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Biochemical and histological studies on prostates in castrated dogs after treatment with androstanediol, oestradiol and cyproterone acetate.

The effect of cyproterone acetate (CA) on experimentally induced benign prostatic hyperplasia (BPH) in the castrated dog was investigated. BPH was induced by 6 months' treatment with 3 alpha-androstanediol (3 alpha-diol) alone and in combination with 17 beta-oestradiol (Oe2). RNA, DNA and zinc content of the glands were determined in addition to histological examination and measurement of the prostates. Two different types of prostatic enlargement were observed. First, 3 alpha-diol induced typical diffuse canine hyperplasia with replacement of functional activity. DNA, RNA and the zinc content of total glands were increased compared with intact controls. Second, 3 alpha-diol plus Oe2 produced on the one hand a more striking increase of prostatic weights, but on the other a loss of typical morphological structure and function. Histologically, transformation of simple glandular epithelium into stratified squamous metaplasia occurred in addition to stimulation of fibromuscular tissue. Biochemically, a relative decrease of DNA per mg tissue was measured with a fall in the RNA to DNA ratio and zinc to the values of castrates. Administration of CA resulted in an abolition of the 3 alpha-diol effect. Biochemical determinations and histological examinations revealed an effect similar to castration after treatment with 3 alpha-diol plus CA. After treatment with 3 alpha-diol plus Oe2 plus CA fibromuscular stimulation as an oestrogen effect predominated in addition to glandular atrophy and metaplastic changes, especially in prostatic ducts. Epithelial hyperplasia is an effect of 3 alpha-diol, whereas metaplastic proliferation only occurs in oestrogenized and androgenized dogs. In both types of prostatic enlargement CA prevents development of hyperplastic prostate.

Androstane-3,17-diol↗

Modulation by photoperiod of gonadotrophin secretion in intact and castrated Djungarian hamsters.

Reproductive activity in the Djungarian hamster, Phodopus sungorus, is suppressed by short daylengths and induced and maintained by long daylengths. To determine the time course of changes in plasma and pituitary gonadotrophin concentrations during the photoperiodic response, sexually immature male hamsters were moved from short (9L:15D) to long days (14D:10D). This induced an increase in testicular weight in 5 days and full sexual maturity in about 1 month. Plasma and pituitary FSH concentrations were significantly elevated after 3 and 5 long days respectively, reaching peak levels after 7--14 days and then declining. In contrast, pituitary and plasma LH concentrations did not increase until 10 and 21 days of photostimulation respectively. Castration of hamsters kept in short days led to a marked increase in plasma and pituitary FSH titres. Transfer to long days further increased plasma FSH although pituitary content did not change. Castration of hamsters kept in long days led to an elevation of plasma and pituitary FSH concentration to these same levels. Transfer to short days reduced plasma FSH to the levels seen in hamsters castrated and kept in short days. Pituitary content did not change. The results suggest that while there is substantial steroid negative feedback in intact animals on both long and short days, the photoperiodic modulation of gonadotrophin secretion does not necessarily involve changes in feedback sensitivity.

Animals↗

Photoperiodic suppression of gonadotrophin secretion in castrated male hamsters.

Male golden hamsters were transferred from long to short days and castrated on the day of transfer (Group SP0) or 1, 2 or 3 weeks afterwards (Groups SP1, SP2 & SP3). Animals in Group LP were castrated and maintained on long days. After 7 weeks of short days, plasma levels of LH and FSH were low in Groups SP1, SP2, and SP3. In Group SP0 LH output was also low and FSH secretion, although greater than in Groups SP1, SP2 and SP3, was lower than in the long-day controls (Group LP). This photoperiodic control of gonadotrophin secretion in castrated hamsters raises doubts about the significance of hypothetical alterations in hypothalamo-pituitary sensitivity to sex steroids.

Animals↗

Effect of castration on the appearance of diabetes in NOD mouse.

To examine the influence of sex hormones on the appearance of overt diabetes in NOD mice, oophorectomy and orchiectomy were performed. Castrated males showed a high incidence of diabetes. The time course of onset was similar to that of the intact females. On the other hand, castrated females showed a intact-male pattern of onset with a low incidence. Clinical determinations demonstrated a close similarity between spontaneous and castration-induced diabetes. These data suggest that sex hormones modulate the expression of overt diabetes in NOD mouse, i. e. androgens have at least a suppressive effect.

Age Factors↗

Acute effects of intravenous infusion of conjugated estrogen on serum levels of LH and FSH in post-menopausal and castrated women.

In order to quantify the changes of feed-back effect of estrogen on the release of pituitary gonadotropin which is regulated by the hypothalamic-pituitary-ovarian system, the responses of LH and FSH to the intravenous infusion of 20 mg of conjugated estrogen were studied in 49 post-menopausal and 20 castrated women. In the group of women within 1 year after menopause, serum LH levels were elevated following the infusion of the conjugated estrogen. The responses of serum LH and FSH levels were different between post-menopausal and castrated women. The data indicated that the difference between the two groups was probably due to the difference of secrection patterns of the gonadotropins in post-menopausal and castrated women.

Adult↗

Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer.

The categorization of prostate cancers that are progressing after castration as 'hormone-refractory' evolved from the clinical observation that surgical or medical castration (i.e. androgen ablation therapy; AAT) is not curative and, despite an initial response, virtually all tumors eventually regrow. Successful AAT is contingent on the dependence of prostate cancer cells for androgen signaling through an intracellular mediator, the androgen receptor (AR) for survival. Current preclinical and clinical data imply that the AR is expressed and continues to mediate androgen signaling after failure of AAT. As AAT does not completely eliminate circulating androgens, sufficient concentrations of dihydrotestosterone may accumulate in tumor cells to maintain AR signaling, especially in the context of upregulated receptor levels or increased sensitivity of the AR for activation. In addition, ligands of non-testicular origin or ligand-independent activation can contribute to continued AR signaling. In many cases, therefore, from the perspective of the AR, a 'hormone-refractory' classification after failure of AAT is inappropriate. Classifying prostate tumors that progress after AAT as 'castration-resistant' may be more relevant. Clinical responses to second- and third-line hormonal therapies suggest that the mechanisms of AR activation are in part a function of previously administered AAT. Accordingly, the increasing trend to utilize AAT earlier in the course of the clinical disease may have a greater influence on the genotype and phenotype of the resistant tumor. In this article, we detail strategies to inhibit the growth of prostate cancer cells that specifically target the AR in addition to those practiced traditionally that indirectly target the receptor by reducing the amount of circulating ligand. We propose that treatment regimes combining AAT with direct AR targeting strategies may provide a more complete blockade of androgen signaling, thereby preventing or significantly delaying the emergence of treatment-resistant disease.

Androgen Receptor Antagonists↗

Effects of castration, and testosterone in vitro, on the hypothalamic synthesis of different peptide fractions.

The incorporation of [3H]tyrosine ([3H]tyr) into different hypothalamic peptide fractions isolated from normal and castrated rats on a Sephadex G-25 column has been studied in vitro. Luteinizing hormone releasing factor (LH-RF) activity was determined in the different fractions by measuring their ability to elicit release of radioimmunoassayable luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in ovariectomized rats treated with oestrogen and progesterone. For a further purification, the fraction with LH-RF activity was applied to a CM-Sephadex G-25 column eluted with a gradient of ammonium acetate. The large radioactive peptides emerged from the Sephadex G-25 column in fraction S-1, while the small peptides with LH-RF activity were eluted in fraction S-2. Gonadectomy significantly increased the incorporation of [3H]tyr into the peptides of fractions S-2. Only in the purified fraction with LH-RF activity was the radioactivity incorporated higher in gonadectomized than in normal rats. The enhanced incorporation in fraction CM-3 observed after castration implies an increase in the hypothalamic synthesis of peptides with LH-RF activity. The addition of testosterone (2 mug/ml) to the incubation medium of hypothalamus from gonadectomized rats, corrected these modifications. Gonadectomy decreased the incorporation of tyrosine into the large peptides, and incubation with testosterone corrected this change. The modifications in the incorporation of [3H]tyr into the large and small peptides produced by castration appear to indicate that gonadectomy, as well as stimulating the production of LH-RF, enhances the synthesis of other hypothalamic peptides while inhibiting the synthesis of proteins. On the other hand an increase in the breakdown of large peptides into small peptides cannot be excluded.

Animals↗

The proliferative response of the coagulating gland of the castrated mouse under continuous androgen stimulation: an experimental and computer simulation model.

The proliferative response of the coagulating gland of the castrated male mouse has been examined during continuous treatment with testosterone propionate. Fourteen days after castration, s.c. daily injections of testosterone propionate were begun. Mitotic (Im) and labelling (IL) index values were obtained at 3 h intervals for up to 100 h after the initial injection. These showed a biphasic response, in which IL reached a maximum at 30 and 70 h, and Im at approximately 45 and 75 h. Fraction-labelled mitoses (FLM) curves were begun 24, 48, and 72 h after the first androgen injection. In each curve the first wave of labelled mitoses rose to 100% and showed a square form indicating little spread in the durations of the G2 and S phases. Values of 7.5, 1.3 and 0.7 h were obtained for the durations of DNA synthesis (ts), the post-synthetic period (tG2) and of mitosis (tm) respectively. In none of the FLM curves was it possible to demonstrate a second wave of labelled mitoses and direct measurement of the cell cycle time (Tc) was not obtained. Continuous tritiated thymidine labelling indices revealed that after a latent period of 25 h, DNA synthesis began and labelling rose rapidly to 80% by 45 h and then more slowly to 95% by 97 h. Cell population changes during androgen stimulation estimated from measurements of total glandular DNA indicated that the number of cells present in the glands remained constant during the first 30 h after stimulation and thereafter increased to approximately 2-3 times the original value. The data are compared with a mathematical model which assumes that the cell population of castrated mice when stimulated passes from a GO compartment through successive waves of DNA synthesis and mitosis. After each cell division the cells may leave or remain in the proliferative cycle. This model has been subjected to computer simulation using the cell cycle parameters obtained in the kinetic experiments. There was good agreement between the stimulation and experimental results in the Im and IL curves, continuous labelling, and total cell number experiments. The simulation of FLM curves was less successful. Although the first wave of labelled mitoses was clearly seen the model predicts a distinct second wave of labelled mitoses. It is concluded that this does not appear because of variation in the duration of G1.

Animals↗

Effects of androgenic and oestrogenic hormones on mating behaviour in rams castrated before and after puberty.

Adult sheep which has been castrated either before or after puberty were treated with a variety of steroids. The administration of testosterone propionate, oestrone, oestradiol-17 beta or diethylstilboestrol to animals castrated before puberty caused them to mount oestrous ewes. Oestradiol-17 alpha was less effective than these hormones in this regard, whilst oestriol, hexoestrol and 5 alpha-dihydrotestosterone were ineffective. The response to oestradiol-17 beta was not altered by the concurrent administration of dexamethasone to block the pituitary-adrenal axis which suggests that oestradiol-17 beta was not exerting its effect indirectly by causing the release of adrenal steroids. When 5 alpha-dihydrotestosterone was administered in conjunction with oestradiol-17 beta intromission and ejaculation were observed in addition to mounting behaviour. When rams were castrated as adults their mating behaviour slowly declined over the course of 2 years. After this time, mounting behaviour was rapidly restored by the administration of oestradiol-17 beta but not by 5 alpha-dihydrotestosterone. These results are consistent with the hypothesis that oestrogens are the ultimate agents responsible for promoting mating behaviour in male animals and hence aromatizable androgens, such as testosterone, are effective whereas non-aromatizable androgens, such as 5 alpha-dihydrotestosterone, are not.

Animals↗

Combined effects of neonatal thyroxine treatment and neonatal castration on sebum production in adult male rats.

Newborn Sprague-Dawley rats were castrated within 24 h of birth and control animals were sham-operated. Intact female rats were also included for comparison. One-half of the rats in each group was treated with 28 micrograms thyroxine (t4) daily for the first week of life. The secretion rate of sebum was measured at the age of 80 days from the amount of skin-surface lipids that could be extracted with acetone and which had been produced during 2 days. Castration of rats at birth decreased the rate of sebum secretion and neonatal castration plus neonatal thyrotoxicosis produced an even lower level of sebum which more nearly approached that seen in female rats with neonatal T4 treatment. It was concluded that a reduction in the response of the sebaceous glands in adult rats made thyrotoxic with high doses of T4 in the early stage of life is not due to a decreased secretion of gonadal steroids.

Animals↗

The pineal gland and the photoperiodic control of luteinizing hormone secretion in intact and castrated Japanese quail.

The effects of pinealectomy on a range of photoperiodic responses were investigated in male Japanese quail by measuring plasma LH concentrations in intact, sham-operated and pinealectomized birds in the following four experiments: (1) transfer of sexually quiescent birds from a short photoperiod of 8 h light: 16 h darkness (8L:16D) to a photostimulatory daylength of 16L:8D; (2) transfer of sexually mature birds from 16L:8D to 8L:16D; (3) castration in 16L:8D and exposure to 13L:11D; (4) castration in 8L:16D and exposure to 13L:11D. There was no evidence of effects of the pineal gland on the photoperiodically induced changes in LH secretion, the quantitative relationship between LH secretion and photoperiod in intact and castrated birds, or the induction of relative photorefractoriness by prolonged exposure to 16L:8D. This suggests that there is no pineal influence on the photoperiodic clock or its effectors in this bird.

Animals↗

Neuropharmacological analysis of the control of LH secretion in gonadectomized male and female rats: altered hypothalamic responses to inhibitory neurotransmitters in long-term castrated rats.

The control of LHRH and LH by neurotransmitters and neuromodulators such as the endogenous opioid peptides is essentially the same in intact adult male and female rats: adrenergic and dopaminergic agonists stimulate LH release and opioid agonists inhibit it. Several weeks after gonadectomy, however, the contribution of the endogenous ligands of adrenergic, dopaminergic and opioidergic receptors to the control of LHRH is altered. A detailed pharmacological analysis in long-term ovariectomized females confirmed previous reports that adrenergic and dopaminergic agonists still enhance secretion of LHRH and LH and opioid receptor agonists still suppress it. A similar investigation in long-term castrated males also confirmed previous reports that opioid agonists fail to block LH secretion. In addition, we have found that while adrenergic and dopaminergic agonists cause increases in serum concentrations of LH, adrenoreceptor and dopamine receptor antagonists do not inhibit LH release in long-term castrates. Furthermore, the opioid antagonist naloxone does not raise serum LH levels in either sex after long-term gonadectomy. These observations therefore imply reduced opioidergic, dopaminergic and adrenergic transmission, in relation to LHRH release, after long-term castration. In addition, opioid receptor activity (assessed by responsiveness to an opioid receptor agonist) of female rats is maintained, whereas that of male rats is lost, after long-term gonadectomy.

Adrenergic Agonists↗

Castration anxiety and phobias.

Based on Freud's case study of "Little Hans," the authors tested the hypothesis that men with phobias would score higher on castration anxiety than men without phobias. College men with either average or high scores on the Fears Scale of the MMPI-2 (n = 10 men in each group) responded to the Thematic Apperception Test, which was scored for castration anxiety. Men with high scores on the Fears Scale had higher scores on castration anxiety than men with average scores on the Fears Scale. The findings are consistent with Freud's hypothesis about phobias.

Adolescent↗

Pulsatile luteinizing hormone secretion in the castrate male bovine: effects of testosterone or estradiol replacement therapy.

Luteinizing hormone (LH) secretory profiles have been determined for the male bovine following castration and steroid replacement therapy. Serum LH concentrations increased approximately threefold during the first week following castration and thereafter remained elevated (6.6 +/- .7 ng/ml). Castrates not receiving steroid replacement showed a rhythmic pattern of LH release that was of high frequency (mean pulse interval; 85 +/- 5 min) and high amplitude (mean peak concentration, 11.2 +/- 1.4 ng/ml). Chronic administration of estradiol-17 beta via subdermal Silastic implants reduced mean serum LH concentrations (2.1 +/- .3 ng/ml) and blocked the pulsatile pattern of LH release in all steers. Similar administration of testosterone suppressed mean serum LH and blocked pulsatile LH release in two of four animals. The number of implants used in this study provided physiological concentrations of estradiol (9.8 +/- 1.5 pg/ml) and testosterone (4.1 +/- .2 ng/ml) in systemic blood for the two respective treatment groups. Differences in the LH secretory profiles among testosterone-implanted steers may have been related, in part, to differences in the amounts of steroid not bound to serum proteins. These findings demonstrate that estradiol is a particularly potent inhibitor of pulsatile LH secretion in the male bovine and suggest that gonadal steroid feedback on LH secretion may, in part, be imposed at the level of the hypothalamus. The mechanism for pulsatile LH release is discussed relative to a centrally-located luteinizing hormone releasing hormone pulse generator.

Animals↗

The effect of castration, estradiol and LHRH on LH secretion of lambs fed different levels of dietary energy.

To examine the effect of diet on luteinizing hormone (LH) secretion, basal and luteinizing hormone releasing hormone (LHRH)-induced LH release was compared in intact or castrated-estradiol-17 beta implanted Finn-Dorset lambs. Ten to 12 wk old ram (n = 20) and ewe lambs (n = 20) were maintained under a 8L:16D photoperiod and fed for high (HG, 163 to 168 g/d) or low (LG, 76 to 103 g/d) rates of gain. Eight to 10 wk later, baseline LH concentrations were determined in blood samples collected at 20 min intervals for 7 h. The following day, lambs were given an iv injection of 5 micrograms of estradiol-17 beta followed within 4 h by LHRH (.5 or 2.5 micrograms). Baseline concentrations of LH for HG ewes were threefold greater than for LG ewes (4.2 vs 1.4 ng/ml), respectively. Time to peak response was inversely related to dietary energy level (P less than .025). Basal LH levels were similar across diets in rams. Total LH release following LHRH was dose-dependent (P less than .005). Effects of gonadal feedback were tested in a second group (n = 24) of castrated lambs. Changes in LH secretion were not different between diets within 3 to 4 wk after castration. A subcutaneous silastic implant (22 mm) of estradiol-17 beta inhibited (P less than .01) LH concentrations across diets in both ewes and rams. No differences in estradiol feedback on LH secretion (at the dose of steroid tested) were detected between HG and LG lambs. Within 8 d, however, basal LH concentrations were 60% lower (P less than .01) in HG vs LG ewes. Furthermore, peak LHRH-induced LH release was greater (P less than .025) in LG vs HG lambs of both sexes. Estradiol inhibited basal LH secretion in ewes and rams but facilitated LH release in lambs with a reduced rate of gain.

Animal Feed↗

Effect of LHRH on cyproterone-acetate-injected adenohypophyses of castrated mice.

Luteinizing hormone releasing hormone (LHRH)-treated adenohypophyses from castrated, cyproterone acetate-injected adult male mice were studied with transmission electron microscopy (TEM). LHRH-treated luteinizing hormone (LH) gonadotrophs (types a and b) in castrated mice showed accumulation of secretory granules at the capillary pole, dilated Golgi apparatus and extensive rough endoplasmic reticulum (RER) profiles. Following treatment, granular content in LH type-a gonadotrophs was decreased and profiles of secretory granules were seen in the intercellular and perivascular spaces. Some RER cisternal hypertrophy was noted, and the Golgi apparatus was dilated. In LH type-b gonadotrophs there were secretory granules lined along the plasma membranes, several lysosomes, multivesicular bodies, and short RER profiles. LHRH stimulated secretory granules release of LH gonadotrophs in cyproterone-acetate-treated castrated mice. Cyproterone acetate may have blocked hypothalamic LHRH stimulation of pituitary LH gonadotrophs.

Animals↗

Histochemical studies on genetical control of hormonal enzyme inducibility in the mouse. VI. Effects of short term castration.

The regional histology and esterase activity of the mouse epididymis after 24, 48, and 72 hr castration is reported. Differential sensitivity to androgen deprivation among the various epithelial cell types is described, allowing of positive identification of the cell types previously observed to survive long-term castration. The possibility of an androgen binding protein, as described in the rat and rabbit, is suggested on morphological grounds. The epididymal body appears to contain a class of highly androgen sensitive cells that degenerate rapidly following castration and a second class that survive from which regeneration occurs on testosterone replacement.

Animals↗

Effect of castration on the metabolism of L-ascorbic acid in rat prostate.

An appreciable decrease in the contents of prostatic ascorbic acid and dehydroascorbic acid along with an increase in diketogulonic acid was seen in rats ten days after castration. Castration caused a decrease in the activities of such biosynthetic enzymes as L-gulono-gamma-lactone oxidase and D-glucuronolactone-delta-hydrolase with no significant alteration in the activity of L-gulono-gamma-lactone hydrolase in the rat prostate. The activity of dehydroascorbatase, one of the degrading enzymes was, however, found to be elevated in castration. The implication of these results has been discussed.

2,3-Diketogulonic Acid↗