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Steven Grinspoon

Publications and source records attributed to Steven Grinspoon.

At least 37 records · Page 2Linked to original sources
PubMed2004

Effects of growth hormone-releasing hormone on bone turnover in human immunodeficiency virus-infected men with fat accumulation.

GHRH is a potentially appealing strategy to simultaneously improve fat distribution and increase bone turnover in HIV-infected patients. We investigated the effects of GHRH (1 mg sc twice a day over 12 wk) in 31 HIV-infected men with abdominal fat accumulation (age 46 +/- 1 yr, body mass index 26.2 +/- 0.6 kg/m2) in a randomized, double-blind, placebo-controlled study. We previously reported significant effects of GHRH on IGF-I and truncal fat. In this study, we assessed whether GHRH increased markers of bone turnover. At baseline, 32% of our subjects (n = 10) demonstrated a bone density Z score less than -1.0 sd and greater than or equal to -2.5 sd, and 3% (n = 1) demonstrated a Z score of less than -2.5 sd. IGF-I correlated with N-terminal telopeptide (NTx) (r = 0.49, P = 0.005) and tended to correlate with C-terminal telopeptide (CTx) (r = 0.35, P = 0.06) at baseline. Of the bone resorption markers, CTx increased significantly (0.16 +/- 0.07 vs. -0.03 +/- 0.03 ng/ml, GHRH vs. placebo, P = 0.02), and NTx tended to increase in response to GHRH (2.8 +/- 1.4 vs. -0.5 +/- 1.0 nm bone collagen equivalent, GHRH vs. placebo, P = 0.07). Of the bone formation markers, N-terminal propeptide of type 1 procollagen increased (14.6 +/- 9 vs. -6.8 +/- 3.1 microg/liter, GHRH vs. placebo, P = 0.03) and osteocalcin tended to increase (8.4 +/- 3.0 vs. 2.0 +/- 1.6 ng/ml, GHRH vs. placebo, P = 0.06) in response to GHRH. The calciotropic hormones, calcium and phosphorus, did not change significantly. The change in IGF-I correlated with the change in NTx (r = 0.45, P = 0.02), CTx (r = 0.38, P = 0.05), and osteocalcin (r = 0.55, P = 0.002). GHRH improves fat distribution and bone metabolism in men with HIV-related fat accumulation. Long-term studies are needed to determine whether the stimulatory effects of GHRH on bone turnover will translate into increased bone density in this population.

Adult↗
PubMed2004

Growth hormone (GH) responses to GH-releasing hormone-arginine testing in human immunodeficiency virus lipodystrophy.

Prior studies suggest reduced overnight GH secretion in association with excess visceral adiposity among patients with HIV lipodystrophy (LIPO, i.e. with fat redistribution). We now investigate GH responses to standardized GHRH-arginine in LIPO patients (n = 39) in comparison with body mass index- and age-matched control groups [HIV patients without fat distribution (NONLIPO, n = 17)] and healthy subjects (C, n = 16). IGF-I [242 +/- 17; 345 +/- 38; 291 +/- 27 ng/ml (P < 0.05 vs. NONLIPO)] was lowest in the LIPO group. Our data demonstrate failure rates of 18% for the LIPO group vs. 5.9% for the NONLIPO group and 0% for the C group, using a stringent criterion of 3.3 ng/ml for peak GH response to GHRH-arginine (P < 0.05 LIPO vs. C). Using less stringent cutoffs, the failure rate in the LIPO group rises to 38.5% at 7.5 ng/ml. Among the LIPO patients, the peak GH response to GHRH-arginine was significantly predicted by visceral adipose tissue (P = 0.008), free fatty acid (P = 0.04), and insulin level (P = 0.007) in regression modeling controlling for age, body mass index, sc fat area, and triglyceride level. These data demonstrate increased failure rates to standardized stimulation testing with GHRH-arginine in LIPO patients, in association with increased visceral adiposity. The effects of low-dose GH should be assessed in the large subset of LIPO patients with abnormal GH stimulation testing.

Adult↗
PubMed2004

Growth hormone-releasing hormone in HIV-infected men with lipodystrophy: a randomized controlled trial.

CONTEXT: Reduced growth hormone (GH) concentrations are observed in men with human immunodeficiency virus (HIV) lipodystrophy. OBJECTIVE: To investigate the effects of growth hormone-releasing hormone (GHRH), a GH secretagogue, in treatment of HIV lipodystrophy. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial conducted at a research center in the United States between October 2002 and June 2003 and enrolling 31 HIV-infected men aged 18 to 60 years with evidence of lipodystrophy. INTERVENTIONS: Participants were assigned to receive GHRH (1 mg subcutaneously twice daily) or placebo for 12 weeks. MAIN OUTCOME MEASURES: The primary outcome was change in concentrations of insulin-like growth factor 1 (IGF-1) to detect overall change in GH levels in response to GHRH. Secondary end points included body composition by dual-energy x-ray absorptiometry and computed tomography, lipodystrophy ratings, and levels of glucose, insulin, and lipids. RESULTS: Mean (SD) IGF-1 concentrations increased significantly in the GHRH group vs the placebo group (104 [110] ng/mL vs 6 [44] ng/mL, P =.004). Lean body mass significantly increased in the GHRH group vs the placebo group (0.9 [1.3] kg vs -0.3 [1.7] kg, P =.04), trunk fat significantly decreased (-0.4 [0.7] kg vs 0.2 [0.6] kg, P =.03), and the ratio of trunk to lower extremity fat improved significantly (-0.22 [0.32] vs 0.14 [0.29], P =.005). Abdominal visceral fat was reduced (-19.2 [36.6] cm2 vs 2.3 [24.3] cm2, P =.07) and the ratio of abdominal visceral fat to abdominal subcutaneous fat improved significantly more in the GHRH group (-0.19 [0.28] vs 0.07 [0.27], P =.02). Both physician and patient rating of lipodystrophy in the arms, legs, and abdomen also improved significantly. Levels of glucose, insulin, and lipids did not change significantly. CONCLUSIONS: GHRH was well tolerated and effectively increased levels of IGF-1 in HIV-infected men with lipodystrophy. Total and regional body composition improved in response to GHRH, with increased lean mass and reduced truncal and visceral fat. Use of GHRH may potentially be a beneficial treatment strategy for this population.

Adult↗
PubMed2004

Metabolic effects of rosiglitazone in HIV lipodystrophy: a randomized, controlled trial.

BACKGROUND: Patients with HIV infection who are treated with antiretroviral agents often lose subcutaneous fat and have metabolic abnormalities, including insulin resistance and reduced adiponectin levels, which may be related to disrupted subcutaneous adipogenesis and altered peroxisome proliferator-activated receptor-gamma signaling. OBJECTIVE: To investigate the effects of rosiglitazone (4 mg/d), a peroxisome proliferator-activated receptor-gamma agonist, in HIV-infected men and women with hyperinsulinemia and lipoatrophy. DESIGN: A randomized, double-blind, placebo-controlled, 3-month study. SETTING: University hospital. PATIENTS: 28 HIV-infected men and women with hyperinsulinemia and lipoatrophy. MEASUREMENTS: Insulin sensitivity measured by euglycemic hyperinsulinemic clamp testing; subcutaneous leg fat area measured by computed tomography; adiponectin, free fatty acid, and lipid levels; and safety variables. RESULTS: Rosiglitazone, when compared with placebo, improved insulin sensitivity (mean [+/-SD] change, 1.5 +/- 2.1 mg of glucose/kg of lean body mass per minute vs. -0.4 +/- 1.6 mg/kg per minute; P = 0.02), increased adiponectin levels (mean [+/-SD], 2.2 +/- 2.2 micro g/mL vs. 0.1 +/- 1.1 microg/mL; P = 0.006), and reduced free fatty acid levels (mean [+/-SD], -0.09 +/- 0.1 mmol/L vs. 0.01 +/- 0.1 mmol/L; P = 0.02). Mean percentage (+/-SD) of body fat (1.38% +/- 3.03% vs. -0.83% +/- 2.76%; P = 0.03) and subcutaneous leg fat area (2.3 +/- 8.4 cm2 vs. -0.9 +/- 1.9 cm2; P = 0.02) increased significantly with rosiglitazone compared with placebo. Mean total cholesterol levels (+/-SD) also increased with rosiglitazone compared with placebo (0.6 +/- 1.0 mmol/L [25 +/- 37 mg/dL] vs. -0.4 +/- 0.6 mmol/L [-15 +/- 25 mg/dL]; P = 0.007). LIMITATIONS: The study was relatively small and of short duration. CONCLUSIONS: The authors demonstrated positive effects of rosiglitazone on lipoatrophy; insulin sensitivity; and metabolic indices, including adiponectin levels, in HIV-infected patients with lipoatrophy and insulin resistance. Peroxisome proliferator-activated receptor-gamma agonists may correct the metabolic abnormalities associated with disrupted adipogenesis in this population. Further studies must determine the clinical utility of such agents in HIV-infected patients.

Adiponectin↗
PubMed2004

Effects of testosterone administration in human immunodeficiency virus-infected women with low weight: a randomized placebo-controlled study.

BACKGROUND: The prevalence of human immunodeficiency virus (HIV) disease is increasing among women, many of whom remain symptomatic with low weight and poor functional status. Although androgen levels may often be reduced in such patients, the safety, tolerability, and efficacy of testosterone administration in this population remains unknown. METHODS: A total of 57 HIV-infected women with free testosterone levels less than the median of the reference range and weight less than 90% of ideal body weight or weight loss greater than 10% were randomly assigned to receive transdermal testosterone (4 mg/patch) twice weekly or placebo for 6 months. Muscle mass was assessed by urinary creatinine excretion. Muscle function was assessed by the Tufts Quantitative Muscle Function Test. Treatment effect at 6 months was determined by analysis of covariance. Results are mean +/- SEM unless otherwise specified. RESULTS: At baseline, subjects were low weight (body mass index [calculated as weight in kilograms divided by the square of height in meters] 20.6 +/- 0.4), with significant weight loss from pre-illness maximum weight (18.7% +/- 1.2%), and demonstrated reduced muscle function (upper and lower extremity muscle strength, 83% and 67%, respectively, of predicted range). Testosterone treatment resulted in significant increases in testosterone levels vs placebo (total testosterone: 37 +/- 5 vs -2 +/- 2 ng/dL [1.3 +/- 0.2 vs -0.1 +/- 0.1 nmol/L] [P<.001]; free testosterone: 3.7 +/- 0.5 vs -0.4 +/- 0.3 pg/mL [12.8 +/- 1.7 vs -1.4 vs 1.0 pmol/L] [P<.001]) and was well tolerated, without adverse effects on immune function, lipid and glucose levels, liver function, or body composition or the adverse effect of hirsutism. Muscle mass tended to increase (1.4 +/- 0.6 vs 0.3 +/- 0.8 kg; P =.08), and shoulder flexion (0.4 +/- 0.3 vs -0.5 +/- 0.3 kg; P =.02), elbow flexion (0.3 +/- 0.4 vs -0.7 +/- 0.4 kg; P =.04), knee extension (0.2 +/- 1.0 vs -1.7 +/- 1.3 kg; P =.02), and knee flexion (0.7 +/- 0.5 vs 0.3 +/- 0.7 kg; P =.04) increased in the testosterone-treated compared with the placebo-treated subjects. CONCLUSIONS: Testosterone administration is well-tolerated and increases muscle strength in low-weight HIV-infected women. Testosterone administration may be a useful adjunctive therapy to maintain muscle function in symptomatic HIV-infected women.

Adult↗
PubMed2004

Reduced bone density in HIV-infected women.

OBJECTIVES: Although bone density has been previously investigated in HIV-infected men, little is known regarding bone density in HIV-infected women. METHODS AND DESIGN: Bone density was measured by dual-energy X-ray absorptiometry in 84 ambulatory, HIV-infected females and 63 healthy female control subjects similar in age (41 +/-1 versus 41+/- 1 years, P = 0.83), body mass index (26.0 +/- 0.6 versus 27.0 +/- 0.5 kg/m, P = 0.44) and racial background (% non-Caucasian, 61 versus 51%; P = 0.24, HIV-infected versus control). RESULTS: Lumbar spine (1.02+/- 0.02 versus 1.07 +/- 0.02 g/cm, P = 0.03) and total hip (0.93 +/-0.01 versus 0.99 +/- 0.01 g/cm, P = 0.004) bone density were reduced in HIV-infected compared with control subjects. Osteopenia was demonstrated in 54 versus 30% (P = 0.004) of HIV-infected versus control subjects and was 2.5 times more likely in a multivariate model accounting for age, race, menstrual function and body mass index. Urinary N-telopeptides of type 1 collagen (NTx) (39.6 +/- 3.5 versus 29.9 +/- 2.0 nM/mM urine creatinine, P = 0.03) and osteoprotegerin (4.76 +/- 0.23 versus 3.39 +/- 0.17 pmol/l, P < or = 0.0001) were increased in HIV-infected compared with control subjects. Among the HIV-infected women, bone density correlated with weight (r = 0.41, P < 0.001) and inversely with urinary NTx (r = -0.28, P = 0.01). Bone density did not differ by current or past protease inhibitor, nucleoside reverse trancriptase inhibitor, or non-nucleoside reverse transcriptase inhibitor exposure. CONCLUSIONS: HIV-infected women demonstrate reduced bone density. Altered nutritional status, hormonal function and body composition may contribute to lower bone density in HIV-infected women. Consideration should be given to testing bone density in HIV-infected women with risk factors for osteopenia.

Adult↗
PubMed2004

Fat fractions and spectral T2 values in vertebral bone marrow in HIV- and non-HIV-infected men: a 1H spectroscopic imaging study.

Fat fractions and spectral T2 values of fat and water within the vertebral marrow of non-HIV- and HIV-infected men were measured with the use of a Carr-Purcell-Meiboom-Gill (CPMG) line scan spectroscopic imaging sequence. The fat fraction for the HIV-infected men (0.29 +/- 0.08) was significantly lower (P < 0.05, Student's unpaired t-test) than the fat fraction found in non-HIV-infected men (0.40 +/- 0.12). The mean water and fat T2 values did not differ between the two groups, and did not show any systematic dependence on fat fraction over the wide range of fat fractions encountered in this study. The marrow water and fat T2 values measured with the CPMG approach were markedly longer than the spectral T2 values reported by other groups using the more common point-resolved spectroscopy (PRESS) and stimulated-echo acquisition mode (STEAM) acquisitions. Proton spectroscopic studies of vertebral marrow revealed differences between non-HIV- and HIV-infected men that may prove useful for studying the effects of this disease and/or antiretroviral agents on body composition.

Adult↗
PubMed2004

Acute regulation of adiponectin by free fatty acids.

Little is known about the acute regulation of adiponectin in humans. In animal studies, adiponectin increases the clearance of free fatty acids (FFA) from the circulation by increasing skeletal uptake and oxidation of lipid, thereby regulating the FFA concentration. However, it is unknown if FFA regulate adiponectin. The aim of the present study was to investigate the effect of an acute reduction in free fatty acids on adiponectin concentration in healthy subjects. Ten normal male subjects were admitted for 2 inpatient visits and randomized to receive either acipimox (500 mg orally at 2 am and again at 6 am) or placebo on the first visit and vice versa on the second visit. Adiponectin, FFA, insulin and glucose were measured at 7:45 am. FFA concentrations were significantly lower after acipimox than placebo administration (0.08 +/- 0.02 mEq/L v 0.35 +/- 0.53 mEq/L, P <.05). Adiponectin concentrations were also significantly lower after acipimox than placebo administration (7.4 +/- 1.2 microg/mL v 10.3 +/- 1.7 microg/mL, P <.05). The change in FFA between acipimox and placebo correlated significantly with the change in adiponectin (r = 0.66, P <.05), eg, the larger the reduction in FFA in response to acipimox, the larger the reduction in adiponectin. These results suggest that acute lowering of FFA is associated with decreased adiponectin concentrations.

Adiponectin↗
PubMed2004

HIV-associated lipodystrophy: pathogenesis, prognosis, treatment, and controversies.

Potent antiretroviral agents markedly suppress HIV and have dramatically improved the clinical course, prognosis, and survival of HIV-infected patients. Unfortunately, highly active antiretroviral therapy is often compromised by metabolic complications, including insulin resistance, dyslipidemia, and fat redistribution. Together these changes have been termed the HIV-lipodystrophy syndrome, which is estimated to affect a majority of patients treated with potent combination antiretroviral therapy. Routine testing of fasting glucose is recommended for all HIV-infected patients, particularly those who are obese, have a family history of diabetes mellitus, or are receiving protease inhibitor therapy. Preliminary investigations have demonstrated the potential utility of insulin-sensitizing agents and lipid-lowering therapies to ameliorate these metabolic disturbances. Patients with HIV infection who demonstrate fat redistribution and develop hyperinsulinemia and dyslipidemia may be at increased risk of cardiovascular disease. However, the long-term effects on cardiovascular disease have not yet been determined.

HIV-Associated Lipodystrophy Syndrome↗
PubMed2004

Differential effects of metformin and exercise on muscle adiposity and metabolic indices in human immunodeficiency virus-infected patients.

The HIV-lipodystrophy syndrome is associated with fat redistribution and metabolic abnormalities, including insulin resistance (IR). The mechanisms and treatment strategies for IR in HIV-lipodystrophy are unclear, but data suggest that intramuscular lipids contribute to IR in this population. We previously showed that metformin and exercise improve hyperinsulinemia more than metformin alone in HIV-lipodystrophy. Now we investigate the effects of these treatment strategies on thigh muscle adiposity measured by computed tomography and additional body composition measures. Twenty-five HIV-infected patients on stable antiretroviral therapy with hyperinsulinemia and fat redistribution participated in a prospective, randomized, 3-month study of metformin alone or metformin and resistance training three times a week. Thigh muscle adiposity decreased significantly more as shown by increased muscle attenuation [2.0 (range, 0.5-5.0) vs. -1.0 (-3.5-0), P = 0.04] and sc leg fat tended to decrease more [-3.3 (-7.5-4.3) vs. 0.8 (-2.1-9.5), P = 0.06] in the combined treatment group in comparison with metformin alone. In multivariate analysis, change in thigh muscle adiposity remained a significant predictor of change in insulin (P = 0.04), controlling for changes in other body composition measurements. These data suggest that muscle adiposity, in addition to other fat depots, is an important determinant of hyperinsulinemia and that exercise has complex effects on regional fat depots in HIV-infected patients. Reduction in muscle adiposity may be an important mechanism by which exercise improves hyperinsulinemia in this population.

Adipose Tissue↗
PubMed2004

Effects of risedronate on bone density in anorexia nervosa.

Anorexia nervosa (AN), a psychiatric disease characterized by chronic starvation, is complicated by severe bone loss (1), for which there is no effective, available therapy. Although bone resorption is markedly increased in these patients, estrogen is an ineffective anti-resorptive therapy in the setting of undernutrition. We hypothesized bisphosphonate administration would result in a decrease in bone resorption and an increase in bone density in women with AN and bone loss, despite undernutrition. We therefore administered risedronate 5 mg daily for nine months to 10 women with AN, all of whom had osteopenia (mean AP spine T score: -2.7 +/- 2) and compared NTX and bone density with baseline values and with those from available control data prospectively followed for the same time period. Bone density increased significantly in patients who received risedronate compared with controls and compared with baseline, despite lack of significant weight gain, for an increase of AP spine bone density of 4.1 +/- 1.6% at six months and 4.9 +/- 1.0% at nine months. Bone resorption, as measured by NTX, decreased 23.8% at one month and 29.6% at three months, from the high-normal to mid-normal range of young women. Our data suggest that risedronate 5 mg daily administered to women with AN and osteopenia may increase in bone density at the AP spine despite low weight. This is the first study to demonstrate marked increases in bone density in women with AN. Because of the lack of data regarding the safety of such medications in women of reproductive age, bisphosphonates are not approved in the U.S. for premenopausal women other than those receiving glucocorticoids. Further studies are needed to establish the efficacy and safety of bisphosphonate therapy in this population.

Adult↗
PubMed2004

Effects of testosterone administration on growth hormone pulse dynamics in human immunodeficiency virus-infected women.

The effects of testosterone administration on the GH axis in androgen-deficient HIV-infected women are unknown. In this study, we determined the effects of transdermal testosterone administration on GH secretory dynamics and pulse characteristics in this population. GH-IGF-I parameters were determined in response to testosterone (4.1 mg/patch, twice a week; estimated delivery rate, 150 microg/d) vs. placebo over 6 months in 31 HIV-infected women. IGF-I increased significantly in the testosterone-treated compared with the placebo-treated patients [37 (-4, 73) vs. -30 (-98, 39) ng/ml, P = 0.01; 4.8 (-0.5, 9.6) vs. -3.9 (-12.8, 5.1) nmol/liter]. GH pulse frequency increased significantly in the testosterone-treated compared with the placebo-treated subjects [1.0 (1.0, 2.0) vs. 0.0 (-0.5, 1.5) peaks per 12 h, respectively; P = 0.02]. Before testosterone administration, overnight GH pulse amplitude was significantly related to IGF-I in univariate (r = 0.41, P = 0.03) and multivariate regression analysis; however, free testosterone, estradiol, and body mass index were not significantly correlated with baseline IGF-I. In contrast, after 6 months of treatment with testosterone, the change in IGF-I was significantly correlated to the change in free testosterone in univariate (r = 0.40, P = 0.04) and multivariate regression analysis. For each 1.0 pg/ml (3.5 pmol/liter) increase in free testosterone, IGF-I increased 19 ng/ml (2.5 nmol/liter), controlling for estradiol, body mass index, and GH pulse parameters (r(2) = 0.64). We demonstrate that IGF-I increases in response to physiologic, transdermal testosterone in HIV-infected women. The mechanism of this effect is unknown, but may involve a direct effect of testosterone on IGF-I, independent of changes in GH pulse dynamics.

Administration, Cutaneous↗
PubMed2004

Diagnostic errors after inferior petrosal sinus sampling.

Although inferior petrosal sinus sampling (IPSS) is useful in the evaluation of Cushing's syndrome, false negative cases have been described, and many patients presumed to have ectopic tumors based upon negative IPSS remain without a final diagnosis. These patients are often managed as if they have as yet undiscovered ectopic tumors. To test this assumption, we conducted a retrospective review of our results to determine the ultimate diagnoses after IPSS. Between 1986 and 2002, 179 patients underwent 185 IPSS procedures as part of their evaluation for Cushing's syndrome. Confirmed diagnoses were available for 149 patients (83%): 139 patients had pituitary adenomas (94%), eight had bronchial carcinoids (5%), and two had adrenal tumors (1%). Threshold criteria for a pituitary source were defined as an inferior petrosal sinus to peripheral (IPS:P) basal ratio of 2:1 or greater without CRH or an IPS:P ratio of 3:1 or greater after CRH stimulation. There were nine patients in whom the IPS:P ratio failed to meet threshold criteria after successful sampling, but were nonetheless found to have pituitary tumors after transsphenoidal exploration (false negatives). Eight of these had received CRH and had a significant rise (>35%) in peripheral ACTH levels after CRH treatment, even though the IPS:P ratio did not reach the threshold. There were two patients in whom the IPS:P ratio reached threshold criteria, and ectopic tumors were demonstrated as the source of ACTH overproduction (false positives). The sensitivity after CRH stimulation was 90% (95% confidence interval, 80.8-95.5%) with a specificity of 67% (95% confidence interval, 11.4-94.5%). The positive and negative predictive values were 99 and 20%, respectively. Our data show that patients with an IPS:P ratio suggestive of a nonpituitary source of ACTH overproduction may still have Cushing's disease. Analyzing the CRH-stimulated peripheral ACTH levels in addition to the standard IPS:P ratios may provide improved diagnostic accuracy. Transsphenoidal exploration should be considered in all cases of unsuccessful sampling and in those cases for which no ectopic source can be identified after further body imaging, even if the IPSS is negative, and especially if peripheral ACTH levels rise significantly with CRH stimulation.

Adolescent↗
PubMed2004

Effects of estrogen and recombinant human insulin-like growth factor-I on ghrelin secretion in severe undernutrition.

Ghrelin is a nutritionally regulated gut peptide that increases with fasting and chronic undernutrition and decreases with food intake. Sex steroid levels change in chronic undernutrition and might signal changes in ghrelin. At the same time, chronic undernutrition is characterized by low IGF-I that might also influence ghrelin, either directly or through changes in the GH axis. Little is known regarding sex steroid regulation of ghrelin and the effects of IGF-I on ghrelin in severe undernutrition. We investigated the effects of sex steroids and IGF-I on ghrelin in 78 female subjects with anorexia nervosa simultaneously randomized to receive estrogen (Ovcon 35, 35 microg ethinyl estradiol, and 0.4 mg norethindrone) as well as recombinant human (rh)IGF-I (30 microg/kg sc twice a day) in a two-by-two factorial model, in which the individual effects of estrogen (E) and rhIGF-I on ghrelin could be determined. Subjects were 24.9 +/- 0.7 (mean +/- sem) yr of age and had low weight (body mass index, 16.7 +/- 0.2 kg/m(2)). At baseline, ghrelin was inversely correlated with body mass index (r = -0.39, P = 0.0005) and IGF-I (r = -0.30, P = 0.01). IGF-I increased significantly more in subjects receiving rhIGF-I alone (Delta 23.0 +/- 5.8 nmol/liter) and rhIGF-I and E (Delta 34.9 +/- 6.3 nmol/liter) compared with subjects receiving E alone (Delta -3.2 +/- 1.9 nmol/liter) or control (C; rhIGF-I placebo and no E) (Delta 0.4 +/- 2.0 nmol/liter) (overall P < 0.0001 by multivariate analysis of variance, P < 0.0001 for rhIGF-I vs. C, P < 0.0001 for rhIGF-I and E vs. C). Ghrelin increased significantly more over 6 months in response to E alone (Delta 150 +/- 86 pg/ml), rhIGF-I alone (Delta 198 +/- 116 pg/ml), and the combination (E and rhIGF-I) (Delta 441 +/- 214 pg/ml) compared with C (Delta -39 +/- 48 pg/ml) (overall P = 0.02 by multivariate analysis of variance, P = 0.01 for E vs. C, P = 0.04 for rhIGF-I vs. C, and P = 0.001 for rhIGF-I and E vs. C). Weight, caloric intake, and morning GH levels did not change significantly between the groups, but the change in ghrelin was inversely related to the change in GH among all subjects (r = -0.27, P = 0.03).Our data demonstrate that, in a model of severe undernutrition, rhIGF-I and E individually increase ghrelin levels. The mechanisms of these effects are unknown and may relate to direct effects on ghrelin or changes in GH. Further studies are needed to determine the mechanisms by which rhIGF-I and E increase ghrelin in human physiology.

Adult↗
PubMed2004

Endocrine and metabolic effects of physiologic r-metHuLeptin administration during acute caloric deprivation in normal-weight women.

Leptin is a nutritionally regulated hormone that may modulate neuroendocrine function during caloric deficit. We hypothesized that administration of low-dose leptin would prevent changes in neuroendocrine function resulting from short-term caloric restriction. We administered physiologic doses of r-metHuLeptin [(0.05 mg/kg sc daily or identical placebo in divided doses (0800, 1400, 2000, and 0200 h)] to 17 healthy, normal-weight, reproductive-aged women during a 4-d fast. Leptin levels were lower in the placebo-treated group during fasting (3.3 +/- 0.2 vs. 9.6 +/- 1.0 ng/ml, P < 0.001, placebo vs. leptin-treated at end of study). Fat mass decreased more in the leptin than the placebo-treated group (-0.6 +/- 0.1 vs. -0.2 +/- 0.1 kg, P = 0.03). Both overnight LH area (38.9 +/- 21.5 vs. 1.2 +/- 11.1 microIU/ml.min, P = 0.05) and LH peak width increased (15.8 +/- 7.1 vs. -2.3 +/- 6.7 min, P = 0.06) and LH pulsatility decreased (-2.0 +/- 0.9 vs. 1.0 +/- 0.8 peaks/12 h, P = 0.03) more in the leptin vs. placebo group. LH pulse regularity was higher in the leptin-treated group (P = 0.02). Twenty-four-hour mean TSH decreased more in the placebo than the leptin-treated group, respectively (-1.06 +/- 0.27 vs. -0.32 +/- 0.18 microIU/ml, P = 0.03). No differences in 24-h mean GH, cortisol, IGF binding protein-1, and IGF-I were observed between the groups. Hunger was inversely related to leptin levels in the subjects randomized to leptin (r = -0.76, P = 0.03) but not placebo (r = -0.18, P = 0.70) at the end of the study. Diminished hunger was seen among subjects achieving the highest leptin levels. Our data provide new evidence of the important role of physiologic leptin regulation in the neuroendocrine response to acute caloric deprivation.

Adult↗
PubMed2003

Metabolic regulation of growth hormone by free fatty acids, somatostatin, and ghrelin in HIV-lipodystrophy.

Human immunodeficiency virus (HIV)-lipodystrophy is a syndrome characterized by changes in fat distribution and insulin resistance. Prior studies suggest markedly reduced growth hormone (GH) levels in association with excess visceral adiposity among patients with HIV-lipodystrophy. We investigated mechanisms of altered GH secretion in a population of 13 male HIV-infected patients with evidence of fat redistribution, compared with 10 HIV-nonlipodystrophic patients and 11 male healthy controls similar in age and body mass index (BMI). Although similar in BMI, the lipodystrophic group was characterized by increased visceral adiposity, free fatty acids (FFA), and insulin and reduced extremity fat. We investigated ghrelin and the effects of acute lowering of FFA by acipimox on GH responses to growth hormone-releasing hormone (GHRH). We also investigated somatostatin tone, comparing GH response to combined GHRH and arginine vs. GHRH alone with a subtraction algorithm. Our data demonstrate an equivalent number of GH pulses (4.1 +/- 0.6, 4.7 +/- 0.8, and 4.5 +/- 0.3 pulses/12 h in the HIV-lipodystrophic, HIV-nonlipodystrophic, and healthy control groups, respectively, P > 0.05) but markedly reduced GH secretion pulse area (1.14 +/- 0.27 vs. 4.67 +/- 1.24 ng.ml(-1).min, P < 0.05, HIV-lipodystrophic vs. HIV-nonlipodystrophic; 1.14 +/- 0.27 vs. 3.18 +/- 0.92 ng.ml(-1).min, P < 0.05 HIV-lipodystrophic vs. control), GH pulse area, and GH pulse width in the HIV-lipodystrophy patients compared with the control groups. Reduced ghrelin (418 +/- 46 vs. 514 +/- 37 pg/ml, P < 0.05, HIV-lipodystrophic vs. HIV-nonlipodystrophic; 418 +/- 46 vs. 546 +/- 45 pg/ml, P < 0.05, HIV-lipodystrophic vs. control), impaired GH response to GHRH by excess FFA, and increased somatostatin tone contribute to reduced GH secretion in patients with HIV-lipodystrophy. These data provide novel insight into the metabolic regulation of GH secretion in subjects with HIV-lipodystrophy.

Adult↗
PubMed2003

Neurocognitive function in HIV-infected patients with low weight and weight loss.

OBJECTIVE: To determine neurocognitive function in HIV-infected subjects with low weight and weight loss. DESIGN: Cross-sectional cohort. METHODS: Baseline data from male and female participants in longitudinal treatment studies of AIDS wasting were analyzed. Fifty-seven HIV-infected women (age: 38 +/- 5 years, education level: 12.3 +/- 2.3 years) and 24 HIV-infected men (age: 37 +/- 5 years, education level: 13.5 +/- 2.9 years) with weight <90% IBW or loss of >10% of preillness weight maximum underwent standardized neurocognitive testing to measure intellectual functioning, attention, memory, and fine motor dexterity. The z scores were determined using age- and gender-specific normative data. RESULTS: Among women, IQ (87 +/- 13, z score: -0.8 +/- 0.8 SD) and executive functioning scores (-0.7 +/- 1.2 SD) were below average but within normal limits. In contrast, performance (z scores) on measures of verbal learning (-2.5 +/- 1.5 SD), visuospatial abilities (-2.5 +/- 2.0 SD), and motor coordination (-2.3 +/- 3.3 SD) fell significantly below normal limits. Among men, IQ score was 96 +/- 13 SD (z score: -0.3 +/- 0.8 SD). Performance was below average on measures of verbal learning (-1.0 +/- 1.7 SD) and visual construction (-1.6 +/- 1.7 SD) but within normal limits on executive functioning (-0.1 +/- 1.0 SD). CONCLUSIONS: HIV-infected women at low weight demonstrate significantly reduced verbal learning, memory, and motor function, whereas HIV-infected men at low weight demonstrate more moderate impairment in verbal learning and other measures of neurocognitive function.

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