49,596 on steroid-induced prostatic growth, histomorphology, and secretory function were studied in the castrate male beagle dog. At oral doses ranging from 0.625 to 40 mg/kg/day for 12 weeks, Win 49,596 inhibited prostatic growth in terms of both weight and total DNA in a dose-dependent manner. In addition, both the incidence and severity of diffuse glandular hyperplasia/hypertrophy were dose-dependently inhibited by Win 49,596, resulting in diffuse glandular atrophy. Prostatic secretory function was also inhibited by Win 49,596 treatment. The effects of Win 49,596 at a dosage of 40 mg/kg/day were similar to that observed for the nonsteroidal androgen receptor antagonist flutamide at 10 mg/kg/day. Oral administration of Win 49,596 to castrate dogs at a dosage of 40 mg/kg/day for 12 weeks failed to produce any evidence of agonist activity. These results demonstrate that Win 49,596 prevented the experimental induction of benign prostatic hyperplasia in dogs and suggest that on further evaluation this compound may be efficacious in the treatment of the human disease.

Androgen Antagonists↗
PubMed1990

Effects of prolactin and androgens on the prostatic lipids of castrated mature bonnet monkeys.

The effects of prolactin (PRL), bromocriptine (Br), testosterone propionate (TP), dihydrotestosterone (DHT), and the combinations of these androgens with PRL/Br on total lipid, total cholesterol, total glyceride glycerols, and total phospholipid and their fractions in cranial and caudal prostates of castrated mature monkeys were studied. Glyceride glycerols formed the major portion of total lipids (50%) in normal monkeys. Cholesterol and phospholipids were of equal share (25%). Esterified cholesterol formed the major share (75%) of total cholesterol. Diacyl glycerol was the major (60%) glyceride glycerol and phosphatidyl choline and ethanolamine were the major phospholipid classes. Except triacyl glycerol castration markedly decreased all the lipid classes in both the lobes. PRL restored normal free and esterified cholesterol and phosphatidyl inositol but Br invariably decreased all the lipid classes. TP/DHT treatment stimulated the free and esterified cholesterol more than the control; it restored the normal glyceride glycerols in both the lobes. Phosphatidyl inositol, choline, and ethanolamine were stimulated by androgens and other phospholipid classes were brought to normal in both the lobes. Addition of PRL + TP/DHT markedly increased esterified cholesterol, phosphatidyl inositol, choline, ethanolamine, and phosphatidic acid in both the lobes. Br counteracted the effects of androgens and prolactin. In general, the influence of prolactin was more in the caudal lobe than cranial. The results are discussed in detail with available literature.

Animals↗
PubMed1993

Effects of p-nitrophenyl-beta-D-xylopyranoside (beta-D-xyloside) on the androgen-induced growth of the lateral prostate of the prepubertally castrated guinea pig.

The aim of this study was to examine the effects of beta-D-xyloside (XYL), a compound which interferes with stromal proteoglycan (PG) synthesis, on androgen induced growth of the lateral prostate (LP). Young male guinea pigs were castrated at 3 weeks of age and divided into three groups 6 weeks after castration. In group one, the animals were injected subcutaneously daily with 80 mg/kg of XYL, followed 3 days later by a daily dose of 10 mg/kg of dihydrotestosterone (DHT) for 2 more weeks. The second group served as control and received DHT only. In the third group, animals were treated first with XYL, like those in group one, and then followed by DHT alone for 2 weeks to check reversibility of the XYL effect. At the end of the experiment, the lateral prostate was removed and processed for morphological and cytochemical examination. The results showed that XYL inhibited the DHT stimulated growth of the lateral prostate. The fibroblasts showed a dilated granular endoplasmic reticulum filled with granular substances. In the interstitial spaces, there was a drastic increase in Cuprolinic Blue (CB) positive filaments and polygonal granules believed to be PGs or glycosaminoglycans (GAGs). Their number was much greater than the control. The distribution and density of the collagen fibers appeared similar to the control. The secretory alveoli were lined by epithelium with few secretory granules of low electron density and a larger number of clear vesicles. There was a slight reduction in glycoconjugate reactivities in the epithelial cells. The lectin binding patterns and the structural features were comparable between the control and recovery groups, indicating the XYL effects were reversible. The results suggest that stromal PG biosynthesis may play a role in epithelial function and an altered stromal matrix would hamper the effects of DHT on the target organ.

Animals↗
PubMed1993

Effects of cis-4-hydroxy-L-proline on the androgen-induced growth of the lateral prostate of the prepubertally castrated guinea pig.

The present study examined the effects of cis-4-hydroxy-L-proline (CHP), a proline analog, on the androgen-induced growth of the lateral prostate of prepubertally castrated guinea pigs. Prepubertal male guinea pigs were castrated at the age of 3 weeks and allowed to recover completely before subjection to an experimental regime to alter the stromal collagen synthesis by CHP. The animals were kept on a special proline-deficient diet (PDD) for a week before the subcutaneous injection of CHP (200 mg/kg/day) for 3 days, followed by a combined injection of CHP and dihydrotestosterone (DHT) (10 mg/kg/day) for 10 days. Control animals were injected with saline and DHT only. At the end of the experiment, the lateral prostate was removed and examined by 1) conventional transmission electron microscopy (TEM), 2) staining of proteoglycans (PGs) by Cuprolinic Blue (CB) using the critical electrolyte concentration (CEC) method, 3) carbohydrate and lectin histochemistry, and 4) electron microscopy (EM) lectin-gold labelling. The results showed that the wet weight of prostate from CHP-treated animals was significantly lower than the control and recovery groups. The epithelium was low columnar with an obvious increase in intercellular spaces and number of basal cells. The glandular cells showed little secretory activity with a decrease in number of granular endoplasmic reticulum (GER) profiles, secretory granules, and a small Golgi apparatus. The stroma was composed of stromal cells separated by large intercellular spaces with very sparse collagen fibrils, and a decrease in stromal PGs especially those PGs normally associated with collagen fibrils. CHP treatment also caused perturbation and disorganization in the epithelial basement membrane. The results suggested that stromal collagen is essential in mediating the response of glandular cells to DHT stimulation. Defective stromal collagens hamper the responsiveness of prostatic gland to androgen.

Animals↗
PubMed1999

Effects of photoperiod on salmon GnRH mRNA levels in brain of castrated underyearling precocious male masu salmon.

Previous studies have suggested that activation of salmon gonadotropin-releasing hormone (sGnRH)-producing neurons is induced by the combined effects of photoperiod and steroid hormones in underyearling males of the masu salmon, Oncorhynchus masou. The present study further assesses the effects of photoperiod and steroid hormones on sGnRH synthetic activity and examines the changes in sGnRH mRNA levels in the brains of castrated underyearling precocious male masu salmon by manipulating the photoperiod for 60 days from August through October. In castrated males in which plasma testosterone levels decreased to low levels, sGnRH mRNA levels in the preoptic area (POA) increased under a short photoperiod (8L-16D), whereas they remained at low levels under a long photoperiod (16L-8D) for a 2-month duration. In sham-operated males, sGnRH mRNA levels in the ventral telencephalon and those in the POA increased in October with testicular maturation even under a long photoperiod with a delay of 1 month compared with the short photoperiod group. These results suggest that preoptic sGnRH-producing neurons receive short photoperiodic signals and that either short photoperiod or steroid hormone secretion is required for the activation of sGnRH synthesis in underyearling precocious male masu salmon.

Animals↗
PubMed2001

Influence of estradiol on oxidative stress in the castrated rat uterus.

OBJECTIVE: We set out to study how the concentration of estradiol influences oxidative stress (malondialdehyde) and the superoxide dismutase and catalase antioxidant systems in the castrated female Wistar rat uterus. METHODS: We used 28 castrated female Wistar rats: 7 were left to evolve freely and the rest were divided into three groups of 7 animals receiving respective doses of 4, 8, and 16 microg/day of estradiol (E2) for 15 days. At the end of the study period, we determined the plasma concentrations of E2 and the concentrations of malondialdehyde (MDA) and superoxide dismutase and catalase activities in the uterus. RESULTS: There was a significant correlation (P < 0.000028) between the uterine malondialdehyde levels and the logarithm (base 10) of the plasma E2 concentrations and also between malondialdehyde and the uterine catalase activity (P < 0.002). The regression plane that best fitted the correlation among the three variables was MDA = 10.21 + 12.88 x Log [E2] - 0.49 x catalase activity. We found no significant relationships with the superoxide dismutase activity. CONCLUSIONS: There was a linear correlation between the base-10 logarithm of the estradiol plasma concentration and the phenomenon of uterine lipid peroxidation as measured by the MDA concentration in the uterus. This phenomenon was in part modulated by the inverse linear relationship between the antioxidant activity of the uterine catalase and the concentration of uterine MDA.

Animals↗
PubMed1993

Effects of testosterone propionate upon the sexual and aggressive behavior of adult male marmosets (Callithrix jacchus) castrated as neonates.

In New World monkeys of the family Callitrichidae (marmosets and tamarins), females frequently give birth to dizygotic twins. Twins share a placental circulation throughout fetal development and are hemopoietic chimeras. Despite this, there is no masculinization (freemartinism) in females which develop next to a male co-twin. It has been suggested that the organizing effects of testicular androgen upon sexual differentiation of the brain occur mainly during early postnatal development in male callitrichids, rather than in utero. However, this report demonstrates activation of masculine copulatory behavior by testosterone propionate (TP) administered to adult male marmosets (N = 8) which were castrated in infancy (between Days 1-7). Effects of neonatal castration upon aggressive behavior during pair tests with females (high frequencies of aggression) and intact adult males (low frequencies of aggression) were also reversed by TP treatment in adulthood. While early postnatal androgen secretion plays an important role in behavioral development in marmosets, it appears that a substantial degree of neural sexual differentiation occurs in utero in males of this callitrichid species.

Aggression↗
PubMed2001

Testosterone restoration of copulatory behavior correlates with medial preoptic dopamine release in castrated male rats.

The medial preoptic area (MPOA) is an important integrative site for male sexual behavior. We have reported an increase in dopamine (DA) release in the MPOA of male rats shortly before and during copulation. Postcastration loss of copulatory ability mirrored the loss of the precopulatory DA response to an estrous female. The present study investigated the time courses of restoration, rather than loss, of the MPOA DA response to a receptive female and of copulation in long-term castrates. Male rats were castrated and tested for loss of copulatory ability 21 days later. They then received 2, 5, or 10 daily subcutaneous injections of testosterone propionate (TP, 500 microg) or oil. Microdialysate samples were collected from the MPOA during baseline, exposure to a female behind a barrier, and copulation. Extracellular DA was measured using HPLC-EC. None of the six 2-day-TP-treated animals copulated, nor did they show elevated DA release in the MPOA in the presence of a receptive female. Five of the nine 5-day-TP-treated animals ejaculated; three intromitted without ejaculating; and one failed to copulate, with all but the noncopulating animal showing elevated DA release. All of the six 10-day-TP-treated animals copulated and also demonstrated an increase in MPOA DA. None of the oil controls copulated or showed an increase in DA release. Therefore, a consistent relationship between MPOA DA release during exposure to a receptive female and the subsequent ability of the male to copulate was observed.

Analysis of Variance↗
PubMedDate not supplied

Castration increases cell damage induced by porphyrins in the Harderian gland of male Syrian hamster. Necrosis and not apoptosis mediates the subsequent cell death.

It is known that the Harderian gland of male Syrian hamster synthesizes a much smaller amount of porphyrins than the gland of the female and that castration greatly increases this synthesis. We have studied in this experimental model the behavior of the different classes of secretory cells and their role in the synthesis of porphyrins, attempting to clarify the participation of these compounds in the cell damage leading to the formation of clear cells previously described in the gland of females. We have also investigated the mechanism underlying the death of these secretory cells after porphyrin accumulation (necrosis vs apoptosis). To achieve this, we have utilized the following techniques: (a) morphometrical; (b) ultrastructural; (c) biochemical (fluorescence spectrophotometry); and (d) molecular (DNA nick-end labeling in methacrylate sections and dot blot analysis). The glands from male hamsters (serving as control) present a very low rate of damaged cells that progressively rises after castration. This rise runs parallel to that of porphyrin synthesis, porphyrin deposits, and the decrease of Type II secretory cells. The damage and subsequent death of the secretory cells in the gland is produced by the deposit of porphyrins in the mitochondrial membrane. This porphyrin accumulation leads to a complete mitochondrial destruction that finally results in cell death and its secretion into the lumen. We finally conclude that this event is not a physiological cell death (apoptosis) but the consequence of the toxic accumulation of porphyrins (necrosis).

5-Aminolevulinate Synthetase↗
PubMed1990

Combined use of oligo(dt) and 28S cDNA probes for the quantitation of total mRNA in polyribosomes: application to the castration-induced atrophy of the rat prostate.

The castration-induced atrophy of the rat prostate was used as a model for the validation of a sensitive technique allowing the quantitation of total mRNA in polyribosomes. Electron micrographs of polyribosome samples showed a decrease in polyribosomes length 7 days after castration (GDX). Specificity of labeled oligo(dt) probe for poly(A) was demonstrated and the technique was successfully applied to demonstrate that GDX is associated with a decrease in poly(A) mRNA content of polyribosomes. Provided that normalization of the hybridization signal for mRNA is achieved with a rRNA cDNA probe, the assay therefore represents a suitable tool for further studies regarding the translational regulation of total and/or specific mRNAs.

Animals↗
PubMedDate not supplied

Effect of neonatal castration on capacity of male rat brain septal complex neurons for binding sex steroids.

The effect of neonatal castration on neuron capacity for binding septal dorsal, lateral, and medial nuclei, Brock's diagonal fold nucleus, and terminal streak bed nucleus of radio-labeled sex steroids (3H-testosterone and 3H-estradiol) has been studied. Neonatal castration performed on the first day of male postnatal life increased the capacity of brain septal complex neurons for uptake of sex steroids, mainly 3H-testosterone. The strategic position of the septal complex in the brain and the presence of neurons actively taking up sex steroids indicated the important role of this structure of the limbic system of the brain in the formation of neural mechanisms in the regulation of sexual functions in male rats.

Animals↗
PubMed1988

Human hepatocellular carcinoma tumor xenografts. Their androgen-receptor status and growth responses to castration.

Castrated or sham-operated male athymic mice were inoculated with cells from the human hepatocellular carcinoma cell line PLC/PRF/5. There were no significant differences between the two groups with respect to the number of animals developing tumors, the time to tumor development, or the subsequent rate of increase in either tumor base area or mouse serum alpha-fetoprotein concentration. Androgen receptors were assayed in nuclei obtained from three separate liver cancer cell lines and from normal adult human liver. Similar concentrations, ranging from 235 to 550 fmol/mg DNA, of nuclear androgen receptors were detected in all tissues. Low percentages of androgen receptors were retained on DNA-cellulose. Although the presence of receptors implies the potential for metabolic effects of androgens in normal and malignant liver, our in vivo studies suggest that castration does not alter significantly the growth of liver cancer xenografts in athymic mice.

Animals↗
PubMed1997

Gonadotrophin and prolactin secretion in castrated male sheep following subcutaneous or intracranial treatment with testicular hormones.

Interactions between testosterone, estradiol, and inhibin in the control of gonadotrophin secretion in males are poorly understood. Castrated rams were treated with steroid-free bovine follicular fluid (bFF), testosterone, or estradiol and for 7 d (2 x 2 x 2 factorial design). Given independently, none of the exogenous hormones affected follicle-stimulating hormone (FSH) concentrations, but the combination of one or both steroids with bFF reduced FSH secretion. Testosterone and estradiol reduced luteinizing hormone (LH) pulse frequency (there was no synergism), and bFF had no effect. Plasma prolactin concentrations were not affected by any treatment. To locate the central sites of steroid action, castrated rams were bilaterally implanted in the preoptic area (POA), ventromedial nucleus (VMH), or arcuate nucleus (ARC). These implants did not affect FSH or prolactin concentrations, or LH pulse amplitude. The frequency of the LH pulses was not affected by testosterone in any site. Estradiol located in the ARC, but not the POA or VMH, decreased LH pulse frequency. In summary, FSH secretion is controlled by synergistic interactions between inhibin and estradiol or testosterone, whereas GnRH/LH pulse frequency is controlled by testicular steroids. Estradiol acts partly, at least, in the ARC, but the central site of action, testosterone remains unknown.

Animals↗