Differential androgen uptake by the lobes of the rhesus monkey prostate.

The prostate of the rhesus monkey (Mucacca mulatta) consists of a cranial and a caudal lobe. The uptake of [3H] testosterone by these 2 lobes has been measured and compared with control tissues. A significantly higher uptake of radioactivity was found in the caudal lobe when compared to cranial as well as other control tissues. The uptake of radioactivity by the caudal and cranial lobes was suppressed when unlabelled testosterone was introduced into the incubation media. The relationship between these 2 lobes of the monkey prostate and the central and peripheral zones of the human prostate is described.     

A soluble androgen receptor in the cytoplasm of the male mastomys prostate

Summary A steroid receptor protein was isolated from the cytoplasmic fraction of Mastomys prostate. Following in vivo and in vitro labelling of the tissue with tritiated testosterone or dihydrotestosterone, samples were analysed by gel exclusion chromatography or sucrose density gradient centrifugation. A steroid receptor complex was isolated on Sephadex G-200. Analysis of the steroids associated with this complex showed that the major part of the bound radioactivity was 5 -dihydrotestosterone. The binding was inhibited by unlabelled testosterone and could not be demonstrated in the liver cytosol. Using sucrose desity gradient centrifugation, the dihydrotestosterone receptor complex sedimented at 5.6 s together with heavier aggregates. In the presence of 0.4 M KCl a single complex was sedimented at 4. 6 s. The results demonstrate a receptor protein in the cytosol of the Mastomys prostate which binds to dihydrotestosterone and is comparable to that of rat prostate.     

The Extragonadal Origin of 5α-Reduced Androgens in the Peripheral Circulation of the Adult Male Rabbit

The extragonadal source of the high levels of 5α-reduced androgens in the peripheral blood of the male rabbit has been investigated. Adult 3-day castrated rabbits each received a single intravenous injection of ³H-labelled testosterone, and blood plasma was collected at various intervals thereafter. Two h post injection, animals were killed, various accessory sex organs and peripheral tissues removed, and radioactively labelled testosterone and its metabolites quantified by radio-gas-liquid chromatography (radio-g.l.c.). Five min after the injection of ³H-labelled testosterone, the major labelled metabolite in blood plasma was 5α-dihydrotestosterone with small amounts of 3α/3/β-androstanediols and androstenedione. After 2 h significant quantities of ³H-labelled 5α-dihydrotestosterone had accumulated in the accessory sex organs, whereas only small amounts were found in 'non-sexual' peripheral tissues such as skeletal muscle. However, substantial amounts of 5α-dihydrotestosterone were formed by several peripheral tissues of 3-day castrated rabbits, when they were incubated in vitro with ³H-labelled testosterone: the most active were skeletal muscle, liver and abdominal skin. Some formation of 3α/3/β-androstanediols occurred in all tissues. It is concluded that in the male rabbit skeletal muscle and skin are likely to be a significant extragonadal source of 5α-reduced androgens for the maintenance of accessory sex organs such as the prostate and epididymis, which have low 5α-reductase activity but a high capacity to retain 5α-dihydro-testosterone.     

Effect of prolactin and the anti-prolactin bromocriptin on the testosterone uptake and metabolism in androgen-sensitive and insensitive canine organs

Summary Prolactin promotes the growth and function of the prostate in low doses, whereas high doses or previous castration reduce this effect. The antiprolactin bromocriptin should reverse the prolactin action. In the castrated dog the highest accumulation of H³-testosterone given i. v. occured in the prostate as compared with muscle, urethra, penis, liver and kidney. Prolactin pretreatment increased the radiosteroid uptake only in the liver. Conversely, bromocriptin suppressed the tracer incorporation into the liver, but increased prostatic accumulation. The highest testosterone reduction occurred in the prostate of the untreated castrated dogs as compared with other organs. Prolactin suppressed 5-dihydrotestosterone formation but otherwise did not significantly influence testosterone turnover. Bromocriptin, however, stimulated dihydrotestosterone formation in the prostate and caused complete inhibition of hepatic testosterone reduction.Parlodel^R from Sandoz AG, CH-4000 BaselSupported by the Helmut Horten-Foundation     

EFFECT OF EXOGENOUS TESTOSTERONE ON PROSTATE VOLUME, SERUM AND SEMEN PROSTATE SPECIFIC ANTIGEN LEVELS IN HEALTHY YOUNG MEN

Purpose

We investigate and define the effects of exogenous testosterone on the normal prostate.

Materials and Methods

A total of 31 healthy volunteers 21 to 39 years old were randomized to receive either 100, 250 or 500 mg. testosterone via intramuscular injection once a week for 15 weeks. Baseline measurements of serum testosterone, free testosterone and prostate specific antigen (PSA) were taken at week 1. Semen samples were also collected for PSA content and prostate volumes were determined by transrectal ultrasound before testosterone injection. Blood was then drawn every other week before each testosterone injection for the 15 weeks, every other week thereafter until week 28 and again at week 40. After the first 15 weeks semen samples were again collected, and prostate volumes were determined by repeat transrectal ultrasound.

Results

Free and total serum testosterone levels increased significantly in the 250 and 500 mg. dose groups. No significant change occurred in the prostate volume or serum PSA levels at any dose of exogenous testosterone. Total semen PSA levels decreased following administration of testosterone but did not reach statistical significance.

Conclusions

Despite significant elevations in serum total and free testosterone, healthy young men do not demonstrate increased serum or semen PSA levels, or increased prostate volume in response to exogenous testosterone injections.     

Autoradiographic localization of [3H]oestradiol in epididymis, seminal vesicles and prostate of the fetal guinea-pig

The selective uptake and localization of radioactivity in the fetal male reproductive organs (epididymis, seminal vesicles and prostate) of the guinea-pig (50-60 days of gestation) after in-vivo and in-situ subcutaneous injection of [3H]oestradiol was investigated by autoradiography. In 50-day-old fetuses, the different areas of the epididymis showed selective retention of radioactivity in the nuclei of peritubular and stromal cells surrounding the epididymal duct; no retention was observed in the epididymal epithelium. A similar distribution of silver grains was observed in the 60-day-old fetus. Seminal vesicles and prostate sections from both 50- and 60-day-old fetuses showed concentration and retention of radioactivity only in stromal cells, whereas the epithelium did not exhibit silver grains. In all the tissues studied, the nuclear labelling was abolished after injection of [3H]oestradiol plus a 100-fold excess of non-labelled oestradiol. As the mesenchyme surrounding the epithelia of the epididymis, seminal vesicles and prostate were labelled selectively with [3H]oestradiol, it is suggested that during fetal life of the guinea-pig the mesenchymal stroma of these fetal male reproductive organs may be considered as a target tissue for oestrogen.     

Low serum testosterone levels are predictive of prostate cancer

Purpose

Although hormones play fundamental roles in prostate growth, their clinical significance is not completely clear. Aims of present study were to assess whether testosterone and serum sex hormone levels are predictors of benign prostatic hyperplasia (BPH) or prostate cancer (PC) and to verify whether prostate cancer is associated with low testosterone levels, and to test association between testosterone levels and known prognostic factors in prostate cancer.

Methods

In 206 consecutive patients with benign prostatic hyperplasia or prostate cancer testosterone, follicle-stimulating hormone, luteinizing hormone and prolactin levels were tested and correlated with disease. In patients with prostate cancer, hormone levels were also correlated with known prognostic factors. Predictive value was assessed for age, prostate-specific antigen (PSA), PSA ratio, PSA density, prostate volume and serum sex hormone levels using multiple logistic regression analysis and receiver operating characteristic curves.

Results

Considering sex hormones, only testosterone levels were significantly lower in patients with prostate cancer than those with BPH; testosterone levels appear to be independent predictor of prostate cancer, enhancing predictive accuracy for BPH and PC. Testosterone levels do not seem to be associated with known clinical prognostic factors.

Conclusions

This study supports experimental findings that testosterone levels are predictor of prostate cancer and that prostate cancer is frequently associated with low testosterone levels. In the diagnostic work-up for prostate cancer, adding testosterone determination to PSA test may improve predictive accuracy.     

前列安栓在大鼠体内的药代动力学研究

目的 :研究前列安栓在大鼠体内的吸收及分布 ,探讨中药复方药代动力学研究的方法 ,并为该药在临床上的合理使用提供依据。　方法 :雄性大鼠直肠给药 ,剂量为 5g生药 (2 0 0 μCi) /kg,于规定时间分批取血、前列腺、直肠及相关脏器测定放射性。　结果 :药后 5min即可从血液中测到放射性 ,血液药 时曲线符合开放型二室模型 ;药后 5min从靶器官 (前列腺 )中也测到放射性 ,药物放射性在前列腺中的富集浓度高于其它器官 (直肠、肝、肾除外 ) ,至 2 4h仍维持一定水平 ;除直肠外 ,药物放射性在肝、肾中的水平最高。　结论 :该药自直肠吸收迅速 ,并迅速到达靶器官 (前列腺 ) ,易于前列腺中富集 ,这对前列腺炎及前列腺增生的治疗有特殊意义 ;肝、肾可能是该药代谢和排泄的主要场所     

32P-玻璃微球间质给药体内生物学分布与代谢

目的 观察32P-玻璃微球(32P-GMS)间质给药后体内生物学分布与代谢.方法 120只小鼠分别经肝脏或肌肉注射32P-GMS,每只(1.80±0.05)MBq/50μl,不同时间点处死取血及脏器计算每克组织百分注射剂量率(%ID/g);12只大鼠肝脏、肌肉每只注射(18.0±0.5)MBq/0.5 ml,收集排泄物测累积排泄率.结果 小鼠肝脏组给药肝叶%ID/g 0时最高为1.38,15 nin降至0.71,非给药肝叶峰值15 min为0.52,4 h之后左右肝叶无区别;肺组织计数率值1 h内上升,肝肺累积分流率为37.9%.肌肉组注射点%ID/g0时为31.47,15 nin～8 h为25.06～11.92(中值20.97),12 h为8.70,24 h～14 d为3.54～2.02(中值2.51),其他主要脏器放射性接近本底水平.大鼠肝脏组粪便和尿液14 d累积排泄率分别为0.0751%和0.0586%;肌肉组分别为0.0401%和0.0385%.结论 32P-GMS间质注射适用于除肝脏以外的体内组织脏器恶性实体瘤的治疗.     

Prostatic carcinoma: Plasma kinetics and intraprostatic metabolism of testosterone in low-dose estrogen-treated patients in vivo

Plasma kinetics, in vivo uptake, and intraprostatic metabolism of ³H testosterone was investigated in 9 patients with advanced carcinoma of the prostate. The metabolic effect of low-dose ethinyl estradiol was studied (estrogen suppressed testosterone, luteinizing hormone, and follicle-stimulating hormone). The production rate of testosterone was lowered, the elimination of androgen from plasma delayed. The uptake of testosterone and metabolites by the prostatic carcinoma was suppressed. Estrogen did not alter significantly the intraprostatic androgen turnover.     

Biodistribution of liposome-associated bupivacaine after extradural administration to rabbits

After one extradural injection of 0.25% bupivacaine 0.3 ml and 3H- bupivacaine 0.005 mCi in multilamellar liposomes, no systemic radioactivity (plasma, liver, heart muscle) was obtained for 1 h, and the labelling was less than that of systemic distribution of plain bupivacaine for the following 3 h. In contrast, radioactivity in the lumbar spinal nerves peaked in the first hour and remained higher than that of plain bupivacaine for 4 h. No radioactivity was measured in cerebrospinal fluid. Small unilamellar vesicles incorporating 3H- cholesterol did not significantly label spinal nerves and central nervous structures indicating that the mode of action of liposomal bupivacaine did not involve uptake by nerve structures. Rapid uptake of radioactivity by spinal nerves suggested exchange of bupivacaine between liposomes and nerve sheaths.      

Comparison of effects of parathyroidectomy and ethane-1-hydroxy-1,1-diphosphonate (EHDP) administration upon bone synthesis of hydroxyproline and urinary excretion of hydroxyproline in rats

Summary Disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) may impair mineralization and reduce turnover of bone. However, its administration has been shown to lead to an accumulation of osteoid in both man and the rat. Using rats, the effects of surgical parathyroidectomy and administration of EHDP (30 mg EHDP/kg body weight by subcutaneous injection daily for 5 days) upon bone composition, uptake of³H-proline into hydroxyproline in bone and the subsequent urinary excretion of labelled and unlabelled hydroxyproline have been compared. Both parathyroidectomized (PTX) rats and EHDP-treated animals accumulated more hydroxyproline in bone and excreted less total urinary hydroxyproline than sham-PTX control animals, the changes induced by EHDP being of greater magnitude than those induced by surgical parathyroidectomy. Skeletal buildup of hydroxyproline was associated with decreased catabolism of mature collagen rather than enhanced synthesis of hydroxyproline in bone. EHDP administration, although decreasing urinary excretion of newly synthesised hydroxyproline, did not alter the skeletal synthesis of hydroxyproline as measured by uptake of³H-proline. In all parameters measured, responses to EHDP were similar in PTX and sham-PTX rats. It is concluded that depression of parathyroid hormone mediated bone turnover may have contributed to, but did not fully account for, the lowering of bone turnover and changes in bone composition induced by EHDP in sham-PTX rats in the present experiment.     

132-hydroxy-bacteriopheophorbidea-methylester pharmacokinetics in mice bearing Lewis lung carcinoma

The photosensitiser 13²-hydroxy bacteriopheophorbide a-methylester (13²-OH-BPME) is characterised by a high absorption coefficient at the far red wavelength 750 nm and a good singlet oxygen quantum yield. The pharmacokinetics of 13²-OH-BPME was studied on the Lewis lung carcinoma in mice after i.v. administration of 5 mg/kg body weight at different incubation intervals. The accumulation dye was chemically extracted from selected tissues and the concentrations were measured by absorption spectroscopy. The parenchymatous organs, liver, spleen and kidney, showed maximum 13²-OH-BPME concentrations after 2 h incubation (liver, spleen) and 4 h postinjection (kidney). A high uptake was detected in the lung with the maximum concentration at 2 h. The malignant tissue accumulated high 13²-OH-BPME concentrations at 2–12 h postinjection with peaking at 8 h. The 13²-OH-BPME concentrations in muscle tissue, representing the normal tumour surroundings, and in the skin were very low. The results of our study suggest that photodynamic therapy (PDT) using 13²-OH-BPME could be effective at an incubation time of about 8 h postsensitiser injection, when the tumour 13²-OH-BPME concentration has reached its maximum and the muscle and skin concentrations are at a minimum.     

In vivo imaging of insulin receptors in monkeys using 18F-labeled insulin and positron emission tomography.

We previously described a prosthetic group methodology for incorporating 18F into peptides and showed that 18F-labeled insulin (18F-insulin) binds to insulin receptors on human cells (IM-9 lymphoblastoid cells) with affinity equal to that of native insulin (1). We now report studies using 18F-insulin with positron emission tomography to study binding to insulin receptors in vivo. Positron emission tomography scans were performed in six rhesus monkeys injected with 0.3-1.4 mCi of 18F-insulin (approximately 0.1 nmol, SA 4-11 Ci/mumol). Integrity of the tracer in blood, determined by immunoprecipitation, was 94% of control for the first 5 min and decreased to 31% by 30 min. Specific, saturable uptake of 18F was observed in the liver and kidney. Coinjection of unlabeled insulin (200 U, approximately 1 nmol) with the 18F-insulin reduced liver and increased kidney uptake of the labeled insulin. Liver radioactivity was decreased by administration of unlabeled insulin at 3 min, but not 5 min, after administration of the tracer, while some kidney radioactivity could be displaced 5 min after injection. Clearance of 18F was predominantly in bile and urine. 18F-insulin is a suitable analogue for studying insulin receptor-ligand interactions in vivo, especially in the liver and kidney.     

Influence of pituitary and adrenocortical hormones on prostatic secretion protein,a major protein in rat prostate

Prostatic secretion protein (PSP) is an androgen-sensitive, quantitatively important protein in rat ventral prostate which has been shown to inhibit the nuclear uptake and decrease the DNA-binding capacity of the androgen-receptor complex. In the present study, the influence of the pituitary, adrenals, and gonads on the concentration of PSP in the prostate was studied. Hypophysectomy decreased the concentration of PSP to about 10% of the control level, an effect similar to that obtained by castration. No effects on prostatic wet weight or PSP concentration were observed following substitution of hypophysectomized rats with human growth hormone, rat prolactin, or rat growth hormone. On the other hand, PSP concentration as well as wet weight of the prostate were normalized in hypophysectomized rats after administration of testosterone propionate. These results are in line with a direct extrahypophyseal effect of androgens on the prostate. Adrenalectomy did not affect the concentration of PSP, nor the wet weight of the prostate. Administration of estramustine decreased the wet weight of the prostate but did not affect the prostatic concentration of PSP in normal rats. Combined treatment with testosterone propionate and estramustine seemed to increase both the wet weight and the concentration of PSP more than administration of testosterone propionate alone. These results indicate a synergistic effect between estramustine and testosterone propionate.     

The liver plays an important role in the regulation of somatostatin-14 in the rat.

Since little is known about the in vivo disposition of circulating somatostatin-14 (SRIF-14), we examined hepatic processing of SRIF-14 in the rat. Three minutes after the intraportal injection of iodine 125 (125I)-labeled SRIF-14, 16.0 +/- 2.0% of the injected dose is localized to the liver. In the presence of unlabeled SRIF-14, hepatic uptake can be decreased by 68%. Five minutes after the intraportal injection of 125I-SRIF-14, 9.5 +/- 1.4% of the tracer is localized to the liver, more than any other organ tested. Serial collections of bile reveal peak radioactivity at between 10 and 20 minutes. Simultaneous administration of unlabeled SRIF-14 decreases biliary radioactivity by 40%. HPLC analysis of radioactive bile reveals a chromatographic profile similar to that of intact SRIF and is 73% immunoprecipitable by an anti-SRIF antibody. Pretreatment with chloroquine, a lysosomal enzyme inhibitor, does not significantly decrease biliary radioactivity. We conclude that the data are consistent with saturable hepatic uptake and predominantly nonlysosomal transcellular transport.     

前列腺组织中睾酮含量状态与前列腺生理和增生的关系

目的：检测前列腺组织中总睾酮、结合睾酮和游离睾酮的含量，并分析其与前列腺生理和组织增生的关系。方法：14例相对年轻正常前列腺组织、22例良性前列腺增生(BPH)组织和ll例相应年龄段前列腺对照组织，制备组织脑浆和胞核提取液，乙醚萃取分离游离和结合睾酮，采用^125I标记睾酮放免试剂盒测定睾酮的含量。结果：前列腺组织中睾酮存在结合和游离2种状态，结合态为多，约占2/3；3组比较，总睾酮、游离和结合睾酮含量无显著差异。结论：前列腺组织中睾酮存在游离和结合二种状态，共同维持局部高水平的总睾酮含量，并且随年龄增长而保持稳定，有利于睾酮在前列腺生理和组织增生过程中的作用。     

Chromatographic analysis and tissue distribution of radiocopper-labelled haematoporphyrin derivatives

The photosensitizers haematoporphyrin derivative (HPD) and dihaematoporphyrin ether/ester (DHE) have been labelled with the radionuclide copper-64 to allow non-invasive measurement of the concentration of photosensitizer in tumour and normal tissues. The effects of labelling have been assessed by gel and high-performance liquid chromatography. Direct comparison of the tissue uptake and clearance of⁶⁴Cu-labelled HPD/DHE with those of [¹⁴C]HPD/DHE has been made in mice bearing intramuscular radiation-induced fibrosarcoma (RIF) tumours, by gamma and beta counting of tumour, skin, liver, muscle, lung, kidney, brain, and blood samples at 1–72 h after intraperitoneal injection of test and control drug. The uptake and clearance curves of⁶⁴Cu-labelled HPD or DHE in tumour, liver and blood agree to within 20% with those for the¹⁴C-labelled control. Non-invasive quantification of⁶⁴Cu-labelled DHE by gamma counting in vivo in rabbits bearing VX2 tumours in the ear shows good agreement with the photosensitizer concentrations in tumour and liver measured post-mortem in tissue samples.     

Endocrine response to a single injection of goserelin 3.6 mg or leuprolide 3.75 mg in men with prostate cancer

Hormonal responses were assessed in men with prostate cancer (T2-4, Nx, Mx) who were randomized to receive either a single injection of goserelin 3.6 mg or leuprolide 3.75 mg. Testosterone increased over the first week, with a significantly higher mean rate of change of total testosterone (day 3) and free testosterone (days 3 and 7) with leuprolide. Following the initial rise in luteinizing hormone (LH), the rate of decrease in LH levels was significantly greater with goserelin by day 28. There are significant differences in endocrine response to goserelin and leuprolide in the 4 weeks following administration.     

Regional Differences in Steroidogenesis and Hormone Levels in the Epididymis and Vas Deferens of Adult Rats

In vivo and in vitro studies with different parts of the epididymis and vas deferens were carried out to determine their inherent capacity to synthesize steroids and to correlate with the endogenous levels with or without the administration of hCG.
Incubation with ¹⁴C-labelled pregnenolone and testosterone demonstrated that caput epididymidis was more active than other parts in synthesizing testosterone from ¹⁴C-pregnenolone and in converting labelled testosterone to 5α-dihydrotestosterone (DHT). The cauda epididymidis and vas deferens accumulated more radioactivity in progesterone and dehydroepiandrosterone (DHEA) than the caput epididymidis.
The levels of DHT, testosterone and 4-androstene-3,17-dione in the caput epididymidis were reduced after ligation of ipselateral efferent ductules indicating the testicular origin of these steroids. The cauda epididymidis and vas deferens had higher levels of progesterone as compared to the other regions of the epididymis, which were decreased after the ligation. Intravenous injection of hCG increased the levels of oestradiol-17β in all tissues and markedly in the cauda epididymidis and vas deferens. The high levels of progesterone and oestradiol-17β present in these organs may be of importance in maintaining fertilizing ability of spermatozoa stored in the cauda epididymidis and vas deferens and their transport.