Whole-Body and Forearm Muscle Protein Metabolism in Patients With Acromegaly Before and After Treatment.

BACKGROUND: Active acromegaly is characterized by increased lean body mass, but the mechanisms underlying the protein anabolic effect are unclear. AIM: To study if active acromegaly induces reversible changes in whole-body and skeletal muscle protein kinetics. PATIENTS AND METHODS: Eighteen patients with acromegaly were investigated before and 47 ± 10 weeks after disease control by surgery (n = 8) and/or medical treatment (n = 10). Labeled phenylalanine and tyrosine tracers were employed to assess whole-body and regional forearm muscle protein kinetics. Intramyocellular protein signaling was assessed in skeletal muscle biopsies, and whole-body dual-energy X-ray absorptiometry scan and indirect calorimetry assessed lean body mass (LBM) and resting energy expenditure, respectively. RESULTS: Disease control induced a 7% decrease in lean body mass (P < .000) and a 14% decrease in LBM-adjusted energy expenditure. Whole-body phenylalanine breakdown decreased after disease control (P = .005) accompanied by a decrease in the degradation of phenylalanine to tyrosine (P = .005) and a decrease in whole-body phenylalanine synthesis (P = .030). Skeletal muscle protein synthesis tended to decrease after disease control (P = .122), whereas the muscle protein breakdown (P = .437) and muscle protein loss were unaltered (P = .371). Unc-51 like autophagy activating kinase 1 phosphorylation, an activator of protein breakdown, increased after disease control (P = .042). CONCLUSIONS: Active acromegaly represents a reversible high flux state in which both whole-body protein breakdown and synthesis are increased, whereas forearm muscle protein kinetics are unaltered. Future studies are needed to decipher the link between protein kinetics and the structure and function of the associated growth hormone-induced increase in lean body mass.

Sex difference in patients with controlled acromegaly-A multicentre survey.

OBJECTIVE: Active acromegaly is subject to sex differences in growth hormone (GH) and Insulin like growth factor 1 (IGF-I) patterns as well as clinical features but whether this also pertains to controlled disease is unclear. DESIGN: In a cross-sectional, multi-centre study, 84 patients with acromegaly (F = 43, M = 41), who were considered controlled after surgery alone (n = 23) or during continued somatostatin receptor ligand (SRL) treatment (n = 61), were examined. METHODS: Serum concentrations of GH, insulin, glucose and free fatty acid (FFA) were measured during an oral glucose tolerance test (OGTT) together with baseline serum IGF-I and completion of two HR-Qol questionnaires (acromegaly quality of life questionnaire [AcroQol] and Patient-assessed Acromegaly Symptom Questionnaire [PASQ]). RESULTS: The mean age at the time of the study was 57 (±1.1) years and the majority of females (were postmenopausal. Females had significantly higher fasting GH but comparable IGF-I standard deviation scores (SDS). Using fasting GH < 1.0 µg/L as cut off, disease control was less prevalent in females (F: 56% vs. M: 83%, p = .007) whereas a comparable figure was observed using IGF-I SDS < 2 (F:79% vs. M:76%, p = .71). Compared with males, female patients showed impaired AcroQol physical score (p = .05), higher fasting FFA (p = .03) and insulin concentrations during the OGTT (p = .04). CONCLUSION: In patients with acromegaly considered controlled, postmenopausal females exhibited higher GH levels than males despite comparable IGF-I levels, which also translated into impaired metabolic health and well-being. Our findings point to the relevance of including GH measurements in the assessment of disease control and suggest that disease-specific sex differences prevail after treatment.

Covert actions of growth hormone: fibrosis, cardiovascular diseases and cancer.

Since its discovery nearly a century ago, over 100,000 studies of growth hormone (GH) have investigated its structure, how it interacts with the GH receptor and its multiple actions. These include effects on growth, substrate metabolism, body composition, bone mineral density, the cardiovascular system and brain function, among many others. Recombinant human GH is approved for use to promote growth in children with GH deficiency (GHD), along with several additional clinical indications. Studies of humans and animals with altered levels of GH, from complete or partial GHD to GH excess, have revealed several covert or hidden actions of GH, such as effects on fibrosis, cardiovascular function and cancer. In this Review, we do not concentrate on the classic and controversial indications for GH therapy, nor do we cover all covert actions of GH. Instead, we stress the importance of the relationship between GH and fibrosis, and how fibrosis (or lack thereof) might be an emerging factor in both cardiovascular and cancer pathologies. We highlight clinical data from patients with acromegaly or GHD, alongside data from cellular and animal studies, to reveal novel phenotypes and molecular pathways responsible for these actions of GH in fibrosis, cardiovascular function and cancer.

Reversible insulin resistance in muscle and fat unrelated to the metabolic syndrome in patients with acromegaly.

BACKGROUND: Patients with active acromegaly exhibit insulin resistance despite a lean phenotype whereas controlled disease improves insulin sensitivity and increases fat mass. The mechanisms underlying this paradox remain elusive, but growth hormone (GH)-induced lipolysis plays a central role. The aim of the study was to investigative the molecular mechanisms of insulin resistance dissociated from obesity in patients with acromegaly. METHODS: In a prospective study, twenty-one patients with newly diagnosed acromegaly were studied at diagnosis and after disease control obtained by either surgery alone (n=10) or somatostatin analogue (SA) treatment (n=11) with assessment of body composition (DXA scan), whole body and tissue-specific insulin sensitivity and GH and insulin signalling in adipose tissue and skeletal muscle. FINDINGS: Disease control of acromegaly significantly reduced lean body mass (p<0.001) and increased fat mass (p<0.001). At diagnosis, GH signalling (pSTAT5) was constitutively activated in fat and enhanced expression of GH-regulated genes (CISH and IGF-I) were detected in muscle and fat. Insulin sensitivity in skeletal muscle, liver and adipose tissue increased after disease control regardless of treatment modality. This was associated with enhanced insulin signalling in both muscle and fat including downregulation of phosphatase and tensin homolog (PTEN) together with reduced signalling of GH and lipolytic activators in fat. INTERPRETATION: In conclusion, the study support that uncontrolled lipolysis is a major feature of insulin resistance in active acromegaly, and is characterized by upregulation of PTEN and suppression of insulin signalling in both muscle and fat. FUNDING: This work was supported by a grant from the Independent Research Fund, Denmark (7016-00303A) and from the Alfred Benzon Foundation, Denmark.

The acute effects of growth hormone in adipose tissue is associated with suppression of antilipolytic signals.

AIM: Since GH stimulates lipolysis in vivo after a 2-hr lag phase, we studied whether this involves GH signaling and gene expression in adipose tissue (AT). METHODS: Human subjects (n = 9) each underwent intravenous exposure to GH versus saline with measurement of serum FFA, and GH signaling, gene array, and protein in AT biopsies after 30-120 min. Human data were corroborated in adipose-specific GH receptor knockout (FaGHRKO) mice versus wild-type mice. Expression of candidate genes identified in the array were investigated in 3T3-L1 adipocytes. RESULTS: GH increased serum FFA and AT phosphorylation of STAT5b in human subjects. This was replicated in wild-type mice, but not in FaGHRKO mice. The array identified 53 GH-regulated genes, and Ingenuity Pathway analysis showed downregulation of PDE3b, an insulin-dependent antilipolytic signal, upregulation of PTEN that inhibits insulin-dependent antilipolysis, and downregulation of G0S2 and RASD1, both encoding antilipolytic proteins. This was confirmed in 3T3-L1 adipocytes, except for PDE3B, including reciprocal effects of GH and insulin on mRNA expression of PTEN, RASD1, and G0S2. CONCLUSION: (a) GH directly stimulates AT lipolysis in a GHR-dependent manner, (b) this involves suppression of antilipolytic signals at the level of gene expression, (c) the underlying GH signaling pathways remain to be defined.

Fibroblast Activation Protein is a GH Target: A Prospective Study of Patients with Acromegaly Before and After Treatment.

BACKGROUND: Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM: To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS: Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, ß-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: Total FGF21, active FGF21 and ß-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION: 1) Circulating FGF21 and ß-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION: NCT00647179.

THERAPY OF ENDOCRINE DISEASE: Growth hormone replacement therapy in adults: 30 years of personal clinical experience.

The acute metabolic actions of purified human growth hormone (GH) were first documented in adult hypopituitary patients more than 50 years ago, and placebo-controlled long-term GH trials in GH-deficient adults (GHDA) surfaced in 1989 with the availability of biosynthetic human GH. Untreated GHDA is associated with excess morbidity and mortality from cardiovascular disease and the phenotype includes fatigue, reduced aerobic exercise capacity, abdominal obesity, reduced lean body mass, osteopenia and elevated levels of circulating cardiovascular biomarkers. Several of these features reverse and normalize with GH replacement. It remains controversial whether quality of life, assessed by questionnaires, improves. The known side effects are fluid retention and insulin resistance, which are reversible and dose dependent. The dose requirement declines markedly with age and is higher in women. Continuation of GH replacement into adulthood in patients with childhood-onset disease is indicated, if the diagnosis is reconfirmed. GH treatment of frail elderly subjects without documented pituitary disease remains unwarranted. Observational data show that mortality in GH-replaced patients is reduced compared to untreated patients. Even though this reduced mortality could be due to selection bias, GH replacement in GHDA has proven beneficial and safe.

Targeting either GH or IGF-I during somatostatin analogue treatment in patients with acromegaly: a randomized multicentre study.

CONTEXT: Discordant GH and IGF-I values are frequent in acromegaly. The clinical significance and its dependence on treatment modality and of glucose-suppressed GH (GHnadir) measurements remain uncertain. OBJECTIVE: To evaluate the effects of targeting either IGF-I or GH during somatostatin analogue (SA) treatment. PATIENTS AND METHODS: 84 patients with controlled acromegaly after surgery (n = 23) or SA (n = 61) underwent a GH profile including an OGTT, at baseline and after 12 months. SA patients were randomized to monitoring according to either IGF-I (n = 33) or GHnadir (n = 28). SA dose escalation was allowed at baseline and 6 months. MAIN OUTCOME MEASURES: GHnadir and IGF-I at baseline and 12 months, and disease-specific Quality of Life (QoL). RESULTS: IGF-I and fasting GH levels were comparable between the surgery and the SA group, whereas GHnadir (µg/L) was lower in the surgery group (GHnadir 0.7 ± 0.1 vs 0.3 ± 0.1, P < 0.01). SA dose increase was performed in 20 patients in the GH group and in 8 patients in the IGF-I group (P = 0.02), which increased the number of concordantly controlled patients (P = 0.01). QoL was only mildly affected at baseline in all groups and did not changed consistently during the study. CONCLUSION: (1) Discordant values in terms of high GH levels are prevalent in SA patients and more so if applying glucose-suppressed GHnadir; (2) targeting discordant levels of either GH or IGF-I translates into SA dose increase and improved biochemical control; (3) even though QoL was not improved in this study, we suggest biochemical assessment of disease activity to include glucose-suppressed GHnadir also in SA patients.

Stress hormone release is a key component of the metabolic response to lipopolysaccharide: studies in hypopituitary and healthy subjects.

OBJECTIVE: Acute and chronic inflammatory and metabolic responses are generated by lipopolysaccharide (LPS) during acute illness and in the pathogenesis of the metabolic syndrome, type 2 diabetes and cardiovascular disease, but whether these responses depend on intact pituitary release of hormones are not clearly identified. We compared the metabolic effects of LPS in hypopituitary patients (HPs) (in the absence of growth hormone (GH) and ACTH responses) and healthy control subjects (CTR) (with normal pituitary hormone responses). DESIGN: Single-blind randomized. METHODS: We compared the effects of LPS on glucose, protein and lipid metabolism in eight HP and eight matched CTR twice during 4-h basal and 2-h hyperinsulinemic-euglycemic clamp conditions with muscle and fat biopsies in each period during infusion with saline or LPS. RESULTS: LPS increased cortisol and GH levels in CTR but not in HP. Also, it increased whole-body palmitate fluxes (3-fold) and decreased palmitate-specific activity (SA) 40-50% in CTR, but not in HP. G(0)/G(1) Switch Gene 2 (G0S2 - an inhibitor of lipolysis) adipose tissue (AT) mRNA was decreased in CTR. Although LPS increased phenylalanine fluxes significantly more in CTR, there was no difference in glucose metabolism between groups and intramyocellular insulin signaling was unaltered in both groups. CONCLUSIONS: LPS increased indices of lipolysis and amino acid/protein fluxes significantly more in CTR compared with HP and decreased adipocyte G0S2 mRNA only in CTR. Thus, in humans intact pituitary function and appropriate cortisol and GH release are crucial components of the metabolic response to LPS.

The solitary sellar plasmacytoma: a diagnostic challenge.

UNLABELLED: Solitary sellar plasmacytomas are exceedingly rare and difficult to distinguish from other pituitary tumors. We report a case of a 62-year-old woman presenting with blurred vision of the right eye and tenderness of the right temporal region, which was interpreted as temporal arteritis. MRI revealed a pituitary mass lesion (20mm×14mm×17mm) without compression of the optic chiasm and her pituitary function was normal. Pituitary surgery was undertaken due to growth of the lesion, and histopathological examination showed a highly cellular neoplasm composed of mature monoclonal plasma cells. Subsequent examinations revealed no evidence of extrasellar myeloma. The patient received pituitary irradiation and has remained well and free of symptoms apart from iatrogenic central diabetes insipidus. Until now, only eight cases of solitary sellar plasmacytoma have been reported. Most frequent symptoms stem from compression of the cranial nerves in the cavernous sinus (III, IV, V), whereas the anterior pituitary function is mostly intact. LEARNING POINTS: A solitary plasmacytoma is a rare cause of a sellar mass lesion.The radiological and clinical features are nonspecific, but cranial nerve affection and intact pituitary function are usually present.The diagnosis is made histologically and has important therapeutic implications.

GH signaling in human adipose and muscle tissue during 'feast and famine': amplification of exercise stimulation following fasting compared to glucose administration.

OBJECTIVE: Fasting and exercise stimulates, whereas glucose suppresses GH secretion, but it is uncertain how these conditions impact GH signaling in peripheral tissues. To test the original 'feast and famine hypothesis' by Rabinowitz and Zierler, according to which the metabolic effects of GH are predominant during fasting, we specifically hypothesized that fasting and exercise act in synergy to increase STAT-5b target gene expression. DESIGN AND METHODS: Eight healthy men were studied on two occasions in relation to a 1 h exercise bout: i) with a concomitant i.v. glucose infusion ('feast') and ii) after a 36 h fast ('famine'). Muscle and fat biopsy specimens were obtained before, immediately after, and 30 min after exercise. RESULTS: GH increased during exercise on both examination days and this effect was amplified by fasting, and free fatty acid (FFA) levels increased after fasting. STAT-5b phosphorylation increased similarly following exercise on both occasions. In adipose tissue, suppressors of cytokine signaling 1 (SOCS1) and SOCS2 were increased after exercise on the fasting day and both fasting and exercise increased cytokine inducible SH2-containing protein (CISH). In muscle, SOCS2 and CISH mRNA were persistently increased after fasting. Muscle SOCS1, SOCS3, and CISH mRNA expression increased, whereas SOCS2 decreased after exercise on both examination days. CONCLUSIONS: This study demonstrates that fasting and exercise act in tandem to amplify STAT-5b target gene expression (SOCS and CISH) in adipose and muscle tissue in accordance with the 'feast and famine hypothesis'; the adipose tissue signaling responses, which hitherto have not been scrutinized, may play a particular role in promoting FFA mobilization.

An unusual case of an ACTH-secreting macroadenoma with a germline variant in the aryl hydrocarbon receptor-interacting protein (AIP) gene.

UNLABELLED: A patient of Cushing's disease (CD) characterized by a large tumor and only subtle symptoms of hormonal hypersecretion was examined. The patient had a germline variant in the aryl hydrocarbon receptor-interacting protein (AIP) gene. A 50-year-old male presenting with headache was diagnosed with a large pituitary tumor by magnetic resonance imaging (MRI). His visual fields were intact and he exhibited no features of CD. Owing to an exuberant response to synacthen, an overnight dexamethasone suppression test was performed revealing inadequate suppression of plasma cortisol (419 nmol/l). Owing to tumor growth and visual field impairment, he underwent transsphenoidal surgery and developed hypocortisolemia. The pathology specimen revealed a sparsely granulated corticotrope adenoma. Postoperative MRI showed a large tumor remnant. The patient developed skin hyperpigmentation and a synacthen test demonstrated high basal and stimulated cortisol levels; an overnight dexamethasone suppression test showed no suppression (791 nmol/l) and elevated plasma ACTH levels (135 ng/l). A transcranial operation was performed followed by radiotherapy. Two months after radiotherapy, he developed secondary adrenocortical failure. Genetic testing revealed an AIP variant of unknown significance (p.R16H) without loss of the normal AIP allele in the tumor. A literature review showed ten CD patients with AIP gene variants, of whom five (including our case) were p.R16H. CD is occasionally dominated by pituitary tumor growth rather than symptoms of hypersecretion. The particular AIP gene variant identified in our patient is shared by four other reported cases of CD. Future studies are needed to assess whether the reported AIP gene variant is more than just coincidental. LEARNING POINTS: CD is occasionally dominated by pituitary tumor growth rather than symptoms of hypersecretion.Resolution of both tumor remnant and hormonal hypersecretion may occur within 2 months after postoperative radiotherapy.The particular AIP gene variant identified in our patient is shared by four other reported cases of CD.

Intact pituitary function is decisive for the catabolic response to TNF-α: studies of protein, glucose and fatty acid metabolism in hypopituitary and healthy subjects.

CONTEXT: TNF-α generates inflammatory responses and insulin resistance, lipolysis, and protein breakdown. It is unclear whether these changes depend on intact hypothalamo-pituitary stress hormone responses to trigger the release of cortisol and growth hormone. OBJECTIVE: To define differential effects of TNF-α on glucose, protein, and lipid metabolism in hypopituitary patients (without intact hypothalamo-pituitary axis) and healthy controls. DESIGN: Randomized, placebo controlled, single-blinded. Setting, Participants, and Intervention: We studied eight hypopituitary (HP) patients and eight matched control subjects [control volunteers (CTR)] twice during 4-h basal and 2-h hyperinsulinemic clamp conditions with isotope dilution during infusion of saline or TNF-α(12 ng/kg/h) for 6 h. MAIN OUTCOME MEASURES: Phenylalanine, urea, palmitate, and glucose fluxes and fat biopsies in basal and clamp periods. RESULTS: TNF-α infusion significantly increased cortisol and GH levels in CTR but not in HP. TNF-α increased phenylalanine fluxes in both groups, with the increase being significantly greater in CTR, and raised urea flux by 40 % in CTR without any alteration in HP. Endogenous glucose production (EGP) was elevated in CTR compared to HP after TNF-α administration, whereas insulin sensitivity remained similarly unaffected in both groups. TNF-α increased whole body palmitate fluxes and decreased palmitate specific activity in CTR, but not in HP without statistical difference between groups. We did not detect significant effects TNF-α on lipase expression or regulation in fat. CONCLUSIONS: TNF-α increased both urea and amino acid fluxes and EGP significantly more in CTR compared to HP, suggesting that increases in endogenous cortisol and GH release are significant components of the metabolic response to TNF-α.

Giant prolactinoma presenting as a skull base tumor with erosion of the cervical vertebrae: pronounced responsiveness to dopamine agonist treatment.

Giant prolactinomas are rare and usually associated with symptoms attributable to hypopituitarism and compression of juxtasellar structures such as the cranial nerves of the cavernous sinus and the optic chiasm. Occasionally, they masquerade as skull base tumors with atypical symptoms. We describe a patient who presented with a low-energy trauma in the neck region that led to the initial diagnosis of a large skull base tumor eroding the cervical vertebrae. After stabilizing surgery, the patient responded to dopamine agonist therapy with normalization of serum prolactin levels and pronounced reduction in tumor volume.

Direct effects of TNF-α on local fuel metabolism and cytokine levels in the placebo-controlled, bilaterally infused human leg: increased insulin sensitivity, increased net protein breakdown, and increased IL-6 release.

Tumor necrosis factor-α (TNF-α) has widespread metabolic actions. Systemic TNF-α administration, however, generates a complex hormonal and metabolic response. Our study was designed to test whether regional, placebo-controlled TNF-α infusion directly affects insulin resistance and protein breakdown. We studied eight healthy volunteers once with bilateral femoral vein and artery catheters during a 3-h basal period and a 3-h hyperinsulinemic-euglycemic clamp. One artery was perfused with saline and one with TNF-α. During the clamp, TNF-α perfusion increased glucose arteriovenous differences (0.91 ± 0.17 vs. 0.74 ± 0.15 mmol/L, P = 0.012) and leg glucose uptake rates. Net phenylalanine release was increased by TNF-α perfusion with concomitant increases in appearance and disappearance rates. Free fatty acid kinetics was not affected by TNF-α, whereas interleukin-6 (IL-6) release increased. Insulin and protein signaling in muscle biopsies was not affected by TNF-α. TNF-α directly increased net muscle protein loss, which may contribute to cachexia and general protein loss during severe illness. The finding of increased insulin sensitivity, which could relate to IL-6, is of major clinical interest and may concurrently act to provide adequate tissue fuel supply and contribute to the occurrence of systemic hypoglycemia. This distinct metabolic feature places TNF-α among the rare insulin mimetics of human origin.

Cotreatment with pegvisomant and a somatostatin analog (SA) in SA-responsive acromegalic patients.

CONTEXT: Cotreatment of acromegaly with pegvisomant and a somatostatin analog (SA) has proven feasible. Previous studies in the field have focused on patients with an insufficient response to SA monotherapy in whom pegvisomant was added without changing the SA dose. OBJECTIVE: The objective of the study was to study whether patients sufficiently controlled on SA monotherapy can be transferred to combination therapy with low-dose pegvisomant and a reduced SA dose. DESIGN: Eighteen acromegalic patients well controlled on SA monotherapy, mean ± se aged 54 ± 3 yr, were randomized in a parallel study over 24 wk to unchanged SA monotherapy or cotreatment with pegvisomant (15-30 mg twice a week) and SA (half the usual dosage). SETTING: This was an investigator-initiated study in a single tertiary referral center. MAIN OUTCOME MEASURES: Glucose tolerance, substrate metabolism, insulin sensitivity, body composition, and quality of life were measured. RESULTS: Median pegvisomant dose was 52.5 mg/wk (range 30-60). IGF-I (micrograms per liter) was comparable both at baseline (P = 0.88) and after 24 wk of treatment (P = 0.48). The change in IGF-I between baseline and wk 24 also did not differ between groups (P = 0.15). Apart from increased peak insulin levels during the oral glucose tolerance test in the cotreatment group, no substantial differences between the two groups were detected. Moderately elevated liver enzymes were found in 17% of the patients on pegvisomant therapy. CONCLUSION: Acromegalic patients well controlled on SA monotherapy can maintain safe IGF-I levels during 24 wk of cotreatment with low-dose pegvisomant and a 50% reduced SA dose. This treatment modality, however, does not seem to provide significant benefits for the patients.

Insulin and GH signaling in human skeletal muscle in vivo following exogenous GH exposure: impact of an oral glucose load.

INTRODUCTION: GH induces acute insulin resistance in skeletal muscle in vivo, which in rodent models has been attributed to crosstalk between GH and insulin signaling pathways. Our objective was to characterize time course changes in signaling pathways for GH and insulin in human skeletal muscle in vivo following GH exposure in the presence and absence of an oral glucose load. METHODS: Eight young men were studied in a single-blinded randomized crossover design on 3 occasions: 1) after an intravenous GH bolus 2) after an intravenous GH bolus plus an oral glucose load (OGTT), and 3) after intravenous saline plus OGTT. Muscle biopsies were taken at t = 0, 30, 60, and 120. Blood was sampled at frequent intervals for assessment of GH, insulin, glucose, and free fatty acids (FFA). RESULTS: GH increased AUC(glucose) after an OGTT (p<0.05) without significant changes in serum insulin levels. GH induced phosphorylation of STAT5 independently of the OGTT. Conversely, the OGTT induced acute phosphorylation of the insulin signaling proteins Akt (ser(473) and thr(308)), and AS160.The combination of OGTT and GH suppressed Akt activation, whereas the downstream expression of AS160 was amplified by GH. WE CONCLUDED THE FOLLOWING: 1) A physiological GH bolus activates STAT5 signaling pathways in skeletal muscle irrespective of ambient glucose and insulin levels 2) Insulin resistance induced by GH occurs without a distinct suppression of insulin signaling proteins 3) The accentuation of the glucose-stimulated activation of AS 160 by GH does however indicate a potential crosstalk between insulin and GH. TRIAL REGISTRATION: ClinicalTrials.gov NCT00477997.

Hypersecretion of the alpha-subunit in clinically non-functioning pituitary adenomas: Diagnostic accuracy is improved by adding alpha-subunit/gonadotropin ratio to levels of alpha-subunit.

BACKGROUND: In vitro, the majority of clinically non-functioning pituitary adenomas (NFPAs) produce gonadotropins or their alpha-subunit; however, in vivo, measurements of alpha-subunit levels may not accurately detect the hypersecretion of the alpha-subunit. AIM: We wanted to estimate the reference intervals and decision limits for gonadotropin alpha-subunit, LH and FSH levels, and aratio (alpha-subunit/LH+FSH), especially taking into consideration patient gender and menstrual status. Furthermore, we wanted to examine if the diagnostic utility of alpha-subunit hypersecretion was improved when the alpha-ratios, rather than simply the alpha-subunit levels, were measured in patients with NFPAs. MATERIAL AND METHODS: Reference intervals for gonadotropin alpha-subunit serum levels and alpha-ratios were established in 231 healthy adults. The estimated cut-off limits were applied to 37 patients with NFPAs. Gonadotropin alpha-subunit, LH and FSH levels were measured and alpha-ratios were calculated. RESULTS: In healthy adults, the cut-offs for alpha-subunit levels were significantly different between men and pre- and postmenopausal women: the cut-offs were 1.10, 0.48 and 3.76 IU/l, respectively. Using these estimated cut-offs, increased alpha-subunit levels were identified in 10 out of 37 (27%) patients with NFPAs. By adding alpha-ratio, in combination with alpha-subunit levels, 23 patients out of 37 (62%) were identified as having elevated alpha-subunit hypersecretion, and 22 out of these 23 patients (96%) had increased alpha-ratios. One premenopausal patient out of 23 had elevated alpha-subunit level but a normal alpha-ratio. CONCLUSION: Our data suggest that adding the simple calculation of alpha-ratio improves the ability of detecting gonadotropin alpha-subunit hypersecretion and thereby indentifying patients with NFPAs.

Discontinuation of hormone replacement therapy in young GH-treated hypopituitary women increases liver enzymes.

OBJECTIVE: Hypopituitarism, often characterized by hypogonadism, is associated with central obesity, increased cardiovascular and endocrine morbidity and mortality. In Turner syndrome, which is also characterized by hypogonadism liver enzymes are often elevated, but readily suppressed by a short course of hormone replacement therapy (HRT). We investigated the effect of HRT on liver enzymes, lipid levels and measures of insulin sensitivity 26 in hypopituitary women. DESIGN: We studied 26 hypopituitary women (age 38.8+/-11.0 (mean+/-SD years), BMI 27.4+/-5.1kg/m(2)) during HRT and 28days off therapy. METHODS: We measured liver enzymes, fasting levels of lipids, insulin and glucose as well as adiponectin and leptin levels. Body composition was assessed by means of anthropometry and bioimpedance. RESULTS: Alanine transaminase (ALT) and aspartate transaminase (AST) increased after discontinuation of HRT (ALT; treated: 22.3+/-11.5 vs. untreated: 27.1+/-11.1 (U/L) (P<0.02); AST; treated: 20.4+/-6.1 vs. untreated: 24.6+/-8.9 (U/L) (P<0.002)), whereas other liver function tests remained unchanged. Measures of insulin sensitivity and fasting lipids were also unaffected by HRT, whereas leptin levels decreased with cessation of HRT (leptin; treated: 23 (8-71) vs. untreated: 20 (8-64) (mug/L) (P<0.0005)). CONCLUSION: Short time discontinuation of HRT in young hypopituitary women increased liver enzymes, whereas measures of insulin sensitivity and lipid levels remained unchanged. We speculate that the estrogen component of HRT has beneficial effects on hepatic metabolism through various pathways. Further studies including liver imaging and with a time-dependent design are needed to clarify the role of HRT on liver enzyme levels, metabolic variables and liver fat content.