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PubMed1990

[Chemical castration using a depot LHRH-agonist as a palliative therapy concept in prostatic carcinoma--clinical, endocrinological and experimental studies].

79 patients with locally advanced and/or metastatic prostate cancer were treated by means of a biodegradeable depot formulation of the luteinizing hormone releasing hormone analogue Goserelin (Zoladex). All patients received 3.6 mg depot Goserelin (Zoladex 3.6 mg implantate) subcutaneously into the anterior abdominal wall at 4 weekly intervals. The average time of observation was 24.2 months. The best objective response rate was found in 62%. Serum testosterone levels initially increased after the first depot injection and then decreased ultimately to castrate range (less than 0.6 ng/ml) between day 15 and day 27 (median 21) in the majority of patients. Castrate testosterone levels were still found 48 months after the start of treatment with depot Goserelin. 6 months after institution of treatment in 66.7% of cases evident signs of histological regression were found in the primary tumour tissue. Adenocarcinoma presented with a highly significantly better response pattern than anaplastic carcinoma. In animal experiments a single dose of 1 mg depot Goserelin was administered to adult male rats and the effect on serum testosterone levels and target organs (testes and ventral prostate) were investigated. Mean testosterone levels (mean = 0.31 ng/ml) decreased to castrate range (less than 0.3 ng/ml). 4 weeks after depot injection weight of the testes and prostate weight were significantly reduced. However 8 weeks after administration of 1 mg depot Goserelin there was no significant between the control group and the treated group. We conclude that the depot formulation of Goserelin (Zoladex) is effective, simple, practicable and safe in the treatment of advanced prostatic cancer. Current clinical studies are confirming the importance of reversible medical castration by LHRH agonists before radical prostatectomy.

Adenocarcinoma↗
PubMed1990

Development of the median eminence in the male mouse. Karyometric effect of neonatal and prepuberal castration.

We have studied the karyometric development of the ependymocytes of the median eminence and ependyma adjacent of the arcuate nucleus in a control group of male albino mice from the 5th to the 160th postnatal day, and in other two experimental groups of animals that were castrated at two different days: the first and the 20th day of life. We have found differences in the spontaneous development of both ependymocytes showing the median eminence ependyma a more closely relationship to changes of gonadal hormone levels around puberty. In both zones, the response of the ependymocytes to neonatal castration was clearly more significative than that obtained after prepuberal castration, with lower values in the castrated animals than in the control mice. We suggest that this could be related to nervous and hormonal mechanisms.

Animals↗
PubMed1985

Castration increases luteinizing hormone subunit messenger RNA levels in male rat pituitaries.

The effect of castration on pituitary common alpha and LH-beta subunit mRNA levels was examined in adult male rats in a dot-blot hybridization assay using cytosolic mRNA and 32P labelled plasmids containing cDNA encoding sequences of the subunits. Orchidectomy increased alpha subunit mRNA levels threefold by day 4 with no further rise at 2 months. The LH-beta subunit mRNA levels increased by threefold at 2 months. Serum LH levels increased by up to fortyfold (2 months). Pituitary LH content increased by fourfold at 2 months, though was reduced at 4 days after castration. These results suggest that transcription of the alpha and LH-beta genes are similarly regulated after castration. However the greater magnitude of serum LH increase after castration than that of both LH subunit mRNA levels and the bidirectional changes in pituitary LH content implies additional translational/post-translational control of gonadotrophin biosynthesis by gonadal hormones.

Animals↗
PubMed1989

[Qualitative and quantitative changes of luteinizing hormone (LH) in the pituitary glands in female Japanese monkeys (Macaca fuscata) during the menstrual cycle and after castration].

The present study was designed to investigate qualitative and quantitative changes in luteinizing hormone (LH) in the pituitary glands of female Japanese monkeys (Macaca fuscata) during the menstrual cycle and after castration. The pituitary glands were removed from 10 intact cycling Japanese monkeys and 3 castrated ones: The former sacrificed in the early, late follicular phase, and mid luteal phase, and the latter 8 weeks after castration. All 13 pituitary glands were fractionated by isoelectrofocusing (IEF). The mid cycle peaks of estradiol (E2) and bioactive LH occurred simultaneously in 11 out of 13 monkeys. No animals showed luteal phase peaks in the plasma E2 concentration. Bioactive LH content (IU/mg wet weight) in the pituitary gland was significantly correlated with plasma E2 levels in the cycling monkeys (R2 = 0.974) and it was the highest in monkeys in the late follicular phase. Bioactive LH in the pituitary gland was separated into 6 distinct species in terms of pI values by IEF; A(9.31 +/- 0.19), B(8.88 +/- 0.17), C(8.36 +/- 0.17), D(7.92 +/- 0.18), E(7.32 +/- 0.16) and F(acidic LH). Among alkaline LH species, the most predominant ones were Fractions B, C and D in the early follicular phase, Fraction A followed by B in the late follicular phase and Fraction B followed by C in the mid luteal phase. The neutral and acidic LH (Fraction E and F) was increased more in the early follicular phase and in the castrates. In conclusion, LH species separated by IEF may correspond to the stage of molecular maturation of pituitary LH.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Treatment of castration-induced osteoporosis by a capacitively coupled electrical signal in rat vertebrae.

Castrated male Sprague Dawley rats were subjected to various capacitively coupled electrical fields for six and eight weeks at two and 4.5 months after castration, respectively, with pairs of electrodes that were located paraspinally on the surface of the skin dorsally at the eleventh thoracic and fourth lumbar levels. When the animals were killed, dry and ash weights per unit of volume (apparent density), elastic modulus, ultimate stress, work to failure, trabecular area fraction, and mean trabecular width were determined for selected vertebrae. The results indicated that a sixty-kilohertz, 100-microampere signal (a calculated current density of five microamperes root-mean-square per square centimeter and a field of twelve millivolts root-mean-square per centimeter) significantly reversed the castration-induced osteoporosis in the lumbar vertebrae and restored bone mass per unit of volume in rats that had been stimulated for eight weeks after castration.

Animals↗
PubMed1987

The influence of castration and antiandrogenic treatment on the sensitivity of rat seminal vesicle to sympathomimetic drugs.

The sensitivity of seminal vesicles to sympathomimetic drugs and the plasma concentrations of testosterone and gonadotropins (LH and FSH) were examined in adult male albino rats divided into three groups: normal, castrated and Androcur-treated. Dose-effect curves for adrenaline and noradrenaline were obtained in the presence and absence of cocaine or corticosterone and the parameter pD2 was determined. Castration and Androcur treatment induced a decrease in seminal vesicle sensitivity to drugs (shifting of dose-effect curves to the right, decreased pD2). Cocaine shifted the adrenaline and noradrenaline dose-effect curves to the left in three groups. Corticosterone did not modify the dose-effect curves of adrenaline and noradrenaline. Plasma testosterone levels were decreased by castration and Androcur-treatment although the LH and FSH concentrations were markedly altered by castration but were unaltered by the antiandrogenic treatment. The results suggest that the androgen may play an important role in the sensitivity of the seminal vesicle to sympathomimetic drugs through control of the neuronal uptake of catecholamines.

Androgen Antagonists↗
PubMedDate not supplied

Ultrastructural changes in the principal cells of epididymis of adult rhesus monkey (Macaca mulatta) after castration and androgen replacement therapy.

The epididymal epithelium from adult castrated and androgen supplemented, castrated rhesus monkeys was examined with transmission electron microscope. Ninety days after bilateral castration the tubular diameter of all the regions of the epididymis, viz. the initial segment, caput, corpus and cauda portions of epididymis was reduced and was accompanied by a drop in cell size. There was a marked decrease in the number and size of microvilli on the luminal surface. The invaginations of apical membrane into the cell cytoplasm became less prominent. There was a reduction in the amount of smooth and rough endoplasmic reticulum, and Golgi complex. Mitochondria accumulated in the apical cytoplasm. Several vacuoles often associated with lipofuscin pigment granules were common in the cytoplasm. These findings suggest a reduction in both the absorptive and secretory functions of the principal cells. Following androgen replacement therapy for 30 days in monkeys that were castrated 60 days earlier there was a recovery of structural features in the epithelium to near normal state.

Animals↗
PubMed1994

[CO2/O2 anesthesia for the castration of male piglets (preliminary results)].

Introduction of anaesthesia with CO2/O2 (60% to 40%) is possible within 90 and 120 seconds. There are moderate to excessive excitations occurring as part of state II of anaesthesia. Anaesthesia (during castration) in CO2/O2-atmosphere produces excellent analgesia and relaxation. The duration of castration surgery is much shorter under CO2-anaesthesia than without anaesthesia. Blood cortisol levels are significantly higher after castration without CO2-anaesthesia. About 5 minutes after CO2/O2-anaesthesia and castration surgery, piglets are already awake and standing.

Anesthesia, Inhalation↗
PubMed1993

Effects of prolactin and androgens on enzymes of carbohydrate metabolism in seminal vesicles of castrated mature bonnet monkeys, Macaca radiata.

Effects of prolactin(Prl), bromocriptine(Br), testosterone propionate (TP), dihydrotestosterone (DHT) and combinations of these androgens with Prl/Br on the maximum catalytic capacities of seminal vesicular enzymes involved in the glycolytic and pentose phosphate pathways in castrated mature monkeys were studied. Castration decreased the activities of all of the enzymes studied such as hexokinase(HK), 6-phosphofructokinase(PFK), glyceraldehyde-3-phosphate dehydrogenase(G3PD), pyruvate kinase(PK), glucose 6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase(6PGD) in the seminal vesicles. Prl restored the activities of all of the enzymes to their normal values except G3PD. TP/DHT maintained all the enzyme activities at the normal tissue intact level. Prl given along with androgens further enhanced the androgen action with regard to all the enzymes activities except G3PD. Br decreased all of the enzymes but Br with androgens maintained all the enzyme activities at the normal level. Castration decreased significantly serum T/DHT titres but Prl did not alter Prl levels. Prl+TP/DHT elevated Prl levels. Br alone decreased serum Prl, T and DHT titres, but Br+TP/DHT decreased only Prl, elevated T and maintained DHT levels. These results suggest that Prl has a direct as well as a synergistic action with androgens on the activities of the enzymes of glycolysis and pentose phosphate pathways in the seminal vesicles of castrated monkeys.

Androgens↗
PubMed1995

Morphometric evaluation of rat liver after castration: effects of testosterone.

In men and animals subject to orchiectomy, varying degrees of hypotrophy have often been observed, even involving non-reproductive organs. Liver hypotrophy appears particularly interesting in view of the metabolic alterations that could possibly ensue. We have applied the morphometric approach to the study of this kind of hypotrophy in castrated rats and in animals receiving a substitutive, testosterone-based treatment after castration. The morphometric model adopted was built on the basis of an interactive approach, using an image analyser (IBAS) with specially-designed software, and consists of number and size, as well as surface and volume fractions, of hepatocytes, their nuclei, cytoplasm, and the relevant relation to the sinusoidal bed. The effects of castration were revealed by a reduction of the mean volume of hepatocytes, associated with a reduction of the sinusoidal bed. Such reduction is correspondingly associated with an increase of the extraparenchymal components (endothelia, Glisson capsule). In the testosterone-treated group, while no appreciable symptoms of retrieval were yet observable in the volume of hepatocytes, the sinusoidal bed was instead superimposable onto the control group data as far as both volume and blood/hepatocyte interface were concerned. In the castrated animals the number of hepatocytes per mm3 was found to be increased. The group of testosterone-administered rats also showed a high level for this parameter which, associated with the spread of the capillary bed, could be compatible with a picture of precocious hyperplastic response to the therapy. The correlation between the available morphometric data and the biochemical results which are being currently sought will further clarify the meaning of this phenomenon.

Animals↗
PubMed1996

Intrahypothalamic implantation of progesterone in castrated male whiptail lizards (Cnemidophorus inornatus) elicits courtship and copulatory behavior and affects androgen receptor- and progesterone receptor-mRNA expression in the brain.

A primary tenet of behavioral neuroendocrinology is that gonadal steroid hormones act on limbic nuclei to activate mating behavior in vertebrates. Traditionally, research has focused on the regulation of male-typical sexual behavior by testicular androgens and female-typical sexual behavior by ovarian estrogen and progesterone. Indeed, progesterone generally is regarded as an antiandrogen, acting centrally to inhibit sexual behavior in males. However, experiments with lizards, and more recently with rats, have challenged this paradigm. For example, exogenous progesterone induces mating behavior in some, but not all, castrated male whiptail lizards. The present study determined that implantation of progesterone into the anterior hypothalamus preoptic area of castrated, progesterone-sensitive males completely restored sexual behavior but failed to elicit sexual activity in castrated, progesterone-insensitive males. Further, androgen receptor -and progesterone receptor-mRNA expression in specific brain regions was significantly different in progesterone-sensitive versus progesterone-insensitive animals. Progesterone-sensitive males showed significantly higher relative abundance of androgen receptor-mRNA in the preoptic area, amygdala, and lateral septum, as compared with progesterone-insensitive animals receiving the same treatment. In contrast, progesterone receptor-mRNA abundance was lower in preoptic area of progesterone-sensitive males than in progesterone-insensitive males. No differences were found in the baseline abundance of androgen receptor-or progesterone receptor-mRNA in these nuclei between control groups of progesterone-sensitive and progesterone-insensitive males who were castrated but not implanted. This suggests that progesterone differentially regulates its own receptor as well as androgen receptor in areas of the brain involved in the control of sexual behavior of males and that the nature of this regulation shows individual variability.

Amygdala↗
PubMed1996

Expression of G1 cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors in androgen-induced prostate proliferation in castrated rats.

Androgen induces prostate cell proliferation in the castrated rat. We hypothesized that G1 cyclins, cyclin-dependent kinases (cdk), and cdk inhibitors mediate this cellular response to mitogenic signals. In this study, induction of cyclins D1, D2, D3, E, and cdks 2, 4, and 6 expression was observed at various time points during testosterone replacement in the ventral prostate of castrated rats. The induction followed prostate epithelium proliferation, which peaked at 48 h and decreased at 120 h during the treatment. The study of cyclin/cdk complex formation revealed that more cyclin D1/cdk4 and cyclin D1/cdk6 complexes were formed at 48 h than at 120 h of treatment, but cyclin D1/cdk2 complexes remained the same. Furthermore, both hyperphosphorylated and hypophosphorylated forms of Rb were detected at 48 h, but only the hypophosphorylated form was detected at 120 h of treatment. p21Cip1, which was very abundant in the ventral prostate of castrated and intact rats, was not detected when the prostate started proliferation and increased gradually as proliferation decreased during the androgen treatment. Meanwhile, p27Kip1 dramatically increased after androgen treatment, and the induction levels were less at the peak of prostate proliferation and higher when proliferation was low. The results presented here suggest that expression of G1 cyclins and their related kinases and kinase inhibitors are well regulated after androgen replacement in the ventral prostate of castrated rats. The cooperation between these cell cycle regulators leads to a well-controlled prostate regeneration.

Animals↗
PubMed1996

Immunolocalization of glutathione-peroxidase (GSH-PO) in the rat ventral prostate: effects of castration and administration of testosterone.

Immunolocalization of glutathione-peroxidase (GSH-PO) in the rat ventral prostate was studied in the presence and absence of androgen. Male Sprague-Dawley rats were divided into four experimental groups. Group 1 consisted of intact controls. In group 2, rats were sacrificed two days after castration. In groups 3 and 4, rats were injected subcutaneously with 1 mg of testosterone-propionate daily, for three or seven days, beginning two days after castration. The intensity of GSH-PO staining in the glandular epithelial cells of the ventral prostate decreased after castration, but recovered following treatment with testosterone. Furthermore, the prostatic GSH-PO mRNA levels were diminished in the castrated rat ventral prostate but greatly increased by testosterone. These findings strongly suggest that the expression of GSH-PO in the glandular epithelial cells of the rat ventral prostate is dependent on testosterone.

Animals↗
PubMed1998

[Surgical or medical castration with LH-RH analogue for prostatic cancer].

Since the discovery by Huggins and Hodges that androgen deprivation therapy is effective for prostatic cancer, surgical castration or the administration of exogenous estrogen has been the mainstay of treatment for advanced prostatic cancer. However, surgical castration is refused by some patients because of psychological impact and estrogen therapy is reported to be associated with significant morbidity and mortality. The chronic administration of superactive analogue of LHRH has been shown to suppress markedly gonadal steroidogenesis. Medical castration with LHRH analogue has been demonstrated to be safe and effective in patients with advanced prostatic cancer. But the traditional surgical castration still remains as another powerful option, because it is more excellent in the points of compliance and cost-benefit than a monthly injection of expensive LH-RH analogue.

Antineoplastic Agents, Hormonal↗
PubMed1999

The effects of castration on relaxation of rat corpus cavernosum smooth muscle in vitro.

PURPOSE: This study was conducted to investigate the role of testosterone (T) in regulating the relaxation of isolated rat corpus cavernosum strips in vitro. MATERIALS AND METHODS: Male rats were divided into treatment groups of intact, castrate, and castrate with T replacement. Norepinephrine (NE) was added to contract each of the tissue strips. Next, sodium nitroprusside (SNP), experiment I, or 8-Br-cGMP, experiment II, was added to relax the cavernosum tissue. Percent relaxations were recorded for each treatment group at each dose level. RESULTS: SNP was added to the NE-contracted tissues in doses of 10(-4) and 10(-3) M. In this experiment, castration significantly reduced tissue responsiveness to SNP and T replacement restored the response to intact levels. In the second experiment 8-Br-cGMP was added to the NE-contracted tissues in doses of 10(-5) and 10(-4) M. 8-Br-cGMP 10(-4) M was significantly less effective in relaxing tissue from castrate animals as compared with intact controls. Again, T treatment restored the response to intact levels. CONCLUSIONS: Our results show a clear role of T in regulating the ability of corpus cavernosum tissue to relax when treated with SNP or 8-Br-cGMP in vitro. In addition, the data suggests that T regulates sites distal to the formation of cGMP in the relaxation pathway.

Animals↗
PubMed2026

Establishment and Characterization of Patient-Derived Xenograft Organoids for Personalized Treatment of Castration-Resistant Prostate Cancer.

BACKGROUND: Basic research on castration-resistant prostate cancer (CRPC) is limited by the lack of clinically relevant models. This study aimed to establish patient-derived xenografts (PDX) and PDX-derived organoids from clinical CRPC specimens to develop a bidirectional experimental platform for in vivo xenografts and ex vivo organoids. METHODS: We established a new PDX library (KUCaP PDX series) using CRPC clinical specimens and derived prostate cancer organoids. Comprehensive biological characterization of clinical specimens, PDXs, PDX-derived organoids, and organoid-derived xenografts (ODXs) was performed to confirm the preservation of the original tumor features. Using our PDX library, we conducted genetic engineering and drug testing to explore novel therapeutic approaches. RESULTS: PDX-derived organoids were successfully established from all eight KUCaP PDX lines (100%). Four of the eight lines (50%) were maintained during the long-term culture experiments for over ten passages. Key features observed in the original clinical specimens, including genetic alterations and castration responsiveness, were maintained across the PDX, PDX-derived organoid, and ODX models. RNA sequencing revealed that transcriptomic profiles were consistently maintained across clinical specimens, PDXs, PDX-derived organoids, and ODXs. One PDX and organoid (KUCaP19) which exhibited a high homologous recombination deficiency (HRD) score, without any pathogenic homologous recombination repair (HRR) gene alterations, showed sensitivity to a poly ADP-ribose polymerase (PARP) inhibitor. In contrast, KUCaP12, which had no HRR alterations and a low HRD score, did not respond to PARP inhibition. CONCLUSIONS: We developed the KUCaP library as a novel experimental platform for CRPC research by integrating clinical specimens with PDX, organoid, and ODX models along with their genomic and transcriptomic data. These models largely retained the genetic profiles and responses to castration observed in the original tumors. The bidirectional use of personalized PDX and organoids will facilitate the elucidation of the molecular mechanisms of CRPC.

Male↗
PubMed2000

Inhibition of progression to androgen-independence by combined adjuvant treatment with antisense BCL-XL and antisense Bcl-2 oligonucleotides plus taxol after castration in the Shionogi tumor model.

We have reported that antisense Bcl-2 oligodeoxynucleotide (ODN) delays progression to androgen independence in the androgen-dependent (AD) mouse Shionogi tumor model. Here, we characterize changes in bcl-xL, another important anti-apoptotic gene, and test the efficacy of adjuvant antisense Bcl-xL ODN therapy either alone or in combination with antisense Bcl-2 ODN and chemotherapy after castration in the Shionogi tumor model. Bcl-xL mRNA levels increased up to 3-fold postcastration and remained 1. 5-fold higher in androgen-independent (AI) recurrent tumors compared with AD tumors before castration. Treatment of Shionogi cells with antisense Bcl-xL ODN inhibited Bcl-xL expression in a dose-dependent and sequence-specific manner. Systemic administration of antisense Bcl-xL ODN in mice bearing Shionogi tumors after castration delayed emergence of AI recurrent tumors. We then examined whether combined adjuvant antisense Bcl-xL and/or Bcl-2 ODNs plus taxol (paclitaxel) therapy further delays time to AI progression. Combined treatment of Shionogi cells with antisense Bcl-xL and Bcl-2 ODNs significantly enhanced taxol chemosensitivity compared with either agent alone, reducing the IC(50) of taxol by more than 1 log. Apoptotic DNA laddering and cleavage of poly(ADP-ribose) polymerase were more substantial after treatment with combined antisense Bcl-2 and Bcl-xL ODNs plus taxol than that with either 2 agents. Adjuvant administration of antisense Bcl-xL and Bcl-2 ODNs plus micellar taxol resulted in a significantly delayed time to AI recurrence compared with administration of either 2 agents. Our findings suggest that Bcl-xL represents a suitable molecular target for antisense ODN strategy and illustrate the potential additive effects of multi-target pharmacology for cancer therapy.

Androgens↗
PubMed1997

Effects of castration on thiol status in rat spermatozoa and epididymal fluid.

Mammalian spermatozoa gain their fertilizing ability as they mature in the epididymis, a process which is accompanied by oxidation of sperm protein thiols. Since sperm maturation is dependent upon normal androgenic support to the epididymis, the present work was designed to study the effects of castration on thiol status. Spermatozoa and epididymal fluid were isolated from the epididymides of male rats 5 days after castration or after 11 daily injections of the antiandrogen, cyproterone acetate. Spermatozoa and epididymal fluid were labeled with the fluorescent thiol labeling agent monobromobimane. Intact spermatozoa were evaluated by fluorescence microscopy, protein thiols were analyzed by electrophoresis, and fertilizing ability was examined after insemination of sperm suspension into the uterine horns of immature superovulated female rats. We found that both treatments resulted in an increase in cauda sperm thiols as shown by increased fluorescence in the intact spermatozoa. Protamines and nonbasic proteins were found to have increased levels of reactive thiols. The protein profiles of epididymal fluid from castrated rats were different from those of the controls, and the fluorescence patterns corresponded to the protein profiles. Our results indicate that testosterone withdrawal leads to inhibition of sperm thiol oxidation.

Androgen Antagonists↗