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Apomorphine-and oxytocin-induced penile erection and yawning in intact and castrated male rats: effect of sexual steroids.

The effect of apomorphine (80 micrograms/kg s.c.) and oxytocin (30 ng i.c.v.) on penile erection and yawning was studied in intact and castrated male rats. In castrated rats both apomorphine and oxytocin responses were abolished. In these animals, testosterone (100 microgramS/kg s.c. once a day for 3 days), restored penile erection while estradiol benzoate (10 micrograms/kg s.c. once a day for 3 days) restored yawning induced by both compounds. 5-Dihydrotestosterone (DHT) or progesterone (each at a dose of 100 micrograms/kg s.c. once a day for 3 days) were ineffective. Given together, estradiol benzoate and DHT partially restored apomorphine- and oxytocin-induced yawning and penile erection, whereas estradiol benzoate and progesterone restored only yawning. Estradiol benzoate-induced recovery of yawning was prevented by the antiestrogen tamoxifen (1 mg/kg s.c. once a day for 3 days). In intact rats, progesterone increased and estradiol benzoate decreased apomorphine- and oxytocin-induced yawning without modifying penile erection, although oxytocin-induced yawning was prevented much less by estradiol benzoate than that induced by apomorphine. Testosterone or DHT were ineffective on both responses. Estradiol benzoate inhibition of apomorphine- and oxytocin-induced yawning was prevented by tamoxifen, which per se failed to modify apomorphine and oxytocin responses, as well as by testosterone or progesterone. The present results suggest that apomorphine- and oxytocin-induced penile erection and yawning are endocrine-dependent and differentially modulated by sexual steroids, suggesting that the mechanisms controlling the two behaviors are different even though they are often associated.

Animals↗

Castration cells in rat adenohypophysis after long-term alcohol consumption.

Histological and ultrastructural changes of hypophyseal gonadotropic cells of rats which received a 15% solution of ethyl alcohol for 6 months were studied. Light microscopy revealed hyperplasia and hypertrophy of these cells; some contained a vacuole of varying size. Ultrastructural analysis showed that this vacuole originated from, and anastomosed with, dilated cisternae of the granulated endoplasmic reticulum. Vacuolated cells in the pituitary of alcoholized rats were identical with cells observed after surgical or chemical castration. The development of these alcohol-induced castration cells is achieved in four stages. The first stage was characterized by beginning hydropic degeneration and other still reversible alterations. Cells in the second and third stages seemed already irreversibly on their way to decay. The fourth stage was represented by typical signet-ring cells. Our results offer a morphological basis to the adoption of a biphasic effect of alcohol on gonadotropic secretion.

Alcohol Drinking↗

Influence of testicular secretions on differentiation in the rat epididymis: ultrastructural studies after castration, efferent duct ligation and cryptorchidism.

The differentiation of the rat epididymis was studied in prepubertal castrated, ligated or cryptorchid rats, in order to assess the influences of blood-borne and luminal androgens. The principal cells showed partial differentiation: decrease in cell height, decreased numbers of cytoplasmic organelles implicated in the elaboration phenomena (Golgi apparatus, smooth endoplasmic reticulum), whereas the organelles implicated in the absorptive function remained relatively intact. The lamina densa of the basement membrane underlying the epithelium was irregular, thicker than normal and followed the irregular outline of the basal parts of the epithelial cells. These changes were evident in castrated rats, to a lesser degree in ligated and cryptorchid rats, and were more prominent in the initial part of the duct. On the other hand, the narrow cells and the clear cells followed a normal differentiation pattern in the experimental rats, suggesting that a differential androgen dependence exists among the various type of epididymal cells.

Androgens↗

Benign prostatic hyperplasia treated by castration or the LH-RH analogue buserelin: a report on 6 cases.

This article presents the clinical data of 5 patients treated by castration and 1 patient treated with an LH-RH analogue to relieve chronic urinary retention due to benign prostatic hyperplasia (BPH). Besides the clinical data related to prostatism, prostatic volume was studied in 4 of the 5 patients by means of transrectal ultrasonography. All 5 patients showed a marked decrease of prostatic volume, which averaged 31.4% (range 19-55%) after 2-3 months. This correlated well with a relief of urinary obstruction. In all 5 patients, the indwelling catheters could be removed, symptoms decreased or disappeared and all 5 patients became free of residual urine. LH-RH analogues, because of the reversibility of their effect, may be more acceptable for the treatment of BPH than castration. At this moment however, it remains unknown whether prostatic volume will increase again after cessation of androgen withdrawal.

Aged↗

Relative potency of testosterone and dihydrotestosterone in preventing atrophy and apoptosis in the prostate of the castrated rat.

Although dihydrotestosterone (DHT) is the principal androgen in the prostate, testosterone can also act as an androgen in this tissue. To determine the relative potencies of testosterone and DHT in preventing prostate regression, castrated rats were implanted for 4 d with varying doses of testosterone in the presence or absence of the 5alpha-reductase inhibitor finasteride. In the absence of finasteride, testosterone in the prostate is converted to DHT, creating an intraprostatic DHT dose response. In the presence of finasteride, this conversion is blocked, and an intraprostatic testosterone dose response is achieved. DHT was 2.4 times more potent than testosterone at maintaining normal prostate weight and duct lumen mass, a measure of epithelial cell function. The two androgens were equipotent at preventing DNA fragementation and expression of testosterone-repressed prostate message, two measures of apoptosis (cell death). The intraprostatic testosterone concentration that results from finasteride treatment in rats is sufficient to inhibit apoptosis but will not maintain normal epithelial cell activity. In conclusion, whereas DHT is more potent than testosterone at stimulating prostate epithelial cell function as measured by ductal mass, the two androgens are equipotent at preventing prostate cell death after castration. These results explain why finasteride causes prostate involution in the rat with minimal evidence of prostate cell death.

Animals↗

Medical castration with zoladex: a conservative approach to premenopausal breast cancer.

For almost a century surgical castration represented the initial standard therapy for metastatic breast cancer in premenopausal women with hormone dependent tumors. Today the suppression of ovarian function can also be obtained by the administration of supraphysiologic doses of luteinizing hormone releasing hormone (LHRH) agonists. From April 1987 to February 1989, 23 premenopausal patients with advanced breast cancer (median age 39 years, range 28-52, ER positive 20, unknown 3; prior chemotherapy 17) were treated with the LHRH agonist goserelin depot (Zoladex) at the dose of 3.6 mg. every 4 weeks. Twenty-two patients were evaluable. Serum levels of 17 beta estradiol, progesterone, FSH and LH were suppressed by goserelin and fell to postmenopausal values within 8 weeks of therapy in 77% of cases. Complete response (CR) plus partial response (PR) was documented in 7 of 22 (32%) and occurred in all major sites of disease. Five patients achieved CR (soft tissue 3, viscera 2). Response rate was higher in patients not previously treated with chemotherapy (4/6). In the present series, all responses were seen in women greater than 35 years old, regularly menstruating at the start of treatment. Time to progression for the entire case series was 22 weeks and for responders 64 weeks. Oophorectomy was performed after disease progression in four patients without success. Goserelin was well tolerated. Local cutaneous dyschromia occurred in 45% and hot flushes in 82%. Treatment efficacy of goserelin is comparable to that of oophorectomy, without the psychological trauma and the morbidity related to surgical castration.

Breast Neoplasms↗

Circannual variations in plasma luteinizing hormone levels in castrated male European starlings (Sturnus vulgaris).

Intact and castrated male European starlings were held for about 2 years in a constant 12-hr photoperiod and constant temperature conditions. At 1- to 2-month intervals, testicular width was measured by laparotomy, and blood samples were taken for analysis of plasma luteinizing hormone (LH). Most of the control birds went through at least one circannual cycle of testicular width and plasma LH concentration. In the castrates, a similar proportion of birds went through circannual LH cycles with periods indistinguishable from those of the controls. It is concluded that the testes and their hormones are not essential components of the mechanism that generates circannual gonadal cycles in male European starlings.

Animals↗

Changes in PACAP levels in the central nervous system after ovariectomy and castration.

The aim of the present article was to investigate the influence of gonadectomy on pituitary adenylate cyclase-activating polypeptide (PACAP) levels in different brain areas. In males, there seems to be an inverse relationship between gonadotropins and PACAP in the brain in the acute phase of castration: PACAP levels decreased in almost all brain areas examined within the first week after castration. In females, such pattern was observed in the hypothalamus, brain stem, and temporal cortex. In the pituitary, levels decreased only on the first day after ovariectomy, and later, as in the thalamus, increases were observed. Although the pattern of change showed gender differences, our results provide further evidence that levels of gonadotropins and possibly gonadotropin-releasing hormone influence PACAP levels and that PACAP is involved in the regulation of gonadal functions.

Animals↗

Comparative study of the effects of PACAP in young, aging, and castrated males in a rat model of Parkinson's disease.

We have previously shown that PACAP ameliorates the neurological symptoms and reduces the dopaminergic cell loss in young male rats, in a 6-hydroxydopamine (6-OHDA)-induced lesion of the substantia nigra, a model of Parkinson's disease. In the present study, we compared the effects of PACAP in young, aging, and castrated males. Our results show that PACAP significantly reduced the dopaminergic cell loss in young and aging males. In castrated males, 6-OHDA did not induce such a severe cell loss, and it was not altered by PACAP. However, PACAP effectively ameliorated behavioral symptoms in all groups, with a degree of recovery depending on age and endocrine status.

Aging↗

Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration.

PURPOSE: To develop a pretreatment prognostic model for survival of patients with progressive metastatic prostate cancer after castration using parameters that are measured during routine clinical management. PATIENTS AND METHODS: Pretreatment clinical and biochemical determinants from 409 patients enrolled onto 19 consecutive therapeutic protocols from June 1989 through January 2000 were evaluated. The factors selected were age, Karnofsky performance status (KPS), hemoglobin (HGB), prostate-specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALK), and albumin. These factors were combined in an accelerated failure time regression model to produce a nomogram to predict median, 1-year, and 2-year survival. The nomogram was validated internally and externally using data from a multicenter randomized trial of suramin plus hydrocortisone versus hydrocortisone alone. RESULTS: The median survival of the entire group was 15.8 months (range, 0.9 to 77.8 months); 87% have died. In multivariable analysis, KPS, HGB, ALK, albumin, and LDH were significantly associated with survival (P <.05), whereas age and PSA were not. All seven factors were included in the nomogram. When applied to the external validation data set, the nomogram achieved a concordance index of 0.67. Calibration plots suggested that the nomogram was well calibrated for all predictions. CONCLUSION: A nomogram derived from pretreatment parameters that are measured on a routine basis was constructed. It can be used to predict the median, 1-year, and 2-year survival of patients with progressive castrate metastatic disease with reasonable accuracy. The information is useful to assess prognosis, guide treatment selection, and design clinical trials.

Adult↗

Suppressive effect of prostaglandin (PG)D2 on pulsatile luteinizing hormone release in conscious castrated rats.

The effect of intraventricular administration of prostaglandin (PG)D2 on pulsatile LH release was studied in castrated conscious rats. The administration of 5 micrograms of PGD2 into the lateral ventricle inhibited pulsatile discharge of LH secretion, in contrast to the stimulatory effect of PGE2. Intraventricular administration of 13,14-dihydro-15-keto-PGD2, a metabolite of PGD2, had no significant effect. Intravenous administration of 100 micrograms of PGD2 caused only a slight decrease in LH secretion. Intravenous administration of naloxone, a specific opiate antagonist, blocked the suppressive effect of PGD2 on Lh release. These results suggest that PGD2 plays an inhibitory role in pulsatile LH secretion in castrated male rats and that opiate receptors are involved in the PGD2-induced inhibition of LH secretion.

Animals↗

Inhibition of gonadotropin secretion in castrated male rhesus monkeys (Macaca mulatta) induced by dietary restriction: analogy with the prepubertal hiatus of gonadotropin release.

The purpose of this study was to examine further the notion that in higher primates, analogous neuroendocrine mechanisms may underlie the hiatus in LH and FSH secretion during prepubertal development and the suppression of gonadotropin release in adults during states of malnutrition. To this end, the metabolic sequelae and the gonadotropin response to restricted food intake (RFI) were determined in nine castrated male rhesus monkeys. The results obtained were then evaluated in light of current understanding of the neuroendocrine bases of the ontogeny of gonadotropin secretion in primates. A reduction in food intake from approximately 1150 Cal/day to approximately 200 Cal/day for 20-34 days resulted in declines in body weight and circulating LH and FSH concentrations. The reduction in body weight and the suppression of LH secretion were statistically significant (P less than 0.05). The decrease in gonadotropin secretion induced by RFI was fully restored by the chronic iv intermittent infusion of GnRH (0.1 microgram/min for 3 min every hour). These findings graphically demonstrate that RFI, or a sequelae of this nutritional perturbation, inhibits gonadotropin secretion, in the absence of feedback influences by gonadal hormones, by an action at a suprapituitary level that is mediated by interruption of intermittent hypothalamic GnRH discharge. The apparent arrest of the neural mechanism that governs the timing of intermittent GnRH discharge, the so-called GnRH pulse generator, was associated with decreases in plasma insulin (P = 0.078), T4 (P less than 0.05), and T3 (P less than 0.05) concentrations and with a significant (P less than 0.05) elevation in circulating cortisol levels. Although a general decrease in circulating amino acid levels was not observed during RFI, plasma glutamate concentrations were significantly (P less than 0.05) reduced by the nutritional perturbation. RFI resulted in unremarkable hypoglycemia. While the suppression of gonadotropin secretion in castrated male monkeys during RFI resembled, in certain aspects, the hiatus in gonadotropin secretion during prepubertal development, the endocrine and metabolic concomitants of these two physiological states exhibited important differences. Thus, the contemporary notion that the study of dietary restriction in adult primates may provide insights into the neuroendocrine mechanisms that govern the timing of the onset of puberty in these species should not be accepted without careful consideration.

Amino Acids↗

Effect of estrogen on the growth hormone (GH) secretory response to GH-releasing factor in the castrate adult female rat in vivo.

Five groups (n = 11) of 250-g female rats were oophorectomized and immediately thereafter received daily sc injections of estradiol benzoate (EB; 0.05, 0.5, 5.0, and 50.0 micrograms) or vehicle for 28 days. A sixth group underwent sham operation and received injections of vehicle. Somatomedin-C (SmC) concentrations were determined before EB administration. After 4 weeks of EB treatment, the GH response to human GH-releasing factor (1-44) (GRF; 5 micrograms/kg, iv) was determined under pentobarbital anesthesia in seven animals from each group. Serum PRL, LH, and estradiol and plasma SmC concentrations were also measured. The GH secretory response to GRF (delta GH) was greatest in castrated animals receiving vehicle (P less than 0.05) and was significantly blunted in animals receiving 5.0 and 50.0 micrograms EB (P less than 0.05) compared to that in sham-operated animals. A significant negative correlation was observed between delta GH and serum PRL concentrations (r = -0.53; P less than 0.0001). SmC concentrations after treatment were significantly lower in animals receiving 5.0 and 50.0 micrograms EB (P less than 0.01), than in sham-operated animals and were elevated compared to those in sham-operated controls in the group receiving the lowest dose of EB (0.05 microgram; P less than 0.01). Posttreatment SmC levels correlated positively with delta GH (r = 0.58; P less than 0.001) and negatively with serum estradiol concentrations (r = -0.47; P less than 0.01). Pituitary glands from the remaining animals in each group (n = 4) were weighed and assayed for GH, PRL, and LH content. Pituitary PRL content increased with increasing doses of EB replacement and correlated strongly (r = 0.82; P less than 0.0001) with pituitary weight. In the castrated adult female rat, high doses of estrogen inhibited the GH secretory response to GRF in vivo and decreased SmC concentrations. Low dose estrogen increased SmC concentrations, although the GH secretary response to GRF in this group was similar to that in sham-operated rats. The latter observation suggests that the rise in SmC levels associated with low dose estrogen may not be mediated through a change in GH secretion.

Animals↗

Regulation of rat DOC-2 gene during castration-induced rat ventral prostate degeneration and its growth inhibitory function in human prostatic carcinoma cells.

Androgen is a mitogen as well as a morphogen for prostatic epithelium. However, the detailed mechanisms of these distinct androgenic actions have not yet been delineated. Therefore, we employed differential display PCR to unveil any potential genes that may be involved in these processes. In this study, we report the isolation and characterization of two alternative splicing forms (p82 and p59) of C9 complementary DNA, the rat homolog of the human deletion of ovarian carcinoma 2 (DOC-2) gene and mouse p96 phosphoprotein, from rat ventral prostate (VP). We found that C9 was up-regulated in rat VP after castration, suggesting that C9 may be regulated by androgen receptor directly or indirectly during prostate degeneration. A similar regulatory pattern was also observed in both the seminal vesicle and dorsolateral prostate, but not in the coagulating gland or other androgen-independent organs. Immunohistochemical analysis of rat VP demonstrated that C9 is detected in the basal epithelia and surrounding stromal cells after prolonged castration. Ribonuclease protection assay and Western blot analysis revealed that p59 is the predominant C9 isoform in rat VP. To unveil the function of C9 in cell growth, we transfected p59 complementary DNA into the C4-2 cells, a derivative of the LNCaP prostatic carcinoma cell line. The p59 stable transfectants exhibited a slower growth rate and an increase in the cell fraction in the G1 phase under our experimental conditions. These data indicate that C9-p59 has growth inhibitory activity for prostatic epithelial cells. Taken together, our results suggest that C9 is up-regulated during prostate degeneration process and may play an active role in the proliferation and differentiation of prostatic epithelium.

Adaptor Proteins, Signal Transducing↗

Measurement of inhibin concentrations in men: study of changes after castration and comparison with androgen levels in testicular tissue, spermatic venous blood, and peripheral venous blood.

We measured serum inhibin levels in eight untreated patients with prostatic cancer undergoing castration by RIA using an antiserum against 31-kDa bovine follicular fluid inhibin. The inhibin concentrations in testicular tissue and spermatic venous blood were also measured in six of these patients. Serum inhibin levels (mean +/- SD, 377.8 +/- 212.1 U/L), declined rapidly after castration (15 min after, 233 +/- 171.4; 30 min, 224.6 +/- 156.6; 1 h, 181.5 +/- 95.9; 2 h, 174.3 +/- 69.4; 4 h, 122 +/- 6.4; 6 h, less than 120). High concentrations of inhibin were detected in testicular tissue (31,360 +/- 15,180 U/kg), and the levels in spermatic venous blood (3,178.3 +/- 1,386.8 U/L) were approximately 10 times greater than those in peripheral blood (385.5 +/- 233.1 U/L). Testosterone levels were 1,968.2 +/- 992.3 nmol/kg in testicular tissue and approximately 100 times greater in spermatic venous blood (1,631.6 +/- 389.7 nmol/L) than in peripheral blood (18.0 +/- 4.4 nmol/L). These results suggest that circulating inhibin in men mainly originates from testis and that one of the routes of secretion is via the bloodstream.

Aged↗

Differential effects of aromatase inhibition on luteinizing hormone secretion in intact and castrated male cynomolgus macaques.

To understand the role of central aromatization in feedback regulation of LH in nonhuman primates, we treated adult male cynomolgus monkeys with the aromatase inhibitor, 1,4,6-androstatriene-3,17-dione (ATD). We measured LH, testosterone (T), and ATD in systemic sera of blood samples drawn on a diurnal schedule (0900 and 2100 h). Each animal was bled for 4 pretreatment days from a femoral catheter after which they were divided into the following treatment groups: castrated (Cx), n = 2; Cx + T, n = 6; Cx + T + ATD, n = 6; Cx + ATD, n = 3; and sham operated + ATD, n = 3. Silastic capsules or packets containing T or ATD, respectively, were placed sc between the scapulae at the time of Cx or sham treatment. In T-treated animals, T (20 micrograms/kg body weight) dissolved in propylene glycol was injected im at 2100 h to mimic the diurnal rise of T observed in nonhuman primates. Animals were bled for 2 weeks after which they were killed, and selected brain areas were analyzed for aromatase activity and cytosolic and nuclear androgen receptors. Animals treated with ATD had significantly reduced levels of aromatase activity in selected regions of the hypothalamus, preoptic area, and the amygdala (P < 0.05). Even though ATD inhibited brain aromatase activity, it did not prevent the negative feedback actions of T on LH secretion after Cx. In addition, ATD by itself inhibited LH secretion after Cx and activated brain androgen receptors. These latter effects of ATD seemed to have been mediated through a metabolite. In sham-operated intact males, ATD produced variable surges of LH that were accompanied by elevations of T in the systemic circulation. These differential effects of ATD in intact vs. castrated animals demonstrate the importance of selecting the proper model system to study LH control mechanisms. In the intact animal, aromatization seems to play a role in regulating LH secretion, but the postcastration rise of LH seems to be regulated differently.

Androstatrienes↗

Castration increases striatal D-2 dopamine receptors in mid-life rats.

Effect of castration on [3H]-spiperone binding in the striatum of mid-life/mature rats was investigated. Four weeks after castration an increase in D-2 dopamine receptors was noted, and this was partially reduced by testosterone. These results suggest that testosterone may regulate striatal D-2 dopamine receptors in an age-dependent manner.

Aging↗

Failure of buserelin-induced medical castration to control pulmonary lymphangiomyomatosis in two patients.

Two women, aged 44 and 29 years, respectively, were admitted to the hospital in early 1987 for recurrent pneumothorax, dyspnea and a diffuse reticulonodular pattern evidenced on the chest x-ray film. Lung biopsy confirmed LAM in both patients. Both were treated sequentially with medroxyprogesterone and a LHRH agonist (buserelin) to achieve reversible medical castration. Neither subjective nor objective improvement was noted after 13 and 5 months, respectively, of buserelin therapy (900 micrograms/day, nasal spray) despite an effective suppression of the pituitary-gonadal axis. Medroxyprogesterone also was ineffective. Buserelin thus failed to control pulmonary LAM in these two patients, in spite of effective medical castration.

Adult↗