Dose-dependent efficacy of miglitol, an alpha-glucosidase inhibitor, in type 2 diabetic patients on diet alone: results of a 24-week double-blind placebo-controlled study.

AIMS: A double-blind randomised study was performed to compare the dose-effect and dose-tolerability relationships between the alpha-glucosidase inhibitor miglitol in doses of 25 mg, 50 mg, 100 mg and 200 mg all t.i.d. vs placebo t.i.d. in patients with Type 2 diabetes mellitus on diet only. METHODS: After a 6-week placebo run-in period 468 patients with a fasting blood glucose > or = 7 mmol/l as well as a HbA1c between 6.1% and 10.4% were randomised for a 24-week treatment period. RESULTS: The results of 465 patients were valid for safety analysis and of 384 patients for the efficacy analysis. In the placebo group the HbA1c level increased by 0.40+/-1.46% as compared with baseline. The decrease in the mean HbA1c values (corrected for differences in baseline values) was significant and dose-dependent for all miglitol groups compared with placebo, being -0.46% (95% CI: -0.91%, -0.01%) in the 25 mg group, -0.45% (95% CI: -0.90%, -0.003%) in the 50 mg group, -0.84% (95% CI: -1.31%, -0.37%) in the 100 mg group and -1.26% (95% CI: -1.76%, -0.76%) in the 200 mg group. Blood glucose levels following a standardised breakfast tolerance test were significantly and dose-dependently lower for all the miglitol doses at 12 and 24 wk of treatment compared to baseline: in comparison with baseline maximum blood glucose increased by 4% with placebo and decreased by 7%, 14%, 24% and 33% with miglitol 25 mg, 50 mg, 100 mg and 200 mg t.i.d. respectively. The same pattern was seen with postprandial maximal serum insulin levels which decreased by 8% under placebo and by 17%, 26%, 25% and 35% with the 25 mg to 200 mg doses of miglitol. The adverse events reported were mainly of gastrointestinal nature, mostly being flatulence, diarrhoea and abdominal pain and the incidence increased with increasing dose. Although the side effects were not serious, they were troublesome, leading to a considerable drop-out rate increasing with dose. CONCLUSIONS: The alpha-glucosidase inhibitor miglitol in Type 2 diabetic patients on diet alone decreases both HbA1c levels and postprandial glucose and insulin levels in a dose-dependent manner. Gastrointestinal side effects also showed dose-dependency. Combination of efficacy and safety results leads to the conclusion that the optimal dose of miglitol will be in the range of 50 to 100 mg t.i.d.

Growth hormone, insulin-like growth factor I and cognitive function in adults.

This review focuses on the possible contribution of the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis to cognitive function. Binding sites for GH and IGF-I are found in various areas of the brain. Their distribution suggests that GH and IGF-I contribute to the function of the hippocampus, a brain structure important for the maintenance of cognitive functions such as learning and memory. Evidence for cognitive deficits in GH-deficient individuals has been found in various studies, some of which have shown that these deficits can be reversed by GH substitution therapy. In addition to examining conditions of GH deficiency, this article reviews studies evaluating the correlation between the cognitive deficits associated with ageing and age-related decreases in GH or IGF-I secretion. Based on the available data, one might hypothesize that relative GH or IGF-I deficiency could contribute to the deterioration of cognitive functions observed in the elderly.

Long-term residual complaints and psychosocial sequelae after remission of hyperthyroidism.

The issue of residual complaints after treatment for hyperthyroidism in current euthyroid patients was investigated by means of a survey. Patients treated for hyperthyroidism were selected from medical records of the previous 6 years in two Dutch University Clinics. After the exclusion of patients with comorbidity, 303 one-time hyperthyroid respondents were included in the analysis. A total of 77% of these patients had been diagnosed with Graves' Disease. The newly developed Hyperthyroidism Complaint Questionnaire (HCQ), was used to quantify problems of somatic and mental functioning. The SymptomsCheckList-90 (SCL-90) was used to assess self-reported psychopathological symptoms, the Nottingham Health Profile was used to measure perceived health/quality of life. Dysthyroid patients (n = 20) had a mean HCQ-score of 14.5 (+/- 8.1) complaints; patients who reported euthyroidism for less than 12 months (n = 171) had a mean of 9.3 (+/- 7.6) residual complaints; patients who reported euthyroidism for more than 12 months (n = 54) a mean of 6.6 (+/- 6.8) residual complaints. On each dimension of psychopathology covered by the SCL-90, including depression and anxiety, approximately one third of the total sample had a score exceeding 80% of adult females. According to the NHP lack of energy was evident in 53% of all respondents. Over one third of patients with a full-time job were unable to resume the same work after treatment. It appears that many of these patients are in need of psychological support.

GH substitution does not alter the pulsatile pattern of LH in amenorrhoeic growth hormone deficient women.

OBJECTIVE: GH substitution in GH-deficient (GHD) children promotes pubertal development. In some GHD women, secondary amenorrhoea occurs after discontinuation of GH treatment. This study was designed to investigate whether GH substitution directly influences the GnRH pulse generator. For this reason, the pulsatile release of LH was studied in amenorrhoeic GHD women before and during GH substitution. DESIGN: GH deficiency was confirmed by an insulin tolerance test. During a 24-h period, blood samples were drawn every 10 min for determination of LH, FSH and GH levels. Oestradiol and IGF-1 were determined at 1000 h and 2200 h. After the first test day, patients started with GH substitution, 0.25 IU/kg/week. During month 6 of GH treatment, the 24 h blood sampling was repeated. SUBJECTS: Ten amenorrhoeic GH-deficient women participated in the trial. All were diagnosed as GH deficient during childhood or adolescence. Eight of them had been treated with GH during childhood. Seven women suffered from primary amenorrhoea and three from secondary amenorrhoea. Six women were started with GH substitution after the first test day (according to randomization in a larger study). MEASUREMENTS: LH and GH were determined every 10 min and FSH every 60 min. LH pulse detection was conducted using a validated statistical method. RESULTS: Prior to GH treatment, the LH pulse interval did not show a diurnal pattern as found during normal pubertal development. During GH treatment, IGF-1 levels rose significantly. No differences were found in mean LH, LH pulse amplitude and LH pulse interval before and during GH treatment. Oestradiol levels did not change either. CONCLUSIONS: GH substitution in amenorrhoeic GH-deficient women does not alter the pulsatile pattern of LH. This may suggest that GH treatment does not influence central nervous system control of gonadotropin secretion in GHD patients.

The influence of growth hormone (GH) deficiency and GH replacement on quality of life in GH-deficient patients.

The total absence of hormones such as cortisol or thyroxine causes death within weeks. Lack of estrogen or testosterone is followed by infertility and impaired sexual functioning. Relative deficiencies of almost all classical hormones have a substantial impact on quality of life (QOL). However, in contrast to virtually all aspects of metabolism, QOL is difficult to measure. Only recently have tests been developed to assess general QOL, whereas specific tests address those aspects of QOL affected only in specific situations or disease states. For example, in rheumatoid arthritis and other chronic disabling diseases, the use of measures of QOL to assess treatment modalities is almost routine. In diseases with overt metabolic disturbances attention is generally focused on changes in metabolic parameters and the issue of QOL is neglected. Although very few practising endocrinologists will not support the idea that they specialize in improving QOL, its assessment in patients with endocrinological disorders began only recently--in patients with growth hormone (GH) deficiency only 10 years ago. It became apparent that GH deficiency in adult life is unmistakably followed by changes in parameters that determine QOL. In adults with childhood-onset GH deficiency, the unemployment rate is higher and the marriage rate lower than in the general population. Another symbol of success in life, the possession of a driver's licence, is less frequently attained by these patients. Most patients with adult-onset GH deficiency score unfavourably in questionnaires such as the Nottingham Health Profile. GH substitution is now available on a scale large enough to enable studies to be made of the effects on QOL in adults. The first studies were reported in 1989. However, only in the last few years have studies appeared in which sufficient number of patients and sufficient length of treatment were reported to allow a more objective judgement of the effectiveness of GH substitution. Although there is still room for improvement in the methods used to assess the effects of GH treatment on QOL in GH-deficient adults, there is now little doubt as to its beneficial effect.

Long-term effects of growth hormone (GH) replacement in men with childhood-onset GH deficiency.

Short term GH replacement therapy has been shown to improve body composition and exercise capacity. It is not yet known whether GH replacement remains beneficial over the long term. We assessed the effects of long term GH replacement on body composition, bone mineral density, and cardiac function. Thirty-eight men with childhood-onset GH deficiency were studied for a period of 3-5 yr. Measurements included anthropometry, computed tomographic scanning of abdomen and upper leg, bone densitometry, echo cardiography, and bicycle ergometry. The initial GH dose of 1-3 IU/m2 x day (9-27 microg/kg) was gradually tapered to 1.30+/-0.38 IU/m2 x day (11 g/kg), aiming at physiological insulin-like growth factor I levels. During the study, leg muscle mass progressively increased by 28.7% (P<0.001). Subcutaneous and intraabdominal fat decreased by 30.9% and 46.0%, respectively, after 1 yr (both P<0.001), but demonstrated a partial regain thereafter. Bone mineral density at the lumbar spine, femoral neck, and trochanter gradually increased by 9.6%, 11.1%, and 16.2%, respectively (all P<0.001). Left ventricular mass exceeded baseline values by 14.1% after 1 yr (P<0.001), but returned to pretreatment values thereafter. Stroke volume and cardiac output increased by 16.3% (P = 0.002) and 33.4% (P<0.001), respectively. Maximal work load increased from 189+/-30 to 232+/-41 watts (P<0.001). Thus, long term GH replacement is safe and beneficial. It improves cardiac performance without inducing left ventricular hypertrophy and progressively increases bone mineral density.

Insulin-like growth factor-I and cognitive function in healthy older men.

The GH/insulin-like growth factor-I (GH/IGF-I) axis is known to be involved in aging of physiological functions. Recent studies indicate that the GH/IGF-I axis may be associated with cognitive functioning. The aim of the present study was to determine whether the age-related decline in circulating levels of IGF-I, as an index of anabolic status, is associated with cognitive functions that are known to decline with aging, but not with cognitive functions not sensitive to aging. Twenty five healthy older men with well-preserved functional ability participated in the study. We also administered neuropsychological tests of general knowledge, vocabulary, basic visual perception, reading ability, visuoconstructive ability, perceptual-motor speed, mental tracking, and verbal long-term memory. Performance on the last four tests decline with aging, whereas the first four of these tests have been shown not to be sensitive to cognitive aging. Mean age of the subjects was 69.1 +/- 3.4 (SD) yr (range 65-76 yr), their mean body mass index was 27.0 +/- 2.4 kg/m2, and their mean IGF-I level was 122 ng/mL (range: 50-220). We found IGF-I levels to be significantly associated with the performances (controlled for education) on the Digit Symbol Substitution test (r = 0.52, P = 0.009) and the Concept Shifting Task (r = -0.55, P = 0.005), which measure perceptual-motor and mental processing speed. Subjects with higher IGF-I levels performed better on these tests, performance on which is known to decline with aging. In conclusion, the results of this study support the hypothesis that circulating IGF-I may play a role in the age-related reduction of certain cognitive functions, specifically speed of information processing.

Growth hormone (GH) substitution in hypogonadotropic, GH-deficient women decreases the follicle-stimulating hormone threshold for monofollicular growth.

The FSH threshold concept for monofollicular growth (which means that at the time the largest follicle reaches 18 mm there are no other follicles with a diameter of 13-18 mm also present) was used during ovulation induction in hypogonadotropic women, who appeared to be GH deficient. This concept was used to investigate whether 1) GH influences the FSH threshold for monofollicular growth and 2) whether such an influence would depend upon the endogenous GH/insulin-like growth factor I (IGF-I)/IGF-binding protein-3 (IGFBP-3) levels. In six hypogonadotropic women the GH response after an insulin challenge did not exceed 6 microg/L. Patients underwent ovulation induction according to a low dose step-up protocol by hMG during two consecutive cycles. GH substitution was provided only during the second cycle. Except for one GH treated cycle, all cycles were ovulatory. IGF-I levels as well as IGFBP-3 levels significantly increased (P < 0.01) during GH substitution. Monofollicular growth was not achieved in the first cycles. In five of six GH-substituted cycles, monofollicular growth was obtained. FSH threshold levels decreased in all patients during GH substitution. The FSH area under the curve was negatively correlated to IGF-I (r = -0.6; P < 0.05) and IGFBP-3 (r = -0.6; P < 0.05). The results of this study indicate that GH may play a role in the physiological growth of the follicle; most likely this occurs by influencing the IGF-I or IGFBP-3 levels. GH appears to selectively increase the sensitivity of the dominant follicle to FSH, facilitating monofollicular growth.

A five day treatment with daily subcutaneous injections of growth hormone-releasing peptide-2 causes response attenuation and does not stimulate insulin-like growth factor-I secretion in healthy young men.

The synthetic hexapeptide growth hormone-releasing peptide (GHRP)-2 specifically stimulates GH release in man. To determine the effects of prolonged treatment and whether response attenuation occurs in man, we administered to nine healthy subjects a daily s.c. injection of 100 microg GHRP-2 over 5 days. Every day blood samples were taken to determine GH, IGF-I, IGF-binding protein (IGFBP)-3 and osteocalcin levels. On days 1,3 and 5, GH was measured at -20,0,20,40,60,90,120 and 180 min using an immunometric and an immunofunctional assay. Mean-/+S.D). peak GH concentrations were 83+/-31, 59+/-22 and 51+/-13 microg/l on days 1, 3 and 5 respectively. Mean+/-S.D. areas under the curve for days 1, 3 and 5 were 6366+/-2514, 3987 +/- 1418 and 3392+/-1215 mU/l per min. Despite the maintained GH release, analysis of variance revealed that significant response attenuation occurred (P < 0.01). Mean serum IGF-I concentration did not increase after a 5 day treatment with GHRP-2. Mean basal levels were 22, 25,23,25,23,24 nmol/l measured on days 1 to 6. However, osteocalcin, another serum marker of GH activity in tissue, increased significantly from 3.2+/-1.0 to 4.2+/-0.4 microg/l (mean+S.D.) (P< 0.01).

Cognitive changes during growth hormone replacement in adult men.

The present study evaluates the effects of 2 years of growth hormone (GH) replacement therapy on psychological well-being and cognitive performance in adults with childhood-onset growth hormone deficiency (CO-GHD). A total of 48 GHD adult men (mean age: 27 years) were randomly assigned to one of four treatment groups: placebo treatment, or GH replacement in a dose of 1, 2, or 3 IU/m2, respectively. Placebo treatment was given for 6 months. Psychological assessments were made every 6 months. Assessments included somatic and psychological complaints, depression, fatigue, vigor, tension, state/trait anxiety, iconic memory, short-term memory, long-term memory and perceptual-motor skill. GH treatment was considered physiological if the observed insulin-like growth factor-I (IGF-I) levels were within the normal range. It was considered supraphysiological if serum IGF-I rose to a value exceeding the upper normal limit. During the placebo-controlled phase of the study the changes in memory performance were positively correlated to the GH induced changes in serum IGF-I concentration and, more weakly, to the daily GH substitution dose. At 6 months memory only had improved in the group receiving supraphysiological GH treatment, but not in the group of patients who had a normalization of serum IGF-I. However, after 1 year of treatment a normalization of memory functioning was found in both groups of patients and this was preserved during the 2nd year of treatment. No changes were observed in psychological well-being and perceptual-motor skill. We conclude that GH replacement improves memory function in adults with CO-GHD. It has no effect on psychological well-being or perceptual-motor skill. Supraphysiological treatment accelerates the recovery of memory performance. However, the long-term effects are not different from those achieved with physiological GH replacement.

Growth hormone substitution in adult growth hormone-deficient men augments androgen effects on the skin.

OBJECTIVE: To assess whether growth hormone (GH) administration to adult GH-deficient men leads to increased sexual hair. The sexual hair scores are subnormal in these patients, even in the presence of normal serum androgen levels. PATIENTS: Forty-six adult men with childhood-onset of GH deficiency of whom 25 were androgen deficient and received replacement. DESIGN: Double-blind and placebo-controlled. Of the 46 patients, 33 started immediately with GH administration; the remaining 13 received placebo for the first 6 months followed by GH for the next 6 months. Sixty-one age-matched healthy men with normal height and serum concentrations of IGF-I served as a comparison group. MEASUREMENTS: Hair scores at 13 defined body regions were assessed before, and after 6 and 12 months of the intervention. At the same time levels of IGF-I, dehydroepiandrosterone sulphate, androstenedione, dihydrotestosterone (DHT), testosterone and sex hormone binding globulin (SHBG) were measured. From the latter two, the free androgen index (FAI) was calculated. RESULTS: Before GH administration, hair scores in the GH deficient patients were lower than in the comparison group. In the 33 men treated with GH from the beginning, there was an increase in hair scores after 6 months. The increase in hair scores was not seen during 6 months of placebo treatment. When the placebo group switched to GH administration, their hair scores had also significantly increased after 6 months of GH substitution therapy. Upon GH administration both levels of SHBG and testosterone/DHT declined while the FAI remained unchanged. CONCLUSION: GH substitution therapy to GH deficient men has an auxiliary effect on androgen action in the skin without an increase of the FAI.

The effect of growth hormone (GH) on histomorphometric indices of bone structure and bone turnover in GH-deficient men.

We investigated the effects of GH on bone structure and turnover by histomorphometry in GH-deficient adults. Therefore, transiliac bone biopsies were obtained before and after 1 yr of treatment in 36 GH-deficient men (mean age, 28 +/- 4 yr). Thirteen patients had isolated GH deficiency and 23 patients had multiple pituitary hormone deficiencies. Patients were randomly assigned to four treatment groups. Groups 1, 2, and 3 received 1, 2, and 3 IU/m2/day (0.35, 0.69, and 1.3 mg/m2/day) [corrected] GH, respectively, and the fourth group received placebo for the first 6 months and 2 IU/m2/day (5.8 mg/m2/day) GH for the subsequent 6 months. GH treatment resulted in an increase of cortical thickness from 0.98 +/- 0.27 to 1.20 +/- 0.35 mm (P = 0.005), but trabecular bone volume did not change. Bone formation variables increased significantly: osteoid surface increased from 8.5 +/- 5.3 to 15.5 +/- 6.1% (P = 0.0002), mineralizing surface increased from 6.7 +/- 2.5 to 10.8 +/- 4.4% (P = 0.0002), and bone formation rate increased from 0.04 +/- 0.02 to 0.08 +/- 0.04 mm3/mm2/day (P = 0.0001). Eroded surface did not change, but osteoclast number increased from 0.6 +/- 0.5 to 1.25 +/- 0.5 Oc/mm2 (P = 0.0001). The relative formation period increased significantly (P = 0.001), whereas the resorption period, including reversal phase, decreased from 65 to 40 days (P = 0.02). Activation frequency increased from 0.39 +/- 0.17 to 0.74 +/- 0.34 y(-1) (P = 0.0001). These data indicate a stimulated bone turnover as a result of GH treatment and a shorter resorption and reversal time. The increased turnover did not result in an increased trabecular bone volume, but the cortical thickness increased significantly.

Impaired reproductive function in women treated for growth hormone deficiency during childhood.

OBJECTIVE: There are limited data which suggest that disturbance of reproductive function may occur in GH-deficient women. We have evaluated the consequences of growth hormone (GH) deficiency on reproductive function in women treated for GH deficiency during childhood. DESIGN: Questionnaires were sent to 73 GH-deficient women who had been treated for GH deficiency during childhood. The response rate was 82%. These 60 women were then visited to obtain further information concerning their reproductive status. During these visits, blood samples were obtained from 39 women, to evaluate their hormonal status, and 29 of them had a standard insulin tolerance test (ITT), as part of an adult GH substitution trial. Paediatric and gynaecological records were evaluated in all 60 women. SUBJECTS: Sixty GH-deficient women treated in childhood for this deficiency were included in the study. The median age at follow up was 27 years (range 20-43). GH treatment had been discontinued for 9 years (range 2-26). MEASUREMENTS: In the questionnaire and during the visit, attention was paid to GH treatment, pubertal development, menstrual cycle disturbances and fertility. In the 39 blood samples IGF-1, IGFBP-3, TSH, T4 and T3 were measured. GH responses were measured by a standard ITT. RESULTS: Thirty-four women showed no spontaneous pubertal development. Of the 26 women who did, menarche occurred in 39% at the age of 16 years or older. At the time of the study, menstrual cycles in these 26 women were as follows: 12 had regular menstrual cycles, three had developed secondary amenorrhoea after discontinuation of GH treatment, five had irregular menstrual cycles and six had oligomenorrhoea. The 34 women with disturbed pubertal development and the three with secondary amenorrhoea were infertile because of hypogonadotrophism. Only 13 out of 60 women desired pregnancy or had been pregnant. Three with regular menstrual cycles had primary infertility. Ten had ovulation induced or IVF. Six of these became pregnant after 1-7 cycles. Three were still under treatment, the duration of their treatment varying from 3 to 7 years. One woman discontinued treatment. At the time of the study, nine women had actually conceived. Five out of ten completed pregnancies resulted in Caesarian sections because of cephalo-pelvic disproportion or arrest of labour. During the ITT three of 29 women showed GH responses exceeding 5 micrograms/l (10 mU/l), ruling out complete GH deficiency. Higher GH peaks (NS), IGF-1 (P , 0.01) and IGFBP-3 (P < 0.01) levels were found in women with regular menstrual cycles, compared to women using sex-steroid substitution and amenorrhoeic women. CONCLUSIONS: From this study, it can be concluded that disturbances in reproductive function can be expected in women treated for GH deficiency during childhood, so it is advisable to inform these women of this possibility and to maintain follow-up after discontinuation of GH treatment. Whether the somatotrophic axis exerts a direct effect on ovarian function or whether more severe GH deficiency is more frequently accompanied by disturbances in gonadotrophin secretion still has to be elucidated.

Cognitive impairments and mood disturbances in growth hormone deficient men.

In order to establish whether reported psychological complaints in hypopituitary adults are related to growth hormone (GH) deficiency or other pituitary hormone deficiencies, emotional well-being and cognitive performance were evaluated in 31 men with multiple pituitary hormone deficiencies (MPHD) and in 17 men with isolated growth hormone deficiency (IGHD). Assessments included evaluation of somatic and psychological complaints, depression, fatigue, vigor, tension, state and trait anxiety, iconic memory, short-term memory, long-term memory and perceptual-motor skill. The control group consisted of 41 healthy men, matched for age. Growth hormone secretion was more severely impaired in MPHD than in IGHD patients. Despite oral replacement therapy, MPHD patients also had lower serum testosterone levels than IGHD subjects. The MPHD patients were found to have lower vigor scores, higher state anxiety scores, worse perceptual-motor skill and worse memory performance than controls. In contrast, IGHD patients only showed subnormal memory performance. It was concluded, therefore, that the cognitive impairment in both MPHD and IGHD was related to GH deficiency. The subnormal vigor scores in MPHD patients were attributed to the reduced testosterone levels. The worse perceptual-motor skill in MPHD patients might be related specifically to ACTH deficiency. Finally, the higher state anxiety in MPHD was attributed to a low self-esteem, which may be the psychological consequence of the hypogonadal appearance these patients have. We conclude that, from a psychological point of view, MPHD and IGHD adult patients are quite distinct groups.

[Glucose intolerance in elderly persons in The Netherlands; the Twello Study]. / Glucose-intolerantie bij ouderen in Nederland; het Twello-onderzoek.

OBJECTIVE: To determine the prevalence of grades of glucose intolerance in subjects over 64 years of age. DESIGN: Point prevalence study. SETTING: Twello, a rural village in the Netherlands. METHODS: Of a total of 696 persons aged over 64 years recruited from a general practice, 460 subjects had an oral glucose tolerance test (OGTT) in 1985, 56 were known with non-insulin-dependent diabetes mellitus. Glucose estimations were done in capillary whole blood with a Glucometer. OGTT results were classified according to WHO 1985 recommended cut-off points and combination rules. RESULTS: The prevalence of normal glucose tolerance was 42%, of impaired glucose tolerance 27% and of diabetes mellitus 31%. The estimated prevalence in the source population were 45% (44.4-44.6), 28% (28.3-28.5) and 27% (95% CI: 27.1-27.2) respectively, adjusted for age and gender by standardization to the Dutch population of 1985. Re-evaluation of the earlier diagnoses of 'diabetes mellitus' according to the new WHO guidelines revealed that 55% of earlier diabetic with diet as the only therapy were no longer classified as diabetics. The prevalence of diabetes mellitus in persons over 64 was 10% before the investigation took place, and 30% afterwards. CONCLUSIONS: Te prevalence of diabetes mellitus as well as of impaired glucose tolerance from the Twello study rank among the higher rates reported in Caucasian populations. Case finding of glucose intolerance in those at risk over 64 years of age is recommended.

Lipase inhibition and hormonal status, body composition and gastrointestinal processing of a liquid high-fat mixed meal in moderately obese subjects.

The effect of Orlistat, a lipase inhibitor used in the treatment of obesity was studied on gastrointestinal transit time, on body composition and on hormones known to be influenced by the degree of hydrolysis of nutritional triglycerides or by reduced nutrient intake and absorption. After a placebo run-in period 14 patients were randomized to a 12-week treatment period on Orlistat 360 mg per day (mean body weight 93.1 +/- 9.8 kg) or placebo (mean body weight 90.7 +/- 10.5 kg). At randomization and after 12 weeks body weight, body composition, thyroid hormones, catecholamines, insulin-like growth factor I (IGF-I) and IGF-binding protein 3 were measured. During 4 hours after consumption of a liquid fat-rich mixed meal containing study medication, 15 g lactulose and 25 g xylose, blood levels of glucose, insulin, c-peptide, glucagon, triglycerides, free fatty acids, cholecystokinin, pancreatic polypeptide and xylose and expiration air levels of hydrogen were measured. Weight loss was 4.2 +/- 3.5 kg in the Orlistat group versus 3.0 +/- 1.9 kg in the placebo group. Fat mass decreased to an equal degree, whereas lean body mass remained stable. No differences were found for thyroid hormones, catecholamines, IGF-I and IGFBP-3 levels. By comparing the areas under the curve (AUC) and the peak levels at randomization (acute effects) of insulin and c-peptide a tendency was found to be increased in the Orlistat group, whereas those of xylose were increased significantly, suggesting faster gastric emptying after Orlistat. No differences were found in the other parameters. By comparing the changes in responses (longer term effects) no significant differences were found. In conclusion, the presence in the gut of undigested and unabsorbed fat does not seem to have a relevant influence on hormonal status and body composition in a small group of moderately obese patients.

The influence of chronic administration of the serotonin agonist dexfenfluramine on responsiveness to corticotropin releasing hormone and growth hormone-releasing hormone in moderately obese people.

Evidence exists that the serotoninergic system influences the hypothalamo-pituitary-adrenal axis and pituitary GH secretion. The effect was investigated of chronic (9 weeks) administration of the serotonin receptor agonist dexfenfluramine (DF) (15 mg twice daily) versus placebo on both systems in 24 moderately obese patients with an overconsumption of snacks. Before as well as after treatment, 100 micrograms GHRH and 100 micrograms CRH was administered iv. Weight loss after 9 weeks was 3.1 +/- 2.3 kg in the DF group and 0.1 +/- 1.2 in the placebo group (p < 0.001). No significant difference between the changes in the apparently normal ACTH and cortisol response in both groups was found. The apparently low GH response did not increase or normalize, but on the contrary decreased further after DF. No changes were shown in urinary free cortisol excretion and serum IGF-I levels. It can be concluded that in moderately obese patients the use of DF during a 9-week period induced a significant weight loss, did not influence the responsiveness of the pituitary gland to CRH nor the overall activity of the pituitary adrenal axis and finally, did not normalize the blunted GH response after GHRH.

First clinical studies with orlistat: a short review.

Lipase inhibition, leading to decreased intestinal fat adsorption can be used in the treatment of obesity. Orlistat, a lipase inhibitor, in a dose of 50 mg three times a day leads to a significant increase in weight loss compared to placebo in moderately obese people. These results are confirmed in a multiple-dose study using 10 mg, 60 mg and 120 mg Orlistat three times a day vs. placebo. The use of lipase inhibition has no significant influence on fasting levels of several hormonal systems, including thyroid hormones, catecholamines and IGF-I. The same is true for the responses of several gastrointestinal and pancreatic hormones after a liquid high-fat mixed meal. In general, Orlistat is tolerated very well, although a higher occurrence of gastrointestinal side effects is seen.