Effect of antiandrogen cyproterone acetate on the action of testosterone on mouse kidney.

The loss of endogenous testosterone in castrated male mice leads to a marked decrease in seminal vesicle and kidney tissue weight. 21 days' administration of exogenous testosterone abolished the effect of castration on the seminal vesicles and kidney tissue. The antiandrogen cyproterone acetate produced significant changes in the target tissue for androgens, i.e. in the seminal vesicles. In every case it blocked the action of both exogenous and endogenous testosterone on the seminal vesicles, but failed to block the "renotropic" action of testosterone, expressed as relative kidney weight. Contrary to its effect on the seminal vesicles, it did not influence relative kidney weight in normal animals. It likewise did not block the effect of exogenous testosterone on kidney tissue. The mechanism of the action of cyproterone acetate in androgen-dependent tissues is known to consist in inhibition of androgen binding to specific cell receptors in the target tissues. Some of the specific androgen receptors in mouse kidney are evidently different in character from those in the accessary sex glands, that being the reason why cyproterone acetate has an antiandrogenic, but not an antirenotropic effect. In agreement with experiments on rats, adrenal weight also decreases in mice after the administration of cyproterone acetate.     

Differential regulation of androgen receptors in the separate rat prostate lobes: androgen independent expression in the lateral lobe

In order to understand the hormonal regulation of androgen receptors (AR) in the separate lobes of the rat prostate gland, the present study examined AR levels in the ventral, dorsal and lateral prostate lobes as a function of androgen withdrawal to complete prostatic regression and subsequent testosterone replacement. In the intact rat, the 3 prostate lobes contained significantly different amounts of androgen binding sites. Mean number of total cellular AR in the ventral, dorsal and lateral lobes was 7370, 1690, and 1015 fm/mg DNA, respectively. These receptors were primarily localized within the nuclear fraction of homogenized tissue: ventral, 86%; dorsal, 83%; and lateral, 100% nuclear localization. Androgen withdrawal was initiated via castration and rats were sacrificed 1, 2, 3, 5, 7, 10 and 14 days thereafter. Nuclear AR levels fell rapidly to 5, 24 and 30% of intact values by 48 h in the ventral, dorsal and lateral lobes, respectively. Levels of nuclear AR continued to decline in the ventral and dorsal lobes to undetectable levels by Day 10. In marked contrast, lateral lobe nuclear AR began to increase on Day 3 postcastration, reaching intact values by Day 7 and 133% intact levels by Day 14. Cytosolic AR in the ventral and dorsal lobes initially increased following castration, but subsequently declined to low levels by Day 14. Cytosolic AR were not detectable in the lateral prostate at any time point following castration. To determine the nuclear AR response to testosterone at this time, 14 day castrate rats were given 2 cm testosterone implants and sacrificed 1, 3, 5, 7, 10 and 14 days thereafter. As expected, nuclear AR rapidly returned in the ventral and dorsal lobes by Day 1 and reached a plateau by Day 5. A short term response to androgen exposure occurred in the lateral lobe where an immediate 9-fold increase in nuclear AR quantity was observed; however, these levels rapidly declined to pre-implant values by Day 5 and remained at that level despite continued exposure to testosterone. These f findings indicate that while nuclear AR levels in the ventral and dorsal prostate are primarily regulated by androgens, a testosterone-independent component exists within the lateral lobe.     

Metalloproteinase activities expressed during development and maturation of the rat prostatic complex and seminal vesicles.

The objective of this study was to characterize proteinase activities expressed during development and maturation of the prostate gland and seminal vesicles of the rat by using gelatin-and casein-containing SDS polyacrylamide gel zymography. The prostatic complexes of 2- and 10-day-old animals and the individual lobes of the prostate (ventral, dorsolateral, and anterior [coagulating gland]) and the seminal vesicles of 15-day-old animals expressed prominent gelatinolytic activities of approximately 64, 71, and 76 kDa. These activities had properties of metalloproteinases; i.e., they were stimulated by Ca2+ and inhibited by EDTA and EGTA. They were greatly diminished by 52 days of age (immediately postpuberty) and were not detected in the dorsal lobe of the adult. Less active gelatinolytic proteinases with molecular masses of approximately 34 and 43 kDa were expressed in the developing prostatic complexes and individual lobes and seminal vesicles, but they were not detected in postpubertal animals. Weak gelatinolytic activities of 82, 85, and 89 kDa were found in the prostatic complexes; these activities were greatly diminished in all prostate lobes with sexual maturation but were expressed in the seminal vesicles at all ages. A large-molecular-mass Ca(2+)-independent proteinase of 130 kDa or greater was first detected in the dorsolateral prostate at 21 days of age. This activity was expressed in both the lateral and dorsal lobes of the adult but was greater in the lateral lobe. Proteinase activities of about 22 and 26 kDa that were not stimulated by Ca2+ were detected in the ventral prostate at 15 days of age by means of both gelatin and casein gels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of feed restriction on Hershberger and pubertal male assay endpoints

BACKGROUND: The Hershberger and male pubertal onset assays have been identified as possible Tier I screening tests to detect endocrine‐active compounds (EACs). Both tests rely on changes in reproductive and/or accessory sex gland (ASG) weights in young animals. Because chemical treatment may affect growth rate, the relationship between body weight and reproductive/ASG weights was examined using feed restriction (FR) to produce a targeted 10% decrease in body weight. METHODS: In the male pubertal onset assay, 23‐day‐old rats (12/group) were given ad lib feed or FR until euthanized at 45, 49, 52, 56, or 59 days of age. Despite a 10% body weight differential, pubertal onset was not significantly delayed and testes weights were conserved. Absolute prostate, ventral prostate, seminal vesicle, epididymides, and liver weights were decreased by FR. Relative weights for the prostate, ventral prostate, and seminal vesicles were similar to controls, but relative epididymides and liver weights still exhibited FR‐mediated changes. In the Hershberger assay, male rats (12/group) castrated at 36 days of age were given ad lib feed or FR in the presence or absence of testosterone propionate (T) from 46–55, 50–59, or 56–65 days of age. At 56, 60, and 66 days of age, rats were euthanized. In untreated animals, FR did not alter absolute ventral prostate, seminal vesicles, or Cowper's gland weights; however, absolute and relative weights of the levator ani‐bulbocavernosus muscles (LABC) were affected. In T‐treated animals, absolute organ weights (the ventral prostate, seminal vesicles, LABC, and glans penis) were relatively insensitive to FR. The weight of the Cowper's gland was affected only at 66 days of age. RESULTS: These data show that reproductive and ASG organ weight endpoints in the Hershberger and male pubertal onset assays can be influenced by FR levels that produce a 10% change in terminal body weight. CONCLUSIONS: The establishment of objective criteria for a positive or negative result is problematic due to the confounding effects of body weight on some endpoints. Furthermore, a 10% decrease in body weight seems to be excessive as a requirement for high‐dose toxicity in these assays due to possible indictment of agents that are not EACs, as well as potential masking of EAC effects coincident with body weight changes. Minimally, caution must be used in interpreting assay results in the presence of a 10% body weight change, recognizing the possible confounding effects of this degree of growth suppression. Birth Defects Res B 68:363–374, 2003. © 2003 Wiley‐Liss, Inc.     

Demonstration and partial characterization of cytosol receptors for testosterone.

Androgen uptake was investigated in several peripheral organs after administration of (1,2,6,7 minus -3H)testosterone to castrated male rats. The animals were killed after 30 min, the organs were taken out, and the radioactivity was determined after tissue combustion. A relatively high accumulation of androgen was found in pancreas, adrenals, spleen, thigh muscle, kidneys, and liver in addition to the classical androgen target organs coagulation glands, seminal vesicles, prostate, preputial glands, and harderian glands. In a second serier of experiments, nuclear and cytosol fractions were prepared from prostate, seminal vesicles, coagulation glands, preputial glands, spleen, submaxillary glands, kidneys, and pancreas from castrated male rats give (1,2,6,7 minus -3H)testosterone, and these fractions were then characterized by thin-layer and radio-gas chromatography with respect to their patterns of labeled steroids. Only prostate and seminal vesicles were found to contain significant amounts of nuclear 5alpha-(-3H)dihydrotestosterone. The major nuclear androgen was (-3H)testosterone that was the only detectable labeled steroid in coagulation glands, preputial glands, and spleen and that constituted 70% or more of the nuclear radioactivity in seminal vesicles, submaxillary glands, kidneys, and pancreas. These results indicate that testosterone itself may be the predominant active androgen principle in vivo in most androgen target organs and that conversion to 5alpha-dihydrotestosterone is generally not a prerequisite for androgen activity. Using an ultrasensitive micromodification of isoelectric focusing (cf. M. Katsumata and A. S. Goldman (1974), Biochem. Biophys. Acta 359, 112. It was possible to show that cytosol from kidney; submaxillary gland, thigh muscle, and levator ani muscle and nuclei from kidney and submaxillary gland contained androgen-binding proteins with pI's in the region 4.6-5.1 ("4.6 minus 5.1 Complex"). This complex also formed in vitro after incubation of (1,2,6,7 minus -3H)testosterone with cytosol from kidney and submaxillary gland. (1,2,6,7 minus -3H)Testosterone was bound with high affinity to receptor proteins in cytosol from both kidney, submaxillary gland, and thigh muscle with dissociation constants of 5.0 x 10 minus -12 M (kidney), 3.3 x 10 mi;nus -11 M and 4.1 x 10 minus -10 M (two types of binding sites, submaxillary gland), 2.4 x 10 minus -12 M (thigh muscle) and 1.9 x 10 minus -12 M (levator ani muscle). The number of binding sites was in all cases between 1 and 20 fmol/mg of protein. On the basis of these results the hypothesis is presented that a common class of testosterone receptors is present in most organs and that these receptors can be detected both in vivo and in vitro provided methods sensitive enough are utilized.     

Comparison of the effects of gossypol, estradiol-17 beta and testosterone compensation on male rat reproductive organs

The effects of gossypol acetic acid (GAA) were compared with those induced by estradiol-17 beta (E2), testosterone, and a combination of these steroids. GAA was administered s.c. to adult rats at doses of 25 to 30 mg . kg BW . day for 30 days, while steroids in polydimethylsiloxane tubing of various lengths were implanted s.c. for 30 days or longer. GAA and E2 at the doses used had similar effects: they caused a graded atrophy of sex organs, discriminative degeneration of spermatogenic cells, impairment of Sertoli cells, decrease in serum testosterone, reduction in androgen receptor binding and retardation in body growth. Supplementing GAA and E2 treatments with 14-cm testosterone implants had a counteracting effect on organ weight losses: seminal vesicles recovered above, ventral prostate within and epididymides below control values, whereas the testes did not respond. The organs most refractory to supplementation therapy were those in which GAA and E2 were most effective in depressing androgen receptor binding. Aside from having similar antiandrogenic effects as E2 and other steroids, GAA induced a specific flagellar syndrome which testosterone therapy could not prevent, indicating that this action is hormonally independent.     

Morphological and immunohistochemical comparison of three rat prostate lobes (lateral, dorsal and ventral) in experimental hyperprolactinemia

The prolactin plays an important role in the regulation of growth and differentiation of prostate gland besides androgens. The goal of this study was to reveal the influence of elevated prolactin concentration on epithelial cells of prostate. We compared the morphology of epithelial cells of prostate dorsal, lateral and ventral lobes and expression of androgen receptors in these cells in rats with hyperprolactinemia and in control rats. We used sexually mature male Wistar rats. The experimental rats received metoclopramide; the control group received saline in the same way. The prostate dorsal, lateral and ventral lobes were collected routinely for light and electron microscopy. The intensity of immunohistochemical reaction of androgen receptor in epithelial cells of dorsal, lateral and ventral lobes was evaluated by measure of optical density with computer image analysis. The light and electron (transmission and scanning) microscopes were used for morphological observations. Results: In experimental rats twofold increase in prolactin and twofold decrease in testosterone found. In experimental group the expression of androgen receptor was lower in columnar epithelial cells of dorsal and ventral lobes but higher in lateral one. We observed morphological abnormalities in columnar epithelial cells of lateral and dorsal lobes. The columnar epithelial cells of ventral lobes didn't show any morphological changes in hyperprolactinemia.     

Morphometric analysis of the rat ventral prostate and seminal vesicles during prepubertal development: effects of neonatal treatment with estrogen

In a morphometric study on the ventral prostate and seminal vesicles in the rat, we investigated the changes in fibromuscular stroma, glandular epithelium, and glandular lumen. Animals were studied at 15, 30 and 45 days of age. The rapid prepubertal growth started earlier in the ventral prostate than in seminal vesicles. In addition, the effects of neonatal administration of estrogens on the different tissue compartments were studied, comparing rats that had been castrated and/or treated with estrogen at birth to intact animals at 15 days of age. Estrogens caused a decrease in the volume of the glandular epithelium and increased the volume of the fibromuscular stroma in both ventral prostate and seminal vesicles. Castration partially abolished the estrogen-induced growth of the stroma, which suggests that the growth is dependent on testicular factors. The difference in proportion of the fibromuscular stroma between the two glands is evidence that the size of the whole seminal vesicles has increased whereas the size of the ventral prostate has decreased.     

Androgen receptors from the epididymis of the rhesus monkey

The demonstration and partial characterization of androgen "receptors" in the epididymis of the rhesus monkey are reported. The affinity of specific binding sites for dihydrotestosterone was higher than that for testosterone while cortisol and corticosterone did not compete. Density gradient analysis of the cytosol revealed that macromolecules responsible for specific binding have a sedimentation coefficient of 8 S. The isoelectric point of the complex was 5.5 and thermoability was evidenced by the release of hormone during incubation at 27 degrees C (20% and 44% after 30 and 60 minutes, respectively.) A concomitant decrease in radioactivity bound to 8 S cytoplasmic components suggests the translocation into the nuclei of a modified 8 S-receptor complex. These data indicate the presence of similar cytoplasmic and nuclear androgen receptors in the monkey seminal vesicles and prostate gland.     

Prostate androgen receptor: immunohistological localization and mRNA characterization

Four androgen receptor (AR) specific monoclonal antibodies were used for the immunohistochemical localization of AR in the human prostate tissue. The prostate tissue consisted of alveoli embedded in fibromuscular stroma and lined with a single layer of columnar secretory epithelial cells. The immunoreactive ARs were found predominantly in the nuclei of epithelial cell, suggesting ARs, like estrogen receptors and progesterone receptors, are mainly nuclear proteins. Northern blot hybridization showed that AR mRNA is about 9 kilobases (kb) and relative abundant in the androgen-sensitive organs, such as ventral prostate, dorsolateral prostate and seminal vesicle.     

Pneumadin in the ventral prostate and seminal vesicles of estradiol-treated rats: RIA and immunocytochemical studies

Pneumadin (PNM) is a decapeptide (the rat peptide: Tyr-Gly-Glu-Pro-Lys-Leu-Asp-Ala-Gly-Val-NH2) isolated from mammalian lungs. Human and rat PNM differ only by substitution of one amino acid--Tyr/Ala. PNM evokes an antidiuretic effect via a potent stimulation of arginine-vasopressin (AVP) release. By means of recently established, highly specific RIA method, high concentration of PNM had been found in the rat ventral prostate. Castration resulted in a profound drop in PNM concentration, an effect prevented by testosterone replacement. The present studies were aimed at investigating the effect of prolonged estradiol administration on PNM concentration, content and localization in the prostate and seminal vesicles of the rat. Depo estradiol (estradiolum valerianicum) administration to adult male rats resulted in a notable atrophy of ventral prostate and seminal vesicles. During the entire experiment (till day 30 after administration), PNM concentration in ventral prostate was similar to that seen in intact animals, while peptide content per gland was markedly lowered. PNM immunostaining was observed in prostate epithelium of estradiol-treated rats and its localization resembled that observed in intact animals. Nearly 40 times lower PNM concentration than in ventral prostate was found in seminal vesicles. In contrast to prostate, on days 20 and 30 of estradiol treatment PNM concentration in seminal vesicles was higher than in intact rats. However, due to profound seminal vesicle atrophy, PNM content per entire gland was notably lowered in estradiol-injected rats. By immunocytochemistry, PNM-immunoreactive substances were not found in seminal vesicles of either intact or estradiol-administered rats. High PNM concentration in the rat prostate suggests its important role in the function of the gland.     

Androgen regulation of androgen receptor content and distribution in the ventral and dorsolateral prostates of aging AXC rats

Total androgen receptor content of ventral or dorsolateral prostate of intact, aged (730–740 day old) rats is decreased 50% when compared to intact, young mature (150–170 day old) rats. Treatment with exogenous testosterone increased ventral and dorsolateral prostate androgen receptor content per cell in aged rats to values identical to those of prostates of young mature rats. The increase in prostate receptor content was not attributable to testosterone mediated cellular hypertrophy or hyperplasia. At 24 hr post-orchiectomy ventral prostate cytoplasmic androgen receptors are depleted of endogenous androgen, without any decrease in number of receptors per cell, and nuclear androgen receptors are undetectable. During 30 to 60 min after a single 200 μg testosterone injection, ventral prostate nuclear receptor content increased to the level of intact control rats without producing any reduction in total cytoplasmic androgen receptor content. Although dorsolateral prostate is devoid of cytoplasmic androgen receptor, the effects of orchiectomy and testosterone treatment upon nuclear androgen receptor are comparable to those seen in ventral prostate. These effects of orchiectomy and testosterone injection upon prostatic receptor content and distribution were identical in prostates of young and aged rats. Our studies show that receptor processing in prostates of young and aged rats does not involve a process by which nuclear receptor is derived by depletion of cytoplasmic receptor. Moreover, our studies of the effect of short-term (48 hr) exogenous testosterone treatment upon androgen receptor content in prostates of aged rats are the first demonstration that androgen receptor content may be enhanced independent of generalized androgen mediated anabolic effects in prostate.     

Farnesyl diphosphate synthase is abundantly expressed and regulated by androgen in rat prostatic epithelial cells

Farnesyl diphosphate synthase (FPPS) has been identified as an androgen-response gene in the rat ventral prostate using a highly sensitive PCR-based cDNA subtraction technique. FPPS is an essential enzyme that catalyzes the synthesis of farnesyl diphosphate (FPP), which is required for cholesterol biosynthesis as well as protein prenylation. We have characterized the expression of FPPS in the rat prostate in response to androgen manipulation. Northern blot analysis showed that castration induced a 10-fold down-regulation of FPPS mRNA within 24 h in the ventral prostate and androgen replacement up-regulated FPPS mRNA rapidly in the regressed ventral prostate of a castrated rat. The expression of FPPS was also regulated by androgen in the lateral and dorsal prostate, indicating that FPPS is important to androgen action in all three lobes of the prostate. Western blot analysis showed that FPPS protein level was also regulated by androgen in the prostate. Northern blot analysis of tissue specificity indicated that FPPS was most abundantly expressed in the ventral prostate of a mature rat and was responsive to androgen manipulation in the prostate and seminal vesicles, but not in other tissues. In situ hybridization study showed that FPPS mRNA was localized to the prostatic epithelium. Interestingly, the expression of FPPS was elevated in Dunning rat prostate tumor cell lines. The above findings suggest that FPPS has the potential to play an important role in androgen action and prostate cancer progression.     

Age dependent changes in androgen metabolism in the rat prostate

Oxidation and reduction of androstenedione, testosterone, dihydrotestosterone (DHT), 5 alpha-androstan-3 alpha,17 beta-diol and 5 alpha-androstane-3 beta,17 beta-diol (3 alpha- and 3 beta-A'diol) were measured in homogenates from the ventral prostate (VP), dorsal prostate (DP), lateral prostate (LP), the coagulating gland (CG) and seminal vesicles (SV) in intact rats of different ages from young mature (3-6 months) to senescent rats (20-30 months). Some very old intact rats (30-32 months) were treated with testosterone in order to rule out the effect of this hormone on androgen metabolism. The enzymatic activities for young mature rats were significantly altered by increasing age, both with regard to differences between the various organs as well as differences in cofactor requirement. With increasing age, the specific activity of most enzymes gradually decreased. With testosterone as substrate, 5 alpha-reductase activity was significantly reduced in the old rats in all tissues studied and was undetectable in the oldest animals in the VP and the SV. On the other hand, 5 alpha-reductase could not be recorded in any tissue in any tissue in old rats when androstenedione was the substrate. 3 alpha-Hydroxysteroid oxidoreductase (3 alpha-HSOR) in the VP was the only enzyme which did not decrease in activity by increasing age. In the other lobes this enzyme activity decreased similar to 3 beta-hydroxysteroid oxidoreductase (3 beta-HSOR) and the 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR) activity. Administration of testosterone to old rats increased the specific activity of most of the enzymes studied.     

Effects of α-difluoromethylornithine, an enzyme-activated irreversible inhibitor of ornithine decarboxylase, on testosterone-induced regeneration of prostate and seminal vesicle in castrated rats

1. Castration of adult rats markedly decreases the amounts of polyamines (putrescine, spermidine and spermine) and of RNA and DNA in the ventral prostate and the seminal vesicle. 2. Daily injections of testosterone propionate to rats castrated 7 days previously increase polyamine and nucleic acid contents more rapidly in the seminal vesicle than in the ventral prostate. 3. After 7 days of androgen treatment, polyamine and nucleic acid contents of the seminal vesicle are significantly higher than those of intact animals. Nucleic acid, but not polyamine, contents return to normal values during the next 4 days of continued treatment. In the prostate, androgen treatment increases polyamine and nucleic acid contents to, but not above, normal values. 4. Repeated doses of alpha-difluoromethylornithine, a potent enzyme-activated irreversible inhibitor of ornithine decarboxylase, totally blocked the testosterone-induced increase of putrescine and spermidine in the ventral prostate and of putrescine in the seminal vesicle. They slowed significantly the accumulation of spermine in the ventral prostate and of spermidine in the seminal vesicle. alpha-Difluoromethylornithine also retarded the testosterone-induced accumulation of RNA in the ventral prostate. However, no clear correlation was apparent between accumulation of polyamines and of nucleic acids in the two organs. 5. alpha-Difluoromethylornithine markedly slows the testosterone-induced weight gain of the prostate, but not of the seminal vesicle. Cytological studies suggest that this effect on the prostate is due to inhibition of the androgen-induced restoration of the secretion content of prostatic acini.     

Regulation of androgen receptor protein and mRNA concentrations by androgens in rat ventral prostate and seminal vesicles and in human hepatoma cells

The effects of androgen withdrawal and replacement on the concentrations of androgen receptor (AR) protein and AR mRNA were investigated in rat ventral prostate and seminal vesicles and in cultured human hepatoma (HepG2) cells. AR mRNA concentrations were determined by Northern blotting with single stranded AR cRNA as the hybridization probe, whereas antibodies raised against two synthetic 17-amino acid long peptides corresponding to the N-terminal and steroid-binding regions of the AR were employed in immunological receptor assays. AR mRNA levels in both prostate and seminal vesicles increased about 2-fold within 24 h after castration and continued to rise within the next 48 h to values that were 9- to 11-fold higher than those in intact controls. Administration of pharmacological doses of testosterone (400 micrograms steroid/day) to 1-day castrated animals for 24-48 h brought about a decrease in AR mRNA levels in accessory sex organs to levels in intact controls. Similar results were obtained in cultured HepG2 cells where a switch to serum- and steroid-free medium elicited a rapid increase (approximately 4-fold in 10 h) in the AR mRNA level, which was prevented by inclusion of 10(-7) M testosterone in culture medium. Similar, but quantitatively less marked, changes occurred in the AR protein concentration in prostate, seminal vesicles, and HepG2 cells, as determined by immunoblotting using antibodies against AR peptides. In addition, immunohistochemical studies showed that AR is a nuclear protein of the prostatic epithelial cells in both intact and castrated rats, and suggested that short term castration increases the concentration of nuclear AR in the prostate. Taken together, these data indicate that androgens down-regulate the concentration of AR protein and AR mRNA in a variety of target tissues.     

Testicular and accessory organ degeneration induced by subcutaneous injection of quinacrine in the gerbil (Meriones hurrianae jerdon)

Quinacrine (an acridine homologue of chloroquine) administration (30 mg kg^?1 day^?1 for a period of 25 days) resulted in mass atrophy of the spermatogenic elements. Seminiferous tubule and Leydig cell nuclear dimensions were reduced. The luminal epithelium was severely damaged. The lumen of epididymides and was deferens were devoid of spermatozoa.Castration followed by quinacrine administration (30 mg kg^?1 for 25 days) denuded the tubules of the caput epididymides. Simultaneous testosterone therapy could not prevent the damage.Quinacrine administration depleted the concentration of RNA, protein and sialic acid in the testes, epididymides and seminal vesicles, whereas the total cholesterol concentration in the testes was elevated. Castration/ castration + quinacrine administration also brought about a significant reduction in the RNA, protein and sialic acid concentrations in the accessory sex organs. Simultaneous testosterone treatment prevented the action of quinacrine on the accessory sex organs and enhanced the production of RNA, protein and sialic acid in epididymides and seminal vesicles of castration/ castration + quinacrine treated gerbils.Serum transaminases (SGOT and SGPT) were moderately elevated, whereas haemoglobin/hematocrit/blood sugar/blood urea levels were in the normal range in quinacrine-treated animals.Histopathological examination of the liver did not show any damage.Leydig cell impairment and decreased production of RNA and sialic acid in the testes points to deficient androgen production following the administration of quinacrine hydrochloride.     

Endocrine profile of Win 49596 in the rat: a novel androgen receptor antagonist

Win 49596 is a new orally active, steroidal androgen receptor antagonist. Win 49596 inhibited ventral prostate, seminal vesicle and levator ani weight gain in either 5 alpha-dihydrotestosterone (DHT) or testosterone propionate-treated castrated, immature male rats. In intact, adult male rats, Win 49596 significantly inhibited weight gain by the ventral prostate, dorsal lateral prostate and seminal vesicles, but not the testes at doses as low as 50 mg/kg/day x 14 p.o. However, daily oral administration of equivalent antiandrogenic doses of either Win 49596, ICI 176,334, or flutamide for 14 days to mature, intact male rats resulted in elevations of circulating testosterone of approximately 3-, 2-, and 10-fold, respectively. At doses as high as 400 mg/kg p.o., Win 49596 did not have androgenic, progestational, estrogenic or antiestrogenic activity in rat or rabbit models. However, in the Clauberg assay, Win 49596 did have weak antiprogestational activity at doses of 25-400 mg/kg/day p.o. These data indicate that Win 49596 is a peripherally selective antiandrogen that has minimal effects on circulating testosterone levels and is devoid of hormone agonist activity. Thus, Win 49596 may be useful for the treatment of androgen dependent conditions such as benign prostatic hyperplasia and prostatic cancer.     

The influence of aging on androgen dynamics in the male rat

Androgen assimilation was investigated in a variety of accessory sex organs (seminal vesicles and anterior, dorsal, lateral, and ventral prostates) and in several nonaccessory sex organs in male Wistar rats. After administration of a pulse dose of [³H]testosterone in vivo to intact young (3–4 months old) rats, [³H]testosterone was the primary radioactive steroid recovered from most organs examined, except for the secondary sex glands where the reduced metabolites, [³H]5α-dihydrotestosterone (DHT) and [³H]5α-androstanediol(s), predominated. At longer postinjection times, [³H]DHT was preferentially retained in the accessory sex glands, presumably reflecting intracellular metabolism of [³H]testosterone to this compound and subsequent specific binding of [³H]DHT to receptor proteins. At the longest postinjection interval investigated, the ventral prostate retained greater concentrations of [³H]DHT than the lateral prostate which in turn had a higher [³H]DHT concentration than the seminal vesicles or anterior or dorsal prostates. The latter three glands retained approximately equal concentrations of [³H]DHT. Scatchard plot analyses of cytosol binding in 24-h castrates indicated that with one exception, the level of high affinity DHT binding sites was generally correlated with the retention of [³H]DHT in vivo in intact rats. Specifically, while the affinity for DHT binding in all accessory sex organs was the same, the number of high affinity binding sites per mg wet tissue weight was on the order of ventral prostate > anterior prostate ≥ seminal vesicles ≥ dorsal prostate > lateral prostate. Studies of the influence of aging to 22–26 months revealed no apparent differences in the affinity of the DHT receptor for its ligand in any of the accessory sex glands from 24-h castrates when the receptors were present in levels sufficiently high to quantify. The concentration of available DHT receptors with advancing age remained constant in the anterior and dorsal prostates, increased in the seminal vesicles, and declined in the ventral and lateral prostates. The decreases observed in the ventral prostate were only partial, but the receptors of the lateral prostate declined to nondetectable levels.     

Carcinogenesis in accessory sex organs of rats induced by 3,2′-dimethyl-4-aminobiphenyl: response to androgen deprivation

 It is generally accepted that early human prostate cancers reveal higher androgen dependency than do advanced ones. In the present study, we examined whether the animal model of prostate cancer has already lost androgen dependency at the early stages of carcinogenesis. At experimental week 46, androgen deprivation was induced in rats and the incidences of atypical hyperplasia and cancer were examined in the ventral, dorsolateral prostate, coagulating glands, and seminal vesicles. Androgen deprivation significantly lowered the incidence of atypical hyperplasia in all four organs. As for the incidence of cancer, no significant differences were observed in the coagulating glands and seminal vesicles. Regarding atypical hyperplasia, androgen deprivation significantly decreased the proliferative cell nuclear antigen labeling index in the coagulating gland and seminal vesicles. The presence of cancer was also decreased in the coagulating gland but not in the seminal vesicles. With control group specimens, more intense staining of androgen receptor was observed in atypical hyperplasias than in cancers. Compared with the atypical hyperplasias, the cancers revealed low androgen dependency at the early stages of carcinogenesis. The cancers in the seminal vesicles also revealed higher androgen independency than did those in the coagulating gland. Accepted: 6 May 1997