Spontaneous maturation of primary follicle. Effects of some peptidergic ovarian regulators.
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Animals↗
Biomedical subjects
P Franchimont
Publications and source records attributed to P Franchimont.
Thymic neurohypophysial-related peptides and T cell selection.
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Animals↗
Effect of transdermal 17 beta-estradiol and oral conjugated equine estrogens on biochemical parameters of bone resorption in natural menopause.
OBJECTIVE: To evaluate and compare the effects or oral and transdermal estrogen replacement therapy on biochemical markers of bone resorption in early postmenopausal women. DESIGN: Controlled, randomized group comparison. SETTING: Outpatient clinic for menopausal women and research into osteoporosis. SUBJECTS: Sixty healthy women menopausal for less than 5 years and who had never received any medications interfering with bone metabolism. INTERVENTIONS: The 60 women were randomly allocated to 3 months therapy with either oral conjugated estrogens (0.625 mg/day) (n = 28) or transdermal estradiol (50 micrograms/day) (n = 32) in cyclical combination with medroxyprogesterone acetate (5 mg/day). MAIN OUTCOME MEASURES: Traditional (urinary calcium/creatinine and hydroxyproline/creatinine) and the new specific (urinary pyridinoline/creatinine and deoxypyridinoline/creatinine) markers of bone resorption were determined before and after 3 months of treatment. RESULTS: In both groups, circulating levels of estrone and estradiol were significantly (P < 0.001) increased during treatment. In women treated with oral conjugated equine estrogens, urinary calcium/creatinine and hydroxyproline/creatinine ratios were significantly (P < 0.05) reduced. Pyridinoline/creatinine ratio fell from 69.1 (4) [mean (SEM)] to 50 (4) mumol/mumol (P < 0.01) and deoxypyridinoline/creatinine ratio fell from 10.8 (1) [mean (SEM)] to 8.3 (0.8) mumol/mumol (P < 0.01). In the group treated with transdermal estradiol, urinary hydroxyproline/creatinine ratio was significantly (P < 0.05) reduced. Pyridinoline/creatinine ratio fell from 66.3 (4) [mean (SEM)] to 46.2 (3) mumol/mumol (P < 0.01) and deoxypyridinoline/creatinine ratio fell from 11.5 (1.5) [mean (SEM)] to 7.7 (0.6) mumol/mumol (P < 0.01). There were no differences between the evolution of the biochemical variables in the two groups. CONCLUSION: These results suggest that oral conjugated equine estrogens and transdermal estradiol, in the given doses, are equally effective in reducing postmenopausal bone resorption.
Administration, Cutaneous↗
Prevention of osteoporosis with nasal salmon calcitonin: effect of anti-salmon calcitonin antibody formation.
The amino acid sequence of salmon calcitonin (SCT) differs considerably from that of the human hormone and specific antibodies (Ab) develop in a significant proportion of patients after parenteral or nasal administration of SCT. Controversy remains regarding the functional importance of these Ab. We report on the development of specific anti-SCT Ab in a population of postmenopausal women receiving nasal SCT for prevention of postmenopausal bone loss, and compare the effects of nasal SCT in women with or without Ab. Thirty-nine per cent of women developed Ab after 6 months of treatment with SCT, 52% after 12 months, and 61% after 18 and 24 months. After 24 months the AB titre was 3.47-17.7 x 10(-9) M/l (mean +/- SD: 13.3 +/- 3.1 x 10(-9) M/l). No significant differences appeared between the changes in lumbar bone mineral density (BMD) measured in the whole population (n = 44) (mean +/- SD: +1.06 +/- 3.9%), the patients without Ab (n = 17) (+0.05 +/- 3.7%) or in those with Ab (n = 27) (+1.7 +/- 4.6%). During the same period, a control population randomly assigned to a 500 mg/day calcium intake showed a significant loss of lumbar BMD (-4.57 +/- 4.9%) (p < 0.01). In conclusion, in healthy postmenopausal women nasal SCT seems to maintain the same preventive effect against bone loss whether or not Ab are present.
Administration, Intranasal↗
Acute biochemical variations induced by four different calcium salts in healthy male volunteers.
Calcium (Ca) supplements have positive effects in growing children, reduce bone loss in late-postmenopausal women with a low calcium diet and, in association with vitamin D3 supplements, may reduce non-vertebral fracture rates in elderly women. However, for many formulated pharmaceutical products their relative beneficial effects have not been conclusively established. We have compared the acute (6 h) metabolic responses following oral administration of two preparations of calcium gluconolactate and carbonate (CG and CG'), tricalcium phosphate (TCP) and calcium citrate (CC), given on separate occasions in each of 10 healthy young male volunteers. The subjects fasted overnight for 12 h and continued to fast during the experimental procedure. A 1000 mg dose of each Ca salt was ingested at weekly intervals. Blood was drawn after 30, 60, 90, 120, 180, 240, 300 and 360 min for measurement of serum Ca, phosphorus (P), parathyroid hormone (PTH) and whole plasma calcitonin (iCT). All Ca supplements induced significant (+6.4% to +8.1%; p < 0.01) increases in Ca and significant suppression of PTH (-37.4% to -57.4%; p < 0.01). Comparison of response curves revealed significantly (p < 0.01) more marked Ca increase and PTH suppression with CC than with the other three Ca salts. CG' and CC induced marginal decreases in serum P and the overall curve of P variations was different for TCP compared with CG, CG' and CC. No significant variation of iCT was recorded during the test.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Control of pulsatile secretion of gonadotrophin releasing hormone from hypothalamic explants.
We have studied the secretion of gonadotrophin releasing hormone (GnRH) from hypothalamic explants of male rats at different ages in an attempt to delineate the neuroendocrine mechanism of the onset of puberty. In this paper, we review some of our recent studies and we provide evidence of a dual control played by receptors to neuroexcitatory amino acids. We showed previously that isolated explants of rat hypothalamus could secrete GnRH in a pulsatile manner. The onset of puberty was characterized by a 2-fold increase in frequency of GnRH secretory pulses. This reduction of the interval between GnRH pulses involved an inhibitory autofeedback effect of GnRH on the pulse generator which was shut off following a secretory episode. This period of refractoriness was longer before puberty than after the onset of puberty. Activation of receptors to neuroexcitatory amino acids (N-methyl-D-aspartate; NMDA-type) was involved in the mechanism of pulsatile GnRH secretion. Striking developmental changes in NMDA-receptor-mediated GnRH secretion were demonstrated with a maximal activity around the time of the onset of puberty. Similar changes occurred in orchidectomized animals, indicating that this maturational process was gonad-independent. While evidence accumulated that NMDA receptors were involved in a stimulatory control of GnRH secretion, we found that NMDA receptors mediated an inhibitory effect on GnRH secretion. This inhibitory effect was very potent in the immature hypothalamus and it showed a marked reduction in potency before onset of puberty.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Production of active oxygen species by isolated human chondrocytes.
The ability of isolated human chondrocytes to produce active oxygen species has been investigated. The two methods for determining H2O2 and hydroxyl radicals (.OH) production were, by a fluorimetric method (production of dichlorofluorescein from a precursor in the presence of horseradish peroxidase and H2O2) and by a chromatographic method (measurement of ethylene production from gamma-methiol-keto-butyric acid after .OH attack). Chondrocytes were tested, both with and without activation by phorbol myristate acetate (PMA: 10(-6) M), in the presence of Ca2+ (1 x 10(-4) M) and Mg2+ (2 x 10(-4) M) or after variable periods of anoxia under nitrogen (4 to 12 h) followed by reoxygenation (with 95% O2, 5% CO2). Under these experimental conditions, the PMA-excited chondrocytes produced from 80 to 180 nmol of hydrogen peroxide per 1 x 10(6) cells and chondrocytes subjected to anoxia-reoxygenation produced up to 1700 nmol H2O2 per 1 x 10(6) cells. The hydroxyl radical production by PMA or anoxia-reoxygenation excited cells reached 600% of the production of non-excited cells and 1300% when they were subjected to successive stimulations by PMA and anoxia-reoxygenation. The possible pathological significance of these observations is discussed. The results indicate that stimulated human chondrocytes are capable of producing active oxygen species which could play a major role in joint inflammation and cartilage damage.
Adolescent↗
Effects of growth hormone therapy on the developmental changes of follicle stimulating hormone and insulin-like growth factor-I serum concentrations in Turner's syndrome.
OBJECTIVE: The aim was to investigate whether, in the absence of gonads, GH could bring forward the age of neuroendocrine activation resulting in onset of puberty. DESIGN: In girls with Turner's syndrome, we evaluated the effects of GH therapy on developmental changes in FSH serum concentrations used as an indicator of neuroendocrine maturation in the absence of gonads. PATIENTS: Thirty-nine girls with Turner's syndrome aged 4.0-17.1 years were treated using GH (25 IU/m2 week) for 1 year. MEASUREMENTS: Serum levels of FSH and IGF-I were measured before initiation of GH therapy and 12 months later, after interruption of GH treatment for 2 days. RESULTS: Pretreatment FSH levels were low between 6 and 10 years and increased markedly at 10-11 years of age. This pattern was unchanged after 1 year of GH therapy. Pretreatment IGF-I levels were positively correlated with age and they were uniformly increased after 1 year of GH therapy. CONCLUSIONS: Our data suggest that GH and its effector, IGF-I, do not influence the timing of the onset of puberty through an effect on its neuroendocrine control.
Adolescent↗
Paget's disease of bone treated with a five day course of oral tiludronate.
Chloro-4-phenyl thiomethylene bisphosphonate (tiludronate) is a new drug which can be used as an inhibitor of bone resorption. As it remains in bone for a long time, and as mineralisation defects have only been seen at doses much higher than those required to decrease osteoclastic activity, it could be given at high doses over a short period of time. Eighteen patients with Paget's disease of bone were randomly allocated to three therapeutic groups receiving respectively 600, 800, and 1200 mg/day tiludronate for five days. Serum alkaline phosphatase activity and the urinary hydroxyproline/creatinine ratio were quickly and drastically reduced in all three groups. A significant reduction of serum alkaline phosphatases and the hydroxyproline/creatinine ratio was still present six months after the five day therapeutic course, reflecting a sustained activity of tiludronate even after stopping treatment. Dose dependent short and long term reductions of bone turnover rate were observed. Biochemical assessment of haematological, renal, or hepatic tolerance did not show any toxicity of tiludronate. Fifty per cent of patients treated by a dose of 1200 mg/day reported gastrointestinal disturbances, however, making this dosage unsuitable for clinical practice.
Administration, Oral↗
Acute suppression of gonadotropin-releasing hormone secretion by insulin-like growth factor I and subproducts: an age-dependent endocrine effect.
Using rat hypothalamic explants, we showed previously that activation of N-methyl-D-aspartate (NMDA) receptors was involved in the mechanism of gonadotropin-releasing hormone (GnRH) secretion. (1-3)Insulin-like growth factor I (IGF-I), the N-terminal tripeptide of IGF-I, was suggested to be a possible antagonist at NMDA receptors. Here, we study the effects of IGF-I and its subproducts, (1-3)IGF-I and (4-70)IGF-I, either given in vivo as a single subcutaneous injection or used in vitro, on the secretion of GnRH by hypothalamic explants. At the three ages studied (15, 25 and 50 days), (4-70)IGF-I does not show any effect. At 50 days, the in vivo administration or the in vitro use of IGF-I results in a dose-related inhibition of the GnRH secretion induced by veratridine, a depolarizing agent. In addition, the spontaneous pulsatile secretion of GnRH in vitro is transiently suppressed after the in vivo administration of IGF-I. (1-3)IGF-I results in an inhibitory effect similar to that of IGF-I. At 25 days, IGF-I and (1-3)IGF-I show the same effects as at 50 days though higher concentrations are required. At 15 days, IGF-I does not show any effect whereas a potent inhibition of GnRH secretion is observed using (1-3)IGF-I either in vivo or in vitro. At all ages, the effects of (1-3)IGF-I parallel those of AP-5, a competitive antagonist at NMDA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Tumor necrosis factor-alpha antagonizes follicle-stimulating hormone action in cultured Sertoli cells.
In the present study, we have tested the effect of tumor necrosis factor-alpha (TNF alpha) on FSH action in cultured purified Sertoli cells isolated from immature porcine testes. FSH action was evaluated through three different parameters (aromatase activity, lactate production, and alpha-inhibin production). TNF alpha was shown to reduce (about 40-60% decrease) FSH-stimulated but not basal aromatase activity (evaluated through the conversion of testosterone into estradiol) in a dose- and time-dependent manner. The maximal and half-maximal (IC50) effects were observed with 6 ng/ml (3.5 x 10(-10) M) and 0.6 ng/ml (3.5 x 10(-11) M), respectively, after a long-term (72 h) treatment. TNF alpha (20 ng/ml) also inhibited Sertoli cell aromatase activity when stimulated with 8-bromo-cAMP (0.01-3 mM, 72 h) instead of FSH, suggesting that the antigonadotropin action of the cytokine is probably exerted at a step located beyond cAMP formation. The inhibitory effect of TNF alpha was not limited to the action of FSH on aromatase activity but also extended to the gonadotropin action on lactate and inhibin-alpha chain production in Sertoli cells. As for FSH-induced aromatase activity, TNF alpha reduced FSH-stimulated lactate accumulation with an IC50 of 0.6 ng/ml, after a long-term (72 h) treatment. Again, the cytokine reduced lactate production stimulated by 8-bromo-cAMP, suggesting that TNF alpha antagonistic action against FSH is exerted at post-cAMP levels. Finally, TNF alpha exerted a more pronounced inhibitory effect (> 90% inhibition) on alpha-inhibin than on inhibin heterodimer production. These inhibitory effects of TNF alpha on the gonadotropin action are probably exerted directly on Sertoli cells, since TNF alpha high affinity binding sites (dissociation constant approximately 5.3 x 10(-10) M) are present in primary cultures of purified porcine Sertoli cells. Altogether, the present findings show that TNF alpha antagonizes FSH action on Sertoli cell functions such as aromatase activity and lactate and alpha-inhibin production. Such an inhibitory effect is probably exerted at a biochemical step(s) located beyond cAMP generation.
8-Bromo Cyclic Adenosine Monophosphate↗
Piroxicam-beta-cyclodextrin in the treatment of acute pain of rheumatic disease.
Analgesics continue to be the mainstay of therapy in osteoarthritis. Non-steroidal anti-inflammatory drugs (NSAIDs) play an important role, particularly where there is a significant inflammatory component to the osteoarthritis. Piroxicam-beta-cyclodextrin (PBC) is a new formulation in which piroxicam has been complexed with beta-cyclodextrin, a cyclic oligosaccharide. This results in an increase in the rate of absorption of the active compound and, consequently, in an earlier onset of analgesic action. PBC, like piroxicam, is administered once daily. PBC has been used in the treatment of osteoarthritis. In comparison with piroxicam, PBC showed a more rapid analgesic-anti-inflammatory action after the first administration in patients with active osteoarthritis. Subsequent evaluations at the second, fifth and last day of treatment demonstrated a comparable efficacy of the two drugs. The efficacy and tolerability of PBC was compared with other NSAIDs given intramuscularly, such as diclofenac and ketoprofen. The three compounds provided marked pain relief within thirty minutes and this increased progressively until the third to fourth hour. The efficacy of oral PBC was comparable to that of intramuscular diclofenac or ketoprofen. In comparison with metamisole PBC achieved a more rapid and sustained reduction in pain intensity during the first twelve hours of treatment. This rapid and marked reduction in pain intensity with PBC was also observed in patients with low-back pain when compared with etodolac. In view of its efficacy, tolerability and rapid onset of action, piroxicam-beta-cyclodextrin appears to be an useful analgesic and a prominent progress in the treatment of acute rheumatic pain.
Acute Disease↗
Membrane translocation and relationship with MHC class I of a human thymic neurophysin-like protein.
Thymic epithelial and nurse cells (TEC/TNC) synthesize an oxytocin (OT)-like peptide in association with a neurophysin (NP)-related protein in a way similar to in the hypothalamo-neurohypophysial (NHP) system. The central T-cell tolerance of the NHP neuroendocrine functions have been proposed to be mediated through these thymic NHP-related peptides due to their close homology with the NHP neurohormones OT and vasopressin (VP). In order to investigate their putative presentation by proteins of the major histocompatibility complex (MHC), human thymic membranes were purified and passed through an immunoaffinity column using mAb B9.12 directed to the monomorphic determinant of human MHC class I proteins. This methodology provided the following observations: (1) a NP-like protein is translocated in human thymic membranes and is retained by B9.12 on the column; (2) the MW of this NP-like material (50-55 kD) is quite different from the MW of hypothalamic NP proteins (10 kD), and (3) this thymic NP-like protein could be identified on Western blots with mAb B9.12. The precise extent of this relationship between the thymic NP-like protein and the Ig/MHC superfamily is actually investigated through the characterization of the genetic mechanisms responsible for the thymic expression of NHP-related peptides. Given the physiological importance of OT and of its binding to NP for transport along the axonal processes of the NHP tract, we postulate that, somewhat analogously, the thymic NP-/MHC class I-related protein could be involved in the presentation of the OT-like peptide to immature T-cells.
Amino Acid Sequence↗
Evidence that insulin-like growth factor 2 (IGF2) is the dominant thymic peptide of the insulin superfamily.
The central T-cell tolerance of neuroendocrine functions has been proposed to be primarily induced by the thymic repertoire of neuroendocrine self antigens. The present study aimed at characterizing the human thymic insulin-related autoantigen able to represent the pancreatic B-cell function in face of the developing T-cells. Immunofluorescence studies were performed on human and rat thymic sections, as well as on the rat IT-45R1 thymic epithelial cell line using several antibodies to epitopes of the insulin peptide superfamily. These studies identify beyond any doubt that insulin-like growth factor 2 (IGF2) is the dominant thymic peptide of the insulin family. The sequence of an insulin-derived autoantigen is proposed. This autoantigen is a nonamer and has a hydrophobic residue leucine (L) at position 9. In the human species, this autoantigen would primarily be tolerogenic for the pancreatic B-cell endocrine function during fetal development.
Amino Acid Sequence↗
Insulin-like growth factor II in two human colon-carcinoma cell lines: gene structure and expression, and protein secretion.
Abnormal expression and structural modification of the IGF-II gene in correlation with high IGF-II production have recently been described in human colorectal tumors in comparison with normal adjacent tissues. Here, we have studied IGF-II in 2 human colon-carcinoma cell lines, HT29 and COLO 320DM. RFLP analyses revealed no apparent alteration at the IGF-II locus in these 2 cell lines. HT29 cells weakly expressed IGF-II mRNA in comparison with the high over-expression previously observed in some colorectal tumors, and only the 4.8-kb mRNA species was present. In addition, the serum-free medium conditioned by HT29 cells contained high IGF-II levels (approx. 900 ng/10(8) cells), as measured in a specific IGF-II radioimmunoassay (RIA). After chromatography on Bio-Gel P-60, we observed that 64% of the total IGF-II secreted by HT29 cells were present as a high-molecular-weight form of about 17 kDa. In contrast, no detectable expression of the IGF-II gene was observed in COLO 320DM cells, and low IGF-II levels were secreted by these cells in the serum-free medium, with only 9% total IGF-II represented by the large species.
Carcinoma↗
Active oxygen species, articular inflammation and cartilage damage.
Rheumatoid arthritis and osteoarthritis are age-related diseases, in which degenerative changes (arthrosis) and superimposed inflammatory reactions (arthritis) lead to progressive destruction of the joints. Active oxygen species derived from various sources play a role in this process, which may be influenced by appropriate treatment with antioxidants and free radical scavengers.
Aging↗
Intraoperative cytokines production during orthotopic liver transplantation.
In summary, we established that a significant production of the monokines interleukin-6, tumor necrosis factor apha, and interleukin-1 occurred during orthotopic liver transplantation whereas the lymphokines interferon gamma and interleukin-2 were not detected. Levels of interleukin-6 reached their maximum values before and especially at the end of the anhepatic phase. They remained high after the anhepatic phase, i. e. after reperfusion of the new livers. Tumor necrosis factor alpha and interleukin-1 reached their maximum values after the anhepatic phase. Not only were interleukin-6, tumor necrosis factor alpha, and interleukin-1 present in the serum but they could also be detected in the bile produced by these new livers. Mechanisms of monokine production during orthotopic liver transplantation is multifactorial in origin and further studies will have to evaluate the relative contribution of the various factors involved. The possibility of an association between peroperative monokines and transplant outcome and their potential clinical implication will have to be elucidated.
Cytokines↗
Minimal levels of serum estradiol prevent postmenopausal bone loss.
Biochemical parameters reflecting bone resorption [urinary calcium/creatinine (Ca/Cr) and hydroxyproline/creatinine (OH/Cr)] were related to serum estrogens [estrone (E1) and estradiol (E2)] in 262 healthy women including 158 patients receiving estrogen replacement therapy (ERT) for at least 6 months, 49 eugonadal women, and 55 untreated postmenopausal women. A significant (P < 0.001) correlation exists between serum E2 and Ca/Cr: Ca/Cr (mg/dl) = -0.00044 E2 (pg/ml) + 0.129 (n = 262; r = -0.37), serum E2 and OH/Cr: (OH/Cr (mg/g) = -0.049 E2 (pg/ml) + 18.76 (n = 262; r = -0.36), serum E1 and Ca/Cr: Ca/Cr (mg/dl) = -0.0003 E1 (pg/ml) + 0.127 (n = 261; r = -0.28) but not between serum E1 and OH/Cr. Women with circulating levels of E2 between 60 and 90 pg/ml have a significant (P < 0.01) reduction of Ca/Cr and OH/Cr when compared with those with lower levels of E2. Higher values of E2 do not provide additional benefit. We conclude that in postmenopausal women receiving an estrogen replacement therapy (ERT), a significant reduction of bone resorption is achieved when circulating levels of estradiol reach a value (60 pg/ml) corresponding to the one measured, in eugonadal women, during the last days of the early follicular phase of the menstrual cycle. We suggest that oral or percutaneous ERT should induce a minimal value of 60 pg/ml to prevent postmenopausal bone loss.
Analysis of Variance↗