Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of flutamide on basal and ACTH-stimulated plasma levels of adrenal androgens was investigated in 6 patients with untreated advanced prostate cancer, aged 52-75 yr. Flutamide was administered (250 mg three times daily) for 10 days; before and after treatment, a synthetic ACTH1-24 stimulation test (250 micrograms im, with blood sampling immediately before and 60 min after the stimulus) was performed. Basal plasma 17OH-pregnenolone (delta 5-17OHP), 170H-progesterone (delta 4-17OHP), androstenedione (A), dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) were unchanged by flutamide treatment. In contrast, basal plasma testosterone (T) concentrations significantly increased (p less than 0.05). The response of cortisol delta 4-17OHP, delta 5-17OHP, A and DHEA to ACTH, as well as the ACTH-stimulated delta 5-17OHP/delta 4-17OHP, delta 5-17OHP/DHEA, delta 4-17OHP/A and DHEA/A ratios, were unchanged by flutamide treatment. These findings indicate that: a) Short-term flutamide administration enhances testicular steroidogenesis, via augmented LH pulse frequency; b) Adrenal steroidogenesis seems to be not affected by the drug, since ACTH-stimulated plasma levels of adrenal androgens and precursors/products ratios were unchanged.
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PMID:The effect of flutamide on basal and ACTH-stimulated plasma levels of adrenal androgens in patients with advanced prostate cancer. 285 89

Total androgen blockade has been proposed as a better therapeutic technique than castration alone for the management of metastatic prostate cancer. This is based on the theory that links adrenal androgens to tumor growth. We have carefully examined the role of adrenal androgens in prostate cancer. Work done in our laboratory, as well as the work of many others, has demonstrated the following in regard to the role of adrenal androgens in prostate cancer: (1) The adrenal cortex secretes significant amounts of adrenal androgens into the blood. (2) Adrenal androgens are converted into dihydrotestosterone (DHT), as indicated by studies of labeled DHT recovered from prostates resected one-half hour after infusion of 3H-androstenedione or 3H-dehydroepiandrosterone sulfate into patients. We have also shown that biopsies of prostates from patients who were previously castrated may contain significant amounts of DHT, which could only be derived from adrenal androgens. (3) We have quantified DHT derived from adrenal androgens by measuring prostate DHT concentrations in castrates and in patients treated with combined gonadal and adrenal blockade. The mean difference between these two groups, 0.32 ng/g of DHT lower with combined blockade, is statistically significant and represents DHT derived from adrenal androgens. (4) We have also demonstrated that the small amounts of DHT derived from adrenal androgens may be biologically significant in stimulating prostatic epithelial cell protein synthesis in humans; others have reported similar findings in animals. (5) A review of patients in relapse after castration, who are treated with adrenal androgen blockade, indicates that approximately one out of three patients will show an objective remission based on National Prostate Cancer Project (NPCP) criteria. Despite data supporting the importance of adrenal androgens in prostate cancer, clinical trials using combined adrenal and gonadal blockade in prostate cancer have shown only modest benefit over castration. The largest and best study to date is the Southwest Oncology Group (SWOG) study, which did show a near-significant (P less than 0.065) difference between patients treated for 20 months with a luteinizing hormone-releasing hormone (LH-RH) plus flutamide compared with LH-RH alone. The difference in median time to progression was approximately 2 months between the groups. However, when one considers the fact that two out of three patients are probably not responding to the total androgen blockade, the 2 month difference may actually represent 6 or more months in a subset of one-third of patients receiving that therapy.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Advantages of total androgen blockade in the treatment of advanced prostate cancer. 328 84

Hormonal therapy for metastatic prostate cancer blocks the androgen-mediated action that stimulates the hormone-dependent clone of tumor cells. Such therapy must be directed at all sources of tissue dihydrotestosterone (DHT), including testosterone derived from the testis. Adrenal androgens such as dehydroepiandrosterone (DHEA) sulfate, DHEA, and androstenedione may also diffuse into prostate cells, and although their conversion to DHT is in the range of only 3% to 7% (compared to 50% to 70% for testosterone), the large amount (four to six times that of testosterone) of adrenal androgen substrate may account for up to one sixth of total prostate DHT. The role of adrenal androgens as potential stimuli to the hormone-dependent clone of tumor cells is further supported by studies in which significant amounts of DHT were found in the prostates of patients in clinical relapse after surgical castration. There are reports indicating that both surgical and medical adrenalectomy produce subsequent remissions in about 30% of patients who failed after castration or estrogen. The rationale to suppress all sources of DHT, therefore, is clear. To accomplish this goal successfully, megestrol acetate was combined with DES or estradiol to suppress testicular function to castration levels and to block residual adrenal androgens at the cell level. Studies are underway to compare clinical disease-free intervals in these patients to those patients receiving traditional therapy of castration and estrogen.
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PMID:Rationale for blockade of adrenal as well as testicular androgens in the treatment of advanced prostate cancer. 388 2

To completely eliminate androgens of both testicular and adrenal origin, 37 previously untreated patients with advanced (stages C or D) prostatic cancer received the combination therapy using an LHRH agonist (HOE-766) and a pure antiandrogen (RU-23908). The response criteria developed by the National Prostatic Cancer Project were used. A positive response (assessed by bone scan and/or serum prostatic acid phosphatase measured by radioimmunoassay was observed in 29 of the 30 cases who could be evaluated by these objective criteria (97%). The objective response was parallel to a rapid and marked improvement of the clinical signs and symptoms related to prostate cancer (prostatism, bone pain, and general well being). In marked contrast, the same combination therapy applied to patients previously treated with high doses of diethylstilbestrol (13 patients) showed a positive objective response in only 55% of cases. In 23 previously castrated patients showing relapse, an objective response was seen in only 25% of cases after neutralization of adrenal androgens by the antiandrogen. Previous treatment with chlorotrianisene (TACE) had no detectable effect on prostatic cancer and patients having previously received such treatment had a rate of positive response similar to previously untreated patients (five of five). In the previously untreated patients receiving the combination therapy, a 60% fall in serum prostatic acid phosphatase was observed as early as five days after starting treatment, at a time when the serum androgen concentration was 100% to 200% above control. Combined treatment with the pure antiandrogen completely prevents flare-up of the disease, a complication previously found in a significant proportion of patients treated with an LHRH agonist alone. The present data show that complete withdrawal of androgens by combined hormonal therapy with the LHRH agonist (or castration) and a pure antiandrogen leads to a positive objective response in more than 95% of cases as opposed to 60%-70% as reported by many groups using the previous partial hormonal therapy (castration or high doses of estrogens). Adrenal androgens are most likely responsible for this difference. The present study also shows that the proportion of androgen-sensitive cells decreases from more than 95% in untreated patients to 25% to 55% after previous partial hormonal therapy. Such data clearly indicate that the previous partial hormonal therapy exclusively aimed at neutralizing testicular androgens left 25% to 55% of cancer cells having a relatively low sensitivity to androgens in a hormonal milieu compatible with their continuous growth. No clinical or biochemical side effect could be detected except those related to reduced serum androgen levels.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens. 641 30

Adrenal androgens contribute 40% of total androgens in adult men. The inactive precursor steroids dehydroepiandrosterone (DHEA) and DHEA-sulfate are secreted in large amounts by the adrenals and reach the prostate and other peripheral target tissues, where they are transformed into the potent androgen dihydrotestosterone (DHT). We have cloned and sequenced the cDNAs and/or genes which encode the enzymes responsible for the transformation of DHEA into DHT, namely 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, 17 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase. Blockade of DHT synthesized by these enzymes, with a pure antiandrogen of the class of flutamide, prolongs life in advanced prostate cancer, the effect being much more important when a small number of metastases is present. Most importantly, 3-month combination therapy reduces cancer-positive margins at radical prostatectomy, from 38.5% in control patients to only 13% in those who received combination therapy. Combined with an efficient strategy for detection of early-stage prostate cancer, the present approach could offer the possibility of a cure to more than 80% of prostate cancer patients, compared with the present situation where a cure can be offered to less than 20% of patients, since the first diagnosis of prostate cancer is usually made at a late stage of the disease.
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PMID:Intracrinology: the basis for the rational design of endocrine therapy at all stages of prostate cancer. 826 32

Dehydroepiandrosterone (DHEA) is being evaluated in the basic science laboratories as a potential treatment for adenocarcinomas, with some initial promise for success. However DHEA can be metabolically converted to androgenic compounds, possessing unwanted side effects. A patient with advanced prostate cancer with progressive symptomatology was treated with DHEA after other treatment regimens failed. Many of his symptoms improved on DHEA therapy, but his cancer also flared dramatically during treatment. His previous hormonally unresponsive cancer subsequently responded transiently to third-line hormonal therapy with diethylstilbestrol (DES). Adrenal precursor molecules such as DHEA may have significant therapeutic benefits in a number of diseases of the elderly, however their utility may be limited by potential androgenic side effects including endocrine epithelial cell growth. The development of analogue compounds with less conversion to androgenic metabolites should be considered, as molecules such as DHEA are more widely tested and utilized clinically.
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PMID:Use of DHEA in a patient with advanced prostate cancer: a case report and review. 937 95

Cushing's syndrome, characterized by unregulated cortisol secretion, may be caused by a variety of adrenal, pituitary, or other tumors. The best biochemical test for establishing the diagnosis is determination of 24-h urinary free cortisol. The specific causes for Cushing's syndrome may be further differentiated by plasma adrenocorticotrophic hormone (ACTH). Primary adrenal cortical diseases are associated with low levels of ACTH and are considered ACTH-independent. Pituitary disease and the ectopic ACTH syndrome are associated with normal or elevated ACTH levels and are considered ACTH-dependent. Adrenal forms of Cushing's syndrome may result from either adenoma or carcinoma. The diagnostic approach to Cushing's syndrome and the clinical, biochemical, and radiographic features that distinguish adrenal adenoma and carcinoma are the subjects of this paper. 65-75% of CS [14, 15]. Most cases of Cushing's disease are the result of pituitary adenomas; however, corticotrope hyperplasia is responsible for a small minority of cases. Ectopic production of ACTH from a variety of tumors (bronchial carciniod, thymoma, oat-cell carcinoma, pheochromocytoma, islet-cell tumor, and prostate cancer) accounts for 10-15% of CS. Primary adrenocortical diseases account for the remaining 20-30% of CS, including benign adenoma (10-15%), adrenocortical carcinoma (5-10%), and adenomatous hyperplasia (5%). The purpose of this review is to present a contemporary approach to the evaluation and management of patients with Cushing's syndrome, emphasizing the primary adrenal etiologies pertinent to urologists.
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PMID:Contemporary evaluation and management of Cushing's syndrome. 1009 47

Adrenal androgens function as an androgen source within prostate and androgen target tissue. This study compares the ability of three human prostatic cancer cell lines to metabolize the adrenal androgens, dehydroepiandrosterone (DHEA), and androstenedione under living culture conditions. Androgen-independent cell lines PC-3 and DU145 and androgen-dependent cell line LNCaP were investigated. The effect of glucuronide and sulfate conjugates was also investigated. There was a strong tendency in PC-3 or DU145 to convert androstenedione to DHEA or DHEA-S reservoir. On the other hand, LNCaP was capable of converting DHEA into androstenedione and subsequently into dihydrotestosterone (DHT). Moreover, androgens were converted into a glucuronide conjugate in LNCaP, but not in PC-3 or DU145. As a result, the metabolism of the adrenal precursor shifted to androgen formation in LNCaP. This could be confirmed by means of reverse transcription-PCR of uridine diphosphoglucuronosyl-transferase (UGT) 2B15. Kinetic properties of UGT activity in LNCaP revealed DHT to be a better substrate than testosterone. In conclusion, the findings show that the adrenal precursor pool has the potential to contribute to the regulation of prostatic cells. Moreover, the presence of UGT activities in LNCaP may have a regulatory effect on the active androgen level in the intracellular environment.
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PMID:Adrenal steroids in human prostatic cancer cell lines. 1129 65

It is widely accepted that in women, estrogens provide protection against the development of cardiovascular disease. However, the cardiovascular role of estrogens in men remains uncertain, despite preliminary evidence that endogenous estrogens produced by aromatization of androgenic precursors are of physiological importance. Hypogonadal men have very low levels of circulating estrogen. We studied the responsiveness of forearm resistance arteries to vasoconstrictor and vasodilator agents in 12 men (mean+/-SEM age, 68.7+/-2.6 years) rendered hypogonadal as a result of treatment for prostatic cancer, before and after 8 weeks of estrogen supplementation (estradiol valerate 1 mg daily; n=7) or placebo (n=5). Forearm blood flow was measured by venous occlusion plethysmography, and vasoactive agents were infused through a brachial artery cannula in doses that did not affect blood pressure or heart rate. Estrogen supplementation was well tolerated, with no adverse effects. After estrogen treatment, mean estradiol levels increased from <30 to 308+/-65 pmol/L, and both systolic and diastolic blood pressures were reduced. HDL cholesterol levels increased significantly, and vasoconstrictor responses to the NO synthase inhibitor N(G)-monomethyl-L-arginine (1, 2, 4 micromol/min) were enhanced. Vasoconstrictor responses to angiotensin II (8, 16, 32 ng/min) were markedly attenuated by estrogen treatment, as were vasoconstrictor responses to norepinephrine (25, 50, 100 ng/min). Estrogen did not alter the vasodilator responses to acetylcholine (9.25, 18.5, 37 microgram/min) or to the endothelium-independent agent sodium nitroprusside (1.6 microgram/min). Responses to all vasoactive agents were unchanged after administration of placebo. We conclude that low-dose estrogen supplementation in hypogonadal men is well tolerated, lowers blood pressure, and may affect vascular reactivity in a manner that is potentially beneficial, through several mechanisms, including enhancement of basal NO release and attenuation of vasoconstrictor responses to angiotensin II and norepinephrine. These findings suggest the need to consider a possible clinical role for estrogenic compounds in cardiovascular risk reduction in some groups of men.
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PMID:Low-dose estrogen supplementation improves vascular function in hypogonadal men. 1171 90

Adrenal masses in cancer patients pose diagnostic problems. We report the case of a 59 years old male with a history of prostate cancer who presented to us with serially rising prostate specific antigen. On imaging studies he had bone lesions and in addition had a 1.7 cm left adrenal mass. Since metastasis to the adrenal gland has rarely been reported in prostate cancer, and since the radiological criteria in our case favored malignancy, we proceeded with hormonal evaluation and fine needle aspiration biopsy of the adrenal mass which proved it to be pheochromocytoma. This was followed by an uneventful adrenalectomy.
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PMID:Evaluation of an adrenal mass in a patient with progressive prostate cancer reveals pheochromocytoma. 1683 63


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