Area Under The Response Curve Research Articles

Effects of dietary energy allowance and decline in dry matter intake during the dry period on responses to glucose and insulin in transition dairy cows

We assessed whether high energy intake during the early dry period [144% of metabolizable energy (ME) requirements/d] followed by a gradual restriction of energy intake in the close-up dry period (119% of ME/d; HEI) impaired whole-body insulin sensitivity compared with a controlled energy intake (100% of ME/d; CEI) throughout the 6-wk dry period. Multiparous Ayrshire dairy cows (n = 16) were blocked by body weight, body condition score, and expected date of parturition and were used in a randomized complete block design until 10 d after parturition. Cows were fed either HEI or CEI diets based on grass silage during the first 3 wk of the dry period and grass silage supplemented with a commercial concentrate (30% of ME intake) during the final 3 wk of gestation. After calving, all cows were fed grass silage ad libitum and an increasing amount of commercial concentrate (maximum 9 kg at d 10 postpartum). Intravenous glucose tolerance tests (IVGTT) and intravenous insulin challenges were performed -10 ± 5 d (n = 15) and +10 ± 1 d (n = 14) relative to parturition. Following glucose injection, we did not find any treatment effects on glucose and insulin responses. The prepartal nonesterified fatty acid (NEFA) response of the HEI group was blunted, basal NEFA and the decrement of NEFA were smaller, and the area under the response curve (AUC) of NEFA was less negative in HEI cows than in CEI cows. The NEFA response reversed after parturition; the NEFA AUC of the HEI group was more negative than that of the CEI group. We did not find similar responses after insulin injection. Across the treatments, NEFA AUC correlated strongly with the basal NEFA concentration during the IVGTT pre- and postpartum. Calculated and model-based indices characterizing the overall glucose tolerance and β-cell function and the insulin sensitivity were higher after parturition than during the dry period. Consistent with the lower basal insulin, the acute insulin release after the glucose infusion was smaller in postpartal IVGTT than in prepartal IVGTT. The results suggest that whole-body insulin sensitivity of the cows increased after parturition. However, the role of peripheral insulin sensitivity in the regulation of glucose partitioning seems to be minor relative to the major change in insulin secretion and clearance during the periparturient period.

Reduced perfusion in systemic sclerosis digital ulcers (both fingertip and extensor) can be increased by topical application of glyceryl trinitrate

ObjectivesIn patients with systemic sclerosis (SSc), fingertip digital ulcers (DUs) are believed to be ischaemic, and extensor surface DUs a result of mechanical factors/microtrauma. Our aim was to assess blood flow response to topical glyceryl trinitrate (GTN) compared to placebo in SSc DUs, looking for differences in pathophysiology between fingertip and extensor lesions. MethodThis was a double-blind, randomised, crossover, placebo-controlled study. Sixteen (6 fingertip, 10 extensor) DUs were each studied twice (one day apart): once with GTN and once with placebo ointment. Perfusion at the DU centre (‘DUCore’) and periphery (‘DUPeriphery’), as measured by laser Doppler imaging was performed before and immediately after ointment application, then every 10min, up to 90min post-application. We calculated the area under the response curve (AUC) and the ratio of peak perfusion to baseline, then compared these between GTN and placebo. ResultsPerfusion was lower in the DUCore compared to the DUPeriphery (ratio of 0.52). The microvessels of the DUCore were responsive to GTN, with an increase in perfusion, with a similar effect in both fingertip and extensor DUs. The AUC and peak/baseline perfusion difference in means (ratio, 95% confidence interval) between GTN and placebo at the DUCore were 1.2 (1.0–1.6) and 1.2 (1.0–1.5) respectively, and at the DUPeriphery were 1.1 (0.8–1.6) and 1.0 (0.9–1.2) respectively. ConclusionDUs (both fingertip and extensor) were responsive to topical GTN, with an increase in perfusion to the ischaemic DU centre. If both fingertip and extensor DUs have a (potentially reversible) ischaemic aetiology, this has important treatment implications.

Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain

Despite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacological interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of morphine and gabapentin in range of different dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7mg/kg), gabapentin (10, 30 and 100mg/kg) or their combination (9 combinations in total) were evaluated in the rat plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response ranged between 26 and 58% for the synergistic doses. The finding of dose-dependent synergistic effects highlights that choosing the right dose–dose combination is of importance in postoperative pain therapy. Our results indicate benefit of high doses of gabapentin as adjuvant to morphine. If these findings translate to humans, they might have important implications for the treatment of pain in postoperative patients.

Effects of Cr Methionine on Glucose Metabolism, Plasma Metabolites, Meat Lipid Peroxidation, and Tissue Chromium in Mahabadi Goat Kids

This study was designed to investigate the effects of chromium methionine (Cr-Met) on glucose metabolism, blood metabolites, meat lipid peroxidation, and tissue chromium (Cr) in Mahabadi goat kids. Thirty-two male kids (16.5 ± 2.8 kg BW, 4-5 months of age) were fed for 90 days in a completely randomized design with four treatments. Treatments were supplemented with 0 (control), 0.5, 1, and 1.5 mg Cr as Cr-Met/animal/daily. Blood samples were collected via heparin tubes from the jugular vein on 0, 21, 42, 63, and 90 days of experiment. On day 70, an intravenous glucose tolerance test (IVGTT) was conducted. At the end of the feeding trial, the kids were slaughtered, and the liver, kidney, and longissimus dorsi (LD) muscle samples were collected. Plasma glucose, insulin, and triglyceride concentrations were decreased by Cr supplementation (P < 0.05). LD muscle malondialdehyde (MDA) decreased, and plasma and tissue Cr contents increased with increasing supplemental Cr levels (P < 0.05). Plasma glucose concentrations at 30 and 60 min after glucose infusion were lower in the kids fed 1.5 mg Cr diet than the kids fed control diet (P < 0.05). The IVGTT indicated that the kids supplemented with 1.5 mg Cr had higher glucose clearance rate (K) and lower glucose half-life (T½; P < 0.05). Glucose area under the response curve (AUC) from 0 to 180 min after glucose infusion was decreased linearly (P < 0.01) by supplemental Cr. The results suggested that supplemental Cr may improve glucose utilization and lipid oxidation of meat in fattening kid.

Eicosapentaenoic and docosahexaenoic acids increase insulin sensitivity in growing steers1

An experiment was conducted to determine the effect of dietary n-3 long chain PUFA on insulin sensitivity in growing steers. Steers (n = 12, initial BW = 336.3 kg, SEM = 7.7) were adapted to a basal diet that was 70% concentrate mix and 30% orchardgrass hay. Steers were fed a daily amount of 0.26 Mcal ME per kg BW (0.75). After 3 wk steers were transitioned to 1 of 2 treatment (Trt) diets (n = 6 per diet) containing added Ca salts of fatty acids at 4% of DM using a source of fat that was enriched in n-3 fatty acids, including eicosapentaenoic acid and docosahexaenoic acid (FOFA), or a source of fat without n-3 fatty acids and a greater percentage of C16:0 and C18:1 (LCFA). Three intravenous (i.v.) glucose tolerance tests (IVGTT) were conducted, 1 during the basal diet, and 2 after transition to treatment diets at time 1 (T1; d 4 Trt) and time 2 (T2; d 39 Trt). Three i.v. insulin challenge tests (IC) were conducted the day after each IVGTT. Measurements on the basal diet were used as covariates. For IVGTT, there was a diet by time interaction (P < 0.05) for glucose area under the response curve (AUC). The AUC50 (mM glucose × 50 min) at T1 was less (P = 0.02) for LCFA (126.2) than FOFA (151.8), AUC50 at T2 tended to be greater (P = 0.07) for LCFA (165.9) than FOFA (146.0). Preinfusion insulin concentration was greater (P < 0.001) before the IVGTT and IC for steers fed LCFA (40.4 and 40.2 µIU/mL) than for steers fed FOFA (23.7 and 27.1 µIU/mL), respectively. Glucose clearance did not differ between treatments. For IC, minimum glucose concentration was greater (P = 0.02) and glucose AUC150 was less (P < 0.01) for steers fed LCFA than for steers fed FOFA. Values for glucose concentration were 1.8 mM and 1.5 mM and for AUC150 (mM glucose × 150 min) were 203.1 and 263.6 for steers fed LCFA and FOFA, respectively. Insulin clearance (fraction/min) was greater (P < 0.01) for steers fed LCFA (0.121) than FOFA (0.101). The insulin AUC60 (µIU/mL × 60 min) postinfusion was less for LCFA (17,674) than FOFA (19,997), and tended to be greater (P = 0.06) at T1 (19,552) than T2 (18,119). Plasma NEFA concentrations at T2 during IVGTT were greater (P < 0.05) in steers fed FOFA than in steers fed LCFA. The results indicated that supplementing with long-chain n-3 PUFA (FOFA) increased insulin sensitivity in growing steers compared with feeding a supplement with greater concentration of SFA (LCFA).

Awakening salivary cortisol levels of children with sleep bruxism

The study of factors potentially associated with sleep bruxism (SB) may contribute to a better understanding of its nature and etiology. In this way, this cross-sectional study aimed to evaluate the association between SB and salivary cortisol levels, heart rate, and other parafunctional habits. Data were collected in 100 healthy caries-free children of both genders, aged 7.23 ± 0.60 years, with (n=27) and without (n=73) signs and symptoms of SB by interview with the parents and clinical and physical examination. Salivary cortisol was measured immediately after waking up and 30min after awakening for the determination of the area under the response curve (AURC). Data were analyzed by descriptive statistics, normality test, and Spearman correlation test; a stepwise logistic regression model was used to verify the association between SB, as the dependent variable, and age, gender, body mass index (BMI), heart rate, presence of sucking habit, nail biting, enuresis, and AURC (α=0.05). AURC did not correlate with BMI and heart rate. Only AURC showed a significant negative association with SB, while age, gender, BMI, heart rate and other parafunctional habits did not associate with SB. In the studied sample, children with SB were more likely to present low concentrations of awakening salivary cortisol.

Kisspeptin‐10 stimulates the release of luteinizing hormone and testosterone in pre‐ and post‐pubertal male goats

The aims of the present study were to clarify the effect of kisspeptin-10 (Kp10) on the secretion of luteinizing hormone (LH) and testosterone (T) in pre-pubertal and post-pubertal male ruminants. Four male goats (Shiba goats) were given an intravenous (i.v.) injection of Kp10 (5 µg/kg body weight (b.w.)), gonadotoropin-releasing hormone (GnRH, 1 µg/kg b.w.), or 2 mL of saline as a control at the ages of 3 (pre-pubertal) and 6 (post-pubertal) months. A single i.v. injection of Kp10 significantly stimulated the release of LH and T in both groups. The area under the response curve (AUC) of LH for a 60-min period after the i.v. injection of Kp10 was significantly greater in the pre-pubertal goats (P < 0.05). The AUC of T for a 120 min period post-injection did not differ between the two age groups. A single i.v. injection of GnRH also significantly stimulated the release of LH and T in both groups (P < 0.05). The secretory pattern of LH and T in response to GnRH resembled that in response to Kp10. These results show that the LH-releasing response to Kp10 is greater in pre-pubertal than post-pubertal male goats. They also show that Kp10, as well as GnRH, is able to stimulate the release of T in male goats.

Effects of photoperiod on salsolinol‐induced prolactin secretion in goats

The aim of the present study was to clarify the relation between salsolinol (SAL)-induced prolactin (PRL) release and photoperiod in goats. A single intravenous (i.v.) injection of SAL was given to adult female goats under short (8 h light, 16 h dark) or long (16 h light, 8 h dark) photoperiod conditions at two different ambient temperatures (20°C or 5°C), and the PRL-releasing response to SAL was compared to that of thyrotropin-releasing hormone (TRH) or a dopamine (DA) receptor antagonist, sulpiride. SAL, as well as TRH or sulpiride, stimulated the release of PRL promptly after each injection in both 8- and 16-h daily photoperiods at 20°C (P<0.05). The area under the response curve (AUC) of PRL for the 60-min period after injections of saline (controls), SAL, TRH and sulpiride in the 16-h daily photoperiod group was greater than each corresponding value in the 8-h daily photoperiod group (P<0.05). There were no significant differences in the AUC of PRL among the values produced after the injection of SAL, TRH and sulpiride in 16-h daily photoperiod group; however, the values produced after the injection of TRH were smallest among the three in the 8-h daily photoperiod group (P<0.05). The PRL-releasing responses to SAL, TRH and sulpiride under a short and long photoperiod condition at 5°C resembled those at 20°C. These results show that a long photoperiod highly enhances the PRL-releasing response to SAL as well as TRH or sulpiride in either medium or low ambient temperature in goats.

Bromocriptine inhibits salsolinol‐induced prolactin release in male goats

The secretion of prolactin (PRL) is under the dominant and tonic inhibitory control of dopamine (DA); however, we have recently found that salsolinol (SAL), an endogenous DA-derived compound, strongly stimulated the release of PRL in ruminants. The aim of the present study was to clarify the inhibitory effect of DA on the SAL-induced release of PRL in ruminants. The experiments were performed from late June to early July. Male goats were given a single intravenous (i.v.) injection of SAL (5mg/kg body weight (BW)), a DA receptor antagonist (sulpiride, 0.1mg/kg BW), or thyrotropin-releasing hormone (TRH, 1µg/kg BW) before and after treatment with a DA receptor agonist (bromocriptine), and the effect of DA on SAL-induced PRL release was compared to that on sulpiride- or TRH-induced release. Bromocriptine completely inhibited the SAL-induced release of PRL (P<0.05), and the area under the response curve (AUC) for a 120-min period after the treatment with bromocriptine was 1/28 of that for before the treatment (P<0.05). Bromocriptine also completely inhibited the sulpiride-induced release (P<0.05). The AUC post-treatment was 1/17 that of pre-treatment with bromocriptine (P<0.05). Bromocriptine also inhibited the TRH-induced release (P<0.05), though not completely. The AUC post-treatment was 1/3.8 that of pre-treatment (P<0.05). These results indicate that DA inhibits the SAL-induced release of PRL in male goats, and suggest that SAL and DA are involved in regulating the secretion of PRL. They also suggest that in terms of the regulatory process for the secretion of PRL, SAL resembles sulpiride but differs from TRH.

Cortisol response to individualised graded insulin infusions: a reproducible biomarker for CNS compounds inhibiting HPA activation

To determine the potential of cortisol secretion, in response to a physiological stressor, as a biomarker for centrally active compounds targeting the hypothalamic-pituitary-adrenocortical (HPA) axis. Cortisol response to hypoglycaemia was measured in 26 healthy males in two stages: firstly to derive an algorithm for individualized, graded insulin infusion rates to achieve defined hypoglycaemic targets over 3 h and secondly to determine the inter- and intra-subject variability of cortisol response to hypoglycaemia over two identical periods by measuring the maximum (t(max) ), time to maximum (C(max) ) response and cortisol area under the response curve (AUC). Hypoglycaemia induced a consistent cortisol response starting at approximately 1 h, corresponding to blood glucose concentrations of approximately 3.3 mmol l⁻¹, and peaking approximately 3 h after the start of infusion. The inter- and intra-subject coefficients of variation (CVs) of cortisol response were approximately 19 and 19% (AUC), 15 and 19 % (C(max) ) and 10 and 14% (t(max) ), respectively. The intra-subject CVs for the ratio of maximum cortisol response to baseline concentration and rate of initial cortisol response between study days were more variable (32.8% and 59.0%, respectively). The blood glucose-cortisol response model derived from the study was predictive of the individual observed cortisol responses, and estimated a blood glucose EC(50) associated with onset of the cortisol response of 3.3 mmol l⁻¹. Gradual hypoglycaemia is an effective, reproducible and well-tolerated method of stimulating a cortisol response and may therefore be useful in assessing the neuroendocrine response to HPA axis inhibitors, such as corticotropin-releasing hormone-1 (CRH-1) antagonists.

Reproductive hormonal responses to maximal exercise in endurance-trained men with low resting testosterone levels.

A cross-sectional study was conducted to compare the changes from rest and in response to a maximal exercise bout for select reproductive hormones between age matched groups of endurance trained (ET; distance runners) men with low resting testosterone and untrained (UT) men. Both ET and UT men completed two evaluation sessions: (a) resting hormonal profiling, and (b) a maximal treadmill exercise test to exhaustion. Serial blood samples were taken for four hours at each of the evaluation sessions. Resting and exercise hormonal concentrations were plotted and the area under the response curve (AUC) measured. Percentage change in AUC values were also calculated and compared (exercise vs. resting AUC values). Resting testosterone (16.6 +/- 2.4 vs. 23.9 +/- 3.1 nmol x 1(-1)) and prolactin (3.3 +/- 1.4 vs. 6.0 +/- 2.0 micrograms x 1(-1)) concentrations in the ET men were significantly lower (p < 0.05) than those in the UT men. All other resting hormonal levels did not differ between the groups (p > 0.05). Exercise produced a significant increase (p < 0.05) in the ET men for testosterone, LH, and prolactin AUC values, when compared to resting values. In the UT men the only significant change was a reduction (p < 0.05) in the exercise LH AUC versus the resting AUC value. AUC percentage change values showed between-group differences (p < 0.05) for testosterone, LH and prolactin. The level of change in each of these hormones was found to be greater in the ET than UT group (approximately 20 to 75%). The hormonal changes of the UT men were viewed as "control--reference" responses within a functioning hypothalamo-pituitary-testicular regulatory axis; therefore, it was concluded that the ET men displayed an "atypical" response to exercise to that of UT men relative to this axis.

Cortisol awakening rise in middle-aged women in relation to psychological stress

The cortisol awakening rise (CAR) is defined as cortisol secretory activity in the first 45-60 min immediately post-awakening. It has been suggested that psychological factors may disrupt the normal awakening rise. Recent research has shown that psychological stress may influence the magnitude of the CAR, however the findings have been mixed. This study examined the impact of stress on the CAR and the diurnal mean in a sample of middle-aged women. One hundred and eighteen healthy female participants who reported experiencing high or low stress were recruited. Salivary cortisol levels were measured immediately upon awakening (at 0, 15, 30, and 45 min) and at 3, 6, 9 and 12 h on two consecutive days. A number of metabolic and inflammatory biomarkers were also assessed together with measures of mood disturbance and health behaviour. The magnitude of the CAR, assessed by the area under the response curve (AURC) estimate, was significantly lower in the high stress group compared to the low stress group indicating that participants who experienced high stress secreted lower levels of cortisol. The effect was largely accounted for by differences 30 min after waking. The diurnal mean was also lower for the high stress group. Although participants in the high stress group had a slightly worse inflammatory profile, only low-density lipoprotein levels were found to be significantly higher, compared to the low stress group. Lifestyle indicators and mood were also found to be significantly poorer in the high stress group. The results suggest that psychological stress may be associated with a smaller cortisol awakening rise, a lower diurnal mean, poor lifestyle choices and high levels of psychological distress. These findings may have broader implications for future health risk and for an individual's ability to cope with imminent daily stressors and demands.

Seasonality in sperm parameters in normal men and dyspermic patients on medical intervention

This study attempted to investigate the presence of seasonal variations in sperm parameters and to evaluate the season's impact on the response to treatment in men with idiopathic oligozoospermia (IO). To this end, a retrospective analysis of the records of 294 men, who participated in a controlled study, was performed. This sample included IO men (n = 106) treated with tamoxifen citrate (10 mg b.i.d.) and testosterone undecanoate (40 mg t.i.d.) or placebo (n = 106) and normozoospermic men (n = 82) serving as controls. Outcome measures included sperm parameters, functional sperm fraction (FSF) and incidence of pregnancy. Analysis showed a raised frequency of high FSF values and increased area under the response curve (AURC) for FSF mean during autumn-winter seasons in patients on active treatment compared with those in placebo (P < 0.05-P < 0.04). Moreover, receiver operation characteristics (ROC) curves for a >100% FSF rise significantly discriminated autumn-winter from other seasons (P < 0.001, all), whereas active treatment showed higher than placebo FSF values particularly during autumn and winter (P < 0.001, all). The pregnancy incidence was higher in the autumn in all groups. It is concluded that FSF values showed a better response to active treatment during autumn and winter, indicating that commencement of empirical treatment at this time in IO men may stand a better chance to succeed.

Metformin administration was associated with a modification of LH, prolactin and insulin secretion dynamics in women with polycystic ovarian syndrome

Aim. To elucidate the dynamics of FSH, LH, prolactin (PRL), TSH and insulin secretion in women with polycystic ovarian syndrome (PCOS) treated with metformin (MET).Patients and methods. In a prospective, controlled and randomised trial, 32 women with PCOS and 32 with normal cycle were recruited to receive MET (850 mg b.i.d.) or placebo (n: 16 for each subgroup) for an average of 40 days. Pituitary function and insulin secretion were assessed before and after intervention by GnRH-TRH tests and oral glucose tolerance test induced insulin response.Results. Basal and area under the response curve (AURC) LH values were higher in PCOS than in normal controls before MET and declined following treatment in the former group (P < 0.05). Ovulatory PCOS responders had lower basal LH, AURCLH and AURCPRL values during MET than anovulatory cases (P < 0.05 for all) and AURCins was lower in ovulatory than anovulatory PCOS before and on MET (P < 0.02–P < 0.05), with a rise of QUICKY index in the former group during MET treatment (P < 0.05). FSH and TSH were similar.Conclusions. MET administration lowered LH activity in all PCOS women and in ovulatory responders and also compromised PRL stimulated secretion in the latter cases. These findings were indicative of an effect of MET on pituitary activity.

Prenatal testosterone treatment alters LH and testosterone responsiveness to GnRH agonist in male sheep.

Although evidence is accumulating that prenatal testosterone (T) compromises reproductive function in the female, the effects of excess T in utero on the postnatal development of male reproductive function has not been studied. The aim of this study was to assess the influence of prenatal T excess on age-related changes in pituitary and gonadal responsiveness to GnRH in the male sheep. We used the GnRH agonist, leuprolide (10 microg/kg), as a pharmacologic challenge at 5, 10, 20 and 30 weeks of age. These time points correspond to early and late juvenile periods and the prepubertal and postpubertal periods of sexual development, respectively. LH and T were measured in blood samples collected before and after GnRH agonist administration. The area under the response curve (AUC) of LH increased progressively in both controls and prenatal T-treated males from 5 to 20 weeks of age (P<0.01). The LH responses in prenatal T-treated males were lower at 20 and 30 weeks of age compared to controls (P<0.05). AUC-T increased progressively in control males from 5 through 30 weeks of age and prenatal T-treated males from 5 to 20 weeks of age. The T response in prenatal T-treated males was higher at 20 weeks compared to controls of same age but similar to controls and prenatal T-treated males at 30 weeks of age (P <0.05). Our findings suggest that prenatal T treatment advances the developmental trajectory of gonadal responsiveness to GnRH in male offspring.

Prenatal testosterone treatment alters LH and testosterone responsiveness to GnRH agonist in male sheep

Although evidence is accumulating that prenatal testosterone (T) compromises reproductive function in the female, the effects of excess T in utero on the postnatal development of male reproductive function has not been studied. The aim of this study was to assess the influence of prenatal T excess on age-related changes in pituitary and gonadal responsiveness to GnRH in the male sheep. We used the GnRH agonist, leuprolide (10 microg/kg), as a pharmacologic challenge at 5, 10, 20 and 30 weeks of age. These time points correspond to early and late juvenile periods and the prepubertal and postpubertal periods of sexual development, respectively. LH and T were measured in blood samples collected before and after GnRH agonist administration. The area under the response curve (AUC) of LH increased progressively in both controls and prenatal T-treated males from 5 to 20 weeks of age (P<0.01). The LH responses in prenatal T-treated males were lower at 20 and 30 weeks of age compared to controls (P<0.05). AUC-T increased progressively in control males from 5 through 30 weeks of age and prenatal T-treated males from 5 to 20 weeks of age. The T response in prenatal T-treated males was higher at 20 weeks compared to controls of same age but similar to controls and prenatal T-treated males at 30 weeks of age (P <0.05). Our findings suggest that prenatal T treatment advances the developmental trajectory of gonadal responsiveness to GnRH in male offspring.

Melanocortin Modulation of Inflammatory Cytokine and Neuroendocrine Responses to Endotoxin in the Monkey

alpha-MSH has potent antiinflammatory properties, but little is known about the specific melanocortin receptors (MC-Rs) that mediate these effects or about the role of the melanocortin system in modulating cytokine responses to an inflammatory challenge in the primate in vivo. We, therefore, studied the effects of infusion of the alpha-MSH agonist, [Nle(4),d-Phe(7)]-alpha-MSH (NDP-MSH); the alpha-MSH antagonist, SHU9119; and the selective MC3-R agonist, D-Trp8-gamma-MSH, compared with saline, on proinflammatory cytokine (TNF-alpha, IL-1beta, and IL-6), antiinflammatory cytokine [IL-10 and IL-1 receptor antagonist (IL-1ra)], and pituitary-adrenal responses to endotoxin in ovariectomized monkeys. In the first study NDP-MSH or SHU9119 was infused iv for 7 h starting at 0800 h, endotoxin was injected at 1000 h, and serial blood samples were collected (n = 6). NDP-MSH significantly attenuated proinflammatory cytokine responses to endotoxin. The area under the response curve (AUC) decreased by 61% for TNF-alpha (P = 0.02), 47% for IL-1beta (P = 0.02), and 41% for IL-6 (P = 0.04); there was no effect on IL-1ra or IL-10. SHU9119 did not affect proinflammatory cytokine responses, but decreased the IL-10 response by 31% (P = 0.03). NDP-MSH also attenuated ACTH (P < 0.001) and cortisol (P = 0.02) responses. In a second study, the effects of d-Trp8-gamma-MSH were similarly examined in seven monkeys. The AUC for IL-6 was decreased by 37% (P = 0.04) by d-Trp8-gamma-MSH; the AUC for IL-10 was increased by 22%, but this was not significant. However, the ratio of IL-6 to IL-10 was significantly decreased by d-Trp8-gamma-MSH (P = 0.04), consistent with a relatively more antiinflammatory cytokine environment. These results indicate that NDP-MSH can attenuate proinflammatory cytokine responses in the primate, consistent with previous studies in the rodent, and provide new evidence for a role for MC3-R in this process. Moreover, they show for the first time that SHU9119, a mixed MC3/4-R antagonist, can decrease the IL-10 response, establishing a physiological role for endogenous MSH in modulating the release of an antiinflammatory cytokine.

Hypothalamic-pituitary-adrenal axis function and prolactin secretion in systemic lupus erythematosus.

The objective was to study the response of cortisol and of prolactin (PRL) to specific stimuli in systemic lupus erythematosus (SLE). We measured the response of cortisol to insulin-induced hypoglycemia and of PRL to thyrotropin releasing hormone (TRH) in seven patients with active untreated SLE and in ten paired control subjects. All were women with regular menstrual cycles. With the exception of two patients, they had never received corticosteroids before the study. The basal serum levels of cortisol (12.5+/-2.4 microg/dl) and PRL (10.7+/-1.0 ng/ml) in the SLE group were not significantly different from those of the control group (12.3+/-1.1 microg/dl and 13.7+/-2.4 ng/ml, respectively). The cortisol response after hypoglycemia was significantly lower in SLE patients compared to the control group at 45 min (P=0.01), at 60 min (P = 0.009), and at 90 min (P = 0.001). The integrated cortisol response to hypoglycemia expressed as area under the response curve (AUC) did not differ significantly in either group (1447+/-187 vs 1828+/-84, P = 0.06). Although the peak of PRL after TRH did not differ significantly in both groups (68.0+/-7.4 ng/ml in SLE vs 66.3+/-77 ng/ml in controls) and the AUC of PRL response after TRH was comparable in both groups (4672+/-537 vs 4128+/-541, P = 0.32), the interval-specific 'delta' response was significantly higher in SLE than the control group at 0-60 min (P=0.02) and 0-90 min (P = 0.01) after TRH injection. These findings suggest that active SLE is associated with some degree of dysfunction of the hypothalamic-pituitary-glucocorticoid axis and PRL secretion.

HIGH-INTENSITY EXERCISE ENHANCES GROWTH HORMONE (GH) SECRETION BY A GHRH-DEPENDENT MECHANISM

276 Aim of this study was to gain insight into the mechanism of exercise induced GH release with the help of pharmacological stimulation. In eight healthy, non smoking male subjects (age: 22.1±2.2 yr; BMI: 22.2±2.5 kg/m2; ˙VO2max: 52.2±1.5 ml/min/kg; mean±SD) maximal responses of serum GH were analysed to exercise (EX), to administration of GH-Releasing Hormone (GHRH, 100 mcg iv), to administration of Pyridostigmine (PD, 120 mg orally), which inhibits somatostatin release, as well as to coadministration of GHRH plus EX, and PD plus EX. The combination (PDplusEX) could be administered in only 5 out of 8 subjects. EX was performed on a bicycle ergometer with a stepwisely increased workload protocol with a duration of at least 25 min up to exhaustion. Venous blood for GH analysis (IRMA) was obtained by serial sampling for a time period of 120 min and the area under the response curve (AUC) was calculated. All tests were performed in random order after an overnight fast and at least 3 days apart. Peak GH values after administration of GHRH, PD, and EX alone were 42±9 mcg/1 (mean±SEM), 20±2 and 64±8, and the AUC-data were 3242±839 mcg/1.min, 1721±358 and 2472±408, respectively. A potentiating effect on the GH response was found when coadministering GHRH plus EX. The AUC(GHRHplusEX) of 7807±1221 mcg/1.min significantly exceeded the AUC obtained by arithmetic addition of AUC(GHRH) and AUC(EX): 5714±863, (p<0.05, Wilcoxon signed-ranks test). In contrast, the AUC(PDplusEX) of 3526±752 mcg/1.min was not significantly different from the AUC obtained by arithmetic addition of AUC(PD) and AUC(EX): 3747±706. Because maximally stimulating doses for GH responses are given, these results indicate that high-intensity EX acts via a GHRH-dependent mechanism, and not by a reduction in somatostatinergic tone. Based on the concept of a stratified signaling system for GH secretion, we hypothesize that during high-intensity EX GHRH operates as a primary factor for GH release, with the help of a secondary still unknown releasing factor as co-agonist.

Follicular and luteal phase hormonal responses to low-volume resistive exercise

The purpose of the study was to 1) determine the effects of a low-volume resistive exercise protocol on serum concentrations of estradiol (E2), progesterone (P4), growth hormone (GH), testosterone (T), and androstenedione (AN) and 2) ascertain whether the endocrine responses are affected by the phase of the menstrual cycle. Eleven untrained, healthy women were assigned to either an early follicular or luteal testing group. The subjects completed three sets of bench press, lat-pull, leg extension, and leg curl exercises at a 10 repetition maximum load on fixed machines with 2-min of rest between sets. Blood samples were collected through an indwelling cannula before, during, and after the exercise. Area-under-the-response-curve (AUC) data demonstrated that E2 concentrations were significantly elevated in both follicular and luteal phases with a greater response in the luteal phase. Moreover, data suggest there is a luteal phase-induced increase in GH and AN in response to the low-volume resistive exercise; however, P4 and T concentrations in untrained women are not increased by low-volume resistive exercise with 2-min rest periods, nor does the altered hormonal milieu produced by the phase of the menstrual cycle affect these hormonal responses.