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PubMed1991

Ultrastructural study of the effects of 17 beta-oestradiol on the lateral prostate and seminal vesicle of the castrated guinea pig.

Administration of oestradiol to castrated animals induced hypertrophy of the secretory cells in the lateral prostate and seminal vesicle. In the lateral prostate, increases in the number of small highly electron-dense granules, multivesicular bodies and intercellular spaces were the prevailing effects 2 weeks after oestradiol treatment. There was also an apparent increase in the amount of cytokeratin intermediate filaments. Prolonged oestradiol administration for 4 weeks showed no appreciable changes in the glandular epithelium when compared with 2-week treatment. However, an increase in the thickness of the fibromuscular layer was observed. In the seminal vesicle, basal cell hyperplasia was associated with a concurrent increase in the size of intercellular spaces 2 weeks after oestradiol administration. There were also apparent increases in the volume of the lamina propria and in the number of stromal cells. An apparent increase in the density of collagen fibres in the stroma was observed 2 and 4 weeks after oestradiol administration. In conclusion, the responses of the epithelium of the lateral prostate and seminal vesicle to a pharmacological dose of oestradiol are different. Prolonged oestradiol administration exerts a more prominent effect on the smooth muscle in the lateral prostate but not in the seminal vesicle. The effects of oestradiol may be mediated directly or indirectly through the other hormones.

Animals↗

PubMed1983

Effect of castration on urinary N-acetyl-beta-D-glucosaminidase levels in male beagles.

Urinary N-acetyl-beta-D-glucosaminidase (NAG), a sensitive marker for renal damage, was much higher in male beagles than in females. The daily output of NAG into urine in male beagles was almost three times that in females. Following bilateral vasectomy or castration, marked decreases occurred in urinary NAG output. These results led to the conclusion that the high urinary NAG output in male beagles is largely due to an admixture of secreted fluid from the gonadal system in the bladder. Thus, when using beagles for nephrotoxicity studies with NAG as a parameter, females are preferable.

Acetylglucosaminidase↗

PubMed1984

Humoral autoimmune response to rat male accessory glands. Effect of castration on the humoral response.

The ability to induce antibodies to rat male accessory glands in male and female rats was demonstrated, but a higher response with wider specificity was revealed in female animals. In order to investigate whether this different response may be influenced by sexual hormones we castrated male and female rats at 4 or 30 days after birth. After that we studied the course and specificity of their humoral response to male accessory glands comparing them with that of sham-operated, sex-matched, littermate controls. Orchidectomy in male or oophorectomy in female rats changed neither the course nor specificity of humoral immune response. We conclude, therefore, that hormonal factors do not play any important role in the experimental model under study.

Animals↗

PubMed1981

[Experimental investigations on cell loss and cell proliferation of the rat prostate after castration and androgen administration (author's transl)].

The rat prostate was used to investigate cell loss (numeric atrophy) and altered cell proliferation after castration. Cell loss was determined by the proportion of apoptotic bodies. The apoptotic index was considerable and reached a maximum in the coagulating gland on day 2 and in the other prostate lobes between days 4 and 8. Thereafter, cell loss was reduced and finally corresponded to that of control animals. Cell proliferation decreased and soon ceased at all. Androgen administration caused cell increase in all prostate lobes. Following a latent period of 35--40 h, the 3H-labeling index increased with a maximum on day 3. Values then fell and were minimal above control values. Rhythmically interrupted administration of testosterone resulted in a decreased ability to stimulate cell proliferation. This androgen-induced cell proliferation is a useful model for testing cell proliferation of the prostate. The combined determination of cell loss and the cell proliferation, therefore, may be important for the clinical examination of the hormonal responsiveness of prostatic carcinomas.

Animals↗

PubMed1995

Castration-induced lymphocytosis in prostate cancer: possible evidence for gonad/thymus endocrine interaction in man.

Prompted by evidence from animal studies that castration produces lymphocytosis associated with thymic hyperplasia, this paper has reviewed serial lymphocyte levels in patients with prostate cancer undergoing hormone treatment. On day 7, 5 of 12 patients (58%) showed diminished circulating lymphocyte levels (compared to day 0) reflecting the surge of testosterone after treatment with LHRH analogues, while on day 28 a reversal had occurred and 13 of 17 (77%) had increased lymphocytes (compared to day 0). Possible relevance of these observations to defining a subgroup of patients with hormone-sensitive cancer who might benefit from immunotherapy is discussed.

Castration↗

PubMed2026

Prognostic value of circulating tumor DNA and copy-number alterations in patients receiving tandem [225Ac]Ac-/[177Lu]Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer: a prospective observational study.

BACKGROUND: Prostate-specific membrane antigen-targeted radioligand therapy (PSMA-RLT) demonstrates clinical efficacy in metastatic castration-resistant prostate cancer (mCRPC), yet robust biomarkers for dynamic treatment monitoring and resistance remain lacking. We investigated circulating tumor DNA (ctDNA)-derived tumor fraction (TFx) and genome-wide copy-number alterations (CNAs) as non-invasive biomarkers of treatment response and resistance biology. METHODS: Seventy-eight patients with advanced mCRPC receiving tandem [225Ac]Ac-/[177Lu]Lu-PSMA-617 were prospectively enrolled. Plasma samples collected longitudinally (n = 172) underwent ultra-low-pass whole-genome sequencing. TFx was estimated using ichorCNA, and recurrent CNAs were identified using GISTIC2.0. Associations with progression and overall survival (OS) were assessed using Cox proportional hazards models, including time-dependent analyses. RESULTS: Baseline TFx differed across metastatic disease stages (p = 0.027) and dynamic TFx changes paralleled PSA kinetics during early treatment. Modelled as a time-dependent variable, TFx was associated with a significantly increased risk of progression (HR 4.9, 95% CI 1.2-20.1, p = 0.026). Unsupervised clustering identified distinct high- and low-CNA burden groups strongly correlated with TFx (p = 8.09 × 10⁻8). High CNA burden was associated with shorter median OS (8.3 vs 13.8 months). Multivariable analysis identified baseline logPSA and logALP as independent predictors of OS. Recurrent CNAs affected key tumor suppressors (PTEN, RB1, BRCA2, ATM) and were enriched in pathways related to TP53 signalling, homologous recombination repair, and oncogenic signaling. Longitudinal analyses demonstrated persistence and expansion of specific amplifications at progression. CONCLUSIONS: ctDNA-derived TFx represents a dynamic biomarker of treatment response and progression risk, while CNA profiling provides insight into resistance mechanisms in mCRPC treated with PSMA-RLT. These findings support the integration of ctDNA-based biomarkers into clinical stratification and real-time monitoring strategies.

Humans↗

PubMed2004

Assessment of fertility in male rats after extended chemical castration with a GnRH antagonist.

The purpose of this study was to assess whether male rats whose testosterone levels were suppressed to castration levels (<0.5 ng/mL) for a 1-year period by the sustained delivery of orntide acetate, a GnRH antagonist, would return to fertility (ie, produce offspring) after serum testosterone returned to control levels. Male rats comprising a treatment group (orntide microspheres, dose = 27 mg/kg/y), a vehicle control group, and a control group of proven male breeders were used. For the treatment and vehicle control groups, serum orntide and testosterone levels were monitored at periodic intervals for 14 months from the initiation of treatment. After serum testosterone levels returned to vehicle control levels and orntide serum levels were no longer discernible for the treated group, each of the animals was housed with 2 drug-naive, female, proven breeders. All the breeder females produced offspring with the exception of 1 female housed with a male rat from the treatment group and the 2 females housed with a single male rat from the vehicle control group. The mean size and weight of the litters from each group were not statistically different. Further, fertility of the offspring from each group was assessed. The male and female offspring studied were all shown to be fertile. The results suggest that lack of fertility due to testosterone suppression in male rats is reversible after cessation of treatment with the GnRH analog, orntide.

Animals↗

PubMed1977

Relationship between luteinizing hormone releasing hormone concentration in hypophysial portal blood and luteinizing hormone release in intact, castrated, and electrochemically-stimulated rats.

The concentration of luteinizing hormone releasing hormone (LHRH) in hypophysial portal plasma was determined in pentobarbital anesthetized,intact and castrated rats of both sexes, including proestrous rats following electrochemical stimulation of the medial preoptic area (MPOA). Mean LHRH levels in portal plasma obtained between 1400--1700 h from estrous and diestrous rats and from rats ovariectomized for 8 weeks were similar and ranged from 50--55 pg/ml, but the LHRH levels in proestrous rats were less than 12 pg/ml. In addition, hypophysial portal plasma collected during 1100 to 1400 h from animals orchidectomized for 8 weeks and from intact male rats contained mean LHRH concentrations that ranged from 50--65 pg/ml and 30--35 pg/ml, respectively. Electrochemical stimulation of the MPOA in the female rat on the afternoon of proestrus resulted in a marked increase in the concentration of LHRH in portal plasma. LHRH levels in portal plasma during the 0 to 30, 30 to 60, 60 to 90, 90 to 120, and 120 to 150-min periods after electrochemical stimulation of the MPOA were 105 +/- 24.2, 61 +/- 10.8, 51 +/- 8.2, 36 +/- 5.3, and 32 +/- 4.1 pg/ml, respectively. LHRH levels in portal plasma from the unstimulated rats were not detectable (less than 12 pg/ml) in most of the animals. In another group of proestrous rats, the effect of rabbit anti-LHRH serum or normal rabbit serum (NRS) on the release of LH after electrochemical stimulation of MPOA was examined. Pretreatment of proestrous rats with anti-LHRH serum blocked the release of LH due to MPOA stimulation, whereas pretreatment with NRS did not inhibit LH release. On the basis of these findings, it is concluded that electro-chemical stimulation of the MPOA in proestrous rats increases LHRH levels in portal blood and that the enhanced secretion of LHRH stimulates the release of LH from the pituitary gland.

Animals↗

PubMed1977

Circadian periodicities of serum androgens, progesterone, gonadotropins and luteinizing hormone-releasing hormone in male rats: the effects of hypothalamic deafferentation, castration and adrenalectomy.

Serum testosterone (T), dihydrotestosterone (DHT), progesterone (P), LH, FSH and luteinizing hormone-releasing hormone (LHRH) levels and the LHRH content in the medial basal hypothalamus (MBH) and preoptic area (POA) were estimated during a 24-h period. Circadian rhythms, temporally unrelated to each other, were evident in serum FSH and LHRH and the MBH LHRH content; serum LH fluctuated randomly. In addition, serum T and DHT demonstrated a parallel circadian pattern while serum T and P appeared inversely related. Serum P rhythm persisted in long-term castrate males. Without adversely affecting serum LH, anterior hypothalamic deafferentation abolished both serum T and P rhythms, whereas adrenalectomy obliterated only the serum T periodicity. These studies show that the POA-MBH complex and the adrenals play important roles in the circadian regulation of testicular secretions.

Adrenalectomy↗

PubMed1981

Attenuation by a 5 alpha-reductase inhibitor of the activational effect of testosterone propionate on penile erections in castrated male rats.

Daily administration of an inhibitor of 5 alpha-reductase, 17 beta-testosterone carboxylic acid, significantly attenuated the stimulatory effect of testosterone propionate on penile erections displayed by castrated male rats which were restrained in a supine position. This treatment, however, failed to affect mating behavior in tests with sexually receptive females. The inhibitory effect of 17 beta-testosterone carboxylic acid on erection was reversed by concurrent administration of 5 alpha-dihydrotestosterone propionate, suggesting that the 5 alpha-reduced metabolite(s) of testosterone may normally contribute to the activation of penile erection in the rat.

5-alpha Reductase Inhibitors↗

PubMed1982

Discriminative effects of testosterone on hypothalamic luteinizing hormone-releasing hormone levels and luteinizing hormone secretion in castrated male rats: analyses of dose and duration characteristics.

We have previously reported that in castrated male rats gonadal steroids can raise LHRH levels in the medial basal hypothalamus (MBH). However, there was an important dissociation between episodic LH release and the MBH LHRH response to 17 beta-estradiol. In the present study we have examined the effects of varying the dose of testosterone (T) on the MBH LHRH levels, episodic LH release pattern, and pituitary responsiveness to LHRH; in addition we have determined the duration of T exposure required to elicit the MBH LHRH response. Results show that low serum levels of T (413-638 pg/ml) were just as effective as higher concentrations (1337-1776 pg/ml) in raising the MBH LHRH levels at 96 h; the minimum duration of exposure to T was 72 h. However, whereas higher T levels (greater than 1 ng/ml) suppressed LH release coincident with elevated LHRH levels, low T concentrations did not alter LH release contemporaneous with the MBH LHRH elevations. Analysis of the episodic LH secretion pattern disclosed that these low concentrations of T changed neither the number of pulses per 3 h per rat, pulse amplitude, nor the interpulse interval. On the other hand, as T concentrations were increased, pulse amplitude fell in a dose-related manner while other components of episodic LH secretion remained unchanged. Despite these differential effects of T on the LH release pattern, pituitary sensitivity to exogenous LHRH was reduced by the low as well as high levels of T. These studies show that 1) T can activate those intracellular neurosecretory events that are involved in augmented LHRH supply to the nerve terminals in the median eminence; 2) T can stimulate LHRH accumulation in the MBH by mechanisms that may not involve inhibition of LHRH release; and 3) higher T levels do not alter LH pulse frequency but depress only the pulse amplitude that may result from decrements in the amounts of LHRH released with each neural episode and depressed pituitary sensitivity to LHRH.

Animals↗

PubMed1976

Regulation of estrogen receptors in ovarian-dependent rat mammary tumors. I. Effects of castration and prolactin.

The "ovarian-dependent" rat mammary tumors, induced by 9,10 dimethyl-1,2-benzanthracene, were assayed for their estrogen receptor content by dextran-coated charcoal adsorption and sucrose gradient ultra-centrifugation. The estradiol receptors bound estrogens with a high affinity (KD approximately 0.25 nM), limited capacity and high specificity, and sediment at 8 S in a sucrose gradient. The cytosol receptors were transferred to the nucleus after binding to estrogens either in vivo or in vitro. The tumor area regressed by 70% during the first 10 days of castration while the concentration of estradiol cytosol receptors decreased from 225 to 16 fmoles/mg of protein. Three to five days after in vivo administration of estradiol (2 mug daily) or prolactin (1 mg daily) the concentration of estrogen receptors was increased in spayed rats. In biopsy experiments, prolactin, but not estradiol, was shown to increase the estrogen receptor concentration when endogenous prolactin release was blocked by CB 154. Prolactin did not modify the intracellular distribution of the estrogen receptor or its binding affinity for estrogen. The uterine estrogen receptor sites were not modified by prolactin under the same conditions. We, therefore, suggest that in mammary tumors prolactin sensitizes the action of estrogens at the target level by increasing the concentration of their available receptor sites.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1976

Suppression of luteinizing hormone in castrated women by the administration of human chorionic gonadotropin.

The suppressive effect of human chorionic gonadotropin (hCG) on luteinizing hormone (LH) and/or LH-beta was studied by specific LH-beta radioimmunoassay following hCG administration. Eight castrated women were each administered 10,000 IU of hCG in a single intramuscular injection and five women in the control group were injected with saline. The serum level of hCG increased after the injection, reaching 217.6 mIU/ml after 8 h. There was a significant suppression of LH levels as compared to those of the control group and the pre-injection levels: 68.2% 1 h after injection, 64.7% after 2h, 65.5% after 4 h, 77.0% after 8 h, 78.6% after 12 h, and 78.2% after 24 h. There was no significant suppression of the follicle-stimulating hormone (FSH) as compared to the preinjection and control values. Serum concentration of estradiol1 was not detectable either before or after the hCG injection. We conclude that hCG has a suppressive effect on LH and/or LH-beta secretion not mediated by estradiol.

Adult↗

PubMed1983

Effect of GnRH antagonist, [Ac-delta 3Pro1, pFDPhe2, DTrp3,6] GnRH, on pulsatile gonadotrop in secretion in the castrate male primate.

Three different doses of a potent antagonist to GnRH, [Ac-delta 3Pro1, pFDPhe2, DTrp3,6], GnRH were compared in adult male monkeys to determine the acute effect on pulsatile gonadotropin secretion. In accomplishing these studies, blood was drawn at 15 min intervals over 24-30 h without anesthesia using a mobile vest and tether assembly to support an indwelling cannula. After a 3 to 6 h control period, 2.0, 0.2 or 0.02 mg GnRH antagonist/kg bw in 1 ml corn oil sc, was given to castrate adult monkeys. The highest dose decreased circulating LH (by radioimmunoassay and bioassay) and FSH whereas the intermediate dose decreased LH only. The higher dose produced both a more prolonged and greater reduction in circulating gonadotropins. These data demonstrate that this GnRH antagonist can reduce serum gonadotropins both acutely and for intervals greater than 24 h.

Animals↗

PubMed1977

Erotic imagery and self-castration in transvestism/transsexualism: a case report.

After nearly 30 years of marriage, a 51-year-old man castrated himself in order to fulfill a long-standing fantasy of being a girl. There was a prior history of cross-dressing since childhood, and a reversed erotic role imagery during coitus. There was no history of schizophrenia or psychotic depression. Pair bonding with the wife was very strong. It led the patient to elect low-dose maintenance on androgen so as to permit some degree of continued marital sex. Otherwise the patient would have preferred estrogenization and, perhaps, eventual sex reassignment. The rehabilitative program as a transvestite man has continued for 3 years.

Castration↗

PubMed1981

[Studies on the feedback regulation of gonadotropin concentrations in male rats (I). The effects of hypothalamic implantation of testosterone and its metabolites on gonadotropin release in castrated male rats (author's transl)].

Testosterone (T), 5 alpha-dihydrotestosterone (5 alpha-DHT), 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) and estradiol-17 beta (E) or cholesterol (control) were implanted into the hypothalamic median eminence--arcuate nucleus (ME-ARC) region of long-term castrated male rats. Serum LH and FSH levels were measured before and after the implantation. T or E implantation resulted in a 65.5% (P less than 0.01) or 80.2% (P less than 0.01) decrease in serum LH levels respectively, within 7 days after the intrahypothalamic application. 5 alpha-DHT or 3 alpha-diol implantation in the ME-ARC region also resulted in a significant lowering of serum LH levels, although their inhibitory action was less effective than that of T or E. There were no significant differences in serum LH levels 20 min after the intraperitoneal injection of 2 micrograms/kg of LH-RH between the control group and the T, 5 alpha-DHT, 3 alpha-diol or E group. E implantation also resulted in a 34.7% (P less than 0.01) decrease in serum FSH levels at the 7th day, but other steroids failed to reduce serum FSH levels after the intrahypothalamic application. These studies suggest that aromatization of T to E is not indispensable to the negative feedback effect of androgen on the hypothalamic LH-RH release. It might also be supposed that E is one of the factors regulating the serum FSH level.

Animals↗

PubMed1978

Accumulation and binding of 3H-estradiol-17beta by lymphoid tissues of castrated mice.

The in vivo uptake of 3H-estradiol-17beta by the various lymphoid tissues, fat tissue, skeletal muscle and circulating blood of castrated male and female mice of C57BL strain was studied after an intravenous injection of the hormone. In both sexes the highest uptake was by the bone marrow and fat tissue, followed by the spleen, thymus and mesenteric lymph node. The lowest was by the muscle and the blood serum. The lymphoid tissues in the female took up a slightly more amount of radioactivity than those in the male until 1 hr after the injection, but thereafter the uptake was at almost the same level between both sexes. The lymphoid tissues showed a relative and long-term retention of the radioactivity, as compared with that in the muscle and blood serum. The binding of 3H-estradiol-17beta by the lymphoid tissue cytosol and their binding specificity for the hormone were examined in vitro by Sephadex G-100 column analysis. All the tissue cytosols tested contained estradiol-binding component(-s). Among those the thymic cytosol showed to contain the component(-s) which is fairly specific to this hormone. These results suggest that there is a relatively high uptake and retention of estrogen in the lymphoid tissues in which it is bound to cytoplasmic binding component(-s).

Adipose Tissue↗

PubMed1980

Cytoplasmic estrogen receptor in castrated rat thymus.

Characterization of estrogen-binding components was attempted in cytosol fractions from thymus, spleen and mesenteric lymph node of castrated rats. As shown by sucrose gradient analysis, specific binding of [6,7-3H]estradiol-17 beta in the thymus is associated with a component migrating at 4 S. The binding of [6,7-3H[estradiol-17 beta is highly specific since it is easily displaced by unlabeled estradiol-17 beta and diethylstilbesterol. Affinity of unlabeled estrone, estriol and clomiphene citrate, is much lower, and estradiol-17 alpha, progesterone, testosterone, 5 alpha-dihydrotestosterone and corticosterone have no affinity for the component at all. The dissociation constant of thymic estrogen binding is 0.25 mM in males and 0.3 nM in females. The number of binding sites is 6 fmols/mg protein in both sexes. No specific binding to estrogen is, however, found in cytosol fractions from the other two tissues. Enzyme- and heat-experiments demonstrate that specific estrogen binder in thymic cytosol is heat-labile and at least protein in nature. It is concluded that the rat thymus contains a cytoplasmic estrogen which is in part protein and heat-labile.

Animals↗