Ten patients with prostatic carcinoma six with stage C and four with stage D disease-were treated for 6 weeks to 12 months with agonistic analogues of luteinizing hormone-releasing hormone (LH-RH). [D-Trp6JLH-RH was given subcutaneously once daily at a dose of 100 ,ug and [D-Ser(But)6des-Gly-NH210-LH-RH ethylamide (HOE 766) was given subcutaneously (50 Mg once daily) or intranasally (500 Mug twice daily). In all patients, mean plasma testosterone levels showed a 75% suppression by the third week of treatment and remained low thereafter. This was followed by a decrease or normalization of plasma acid phosphatase levels by the second month of treatment and a 47% decrease in serum alkaline phosphatase by the 10th week of treatment in all but one 'patient. In patients with stage C disease presenting with prostatism or urinary outflow obstruction, there was a noticeable clinical improvement. In two such patients, a decrease in the size of the prostate was confirmed by ultrasonography. In patients with stage D disease manifested by diffuse bone metastases, there was relief of bone pain, and in one patient treated for >12 months the improvement was documented by radioisotope bone imaging. It is concluded that superactive agonistic LH-RH analogues hold promise as therapeutic agents in patients with androgen-sensitive prostatic adenocarcinoma. Furthermore, the analogues ofLH-RH may be used to assess the responsiveness ofpatients to surgical castration. Long-term administration ofLH-RH analogues could become an alternative to surgical castration and estrogen therapy for the treatment of hormone-dependent prostatic carcinoma.There is much evidence that acute administration ofsuperactive analogues of luteinizing hormone-releasing hormone (LH-RH) causes a prolonged release of pituitary gonadotropins, which leads to stimulation of Leydig cell function and an increase in plasma testosterone (T) concentrations (1-8). Chronic administration of large doses of superactive analogues of LH-RH results in suppression of both pituitary, and Leydig cell function in animals and men (1,2,4,5,7,(9)(10)(11)(12)(13)(14)(15)(16). This paradoxical antigonadal effect of superactive analogues of LH-RH can result in regression ofboth mammary and prostatic endocrine-dependent tumors in experimental animals (17, 18). The present report describes the results of administration of two synthetic superactive long-acting LH-RH analogues, LH-RH and [D-Ser(But)6]des-Gly-NH210-LH-RH ethylamide (HOE 766), to 10 patients with prostatic.carcinoma. PATIENTS, METHODS, AND MATERIALSPatients. Ten patients with biopsy-proven prostatic adenocarcinoma were studied. Six presented with signs ofprostatism and two of the six had urinary outflow obstruction requiring frequent catheterization. None ofthese six patients (Cl, C2, C3, C4, C5, C6; 75, 70, 63, 79, 79, and 81 years old, respectively) had evidence of metastasis and therefore were classified as having stage C disease. The four other patients (D1, D2, D3, D4; 65, 71, 78, and 63 years old, respectively) pre...

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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Three boys 3.3 to 3.9 years old, who had precocious puberty that was unresponsive to an analogue of gonadotropin-releasing hormone, were treated with the antifungal agent ketoconazole for up to 12 months. Within 48 hours the serum testosterone concentration fell to normal in two boys and was significantly reduced in the third, paralleling major improvements in behavior. Reciprocal changes in serum levels of 17-hydroxyprogesterone suggested that C17-20 lyase was the principal site of drug action. Although there was evidence of a blunted cortisol reserve during the first week of treatment, the cortisol response to ACTH1-24 had returned to normal by one month of continuous treatment, and normal diurnal cortisol rhythm was preserved. No adverse clinical or biochemical side effects were noted during 9 to 12 months of continuing treatment. During that time, growth velocity was significantly reduced in all three boys, from a mean rate of 1.5 +/- 2.0 cm per year before treatment to 5.9 +/- 0.6 cm per year after ketoconazole therapy. There was a simultaneous retardation of the rate of skeletal maturation. The striking improvements in behavior were sustained for the duration of treatment. These preliminary data suggest that administration of ketoconazole may be a satisfactory treatment for precocious puberty in boys and possibly for other conditions characterized by androgen excess.