[GnRH antagonists. Therapeutic and practical aspects].
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Biomedical subjects
Publications and source records attributed to P Bouchard.
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Pregnancies with many fetuses (triplets and more) have at all times been found interesting and unusual. Their rare and spectacular characteristics have for long been considered as divine punishment for the sin of adultery or bestiality or on the other hand as a mark of fertility and a gift from God. The authors report several legends (the Porcelets, the Trazegnies, la Dame de Montigny...) as well as the celebrated cases of fraud. Since techniques have been developed for medical handling of assisted reproduction, multiple pregnancies have become much more frequent. There is no case of survival of all fetuses when there have been more than six born at a time.
The short and mid-term regenerative therapy in the furcation lesions seems to be promising. The aim of this review is to describe different technics used today. The limits of this therapy, the gain of bone level and/or gain of attachment level and the complementarity of their biological principles are discussed.
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The pulsatile secretion of GnRH is achieved by the fine regulation of oestrogens and progesterone. Progesterone is mainly responsible for a negative feedback effect at the hypothalamic level which decreases GnRH pulse frequency. Oestradiol exerts both a positive and a negative feedback effect, mostly at the pituitary level, and the use of steroids to prevent ovulation combines both effects. Recent developments in steroid research suggest a potential interest in the use of non-androgenic progestins which reproduce the negative feedback effect of progesterone with fewer metabolic side effects. GnRH agonists, although responsible for low plasma levels of oestradiol, may be useful in women at risk for steroid contraception. GnRH antagonists suppress transient gonadotrophin-dependent events in the menstrual cycle. Studies with the second generation GnRH antagonist, Nal--Glu, suggest a potential use of these compounds in suppressing ovulation.
Endometrial progesterone and estrogen receptors were studied by immunocytochemistry using monoclonal antibodies during the menstrual cycle in normal women. We initially compared immunocytochemical staining of progesterone and estradiol receptors on endometrial fragments obtained by either aspiration or endometrial biopsy and found that immunocytochemistry could be performed easily on tissue obtained in either way. The immunocytochemical studies showed that the concentration and distribution of receptors changed markedly during the normal menstrual cycle. These changes were distributed in three characteristic phases. During phase I, corresponding to the midfollicular period (days 7-8), a small proportion (25%) of stromal and glandular cells stained positively for the progesterone receptor, whereas estrogen receptor staining was more intense and more frequent (50% of cells). Phase II, which included both the late follicular and early luteal periods (days 9-19), was characterized by a marked staining of progesterone receptors in the majority of glandular cells (75%) and somewhat less abundant and less frequent staining in stromal cells (50%). Estrogen receptor staining was present in about half of the glandular and stromal cells. Phase III, the mid- and late luteal period (days 21-27), was characterized by the disappearance of estrogen and progesterone receptor staining in glandular cells, although faint staining for both receptors was found in stromal cells. These variations in progesterone receptor staining are potentially useful for determining the effect of progesterone on endometrial maturation.
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The authors report a case of renal and pancreatic transplantation in a patient with renal failure and type I diabetes. The entire pancreas and duodenum were transplanted, the duodenum was drained into the bladder in order to assay the urinary amylase which is an early criterion of rejection of the exocrine pancreas.
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To investigate the effect of LHRH (GnRH) agonists on sperm suppression, we studied the effect of a depot preparation of D-Trp6 LHRH in 10 normal men for 30 weeks. In addition, to determine the role of androgenic substitution on sperm suppression, the volunteers were divided into two groups: group 1 (n = 5) received a low dose T substitution (125 mg of T enanthate every month), while group 2 (n = 5) received a normal T substitution (120 mg of T undecanoate every day). Four men became azoospermic in group 1 and none in group 2. Moreover, administration of additional T injections in 1 volunteer of group 1 resulted in the reappearance of spermatozoa in the ejaculate. Return to the low dose therapy produced azoospermia. These results suggest that testosterone supplementation supports spermatogenesis.
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Various approaches to hormonal treatment of prostate carcinoma are discussed. Eighty-one patients with prostatic carcinoma, eight with stage B, nine with stage C, and 64 with stage D disease, were treated subcutaneously daily for 3 months with the LH-RH agonist D-Trp-6-LH-RH (Decapeptyl) in order to evaluate the incidence of remissions according to WHO recommendations for oncologic trials. The findings were compared to those obtained with other hormonal therapies of prostatic carcinoma according to the statistical method of "expected response rate" as adapted by Lee and Wesley for phase II trials. Treatment with D-Trp-6-LH-RH greatly reduced serum LH and testosterone levels without raising serum prolactin. After 1-2 weeks of therapy, there was relief of subjective symptoms and a reversal of the signs of prostatism as well as a marked decrease in bone pain. At 90 days 52 patients had complete relief of prostatism and 21 had only mild signs and symptoms. Seventy patients were experiencing no bone pain and an additional six had only mild pain. Prostatic size, evaluated by rectal examination and transabdominal ultrasonography, reverted to normal in 26.4% of patients (complete remission) and was reduced by more than 50% in an additional 17.6% (partial remission), the overall rate of complete plus partial regression of prostatic enlargement being 44%. Scans showed a major improvement of bone lesions in 14.8% of cases. This response increased to 37% after more than 6 months of follow-up. Prostatic acid phosphatase levels were decreased by more than 50% in 61% of the patients, but this test appears to be a less valid marker than the lipid-associated sialic acid (LASA). The increase in LASA before treatment and a reduction after treatment can frequently be correlated with the objective volume of the neoplasms. No flare-up of the disease was encountered, and there were no side effects except for impotence. Statistical analyses of results by the method of Lee and Wesley indicated that the incidence of complete and partial regression (CR and PR) observed with D-Trp-6-LH-RH was not significantly different from that recorded in previous studies for another LH-RH analog, Buserelin. However, CR and PR obtained with D-Trp-6-LH-RH (44%) were significantly higher than with subcapsular orchiectomy (22%). Hormonal effects and some other actions of D-Trp-6-LH-RH were compared and contrasted with those produced by castration, estrogens, antiandrogens, and progestogens.(ABSTRACT TRUNCATED AT 400 WORDS)
To investigate the efficacy of the different routes of luteinizing hormone releasing hormone (LHRH) administration upon pituitary responsiveness, we compared plasma LHRH concentrations and pituitary LH responses in four patients with hypothalamic amenorrhea treated with pulsatile LHRH. A portable computerized infusion pump delivered sc or iv LHRH pulses of 5, 10 or 20 micrograms every 90 min. Comparison of the two modes of LHRH delivery was performed using radioimmunoassay of exogenous LHRH and studying its pharmacokinetics for a 3 pulses period. With 10 micrograms of LHRH given iv, plasma LHRH levels increased between 700 and 1000 pg/ml within 3 min and returned to basal levels in 30 min. When given sc (10 micrograms), plasma LHRH levels peaked between 80 and 100 pg/ml in 15 min and returned to basal levels 60 min later. In one patient treated with 5 micrograms per pulse iv or sc, plasma LHRH increased to 380 and 60 pg/ml respectively. In all patients, computerized analysis of LH pulses was performed during sc and iv LHRH administration. LH pulsatile release displayed a similar rhythm period with both routes. However, for the same dose of LHRH (10 micrograms), the adjusted mean of LH plasma levels was lower with the sc route. In conclusions, the pharmacokinetics of LHRH administered sc or iv displayed a similar pattern but, with equivalent doses, higher plasma LHRH levels are attained with the iv route. Concomitantly, the mean LH levels were also greater after iv administration. Ovulation can be successfully induced by both pulsatile iv and sc LHRH therapy. However, with the sc route, a higher dose of LHRH should be used to prevent a delay of ovulation or a luteal deficiency.
Androgen insensitivity has been reported to be present in as many as 40% of patients with severe oligospermia. In order to evaluate further the role of androgen resistance in male infertility we studied 24 men with severe oligospermia. Plasma T and LH were measured by RIA and the T X LH product was calculated. Fibroblasts were grown from genital skin obtained during testicular biopsies and androgen receptor maximal binding capacity (BMAX) and affinity (KD) were measured in fibroblast monolayers. Pubic skin 5 alpha-reductase activity, an androgen-dependent enzyme, was measured in skin homogenates. Plasma T values were in the upper normal range [7.0 +/- 1.7 (SEM) ng ml-1] whereas the T X LH product was high (greater than 50) in only six patients. Mean BMAX and KD values for the androgen receptor were normal [BMAX: 788 +/- 259 fmol mg DNA-1 (patients, n = 20), 726 +/- 227 (normal men, n = 20), and KD: 0.27 +/- 0.24 (patients, n = 20), 0.18 +/- 0.09 (normal men, n = 15), respectively]. However, four men had supranormal KD values. The mean BMAX was also normal when the group of men with sperm densities below 10(6) per ejaculate was considered separately. Public skin 5 alpha-reductase activity was normal in all but four patients (patients: 177.1 +/- 91 fmol/mg skin/h, n = 30, normal men: 210 +/- 45, n = 20 patients). In conclusion, androgen receptor BMAX levels were normal in all patients studied, regardless of the sperm density and the T X LH product. Pubic skin 5 alpha-reductase activity was also normal in all but four patients. In these four patients, a qualitative defect of the androgen receptor cannot be excluded. In this group of patients with severe oligospermia, infertility did not seem to be related to quantitative abnormality of the androgen receptor as was previously reported.