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)

GnRH analogs, both agonists and antagonists, have potential use in androgen-dependent diseases of older men, such as prostatic cancer and benign prostatic hyperplasia. Previous experience with agonists of GnRH has suggested that GnRH analogs may be more effective in aged men than in young men, but little is known about GnRH antagonists in older men. Therefore, we evaluated the hormonal effects of a single dose and a short course of a GnRH antagonist (Nal-Glu) in normal elderly men. Six young men (25-34 yr old) and six older men (66-76 yr) each received single morning injections of Nal-Glu (25, 75, and 250 micrograms/kg), separated by 2 weeks. Serum levels of testosterone (T), immunoreactive LH (LH RIA) and FSH (FSH RIA), and bioactive LH (LH BIO) were evaluated periodically for 7 days after each injection. In addition, six elderly men received 25 and 75 micrograms/kg.day Nal-Glu for 10 consecutive mornings each, and serum levels of T, inhibin, LH RIA, LH BIO, FSH RIA, and bioactive FSH were evaluated. Nal-Glu in all three single doses caused a significant (P less than 0.01) decline in serum levels of T and gonadotropins that was similar in extent in the elderly and young men. For example, T declined to a level of 19% of baseline after the 250 micrograms/kg dose of Nal-Glu in both age groups. For both the young and elderly men, the major effect of increasing the Nal-Glu dose was a prolongation of the period of suppression. Multiple Nal-Glu injections in the elderly men also resulted in a rapid decline in T, inhibin, and bioactive and immunoreactive gonadotropins. For both LH and FSH, bioactivity decreased to a greater extent than immunoreactivity. Local side-effects of Nal-Glu tended to be fewer and of less intensity in the elderly men compared to those in the young men. These results demonstrate that the response to Nal-Glu in healthy elderly men is similar to that in younger men, and extended administration of Nal-Glu in elderly men effectively suppresses gonadal and pituitary function. These results suggest that the role of GnRH antagonists in the effective treatment of androgen-dependent disease in the aging male needs to be explored further.
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PMID:Hormonal responses to a potent gonadotropin hormone-releasing hormone antagonist in normal elderly men. 220 25

Twenty-two patients with advanced prostatic cancer and one with benign prostatic hypertrophy were given the GnRH analogue leuprolide in the form of a slow-release depot formulation by subcutaneous injection at doses of 3.75, 7.5, 15 or 30 mg. Following the first dose, drug levels were measured by a double-antibody RIA over an observation period of 5 weeks. Thereafter patients continued long-term subcutaneous treatment at the same dose every 4 weeks. Serum levels of leuprolide showed a rapid increase immediately after injection, reaching a peak proportional to dose within 3 h (range of mean values 13.1-54.5 ng/ml). Subsequently, mean drug levels declined to a plateau proportional to dose (0.49-1.99 ng/ml at 5 weeks). A significant dose-dependent increase in the area under the serum concentration-time curve from zero to 35 days (AUC0-35 days) from 541.7 to 1653.9 ng/ml.h was also noted (p less than 0.01). With all doses there was an initial rise in serum LH and FSH, followed by a rise in testosterone and dihydrotestosterone, then a sharp decrease within 3 weeks. FSH inhibition was achieved in all the 20 evaluable patients and was maintained in 17 of them (85%) over 5 weeks. Fifteen subjects (75%) had marked suppression of LH levels. In 13 of them (65%) this condition continued for the entire observation time. Castration levels of serum testosterone and dihydrotestosterone, however, were maintained in all patients for up to 5 weeks. Two of the 21 evaluable patients (10%) had a complete response; 15 a partial response (71%) and 3 stable disease (14%). No significant differences were observed in relation to dose. Clinical improvement and serum hormonal changes support this as a new and superior method of administration of leuprolide at a dose as low as 3.75 mg.
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PMID:Pharmacokinetics, endocrine and antitumour effects of leuprolide depot (TAP-144-SR) in advanced prostatic cancer: a dose-response evaluation. 251 76

The purpose of this study was to examine long-term effects of GnRH agonists on human testicular histology and endocrine function. Patients with advanced prostate cancer (n = 7) were treated with the potent GnRH agonist analogue buserelin (Bu, Hoechst), 600 micrograms X 3/day intranasally. After 6 months, the patients were orchiectomized, and the testis tissue was used for histological studies and measurements of endocrine function in vitro. Fourteen other patients with matching ages and extent of the disease were castrated as the first form of therapy, and their testis tissue was used as controls (C). Severe atrophy of seminiferous tubules was seen in light microscopy in the testes of the Bu treated patients. Many tubules showed only Sertoli cells, and the seminiferous epithelium was frequently absent. In contrast, no clear changes were seen in the number of Leydig cells. Testicular content of testosterone (T) decreased greater than 95% by Bu treatment: C = 1.5 +/- 0.2 nmol/g wet wt (x +/- SE); Bu = 0.070 +/- 0.019 nmol/g. Likewise, a drop of 80% occurred in testicular high affinity receptors for FSH: C = 0.37 +/- 0.019 pmol/g; Bu = 0.067 +/- 0.009 pmol/g. In contrast, the number of LH receptors was unaffected by the treatment, C = 0.18 +/- 0.033; Bu = 0.18 +/- 0.032 pmol/g. When testis slices were incubated in the presence of maximally stimulating concentration of hCG (100 ng/ml), both groups of tissue responded similarly with a 50% increase in T production, albeit the absolute production rate was reduced by 95% in the Bu group. When several steroid precursors of T were analyzed in the incubation media, it appeared that decreased androgen synthesis was most clearly due to decreased 3 beta-hydroxysteroid dehydrogenase activity. It is concluded that long-term treatment with GnRH agonists in prostatic cancer patients brings about dramatic damage of seminiferous tubular function and reduces testicular androgen producing capacity, but has no effect on testicular capability of responding immediately to LH stimulation.
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PMID:Histological and functional changes of the testis tissue during GnRH agonist treatment of prostatic cancer. 283 28

The FSH receptor in the human testis has not been well characterized in vivo. Using an immunoperoxidase technique we have attempted the immunocytochemical localization of FSH in testicular tissue from patients with a variety of disorders including oligo- or azoospermia (N = 6), cryptorchidism (N = 3), and prostatic carcinoma (N = 3). Specific staining for hFSH was observed inside the seminiferous tubule, generally near the basal membrane in all except the cryptorchid patients. Specific staining was also localized in the luminal area of the seminiferous tubule. In most cases, FSH-positive cells were also found in the interstitium, with a minority of the cells being macrophages. The latter were more prevalent in the undescended testes and in orchiectomy specimens from patients with prostatic cancer. The pattern of FSH localization observed in this study probably represents receptorbound hormone, and may reflect damage to the Sertoli cell and its tight junctions. Further study of the changes in receptor distribution as an indication of Sertoli cell malfunction, may be helpful in our understanding of human testicular disorders.
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PMID:Immunocytochemical localization of hFSH as an index of Sertoli cell function in the human testis. 289 Dec 36

The hormonal and clinical efficacy of (D-Leu6)-des Gly-NH2(10)-LH.RH ethylamide (Leuprolide, TAP 144) was investigated with 12 prostatic cancer patients. The hormonal studies were performed in 8 patients who were not previously treated by any hormonal therapies including estrogen, castration and others. Serum level of LH and FSH was apparently decreased at the end of 2 weeks after the starting of leuprolide (1 mg/day) subcutaneous injection. At the same time, testosterone level was decreased to the castration level. Clinical efficacy of 1 mg/day of leuprolide was evaluated in 7 patients who were not previously treated. Three of the 4 patients with stage B2 cancer showed a partial response and 1 patient a stable response; and 1 of the 3 patients with stage D2 cancer showed a partial response and patients stable a response. No significant side effects were observed in these 12 patients. These results show that 1 mg/day of leuprolide has the same degree of potency in decreasing the serum testosterone as 20 mg/day.
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PMID:[Hormonal and clinical efficacy of (D-Leu6)-des Gly-NH2(10)-LH.RH ethylamide against prostatic cancer]. 293 56

Forty patients with stage D2 prostatic carcinoma were treated for up to 30 months with D-Trp-6-LH-RH. The analog was given s.c. once daily at a dose of 1 mg/day for the first 7 days. Subsequently, the dose was reduced to 100 micrograms/day. In follow-up studies, 30 men continued this therapy for up to 24 months. Blood samples were taken before the injection of the analog and 1, 2, 4, and 6 hours later. Serum LH, FSH, and testosterone levels were measured by RIA every month for 2 years. The initial administration of 1 mg D-Trp-6-LH-RH caused a marked elevation of LH and FSH, which lasted more than 24 hours. However, 1 month later and throughout the therapy, the basal values of LH and FSH were below the normal range and no increase in serum gonadotropins levels was obtained after administration of the analog. Initial plasma testosterone was within normal limits, but during treatment with D-Trp-6-LH-RH it fell to castration levels, and no increases were seen during the 6 hours following the injection of the analog. These results show that chronic administration of D-Trp-6-LH-RH, at the doses used, blocks the pituitary-gonadal axis and that the escape phenomenon from the effects of the LH-RH agonists-induced blockade does not occur under our conditions in contrast to observations of Kerle et al with the I.C.I. Analog 118630 (8). The accumulated results reinforce the view that long-term therapy with agonists of LH-RH is the preferred alternative to surgical castration or therapy with estrogens in men with metastatic prostate cancer.
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PMID:Persistent blockade of the pituitary-gonadal axis in patients with prostatic carcinoma during chronic administration of D-Trp-6-LH-RH. 294 84

High-dose ketoconazole, 400 mg orally every 8 h, was administered in two groups of patients with metastatic prostate cancer. Group A consisted of 10 patients who had not undergone orchiectomy and Group B, eight patients who had orchiectomy prior to the study. Significant declines in testosterone, androstenedione, and dehydroepiandrosterone levels, reciprocal elevation of the gonadotropin levels (FSH and LH), and a persistent fall in serum acid phosphatase levels were observed in Group A patients. Three Group A patients achieved a partial objective remission (duration 9, 41+, and 69 weeks); four patients, stabilization of their disease for a median of 33.5 weeks (range 16-40+ weeks); and two progressed (The National Prostatic Cancer Project Criteria). Stable disease in two Group B patients (7 and 20 weeks) and progression in four patients were observed. Gastrointestinal irritation was the main toxicity and was similar in both groups. Two Group A patients developed symptomatology consistent with adrenal insufficiency. Ketoconazole can suppress androgen production and has a beneficial role in the hormonal therapy of patients with prostate cancer who have not undergone orchiectomy.
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PMID:High-dose ketoconazole therapy in patients with metastatic prostate cancer. 294 19

Thirteen patients with untreated prostate cancer were treated initially with subcutaneous 0.5 mg D-Trp6-LH-RH daily for the first week, 0.1 mg daily for the next three weeks and thereafter with intramuscular depot preparations of 3.2 mg every three weeks. Serum testosterone was suppressed to castration levels. Serum LH, FSH and prolactin were reduced, serum cortisol did not change. 10/13 patients showed remissions, as shown by transrectal prostate volumetry, cytological regression grading, serum phosphatases and clinical status. 3/13 tumors showing progression were undifferentiated and androgen-resistant. The investigated compound seems to be effective in selecting androgen sensitive tumors and may be a possible alternative to orchiectomy.
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PMID:[Decapeptyl (D-Trp6-LH-RH) in the therapy of prostatic cancer with reference to the intramuscular administration of a depot preparation]. 294 71

The antitumor effect and safety and endocrinological effect of a depot formulation of luteinizing hormone-releasing hormone (LH-RH) analogue ICI 118630 (Zoladex) were studied. Each depot containing 3.6 mg of ICI 118630 (corresponding to the average daily release of 120 micrograms) was subcutaneously injected 3 times at 4 week intervals to 12 prostate cancer patients in total at 4 centers from August 1984 to March 1985. Of the 12 patients, 7 showed an objective clinical response (1 CR and 6 PR patients), 3 showed no change and the remaining 2 showed PD. Overall subjective improvement was obtained in 8 of 10 patients (80.0%). Serum hormone levels (LH, FSH, and testosterone) increased immediately after injection of depot and then significantly decreased during and after 2 weeks of treatment. These changes seen in 100% of the patients were attributable to the pharmacological action of the drug. Medical castration was attained in 3.1 +/- 0.9 weeks on average. Observed side effects included gynecomastia in 1 and hyperlipidemia in 2 patients which were all mild. The trial was continued in the patients who required no special medical treatment. Changes in blood Zoladex concentrations suggested no accumulation. These findings demonstrate the safety and useful endocrinological and antitumor effects of Zoladex in prostate cancer through its pharmacological action, that is, LH-RH agonistic action.
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PMID:[Clinical effect of slow release (depot) formulation of the LH-RH analogue ICI 118630 (Zoladex) in patients with prostatic carcinoma]. 295 79

Eleven patients with prostatic cancer maintained on monthly depot Zoladex (ICI 118,630) from 20 to 23.5 months are described. All are in clinical remission. Castrate levels of testosterone are maintained, and low levels of LH and FSH were observed. Contrary to a prior report, persistent blockage of the pituitary-gonadal axis is achieved and maintained with no detectable adverse side effects.
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PMID:Effective long-term suppression of pituitary-gonadal axis in prostatic cancer by Zoladex (ICI 118,630). 296 64


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