Dispersed, estradiol (E2)-treated, rat pituitary cell cultures were used to examine the intracellular processing of progesterone (P) associated with its modulation of gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone (LH) secretion. Enhancement and suppression of LH release was only observed with acute and chronic exposures to P or other naturally occurring and synthetic progestins avidly bound by pituitary progestin receptors; such responses were inhibited by cotreatment with the antiprogestin RU486 but not with the antiandrogen flutamide, illustrating the importance of the P + receptor interactions. However, cotreatment with a 100-fold molar excess of the 5 alpha-reductase inhibitor 17 beta-N,N-diethyl-carbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA) had no effect on the expression of P's modulatory actions. Additional studies using different E2 pretreatments revealed that P enhanced LH release when progestin receptor levels were elevated. Moreover, the magnitude and duration of P's influences on LH release increased in cells with higher receptor levels. However, there were several instances in which progestin receptor level and P modulation of LH release did not correlate. In several instances E2-induced progestin receptor levels stabilized at a maximal level whereas P enhancement of LH secretion continued to increase in size and duration. These findings underscore the importance of progestin receptors for P-induced modulation of LH secretion and illustrate that 5 alpha-reduction and further metabolism of P is not obligatory for the expression of these responses. In addition, our data demonstrate that the important cellular mechanisms underlying E2 priming of gonadotroph responsiveness to P entail the induction of progestin receptor levels and other as yet unidentified cellular processes.
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Here we demonstrate 2 patients who showed marked hyperglycemia after androgen-deprivation therapy for prostate cancer and the efficacy of the thiazolidinedione pioglitazone on their glycemic control. Case 1 was a 61-year-old man diagnosed with prostate cancer who had type 2 diabetes mellitus for 7 years. His glycemic control had been good for the previous 5 years because of diet therapy and acarbose administration. He was given the gonadotropin-releasing hormone agonist leuprolide acetate and the androgen receptor antagonist flutamide for the treatment of prostate cancer. After the second injection of leuprolide acetate, fasting glucose and hemoglobin A1c (HbA1c) levels were found to be markedly elevated (22.8 mmol/L and 10.5%, respectively). Case 2 was an 81-year-old man whose fasting glucose and HbA1c had been normal 10 months ago. He was injected with leuprolide acetate for the treatment of prostate cancer. Six months after starting the leuprolide treatment, the patient complained of thirst and weight loss and was diagnosed with diabetes mellitus with a fasting glucose of 19.4 mmol/L and HbA1c of 9.9%. The correct homeostasis model assessment evaluation indexes for pancreatic beta-cell function (HOMA-%beta )A and for insulin sensitivity (HOMA-%S) were reduced in these 2 patients compared with control men. Their serum testosterone and 17beta -estradiol concentrations were depressed. After improvement of hyperglycemia by insulin treatment, their glycemic control remained good after treatment with pioglitazone without use of insulin. The values of HOMA-%beta and HOMA-%S increased to control ranges. Insulin resistance after the androgen-deprivation therapy might lead to marked hyperglycemia in these patients.
Although a profound depression in immune function occurs following injury, the mechanism responsible for this is not fully understood. Furthermore, steroid hormones are known to be important mediators in the regulation of immune function. Although dehydroepiandrosterone (DHEA), the most plentiful steroid hormone, has been shown to stimulate immune function in normal animals, it is unknown whether DHEA has any salutary or detrimental effects on immune responses after trauma and haemorrhage. To study this, male mice were subjected to trauma, haemorrhage and resuscitation, following which they received either DHEA or vehicle subcutaneously. DHEA administration restored the normally depressed splenocyte proliferation as well as interleukin 2, interleukin 3, and interferon gamma elaboration following trauma and haemorrhage. In an attempt to determine the mechanisms mediating this effect, T cells were stimulated in vitro in the presence of DHEA and a variety of hormone antagonists. The stimulatory effect of DHEA on splenocyte proliferation was unaltered by the testosterone receptor antagonist flutamide, while the oestrogen antagonist tamoxifen completely abrogated its effect. In addition, DHEA administration normalized the elevated serum corticosterone level typically seen following injury. These results indicate, therefore, that DHEA improves splenocyte function after trauma and haemorrhage by directly stimulating T cells and also by preventing a rise in serum corticosterone.
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The 5-year actuarial overall survival (OS) rates were 89% for A and 78% for B (P = .13). The 5-year actuarial cause specific survival (CSS) rates were A = 90% and B = 79% (P = .01). Biochemical progression-free survival (bPFS) rates were 52% versus 40% (P = .07), for groups A and B, respectively.
This study was undertaken to investigate the protective effects and potential mechanism of testosterone (T) on cognitive performance in adult male rats given bilateral intrahippocampal injections of beta amyloid 1-42 oligomers (Aβ1-42) combined with gonadectomy (Aβ+GDX). A series of experiments were designed to verify the optimal administration time and dose of T and to explore its potential protective mechanisms on spatial ability in Aβ+GDX rats in the Morris water maze test. Aβ1-42 was injected only once two weeks before testing, while T and the androgen receptor (AR) antagonist flutamide (F) were administered daily beginning 2 days before and throughout the 6 days of testing. The Aβ1-42 injection and GDX individually impaired cognitive performance, and the combination of these treatments was additive, leading to even greater impairment. The serum T level peaked at 48 h after administration. T doses ranging from 0.25 to 1.00 mg corresponding to serum T levels of 4.5-21.35 ng/ml improved the spatial ability. Animals administered 0.75 mg of T corresponding to the serum T level of 15.2 ng/ml had the most significantly improved behavioral performances. However, higher T doses of 1.50 and 2.00 mg resulting in serum T levels of 34.8 and 45 ng/ml, respectively, impaired the behavioral performances. F had no effect on the serum T level and spatial ability, but it blocked the activational effect of T. These findings indicate that the effect of T on behavioral performances is partly mediated through ARs.
Mean requirements for injured control swine were 14.6 (± 1.21 standard error of the mean [SEM]) L crystalloid saline and 0.59 (± 0.29 SEM) g epinephrine, compared with 16.30 (± 1.33 SEM) L and 0.54 (± 0.16 SEM) g, respectively, in the FLU-CYD group (both P > 0.05). There were no significant differences in central hemodynamics between control and experimental groups. No significant differences for pH, bicarbonate, fibrinogen, or international normalized ratio were evident. FLU-CYD resuscitation was associated with a significant increase in lactate levels compared with controls (10.1 versus 5.7 mmol/L, P < 0.05). Histologic injury was significantly increased in the livers of FLU-CYD compared with sham (P = 0.022). High serum levels of FLU and the active metabolite FLUOH were measurable throughout the resuscitation period.
The first data analysis of the European Organization for Research and Treatment of Cancer (EORTC) 30853 trial indicated a significantly longer time to progression and duration of survival for the maximal androgen blockade (MAB) treatment arm. However, the MAB treatment arm had a higher frequency of reported side effects.
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Fourteen of the 30 patients (47%) were diagnosed as being downstaged to clinical stage B disease following therapy. No major complications occurred. Pathology staging revealed only three patients (10%) to have organ-confined disease after radical prostatectomy.
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The authors describe the occurrence of high levels of S-adenosyl-L-methionine decarboxylase (SAMDC) activity in the rat epididymis, and its ontogeny and androgenic control. As early as 15 days of age, SAMDC activity exists, although a peak of activity is observed at 25 days. Bilateral orchidectomy resulted in a decline of epididymal SAMDC activity. However, an androgen-independent fraction, accounting for 34% of total activity, appears to exist in the epididymis. In 45-day-old orchidectomized rats, SAMDC activity was stimulated by testosterone treatment in a dose-dependent manner. However, treatment of 45-day-old intact animals with a high dose of the androgen failed to modify SAMDC activity, indicating that, at this age, the enzyme is maximally stimulated by endogenous androgens. The observed effect of testosterone on castrated rats was completely abolished by concomitant treatment with the antiandrogen flutamide. This compound was ineffective on the androgen-insensitive fraction. To assess the contribution of circulating and luminal androgens to the maintenance of epididymal SAMDC, rats were unilaterally orchidectomized and activity was determined in both epididymides after 7 days. The SAMDC activity was identical in epididymides from both sides, suggesting circulating androgens suffice to maintain normal levels of activity. It was concluded that androgens regulate epididymal SAMDC activity, although an androgen-independent fraction appears to exist.
17-(5'-Isoxazolyl)androsta-4,16-dien-3-one (L-39), a novel androstene derivative, was synthesized and evaluated in vitro and in vivo. L-39 showed potent and non-competitive inhibition of human testicular microsomal 17alpha-hydroxylase/C(17,20)-lyase with an IC50 value of 59 nM and Ki of 22 nM. L-39 also showed potent and competitive inhibition of 5alpha-reductase in human prostatic microsomes with IC50 and Ki values of 33 and 28 nM respectively. L-39 (5 microM) has also been shown to manifest anti-androgenic activity in cultures of human prostate cancer cell lines (LNCaP) by preventing the labelled synthetic androgen R1881 (5 nM) from binding to the androgen receptors. Androgen-dependent human prostate cancer xenografts (PC-82) were grown in nude mice and the effects of L-39 (50 mg kg(-1) day(-1)) on tumour growth and prostate-specific antigen (PSA) levels were determined after 28 days. L-39 significantly (P < 0.01) diminished tumour growth and wet weights to a similar extent as castration or flutamide treatment. L-39 also significantly (P < 0.01) reduced serum PSA levels by more than 80% in the mice bearing human prostate cancer xenografts. Pharmacokinetic studies were also conducted in male Balb/c mice. After subcutaneous administration of a single bolus dose, L-39 was rapidly absorbed into the systemic circulation. Peak plasma levels occurred at 0.75 h and then declined with a t(1/2) of 1.51 h. The bioavailability of L-39 after subcutaneous administration was 28.5%. These results demonstrate that L-39 is a potent inhibitor of androgen synthesis and is effective in reducing the growth of human prostate cancer xenografts in nude mice. Although improvements in the bioavailability are necessary, L-39 is a potential lead compound with this profile as an inhibitor of prostate cancer growth.
The hamster flank organ is a widely used model of the control of sebaceous gland activity by androgens and anti-androgens. Finasteride, a 5 alpha-reductase inhibitor, was administered locally on the surface of the right flank organ and right ear twice daily for 4 weeks. The treatment caused similar 12% to 30% reductions in the size of the sebaceous glands in both flank organs. Moreover, relative mRNA levels of the androgen-regulated FAR-17a gene measured by in situ hybridization as well as [3H]-thymidine incorporation and 5 alpha-reductase activity were similarly decreased in the two flank organs after topical application. The pure anti-androgen flutamide, at the same doses, exerted a more potent effect on all the same parameters, and the effect was also comparable on both the treated and untreated sides of flank organs. Finasteride and flutamide significantly decreased ventral and dorsal prostatic weights after topical application. The present data show that the topical administration of finasteride, in analogy with flutamide, causes local inhibition of sebaceous gland growth in both the costovertebral organs and ears. However, as demonstrated by the similar inhibitory effect in the contralateral untreated side and the reduced weight of the dorsal and ventral lobes of the prostate and seminal vesicles, finasteride and flutamide both exert significant systemic effects.
By 1994, the number of cases of prostate cancer diagnosed will increase by 50% over a 2-year period. Treatment of all cases diagnosed decrease prostate cancer mortality; however, not all of these cases are destined to cause symptoms or impact adversely on the quality of life of the patient. For the latter patients, a deferred approach is appropriate. Selecting which patient requires treatment, and if so, which treatment to use remains an area of increasing controversy. For those with tumors outside of the gland, improving local control rates and defining metastatic risk are of importance. In this regard, significant advances in our understanding of the biology of prostatic cancers have been made, and some of the specific genetic abnormalities associated with the metastatic phenotype defined. For those with established metastases, improving the results with standard hormonal therapies is an area of active investigation. Selected patients who progress while using androgen-ablation remain sensitive to second-line therapies such as flutamide withdrawal or other hormonal treatments. A new definition of so-called hormone-independent disease is defined. Ultimately, more effective therapies aimed at hormone-refractory cells will be required to improve survival.
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We studied 11 women with PCOS at an institutional general clinical research center.
Overexpression of the HER2/Neu protooncogene has been linked to the progression of breast cancer. Here we demonstrate that the growth of prostate cancer LNCaP cells can also be increased by the stable transfection of HER2/Neu. Using AG879, a HER2/Neu inhibitor, and PD98059, a MAP kinase inhibitor, as well as MAP kinase phosphatase-1 (MPK-1), in the transfection assay, we found that HER2/Neu could induce prostate-specific antigen (PSA), a marker for the progression of prostate cancer, through the MAP kinase pathway at a low androgen level. Reporter assays and mammalian two-hybrid assays further suggest this HER2/Neu-induced androgen receptor (AR) transactivation may function through the promotion of interaction between AR and AR coactivators, such as ARA70. Furthermore, we found this HER2/Neu --> MAP kinase --> AR-ARAs --> PSA pathway could not be blocked completely by hydroxyflutamide, an antiandrogen used in the treatment of prostate cancer. Together, these data provide a novel pathway from HER2/Neu to AR transactivation, and they may represent one of the reasons for the PSA re-elevation and hormone resistance during androgen ablation therapy in prostate cancer patients.
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To compare disease progression and survival of patients with stage D1 adenocarcinoma after treatment with either early androgen ablation alone or combined with radical prostatectomy.
To understand long-term survival rate after combined androgen blockade (CAB) in patients with advanced prostate cancer.
Sex steroids play a significant role in organizing male social behavior, which is associated with low levels of pro-social behavior and high levels of aggression. However, the role of steroids in organizing behavior in highly social males is unclear. The authors tested the hypothesis that low levels of sex steroids facilitate the expression of pro-social behavior in male prairie voles (Microtus ochragaster), predicting that inhibition of testosterone and estradiol would reduce spontaneous-alloparental behavior. Treatment with the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD) or the androgen receptor blocker flutamide, days 8-14, significantly reduced the expression of alloparental behavior in 21-day old males. While both treatments reduced alloparental behavior and increased pup-directed aggression, there were differential treatment effects. Flutamide altered initial response, increasing latency to enter the pup cage and the likelihood of retreat from initial contact. ATD-treated males that were alloparental showed increases in sniffing and latencies to lick and huddle. Results indicate that endogenous steroids play a role in the development of male pro-social behavior and the effects of estrogens and androgens differ.
Liver function tests, namely measurement of serum aspartate amino-transferase (AST) and alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase (gamma-GT), and prothrombin and thromboplastin times, were performed at 4, 8, and 12 weeks and every 3 months thereafter. Clinical signs and symptoms of liver dysfunction were also sought. The causal link between the antiandrogen used and liver injury was assessed on the basis of the temporal relationship with the use of the drug in the absence of other possible causes and, in two patients, through rechallenge of the putative causative drug after a period of normalization of liver function.
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When present at diagnosis or when developing in the course of disease, the presence of bone metastases from prostate cancer is generally considered an indication to begin endocrine therapy, as this is clearly the most effective form of treatment for this problem. Endocrine therapy can stop progression of prostate cancer in 80-85% of cases. Endocrine therapy can relieve pain, prevent pathologic fractures, and prevent neurologic complications from bone metastases from prostate cancer. Rarely, bone scans may become normal after the start of endocrine therapy, but partial improvement or stabilization of bone scans are more commonly seen. While endocrine therapy has been the first line of treatment of metastatic prostate cancer for the past 50 years, the recent development of newer forms of endocrine therapy have increased the options in the past few years. In addition to orchiectomy and estrogens, newer alternatives include inhibitors of androgen synthesis, the class of agents termed "antiandrogens", and luteinizing hormone releasing-hormone (LHRH) analogues either alone or in combination. Orchiectomy causes a prompt fall in serum testosterone and is regarded by many as the "standard" form of endocrine therapy, but there is concern about the psychologic impact of surgery. Estrogens are being used less frequently today because of their real or potential side-effects, including cardiovascular and thromboembolic complications. The development of analogues of LHRH has resulted in another major choice for endocrine therapy, and one which is therapeutically equivalent to orchiectomy or estrogens. Since LHRH analogues may cause an early rise or "flare" in serum testosterone before it drops to castrate level, these agents should not be given alone to patients with severe pain or neurologic problems. The newly available antiandrogen flutamide can block the "flare", and may also improve survival when used with LHRH analogues or orchiectomy, especially when disease is less advanced. Not all studies of "combination therapy" support this conclusion. However, the use of flutamide is increasing significantly in the United States. Both the LHRH analogues and flutamide are fairly safe, but they are very expensive. Their use, in combination, is likely to become a progressively more common form of initial endocrine therapy in the future. The growing application of prostate specific antigen (PSA) as a tumor marker for prostate cancer has made the difficulty in interpreting changes in bone scans a much less critical problem in determining response to endocrine or other forms of therapy for advanced prostate cancer.
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We report a case of pulmonary tumor embolism involving multiple emboli from an unusual site, an adenocarcinoma of the prostate. A 78-year-old Japanese man was diagnosed with stage IV (1997 version of the TNM classification) moderately differentiated adenocarcinoma of the prostate in December 1997. He underwent bilateral orchiectomy and hormonal therapy with flutamide was started. The patient suffered from relapse in April 1998, and estramustine phosphate was administered as treatment for hormone-refractory prostate cancer. He noticed a dry cough in May 1998, and on June 13, he developed acute progressive dyspnea and was admitted to our hospital. Radiological findings, blood gas analysis, and clinical symptoms suggested pulmonary thrombosis. Despite anticoagulation and oxygen therapy, he remained severely dyspnoeic. He died of respiratory failure 4 days after admission. Autopsy confirmed dissemination of poorly differentiated adenocarcinoma of the prostate to the majority of the pulmonary muscular arteries.
Idiopathic hirsutism (IH) or polycystic ovary syndrome (PCOS) are the most common causes of hirsutism which affects 5-10% of all women. The aim of this study was to evaluate the efficacy of flutamide plus diane 35 in the treatment of idiopathic hirsutism and polycystic ovary syndrome.
An in vitro test system suitable to assess the potency of putative antiandrogens has been developed, using the human benign prostatic tissue obtained at operation. The system circumvents some problems associated with using human tissue, such as the presence of endogenous steroid and contamination with plasma proteins (particularly sex hormone binding globulin). Slices of tissue were incubated in the presence of 3H-testosterone and the uptake into nuclei was determined. The nature of the nuclear radioactivity and the steroid specificity indicates a mechanism similar to the established in the rat ventral prostate. The action of antiandrogens (cyproterone acetate, diethylstilbestrol, flutamide, hydroxylated flutamide and gestonorone capronate) has been studied at various concentrations.
Recent studies have identified novel subgroups in ER-negative breast cancer based on the expression pattern of androgen receptor (AR). One subtype (molecular apocrine) has an over-expression of steroid-response genes and ErbB2. Using breast cancer cell lines with molecular apocrine features, we demonstrate a functional cross-talk between AR and ErbB2 pathways. We show that stimulation of AR and ErbB2 pathways leads to the cross-regulation of gene expression for AR, ErbB2, FOXA1, XBP1, TFF3, and KLK3. As opposed to the physiologic transient phosphorylation of extracellular signal-regulated kinase (ERK1/2) observed with the testosterone treatment, we demonstrate that the addition of ErbB2 inhibition leads to a persistent phosphorylation of ERK1/2, which negatively regulates the downstream signaling and cell growth. This suggests a mechanism for the cross-talk involving the ERK pathway. Moreover, testosterone stimulates the proliferation of molecular apocrine breast cell lines, and this effect can be reversed using antiandrogen flutamide and anti-ErbB2 AG825. Conversely, the growth stimulatory effect of heregulin can also be inhibited with flutamide, suggesting a cross-talk between the AR and ErbB2 pathways affecting cell proliferation. Importantly, there is a synergy with the combined use of flutamide and AG825 on cell proliferation and apoptosis, which indicates a therapeutic advantage in the combined blockage of AR and ErbB2 pathways.
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818 men with locally advanced prostate cancer were randomly assigned to: no androgen deprivation (ie, radiotherapy alone: 66 Gy in 33 fractions of 2 Gy per day over 6.5-7.0 weeks to the prostate and seminal vesicles); 3 months' androgen deprivation with 3.6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day starting 2 months before radiotherapy (same regimen as control group); or 6 months' androgen deprivation, with the same regimen, starting 5 months before radiotherapy (same regimen as control group). Primary endpoints were time to local failure and prostate-cancer-specific survival; secondary endpoints were distant failure, disease-free survival, and freedom from salvage treatment. Analyses were done by intention to treat.
Renal injury and fibrosis were studied in streptozotocin-induced diabetic rats by albuminuria and by gene expression of collagen I and fibronectin. RAS was investigated by analysing the plasma angiotensinogen (AOGEN) and renin activity (PRA) and their renal gene expression. Also, a group of diabetic rats was treated with the anti-androgen flutamide.