Effects of glucocorticoids and of growth hormone on serum leptin concentrations in man

To evaluate cardiopulmonary involvement in schistosomiasis mansoni, 246 patients from an endemic area of Brazil were examined; 152 had been previously treated for schistosomiasis. Based on stool examination and/or abdominal ultrasonography, the patients were divided into those with schistosomiasis (69%) and those in whom the disease was not present (31%). M mode measurements were similar in the 2 groups. Pulmonary pressure was measured by Doppler echocardiography; 25% of the subjects had pulmonary hypertension. Those with pulmonary hypertension had a higher prevalence of schistosomiasis (80%) than those without (64%; P = 0.03). No case of cor pulmonale was diagnosed by electrocardiography or Doppler echocardiography. The prevalence of pulmonary hypertension correlated neither with periportal fibrosis nor with prior treatment for schistosomiasis.     

Reversal of the sex difference in serum leptin levels upon cross-sex hormone administration in transsexuals

Women have higher circulating leptin levels than men. This sex difference is not simply explained by differences in the amount of body fat and is possibly influenced by their different sex steroid milieus. This prompted us to study prospectively the effects of cross-sex steroid hormones on serum leptin levels in 17 male to female transsexuals and 15 female to male transsexuals. Male to female transsexuals were treated with 100 micrograms ethinyl estradiol and 100 mg cyproterone acetate (antiandrogen) daily, and female to male transsexuals received testosterone esters (250 mg/2 weeks, im). Before and after 4 and 12 months of cross-sex hormone treatment, serum leptin levels and measures of body fatness were assessed. Before treatment, female subjects had higher serum leptin levels than male subjects independently of the amount of body fat (P < 0.01). Cross-sex hormone administration induced a reversal of the sex difference in serum leptin levels. Estrogen treatment in combination with antiandrogens in male subjects increased median serum leptin levels from 1.9 ng/mL before treatment to 4.8 ng/mL after 4 months and 5.5 ng/mL after 12 months of treatment (P < 0.0001). Testosterone administration in female subjects decreased median serum leptin levels from 5.6 to 2.6 ng/mL after 4 months and to 2.5 ng/mL after 12 months (P < 0.0001). Analysis of covariance revealed that the changes in serum leptin levels were independent of changes in body fatness in both groups (P < 0.01). In conclusion, these results indicate that sex steroid hormones, in particular testosterone, play an important role in the regulation of serum leptin levels. The prevailing sex steroid milieu, not genetic sex, is a significant determinant of the sex difference in serum leptin levels.     

Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women

Leptin, an adipocyte hormone, is a trophic factor for the reproductive system; however, it is still unknown whether there is a dynamic relation between fluctuations in circulating leptin and hypothalamic-pituitary-ovarian (HPO) axis hormones. To test the hypothesis that fluctuations in plasma leptin concentrations are related to the levels of luteinizing hormone (LH) and estradiol, we sampled plasma from six healthy women every 7 min for 24 h during days 8-11 of the menstrual cycle. Cross-correlation analysis throughout the 24-h cycle revealed a relation between release patterns of leptin and LH, with a lag of 42-84 min but no significant cross-correlation between LH and estradiol. The ultradian fluctuations in leptin levels showed pattern synchrony with those of both LH and estradiol as determined by cross-approximate entropy (cross-ApEn). At night, as leptin levels rose to their peak, the pulsatility profiles of LH changed significantly and became synchronous with those of leptin. LH pulses were fewer, of longer duration, higher amplitude, and larger area than during the day. Moreover, the synchronicity of LH and leptin occurred late at night, at which time estradiol and leptin also exhibited significantly stronger pattern coupling than during the day. We propose that leptin may regulate the minute-to-minute oscillations in the levels of LH and estradiol, and that the nocturnal rise in leptin may determine the change in nocturnal LH profile in the mid-to-late follicular phase that precedes ovulation. This may explain the disruption of hypothalamic-pituitary-ovarian function that is characteristic of states of low leptin release, such as anorexia nervosa and cachexia.     

Determinants of serum leptin levels in Cushing's syndrome

Corticosteroids and insulin increase leptin expression in vivo and in vitro. To investigate whether increased serum cortisol influences serum leptin concentrations in humans, we analyzed fasting serum leptin and insulin levels in 50 patients with Cushing's syndrome [34 female patients: 27 with the pituitary form and 7 with the adrenal form; age, 41.6 +/- 2.7 yr; body mass index (BMI), 29.6 +/- 1.2 kg/m2; 16 male patients all with the pituitary form; age, 39.2 +/- 3.1 yr; BMI, 26.3 +/- 2.3 kg/m2] and in controls matched for BMI, age, and gender. Serum leptin levels were higher in female than in male patients in both the Cushing (P < 0.01) and control (P < 0.001) groups. Disease-specific differences in serum leptin levels were only detected in male (106 vs. 67 pmol/L; Cushing's syndrome vs. control, P < 0.05), not female, patients. Multiple stepwise regression analysis of both patient groups revealed insulin as the best predictor of serum leptin concentrations, accounting for 37% of the variance in serum leptin levels, in contrast to BMI or mean serum cortisol (as measured by sampling in 10-min intervals over 24 h). In the subgroup of patients (n = 9) with pituitary adenoma, serum leptin levels were reduced after tumor resection, with concurrent decreases in serum cortisol, insulin, and BMI. In conclusion, chronic hypercortisolemia in Cushing's syndrome appears not to directly affect serum leptin concentrations, but to have an indirect effect via the associated hyperinsulinemia and/or impaired insulin sensitivity.     

Methylphenidate increases serum growth hormone concentrations

Serum growth hormone (GH) and cortisol concentrations were measured in 12 healthy, young men following oral administration of methylphenidate (20 mgm ) or a placebo. Methylphenidate elicited unequivocal GH elevations in 9 of 12 subjects while only 2 subjects showed GH elevation following placebo. Cortisol concentrations were not affected by methylphenidate.     

Relation of race, age, and sex hormone differences to serum leptin concentrations in children and adolescents

We explored the effects of race, age, and sex hormones on the serum leptin concentrations in 203 white and 88 black children and adolescents (ages 9.3-20.5 years). A significant sex by race interaction on serum leptin levels (p = 0.0301) was observed with lower serum leptin concentrations, adjusted for subscapular thickness and age, in black boys than in white boys. Girls had serum leptin levels that were on average 2.15 times those of boys (p < 0.0001). There was an age by sex interaction (p < 0.0001) with serum leptin concentrations decreasing in boys but not in girls with age. A strongly inverse relationship of serum testosterone levels with serum leptin levels in boys (p = 0.0067) appeared to explain this effect of age. In conclusion, the serum leptin concentration is slightly lower in black boys. A higher testosterone level in boys appears to account for an age-related decline in serum leptin in boys and the overall lower levels in boys than in girls.     

The effects of phenobarbital and gonadal steroids on periovulatory serum levels of luteinizing hormone and follicle-stimulating hormone in the hamster

The occurrence of ovulation and serum levels of LH and FSH (measured by radioimmunoassay) were determined in periovulatory hamsters injected with an ovulation-blocking dose of phenobarbital (Phen) combined with progesterone (P), estradiol-17beta (E2), or testosterone (T). Proestrous hamsters were treated at 1300 h with Phen plus oil, P, P plus E2, E2, T, or a second injection of Phen at 2000 h. Each treatment group was divided into 3 subgroups, each of which was serially bled 4 times at 6 h intervals beginning at 1200, 1400, and 1600 h on proestrus. Phen blocked ovulation on the next morning in all animals, while treatments that included P (1 mg) restored the normal complement of ova in 65-75% of the animals. Neither E2 (1, 10 or 50 mug) nor T (0.1 or 1 mg) overcame the Phen block of ovulation. Control hamsters had peak levels of LH between 1400 and 1800 h and a biphasic release of FSH consisting of a peak at 1600 h on proestrus, a return to basal levels at 2200 h, and a second more sustained surge between 2400 and 0800 h on the morning of estrus. Phen completely depressed the proestrous surge of both gonadotropins but only partially inhibited the second FSH elevation on the morning of estrus. In ovulatory animals, P alone or combined with 1 or 10 mug E2 restored peak LH levels at 1600 h. FSH levels on proestrus in hamsters treated with Phen plus P peaked at 1800 h, while the addition of 1 mug E2 resulted in increased FSH levels at 1600 h; peak levels in both groups were about half of control values. No proestrous increase was detected in ovulatory animals treated with P and 10 mug E2. FSH levels on estrus in hamsters injected with P alone or in combination with E2 were intermediate between those of controls and animals given Phen only. Levels of LH and FSH in animals treated with a single or double dose of Phen or Phen plus E2 or T were not different during the periovulatory period.     

Increase in serum leptin and uterine leptin receptor messenger RNA levels during pregnancy in rats

Pregnancy is a physiological state associated with significant changes in appetite, thermogenesis, and lipid metabolism, functions which are regulated in part by a hormone, leptin, secreted by adipocytes. Leptin has also been shown to have a role in reproduction, promoting centrally-regulated maturation of the reproductive system and signaling the presence of adequate maternal energy stores for fertility. Here we demonstrate that serum leptin levels are modulated during normal rat pregnancy with a 1.8-fold increase during pregnancy followed by a decrease just before parturition. Leptin receptor mRNA levels in the uterus are also regulated with an increase about 2.7-fold during this same period, whereas there is no change in other tissues examined. The results suggest that leptin may play a role during pregnancy, perhaps regulating energy utilization.     

Determination of circulating parathyroid hormone levels and differential diagnosis of hypercalcemia

Primary hyperparathyroidism is the most frequent cause of hypercalcemia in outpatients. In contrast, this electrolyte disorder is very often associated with cancer when detected in hospital, particularly in the frame of tumors of breast, lung or lympho-hematopoietic system. Hypercalcemia results from an imbalance between the fluxes of calcium entering and leaving the extracellular space. Theses fluxes, mainly those at the levels of bone and kidney, are the main regulators of calcium homeostasis. Depending on the etiology, increases in either bone resorption or renal tubular calcium reabsorption can predominate as the cause of elevated calcemia. Thus, an increment of renal tubular reabsorption of calcium plays a prominent role in hypercalcemia resulting from increased serum concentrations of parathyroid hormone, but can also be detected in 50% of malignant hypercalcemias. The ectopic production of authentic parathyroid hormone has convincingly been demonstrated in very few cases. The syndrome of pseudohyperparathyrodism encountered in malignant hypercalcemia can be accounted for by the tumoral secretion of an analog of parathyroid hormone, parathyroid hormone-related protein. Both proteins, which are produced by different genes located on different chromosomes, interact with the same cell membrane receptors and display identical spectrum of actions. Since they are immunologically quite distinct, there is no cross-reactivity in the various competitive or radiometric immunoassays actually available. The determination of circulating levels of parathyroid hormone is an essential step in the differential diagnosis of hypercalcemias, provided the assays offer adequate sensitivity and specificity. Nowadays, this appears to be generally the case.     

The effects of theophylline on serum alprazolam levels

Theophylline and benzodiazepines are frequently combined in clinical practice. Because of a number of case reports about antagonism of benzodiazepine-induced sedation by theophylline, we investigated serum alprazolam levels in a convenient sample of pulmonary medicine inpatients receiving theophylline and no theophylline. One mg of alprazolam was given daily for seven days to 6 patients receiving theophylline and 7 patients not receiving theophylline treatment. On days 2 through 7, trough serum alprazolam levels were measured. On day 7, blood samples were collected before (0 hour), and at 3, 6, 9 and 12 hours after alprazolam administration. In patients receiving theophylline, serum trough alprazolam levels were significantly lower during each day of the study. In patients receiving no theophylline, serum alprazolam levels were in the therapeutic range, except for two patients who had high alprazolam levels. In this small study, serum alprazolam levels were found to be consistently below the therapeutic range in patients receiving chronic theophylline treatment. Previously reported antagonism of anxiolytic effects of benzodiazepines by theophylline is probably due to the lower serum benzodiazepine levels in these patients.     

Acute stress increases thyroid hormone levels in rat brain

BACKGROUND: In experimental animals, exposure to uncontrollable stress induces a number of behavioral and biochemical changes that resemble symptoms seen in human depression and other psychiatric conditions. The present study used a yoked design to examine the effects of uncontrollable footshock stress on brain thyroid hormones in male and female rats. METHODS: Animals in one group received 15 trials where footshock could be terminated by pressing a lever (escapable shock). Rats in a second group received the same amount of shock, but had no control over shock termination (inescapable shock). Control rats received no shock. RESULTS: No significant differences were found among the three groups, for either males or females, in whole brain levels of thyroxine (T4) 3 hours after the footshock session. In contrast, significant group differences in brain levels of triiodothyronine (T3) were found for both males and females. In males, brain T3 was elevated by 21% in the inescapable shock group when compared to controls (p < .012). In females, brain T3 increased by 19% in the escapable shock group when compared to controls (p < .026). Plasma levels of both T3 and T4 were at control levels for all groups. CONCLUSIONS: These results provide the first demonstration that brain T3 levels change rapidly in response to acute stress. The data further suggest that the effects of stress controllability on brain T3 levels may be different for males and females.     

Increased leptin messenger RNA and serum leptin levels in children with Prader-Willi syndrome and nonsyndromal obesity

To study the potential role of the ob gene pathway in childhood obesity, we have investigated leptin mRNA levels in s.c. adipose tissue obtained from nonobese prepubertal children (n = 20), obese nonsyndromal children (n = 6), and children with Prader-Willi syndrome (n = 6) by in situ hybridization histochemistry. We have also investigated the fasting serum leptin levels in such children. Compared with nonobese children, leptin mRNA expression was higher both in children with Prader-Willi syndrome and in children with nonsyndromal obesity (p < 0.01). Furthermore, the serum leptin levels were also significantly higher in both children with Prader-Willi syndrome and nonsyndromal obesity compared with the nonobese children (p < 0.001). However, no significant differences in adipose tissue leptin mRNA or serum leptin levels were observed between children with Prader-Willi syndrome and nonsyndromal obese children. As expected both fasting serum leptin levels and leptin mRNA expression levels correlated to body mass index (rs = 0.80 and 0.73, respectively, p < 0.005). No difference in leptin expression between Prader-Willi syndrome and nonsyndromal childhood obesity could be revealed in the present study. However, differences in the hypothalamic response to leptin between the two forms of obesity cannot be excluded.     

Effect of growth hormone administration on circulating levels of luteinizing hormone, follicle stimulating hormone and testosterone in normal healthy men

A new area of growth hormone (GH) therapy in adults is the treatment of infertility. The aim of this study was to evaluate the effects of pharmacological GH administration on the secretion of pituitary and gonadal hormones in normal men. Eight healthy men, 23-32 years of age (mean 28.1 years), with a normal body mass index were studied in a double-blind, placebo-controlled crossover design. All participants had a normal semen analysis before entering the study. Each participant was treated with placebo and GH (12/IU/day, Norditropin; Novo Nordisk, Denmark) during two different 14-day periods, separated by a 6 week washout period. Administration of GH for 14 days resulted in a significant increase in serum insulin-like growth factor I (IGF-I; P < 0.01) but no changes occurred in IGF-I values during placebo treatment. The concentrations of follicle stimulating hormone and luteinizing hormone displayed no change during the two periods and did not differ between the GH treatment period and the placebo period. The concentration of testosterone was unchanged during the placebo/GH periods and there was no difference between the GH treatment period and the placebo period. We conclude that GH treatment for 14 days in normal healthy men does not affect gonadotrophin or testosterone patterns.     

Lack of effects of growth hormone administration on ovarian function of lactating goats

During method development in support of non-clinical studies in animal models, BMS-186716 was found to be extremely unstable in blood and plasma. Stabilization of the compound was achieved by reacting the compound with methyl acrylate (MA) in blood, from which the plasma was then prepared. While the resulting BMS-186716-MA adduct was found to be stable in dog plasma, and hence it was used as the basis for the method developed for analysis of dog plasma samples, the BMS-186716-MA adduct was found to be unstable in rat plasma as it was readily hydrolyzed to BMS-186716-acrylic acid (AA) by native esterases found in rat plasma. Although the finding of the instability of BMS-186716-MA in rat plasma was not the result of prospective planning, we were able to successfully develop a quantitative bioanalytical method using BMS-186716-AA as the analyte instead of the originally planned BMS-186716-MA analyte. The standard and quality-control (QC) samples were prepared by spiking blank plasma with BMS-186716-MA, and then allowing them to stand at room temperature for 1 h to convert BMS-186716-MA to BMS-186716-AA. After adding the internal standard BMS-188035-AA, each sample was acidified with HCl and then extracted with methyl tert.-butyl ether. The reconstituted extract was injected into a HPLC-electrospray ionization mass spectrometric system for detection by positive ion electrospray ionization. A lower limit of quantitation (LLQ) of 5 ng/ml was achieved, using 0.1 ml plasma and a standard curve range of 5-5000 ng/ml.     

Thyroid dysfunction is not associated with alterations in serum leptin levels

To determine if serum leptin levels are affected by thyroid dysfunction, we measured its concentration in serum samples from 25 euthyroid controls and 25 subjects each with hypothyroidism and thyrotoxicosis collected over a 3-month period. Mean leptin levels in the euthyroid (24.1 +/- 8.3 microg/L), hypothyroid (22.7 +/- 7.0 microg/L) and thyrotoxic (23.3 +/- 4.3 microg/L) groups were not significantly different. Data were available to express leptin in terms of body mass index (BMI) in 11 euthyroid, and 6 untreated hypothyroid and thyrotoxic individuals. There was a significant positive correlation between BMI and leptin level (r = 0.60, p = .0002) for this subgroup, irrespective of their thyroid status. These data suggest that leptin levels are not affected by thyroid dysfunction.     

Opposite effects of growth hormone and estrogens on the pregnancy zone protein serum levels in children and adolescents

A newly developed assay for IgA class antibody to hepatitis E virus (IgA anti-HEV) was used to study 145 serum samples collected during an outbreak of an enterically transmitted hepatitis that occurred in 3 villages in the lower Shebeli region of Southern Somalia between January, 1988 and November, 1989. A total of 52.4% of the afflicted patients were found positive for IgA anti-HEV, and 73.1% of these were also positive for IgM. Both antibodies disappeared during the convalescence period. Similar results were also seen in serum obtained from sporadic cases of acute waterborne hepatitis in Pakistan.     

Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women

BACKGROUND: On the basis of observations in rodents, leptin is thought to play a key role in the regulation of energy expenditure and food intake, but less is known of its influence on ingestive behavior and energy balance in humans. OBJECTIVE: We examined the effect in women of a chronic energy deficit on plasma leptin concentrations and self-reported appetite and explored possible relations between leptin and appetite sensations. DESIGN: Twelve healthy women (body mass index, in kg/m2: 23-37) participated in a metabolic ward study in which 3 wk of neutral energy balance was followed by 12 wk of energy deficit (energy intake reduced by 2 MJ/d and energy expenditure increased by 0.8 MJ/d). Body weight and composition were monitored, fasting leptin concentrations were measured 4 times, and feelings of hunger, fullness, desire to eat, and prospective consumption were monitored hourly throughout the day on 7 selected days. RESULTS: Adiposity-adjusted leptin decreased by 54% after 1 wk of a moderate energy deficit and remained low after 6 and 12 wk. Leptin was associated with self-reported hunger, desire to eat, and prospective consumption (range of r: -0.6 to -0.7, P < 0.01). The greatest hunger increase coincided with the largest percentage drop in circulating leptin and the lowest final leptin concentration. The relation between leptin and hunger was not influenced by amount of weight or body fat loss. CONCLUSIONS: These findings support the idea that leptin is a physiologic regulator of hunger during energy deficits in humans; the role of leptin in the long-term regulation of food intake warrants further study.     

Interleukin-10 reduces circulating levels of serum cytokines in experimental pancreatitis

Over the past few years, evidence has accumulated that implicates proinflammatory cytokines as the mediators responsible for the escalation of acute pancreatitis into a multisystem disease. It has been shown that the degree of serum cytokine elevation, particularly the macrophage-derived cytokines interleukin-1, interleukin-6, and tumor necrosis factor-alpha, correlates with the severity and outcome of acute pancreatitis. Interleukin-10 is an anti-inflammatory cytokine that inhibits cytokine production from the macrophage. The aim of this study was to determine whether interleukin-10 would decrease both the severity of acute pancreatitis and the level of circulating proinflammatory cytokines. Ninety female mice were divided into three equal groups. Group 1 (controls) received intraperitoneal saline solution. Groups 2 and 3 received intraperitoneal cerulein (50 mg/kg/hr) for 7 hours. In addition, group 3 was given 1500 units of intraperitoneal interleukin-10, beginning 1 hour after the induction of acute pancreatitis and every 3 hours thereafter. Animals were killed at 3-hour intervals. Blood samples were obtained for serum amylase and cytokine determinations (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha). Pancreata were dissected free and fixed in formalin for blinded histologic scoring. Interleukin-10 reduced the serum levels of interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and amylase in comparison to untreated animals with pancreatitis (P < 0.05). Pancreatic edema, necrosis, and inflammatory cell infiltrate were also reduced in those animals given interleukin-10 (P <0.05). Histologic score, serum cytokines, and amylase levels are elevated during acute pancreatitis. Interleukin-10 given therapeutically, that is, after the onset of acute pancreatitis, lessened the severity of disease, probably through inhibition of the macrophage. This was associated with a decrease in circulating cytokine levels.     

Changes in thyroid hormone levels in patients with acute viral hepatitis

The authors describe the case of a 21-year-old female patient where for several months anaemia was the only symptom of subsequently diagnosed coeliac disease. They draw attention to the possibility of a monosymptomatic course of coeliac disease and discuss similar observations reported in the literature.