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R Bouillon

Publications and source records attributed to R Bouillon.

At least 127 records · Page 7Linked to original sources
PubMed1997

Decreased osteoblast activity in spontaneously diabetic rats. In vivo studies on the pathogenesis.

Diabetes in both humans and rats is accompanied by low bone formation, which is presumably caused by serum-borne factors. To explore its pathogenesis, we carried out experiments in diabetic and nondiabetic BB rats, using plasma osteocalcin concentrations (OC) as a marker for osteoblast activity. In nondiabetic rats, the i.v. infusion of glucose (30%, 4 d) did not change OC; s.c. insulin infusion (4 U/d, 14 d) reduced OC by 27% (p < 0.01). In diabetic rats, OC were decreased from the first day of glycosuria (71 +/- 5% of paired controls), declining exponentially to 24 +/- 3% after 5 wk. Insulin infusion (1, 2, and 3 U/d, 14 d) produced gradual restoration of OC. OC were better correlated with insulin-like growth factor-I (IGF-I) than with insulin levels in these experiments. OC were dramatically increased 4 d after adrenalectomy (ADX) in all diabetic rats (73 +/- 8 vs 22 +/- 4 micrograms/L before ADX; p < 0.001), but not if corticosterone was administered. Ligand blotting of IGF binding proteins showed a marked decrease in two bands (44-49 and 32-35 kDa) 10-14 d after diabetes onset; the density of these bands was increased, but not normalized after ADX. Thus, decreased osteoblast activity is present from the onset of diabetes, is dependent on endogenous corticosterone, and cannot be reproduced by hyperglycemia in nondiabetic rats.

Adrenalectomy↗
PubMed1997

Age-associated decline in human femoral neck cortical and trabecular content of insulin-like growth factor I: potential implications for age-related (type II) osteoporotic fracture occurrence.

Recent evidence suggests that regulatory peptides such as insulin-like growth factor-I (IGF-I) are released locally from bone during resorption, and may then act in a sequential manner to regulate the cellular events required for the coupling of bone formation to resorption. Among other factors, a decrease in bone-associated IGF-I levels could therefore result in remodeling imbalance and contribute to the gradual loss of bone that occurs with age. As the femoral neck region is of primary concern for the clinical manifestations of osteoporosis, the current study was intended to assess the IGF-I contents in femoral neck cortical and trabecular bone from aging individuals. Bone samples from the neck region were obtained at postmortem from 39 females and 35 males, aged 23-92 years. Concentrations of IGF-I and osteocalcin were measured by radioimmunoassay in the supernatants obtained after EDTA and guanidine hydrochloride extraction. The total amount of protein present in the extracts was determined by spectrophotometry. IGF-I levels were significantly lower in trabecular compared with cortical bone. Though femoral neck total protein did not vary with donor age, both IGF-I and osteocalcin were found to decline markedly. Between the ages of 23 and 92 years, average yearly rates of loss of 0.30 and 0.21 ng IGF-I/mg protein were observed in cortical and trabecular bone, respectively, corresponding with net losses of nearly 35% of the cortical skeletal content of IGF-I and 41% of the trabecular skeletal content of IGF-I. These changes in bone-associated IGF-I paralleled those of osteocalcin, consistent with an overall decrease in osteoblast function with aging. In women, the rate of decline was significantly faster for trabecular than for cortical IGF-I, however in men, age-dependent changes in cortical and trabecular IGF-I were similar. These findings support the hypothesis that changes in the local IGF regulatory system over time could be a pathophysiologic component of the age-related (type II) femoral neck osteoporotic syndrome.

Adult↗
PubMed1997

Estimation of thyroid gland volume by spiral computed tomography.

The objective of this study was to test the accuracy of CT for the estimation of the volume of enlarged thyroid glands. An unenhanced spiral CT scan of neck and upper mediastinum was obtained in 36 patients with an enlarged thyroid gland. By manual segmentation the surface of the thyroid gland on 5-mm-thick slices was calculated; these surfaces were multiplied by the slice interval (10 mm) and summated to obtain the volume of the gland. All patients underwent a total or subtotal thyroidectomy. 1 cm3 of thyroid gland tissue was considered to weigh 1 g. A good correlation was found between the volume estimated by CT and the weight at pathological examination of the resected gland (r = 0.98, p < 0.001), with a mean difference of + 12 % (range: + 57.3 to -13.9 %). The volume calculation is reproducible among different observers (r = 0.99, p < 0.01). Computed tomography allows an easy, reliable and reproducible volume determination of enlarged thyroid glands.

Adult↗
PubMed1997

Synergism between sirolimus and 1,25-dihydroxyvitamin D3 in vitro and in vivo.

The active form of vitamin D, 1 alpha, 25-(OH)2D3, displays immunomodulatory effects in vitro and in vivo at pharmacological levels. We evaluated the dose-effect relationship of 1,25(OH)2D3 and sirolimus (rapamycin, RAP) in vitro, on the inhibition of PHA-stimulated PBMC proliferation, by using the median effect analysis. Pharmacological concentrations of 1,25(OH)2D3 (between 10(-9) and 3 x 10(-6) M) interacted synergistically with RAP (combination index value of 0.01 for 50% suppression of PBMC proliferation). In vivo, the effect of 1,25(OH)2D3 and RAP combinations on the evolution of experimental allergic encephalomyelitis in SJL mice was analyzed. 1,25(OH)2D3, given i.p., in monotherapy, at a dose of 2 micrograms/kg every two days, from day -3 until day +19 after disease induction, or RAP, injected daily at a dose of 0.3 mg/kg for the same period, decreased EAE incidence (paralysis in 70 and 55% of the animals, respectively, versus 98% in the placebo treated group, p < 0.001). The combination treatment using the two drugs in these subtherapeutical doses provided near-total clinical (8% paralysis, p < 0.001 compared to monotherapy with 1,25(OH)2D3 or RAP) and histological protection, comparable to that obtained with RAP in monotherapy at a threefold higher dose (1 mg/kg/d). When the two drugs were given using an alternate day administration schedule (RAP at 0.6 mg/kg and 1,25(OH)2D3 at 2 micrograms/kg, each given on alternate days from day -3 to 19), near total protection was again obtained (13% paralysis, p < 0.001 versus control). These in vitro and in vivo data support the existence of synergistic interactions between 1,25(OH)2D3 and RAP. Considering the narrow therapeutic windows of both RAP and vitamin D-related compounds in autoimmune disease models, combinations of these drugs could find clinical application in reducing their individual therapeutically efficient doses to non-toxic levels.

Animals↗
PubMed1997

Ageing and calcium metabolism.

Ageing alters the metabolism of calcium and vitamin D in a number of ways. Intake of calcium and vitamin D, exposure to sunlight, cutaneous production of vitamin D3, renal production of 1,25-dihydroxyvitamin D (1,25(OH)2D3), intestinal absorption of calcium and the ability to adapt to a low calcium diet may all be reduced in elderly subjects. As a consequence, secondary hyperparathyroidism often occurs with ageing and can contribute to accelerated bone loss. In fact, alterations in calcium and vitamin D metabolism may be widespread in the ageing population and play a central role in the pathogenesis of senile (age-related) osteoporosis. From a preventive point of view, recent intervention studies have indicated the need to optimize calcium intake and to maintain serum 25(OH)D3 levels within the normal range in elderly people.

Aged↗
PubMed1997

Differentiation induction of HL60 cells by 1,25(OH)2D3, all trans retinoic acid, rTGF-beta2 and their combinations.

1,25 Dihydroxyvitamin D3 (D3), all trans retinoic acid (atRA) and the cytokine rTGF-beta2 are growth and differentiation modulators of promyelocytic leukemia. D3 gives rise to a functional monocytic cell population whereas single atRA therapy induces granulocytic cell features. rTGF-beta2 reduces HL60 cell proliferation but has no differentiating capacity. Combination treatment demonstrates additive effects between either D3 and atRA or D3 and rTGF-beta2, resulting in a cell population with mixed characteristics since individual cells exhibit both monocytic as granulocytic cell features. The capacity of single and combined treatments to induce a permanent differentiation was investigated. Therefore, cells were preincubated with the drugs during six days, test drugs were removed and cell number was monitored. The total cell count of populations treated with single agents remains constant for only a few days and then increases rapidly. rTGF-beta2 cooperated with D3 in inducing a long-lasting differentiation state (3 weeks). Addition of atRA to this combination did not significantly alter proliferation or differentiation, but some cells underwent apoptosis. Therefore, a total and permanent differentiation of leukemic cells may be achieved by repeated exposure to a combination of differentiation inducing agents.

Antigens, Neoplasm↗
PubMed1997

Effects of long-term diabetes and/or high-dose 17 beta-estradiol on bone formation, bone mineral density, and strength in ovariectomized rats.

Long-term diabetes in female rats preserves the bone mineral density (BMD) but impairs the strength of the femur. In this study, we have compared the effects of diabetes and high-dose 17 beta-estradiol (E2), two conditions of low bone formation, in ovariectomized (ovx) rats. Spontaneously diabetic BB rats were ovx 0-3 days after onset, and nondiabetic ovx littermates were used as controls; the rats were either untreated or treated with E2 (30 micrograms/day, subcutaneously), for 6 or 12 weeks (n = 9 in each of the eight groups). Analysis included: plasma 1,25-dihydroxyvitamin D3, insulin-like growth factor-I (IGF-I), and osteocalcin concentrations; histomorphometry of the proximal tibial metaphysis (PTM); and DXA and biomechanical testing of the femur. Both E2 treatment and diabetes markedly lowered plasma IGF-I and osteocalcin concentrations, as well as dynamic morphometric parameters of bone formation in the PTM. Plasma IGF-I and osteocalcin were correlated (R2 = 0.55; p < 0.0001). E2 treatment in both control and diabetic ovx rats increased the trabecular bone volume in the PTM and the BMD in the metaphysis of the distal femur; there was no difference between control and diabetic rats, however. The diaphyseal area and BMC were decreased in E2-treated or/and diabetic ovx rats, but the diaphyseal BMD remained unchanged compared with untreated ovx rats. The biomechanical properties of the whole femur (strength, angular deformation, and stiffness) were decreased in E2-treated and diabetic E2-treated ovx rats after 12 weeks. The data indicate that in situations of chronic low bone formation, whole bone strength does not reflect total BMD but correlates better with bone size and bone mineral content measurements.

Animals↗
PubMed1997

Thyrotrophin and prolactin release in prolonged critical illness: dynamics of spontaneous secretion and effects of growth hormone-secretagogues.

OBJECTIVE: Infusion of GH secretagogues appears to be a novel endocrine approach to reverse the catabolic state of critical illness, through amplification of the endogenously blunted GH secretion associated with a substantial IGF-I rise. Here we report the dynamic characteristics of spontaneous nightly TSH and PRL secretion during prolonged critical illness, together with the concomitant effects exerted by the administration of GH-secretagogues, GH-releasing hormone (GHRH) and GH-releasing peptide-2 (GHRP-2) in particular, on night-time TSH and PRL secretion. PATIENTS AND DESIGN: Twenty-six critically ill adults (mean +/- SEM age: 63 +/- 2 years) were studied during two consecutive nights (2100-0600 h). According to a weighed randomization, they received 1 of 4 combinations of infusions, within a randomized, cross-over design for each combination: placebo (one night) and GHRH (the next night) (n = 4); placebo and GHRP-2 (n = 10); GHRH and GHRP-2 (n = 6); GHRP-2 and GHRH + GHRP-2 (n = 6). Peptide infusions (duration 21 hours) were started after a bolus of 1 microgram/kg at 0900 h and infused (1 microgram/kg/h) until 0600 h. MEASUREMENTS: Serum concentrations of TSH and PRL were determined by IRMA every 20 minutes and T4, T3 and rT3 by RIA at 2100 h and 0600 h in each study night. Hormone secretion was quantified using deconvolution analysis. RESULTS: During prolonged critical illness, mean night-time serum concentrations of TSH (1.25 +/- 0.42 mlU/l) and PRL (9.4 +/- 0.9 micrograms/l) were low-normal. However, the proportion of TSH and PRL that was released in a pulsatile fashion was low (32 +/- 6% and 16 +/- 2.6%) and no nocturnal TSH or PRL surges were observed. The serum levels of T3 (0.64 +/- 0.06 nmol/l) were low and were positively related to the number of TSH bursts (R2 = 0.32; P = 0.03) and to the log of pulsatile TSH production (R2 = 0.34; P = 0.03). GHRP-2 infusion further reduced the proportion of TSH released in a pulsatile fashion to half that during placebo infusion (P = 0.02), without altering mean TSH levels. GHRH infusion increased mean TSH levels and pulsatile TSH production, 2-fold compared to placebo (P = 0.03) and 3-fold compared to GHRP-2 (P = 0.008). The addition of GHRP-2 to GHRH infusion abolished the stimulatory effect of GHRH on pulsatile TSH secretion. GHRP-2 infusion induced a small increase in mean PRL levels (21%; P = 0.02) and basal PRL secretion rate (49%; P = 0.02) compared to placebo, as did GHRH and GHRH + GHRP-2. CONCLUSIONS: The characterization of the specific pattern of anterior pituitary function during prolonged critical illness is herewith extended to the dynamics of TSH and PRL secretion: mean serum levels are low-normal, no noctumal surge is observed and the pulsatile fractions of TSH and PRL release are reduced, as was shown previously for GH. Low circulating thyroid hormone levels appear positively correlated with the reduced pulsatile TSH secretion, suggesting that they have, at least in part, a neuroendocrine origin. Finally, the opposite effects of different GH-secretagogues on TSH secretion further delineate particular linkages between the somatotrophic and thyrotrophic axes during critical illness.

Adult↗
PubMed1997

Age-associated endocrine deficiencies as potential determinants of femoral neck (type II) osteoporotic fracture occurrence in elderly men.

Osteoporotic fractures, and especially hip fractures, are a leading cause of morbidity and mortality among elderly men. Among other factors, a decline in bone mass has been identified as the major determinant of the age-related reduction in bone strength and therefore of osteoporotic fracture risk. Recent evidence suggests that age-associated endocrine deficiencies may contribute to femoral bone loss and hip fracture occurrence in elderly men. The decline in circulating androgen levels and the decreased activity of the growth hormone insulin-like growth factor-I axis may result in a reduction in bone formation that contributes to the age-related increase in bone fragility in men. Vitamin D deficiency-induced secondary hyperparathyroidism, on the other band, may further enhance bone loss by activating bone turnover and so increasing the number of bone remodelling units with impaired bone formation. On the basis of these pathophysiological models, guidelines can be developed for the prevention of age-related bone loss in men, but these approaches lack validation. The results of controlled intervention trials will have to be awaited to answer the question of whether hormone replacement therapy attenuates bone loss and reduces fracture incidence in elderly men.

Aged↗
PubMed1997

The prevention or treatment of age-related osteoporosis in the elderly by systemic recombinant growth factor therapy (rhIGF-I or rhTGF beta): a perspective.

Both insulin-like growth factor-I (IGF-I) and transforming growth factor beta (TGF beta) have powerful modulatory effects in a variety of tissues. A major target of action is the skeletal system, where they enhance bone formation and decrease matrix degradation, thus playing a part in the maintenance of bone mass. Because of the potent mitogenic effect of these agents on osteoblasts, recombinant IGF-I (rhIGF-I) and recombinant TGF beta (rhTGF beta) have potential as drugs to stimulate bone formation in the prevention and treatment of osteoporosis. Using biochemical markers, subcutaneous rhIGF-I therapy has been shown to increase bone turnover and bone formation in nonosteoporotic older people. However, a corresponding increase in bone mass has not yet been documented nor have there been reports yet on the effects of systemically administered rhTGF beta in humans. Further investigation is required to define the clinical potential of rhIGF-I and rhTGF beta as therapeutic agents in age-related osteoporosis.

Age Factors↗
PubMed1997

Effects of short-term insulin-like growth factor-I or growth hormone treatment on bone turnover, renal phosphate reabsorption and 1,25 dihydroxyvitamin D3 production in healthy man.

OBJECTIVES: To find out whether insulin-like growth factor-I (IGF-I) mimics the stimulatory effects of growth hormone (GH) on bone turnover and renal tubular phosphate reabsorption. DESIGN: Randomized, crossover study. SETTING: University Hospital, Zürich, Switzerland. SUBJECTS: Seven young healthy male subjects. INTERVENTIONS: Each subject was studied three times at 2-week intervals, treated with saline 0.9% (S), IGF-I [8 micrograms kg-1 h-1] by a continuous subcutaneous infusion and finally with GH (6 U. twice daily s.c.) for 5 days. MAIN OUTCOME MEASURES: 36 h after the start of treatment, IGF-I, biochemical markers of bone turnover, calcium, calcium regulating hormones, kidney function and phosphate reabsorption were measured in serum and in 2 h urine in fasting state. RESULTS: Serum levels of IGF-I were 26.8 +/- 7.3 (S), 119.4 +/- 11.4 (IGF-I) (P < 0.02) and 58.4 +/- 12.9 nmol L-1 (GH) (P < 0.02), respectively. Serum osteocalcin and carboxyterminal propeptide of type I collagen (PICP) as well as the urinary deoxypyridinoline/creatinine and the calcium/ creatinine ratios were all significantly higher after IGF-I (P < 0.02) or GH (P < 0.02) than after saline treatment. PTH levels did not change in response to treatment. Total albumin-corrected calcium increased only after GH treatment (P < 0.05). The free calcitriol index rose from 2.2 +/- 0.5 x 10(-5) (S) to 2.81 +/- 0.25 x 10(-5) (IGF-I) (P < 0.03) and 2.45 +/- 0.25 x 10(-5) (GH), respectively. Serum phosphate and maximal tubular reabsorption divided by glomerular filtration rate (TmP/GFR) were significantly raised by GH (P < 0.03) but not by IGF-I as compared to saline 0.9%. CONCLUSIONS: (i) Similar to GH, IGF-I rapidly activates bone turnover. (ii) IGF-I does not mimic the effect of GH on renal phosphate reabsorption in spite of comparable effects on renal blood flow and glomerular filtration rate. (iii) IGF-I increases free calcitriol index in face of unchanged serum levels of calcium, phosphate and PTH, consistent with a direct stimulatory effect on 25-OHD-1a-hydroxylase.

Amino Acids↗
PubMed1997

Calciotropic hormones and markers of bone remodeling in age-related (type II) femoral neck osteoporosis: alterations consistent with secondary hyperparathyroidism-induced bone resorption.

BACKGROUND: Both a decrease in bone formation and the skeletal consequences of secondary hyperparathyroidism have been implied in the pathogenesis of age-related femoral neck osteoporosis. However, studies using biochemical indices of bone remodeling in hip fracture patients have yielded conflicting results. Similarly, secondary hyperparathyroidism has not been a consistent finding in this population. Some of these inconsistencies might reflect differences in the assays used as well as in the timing of the sampling. Moreover, measurements were mostly performed in a limited number of patients. In this regard, the aim of the present study was to analyze potential alterations in bone metabolism in a large population of elderly hip fracture patients. METHODS: Circulating concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D3], intact parathyroid hormone (PTH), and calcitonin were measured in 117 elderly women (within a few hours after sustaining a fracture of the proximal femur) and in 117 healthy age-matched controls. In addition, serum osteocalcin and urinary excretion of (deoxy)pyridinoline were determined as markers of bone formation and resorption, respectively. RESULTS: Serum levels of 25(OH)D and 1,25(OH)2D3 were decreased in hip fracture patients. When correcting for differences in serum vitamin D binding protein, serum 25(OH)D was still significantly lower in patients than in controls, whereas serum 1,25(OH)2D3 was not. Moreover, 25(OH)D deficiency in hip fracture patients was associated with an increase in circulating PTH and urinary excretion of (deoxy)pyridinoline. Serum osteocalcin, on the other hand, was significantly decreased in fracture patients. There was no statistically significant difference in calcitonin. CONCLUSION: These data suggest that there is reduced bone formation and increased bone resorption in patients with hip fracture. Although limited by its cross-sectional design, the present study emphasizes the role of secondary hyperparathyroidism-induced bone resorption in the pathogenesis of age-related osteoporosis, mainly due to a lack of 25(OH)D.

Aged↗
PubMed1997

Retinoic acid modulates the anti-proliferative effect of 1,25-dihydroxyvitamin D3 in cultured human epidermal keratinocytes.

Both 1,25-dihydroxyvitamin D3 (VD) and retinoids have potent effects on keratinocyte proliferation. Parallelism in their action as steroid hormones, which involves interaction of their receptors, and in their therapeutic efficacy for hyper-proliferative skin diseases provides a rationale to investigate their combined action on proliferation in pre-confluent human epidermal keratinocyte cultures. As shown by [3H]thymidine incorporation, all-trans retinoic acid (atRA) at subpharmacologic concentrations and 9-cis retinoic acid (9cRA) diminished the anti-proliferative effect of VD. Pre-incubation of the cells with the retinoids clearly enhanced this effect. Cell-cycle analysis revealed G1 arrest upon VD treatment that was attenuated by retinoic acid (RA). Moreover, Northern and Western blot analysis demonstrated that retinoic acid opposed VD-induced accumulation of transforming growth factor-beta1, p21WAF1, and p27KIP1. Finally, retinoic acid reduced VD-elicited hypophosphorylation of the retinoblastoma protein. AtRA at micromolar concentrations conversely potentiated most of the aforementioned VD-dependent actions. In addition, atRA and 9cRA (but not VD) caused a rapid, sustained reduction of RXR alpha protein. VD receptor protein was induced by VD regardless of the presence of RA. In conclusion, RA modulates VD-dependent effects at different levels of keratinocyte proliferation. This could have implications for the use of combinations of both drugs for skin diseases.

Calcitriol↗
PubMed1997

Differential stimulation of ERK and JNK activities by ultraviolet B irradiation and epidermal growth factor in human keratinocytes.

Exposure of mammalian cells to solar ultraviolet (UV) radiation leads to the expression of several genes, and UV has been recognized as a major initiator and promoter of skin cancer. The component of the solar radiation that contributes most to human skin malignancy is UVB (280-320 nm) and, to a lesser extent, UVA (320-400 nm), whereas the high-energy UVC (100-280 nm) is absorbed by the earth's upper atmosphere. Sublethal doses of UVB produce strong induction of c-jun and c-fos transcripts in several cells including human primary keratinocytes. The present report confirms that this is also the case in the HaCaT cell line and shows that similar UVB doses are potent inducers of the JNK/SAPK family of mitogen-activated protein kinases but only weak activators of ERKs. Epidermal growth factor (EGF) caused rapid induction of both JNK- and ERK-signaling pathways, and the downmodulation of the EGF-signaling pathway by EGF pre-treatment inhibited the UVB-induced JNK1 activation. Prior UVB irradiation of the cells decreased the level of the ERK2 activation by a subsequent EGF treatment, but this sensitized the cells and allowed for the super-activation of JNK1 after a rechallenge with either UVB or EGF. The antioxidant N-acetylcysteine impaired the UVB- and EGF-induced activation of JNK1. Our data suggest the presence of shared signaling component(s) in the UVB- and EGF-induced cellular response pathways and imply that oxidative stress plays a significant role in the activation of JNK1 by UVB and EGF.

Base Sequence↗
PubMed1997

Relief of sleep apnoea after treatment of acromegaly: report of three cases and review of the literature.

Sleep apnoea syndrome (SAS) is common in acromegalic patients. Occasionally, the relief of apnoeas after treatment of the acromegaly has been documented. We report the cases of three patients with acromegaly and severe obstructive sleep apnoea, who demonstrated a manifest improvement (respiratory disturbance index (RDI) <20) after treatment with octreotide, indicating that this drug may be effective in this disturbance. In one case, SAS disappeared although the growth hormone level was not fully normalized. This raises the intriguing hypothesis that octreotide has an effect on respiratory control or on the upper airway, that is not directly related to its action on production of growth hormone.

Acromegaly↗
PubMed1997

Aromatase inhibition impairs skeletal modeling and decreases bone mineral density in growing male rats.

Aromatization of androgens into estrogens may explain some of the skeletal action of androgens. We examined the effect of the aromatase inhibitor Vorozole (VOR) on skeletal growth and mineral accumulation in growing 6-week-old male Wistar rats. Rats were either Sham-operated (Sham) or Orchidectomized (Orch) and treated with or without the aromatase inhibitor VOR. One Sham-operated group was killed at Baseline (Base); the four other groups (Sham, Sham + VOR, Orch, Orch + VOR) were killed 18 weeks after surgery. As expected, all groups gained body weight, but body weight gain was significantly (-25%) lower in Orch, Orch + VOR, and Sham + VOR. Both bone formation, as assessed by serum osteocalcin, and bone resorption, as assessed by urinary (deoxy)pyridinoline, decreased significantly in all groups compared with Base. Orchidectomy resulted in a relative increase of biochemical markers of bone formation and resorption compared with Sham. Treatment with VOR, however, resulted only in a very moderate increase of (deoxy)pyridinoline compared with Sham. As expected, femoral length increased compared with Base, but orchidectomy reduced the relative growth of the femur whereas VOR did not influence femoral length. Ex vivo, densitometric and geometric properties of the femora were evaluated by peripheral computerized quantitative tomography (pQCT) and dual-energy x-ray absorptiometry (DXA). The lumbar vertebrae were measured by DXA. At the end of the experimental period, volumetric trabecular bone mineral density (vTBMD) measured at the distal end of the femur was significantly lower not only in both Orch groups but also in Sham + VOR. The decrease of cancellous bone density in Sham + VOR was lower than in the orchidectomized animals. A relative decrease of femoral inner and outer diameters compared with Sham and Base was observed in both Orch groups and in Sham + VOR, suggesting that both orchidectomy and VOR-treatment inhibited periosteal bone formation and endosteal bone resorption. Only orchidectomy, however, resulted in a decrease of cortical thickness. Bone area, mineral content, and density of both femora and lumbar vertebrae, measured by DXA, were decreased to a similar extent by VOR and Orch (bone mineral content of the femur was 467 +/- 18 mg in Orch and 461 +/- 10 mg in Sham +/- VOR vs. 521 +/- 11 mg in Sham; P < 0.001). In conclusion, treatment with the aromatase inhibitor VOR impairs body weight gain and skeletal modeling and decreases bone mineral density. Aromatase inhibition had similar final effects on bone mass and size as castration, but with less marked effects on bone turnover.

Absorptiometry, Photon↗
PubMed1997

The somatotropic axis in critical illness: effect of continuous growth hormone (GH)-releasing hormone and GH-releasing peptide-2 infusion.

Prolonged critical illness is characterized by protein hypercatabolism and preservation of fat depots, associated with blunted GH secretion, elevated serum cortisol levels, and low insulin-like growth factor I (IGF-I) concentrations. In this condition, GH is readily released in response to a bolus of GHRH and GH-releasing peptide-2 (GHRP-2) and, paradoxically, to TRH. We further explored the altered somatotropic axis and cortisol secretion in critical illness by examining the effects of continuous GHRH and/or GHRP-2 infusion. Twenty-six critically ill adults (mean age +/- SEM, 63 +/- 2 yr) were studied during 2 consecutive nights (2100-0600 h). According to a weighed randomization, they received one of four combinations of infusions within a randomized cross-over design for each combination: placebo (one night) and GHRP-2 (the other night; n = 10), placebo and GHRH (n = 4), GHRH and GHRP-2 (n = 6), and GHRP-2 and GHRH plus GHRP-2 (n = 6). The peptide infusions (duration, 21 h) were started after a bolus of 1 microgram/kg at 0900 h and infused (1 microgram/kg/h) until 0600 h. Serum concentrations of GH were determined every 20 min, cortisol every hour, and IGF-I at 2100 and 0600 h on each study night. The placebo profiles showed pulsatile GH secretion with low secretory burst amplitude [0.062 +/- 0.008 microgram/L distribution volume (Lv)/min], high burst frequency (6.6 +/- 0.4 events/9 h), and detectable basal secretion (0.041 +/- 0.009 microgram/L/min) in the face of low serum IGF-I (106 +/- 11 micrograms/L). IGF-I correlated positively and significantly with the basal component, the pulsatile component, and the total amount of nightly GH secretion. GHRH elicited a 2- to 3-fold increase in the mean GH concentration (P = 0.006), the GH secretory burst amplitude (P = 0.007), and basal GH secretion (P = 0.03). GHRP-2 provoked a 4- to 6-fold increase in the mean GH concentration (P < 0.0001), the GH secretory burst amplitude (P = 0.002), and basal GH secretion (P = 0.0007), which were associated with a 61 +/- 13% increase in serum IGF-I within 24 h (P = 0.02). Compared to GHRP-2 alone, GHRH plus GHRP-2 elicited a further 2-fold increase in the mean GH concentration (P = 0.04) and GH basal secretion (P = 0.02), and an additional 40 +/- 6% rise in serum IGF-I (P = 0.04). GHRH and GHRP-2 infusion did not alter elevated cortisol levels. In critically ill adults, low serum IGF-I levels were positively correlated with diminished pulsatile and increased basal GH secretion. Both basal and pulsatile GH secretion were moderately increased by continuous infusion of GHRH, substantially increased by GHRP-2, and strikingly increased by GHRH plus GHRP-2. GHRP-2 alone or combined with GHRH elicited a robust rise in circulating IGF-I levels within 24 h without altering serum cortisol levels. These findings open perspectives for GH secretagogues as potential antagonists of the catabolic state in critical care medicine.

Adult↗