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)

Background-The use of sex steroids in oral contraception or hormonal replacement therapy is associated with an increased risk of cardiovascular thromboembolic complications. Although both the estrogen and the progestin components have been involved, the underlying mechanisms responsible are unclear. Methods and Results-This study examined whether sex steroids promote hemostasis indirectly by increasing the procoagulant activity of blood vessels. Treatment of vascular smooth muscle cells with several progestins (progesterone, 3-keto-desogestel, gestodene, and medroxyprogesterone acetate) upregulated proteolytically activatable thrombin receptor (PAR-1) expression, resulting in a potentiated thrombin-induced tissue factor expression and surface procoagulant activity. In contrast, neither the progestins levonorgestrel, norethisterone, and norgestimate nor the synthetic estrogen 17␣-ethinylestradiol had such effects. The effect of the stimulatory progestins, which induce glucocorticoid-like effects in several cell systems, was mimicked by dexamethasone and inhibited by the progesterone and glucocorticoid receptor antagonist RU-38486. In addition, long-term administration of progesterone, 3-ketodesogestrel, or medroxyprogesterone acetate to ovariectomized rats increased PAR-1 protein level in the arterial wall, resulting in an increased responsiveness of isolated aortic rings to thrombin. Conclusions-These data demonstrate that several progestins markedly potentiate the vascular procoagulant effects of thrombin by increasing the availability of membrane thrombin receptors in the smooth muscle, an effect that is most likely due to their glucocorticoid-like activity. (Circulation. 2001;104:2826-2831.)

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As the numbers of young people making a full recovery from haematological malignancy continue to rise, reproductive science must investigate ways of ameliorating the sterilizing effects of high-dose chemotherapy and total body irradiation. Because there is conflicting evidence as to whether lower serum gonadotrophin concentrations have any protective effect on the gonads, a study was designed to test whether either congenital or experimentally induced hypogonadism reduces the radiosensitivity of the mouse ovary. Test subjects were either homozygous for the hpg locus or animals of normal phenotype treated with a gonadotrophin-releasing hormone antagonist. At 14 days after receiving a single dose of 0.1, 0.2 or 0.3 Gy X-rays or a sham procedure, primordial follicles in the ovaries of the two experimental groups and controls were counted in serial histological sections. The doses at which half of the follicles were lost (LD50) were estimated as 0.11 +/- 0.02, 0.19 +/- 0.02 and 0.17 +/- 0.02 Gy respectively. There was no significant difference between the controls and the antagonist-treated animals, but the congenitally hypogonadal group was unexpectedly more sensitive to radiation. Either way, these results do not support the hypothesis that the ovary is protected from radiation injury by lower gonadotrophin concentrations.

The physiological requirement for activation of pituitary gonadotrophin secretion by pulsatile LHRH stimulation is discussed, and compared with the effect of pituitary stimulation by LHRH agonists. Initial stimulation is followed by a phase of progressive pituitary and gonadal inhibition. This inhibition is fully reversible at the end of agonist treatment. Clinical applications of high dose suppression are the treatment of precocious puberty and hormone-dependent tumours (mammary and prostatic carcinoma). In women, agonist administration by nasal spray is a reversible method of inhibiting ovulation, and may also be useful in the treatment of endometriosis. Clinical advantages of agonist therapy are favourable biological tolerance, lack of side effects and rapid reversibility.

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