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.

Insulin resistance induced by growth hormone is linked to lipolysis and associated with suppressed pyruvate dehydrogenase activity in skeletal muscle: a 2 × 2 factorial, randomised, crossover study in human individuals.

AIMS/HYPOTHESIS: Growth hormone (GH) causes insulin resistance that is linked to lipolysis, but the underlying mechanisms are unclear. We investigated if GH-induced insulin resistance in skeletal muscle involves accumulation of diacylglycerol (DAG) and ceramide as well as impaired insulin signalling, or substrate competition between fatty acids and glucose. METHODS: Nine GH-deficient male participants were randomised and examined in a 2 × 2 factorial design with and without administration of GH and acipimox (an anti-lipolytic compound). As-treated analyses were performed, wherefore data from three visits from two patients were excluded due to incorrect GH administration. The primary outcome was insulin sensitivity, expressed as the AUC of the glucose infusion rate (GIRAUC), and furthermore, the levels of DAGs and ceramides, insulin signalling and the activity of the active form of pyruvate dehydrogenase (PDHa) were assessed in skeletal muscle biopsies obtained in the basal state and during a hyperinsulinaemic-euglycaemic clamp (HEC). RESULTS: Co-administration of acipimox completely suppressed the GH-induced elevation in serum levels of NEFA (GH versus GH+acipimox, p < 0.0001) and abrogated GH-induced insulin resistance (mean GIRAUC [95% CI] [mg min-1 kg-1] during the HEC: control, 595 [493, 718]; GH, 468 [382, 573]; GH+acipimox, 654 [539, 794]; acipimox, 754 [618, 921]; GH vs GH+acipimox: p = 0.004). GH did not significantly change either the accumulation of DAGs and ceramides or insulin signalling in skeletal muscle, but GH antagonised the insulin-stimulated increase in PDHa activity (mean ± SEM [% from the basal state to the HEC]: control, 47 ± 19; GH, -15 ± 21; GH+acipimox, 3 ± 21; acipimox, 57 ± 22; main effect: p = 0.02). CONCLUSIONS/INTERPRETATION: GH-induced insulin resistance in skeletal muscle is: (1) causally linked to lipolysis; (2) not associated with either accumulation of DAGs and ceramides or impaired insulin signalling; (3) likely to involve substrate competition between glucose and lipid intermediates. TRIAL REGISTRATION: ClinicalTrials.gov NCT02782208 FUNDING: The work was supported by the Grant for Growth Innovation (GGI), which was funded by Merck KGaA, Darmstadt, Germany. Graphical abstract.

Growth hormone signaling and action in obese versus lean human subjects.

Growth hormone (GH) levels are blunted in obesity, but it is not known whether this relates to altered GH sensitivity and whether this influences the metabolic adaptation to fasting. Therefore, we investigated the effect of obesity on GH signal transduction and fasting-induced changes in GH action. Nine obese (BMI 35.7 kg/m2) and nine lean (BMI 21.5 kg/m2) men were studied in a randomized crossover design with 1) an intravenous GH bolus, 2) an intravenous saline bolus, and 3) 72 h of fasting. Insulin sensitivity (hyperinsulinemic, euglycemic clamp) and substrate metabolism (glucose tracer and indirect calorimetry) were measured in studies 1 and 2. In vivo GH signaling was assessed in muscle and fat biopsies. GH pharmacokinetics did not differ between obese and lean subjects, but endogenous GH levels were reduced in obesity. GH signaling (STAT5b phosphorylation and CISH mRNA transcription), and GH action (induction of lipolysis and peripheral insulin resistance) were similar in the two groups, but a GH-induced insulin antagonistic effect on endogenous glucose production only occurred in the obese. Fasting-induced IGF-I reduction was completely abrogated in obese subjects despite a comparable relative increase in GH levels (ΔIGF-I: lean, -66 ± 10 vs. obese, 27 ± 16 µg/l; P < 0.01; ΔGH: lean, 647 ± 280 vs. obese, 544 ± 220%; P = 0.76]. We conclude that 1) GH signaling is normal in obesity, 2) in the obese state, the preservation of IGF-I with fasting and the augmented GH-induced central insulin resistance indicate increased hepatic GH sensitivity, 3) blunted GH levels in obesity may protect against insulin resistance without compromising IGF-I status.

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.

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.

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.

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.

The effects of growth hormone on adipose tissue: old observations, new mechanisms.

The ability of growth hormone (GH) to induce adipose tissue lipolysis has been known for over five decades; however, the molecular mechanisms that mediate this effect and the ability of GH to inhibit insulin-stimulated glucose uptake have scarcely been documented. In this same time frame, our understanding of adipose tissue has evolved to reveal a complex structure with distinct types of adipocyte, depot-specific differences, a biologically significant extracellular matrix and important endocrine properties mediated by adipokines. All these aforementioned features, in turn, can influence lipolysis. In this Review, we provide a historical and current overview of the lipolytic effect of GH in humans, mice and cultured cells. More globally, we explain lipolysis in terms of GH-induced intracellular signalling and its effect on obesity, insulin resistance and lipotoxicity. In this regard, findings that define molecular mechanisms by which GH induces lipolysis are described. Finally, data are presented for the differential effect of GH on specific adipose tissue depots and on distinct classes of metabolically active adipocytes. Together, these cellular, animal and human studies reveal novel cellular phenotypes and molecular pathways regulating the metabolic effects of GH on adipose tissue.

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.

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.

Soluble Klotho: a possible predictor of quality of life in acromegaly patients.

PURPOSE: Although quality of life (QoL) is improved in patients with acromegaly after disease control, QoL correlates only weakly with traditional biomarkers. Our objective is to investigate a potential relation between the new serum biomarker soluble Klotho (sKlotho), GH and insulin-like growth factor 1 (IGF-1) levels, and QoL. METHODS: In this prospective cohort study, we investigated 54 acromegaly patients biochemically well-controlled on combination treatment with first-generation somatostatin receptor ligands (SRLs) and pegvisomant (PEGV) at baseline and 9 months after switching to pasireotide LAR (PAS-LAR; either as monotherapy, n = 28; or in combination with PEGV, n = 26). QoL was measured by the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and Acromegaly Quality of Life (AcroQoL) questionnaire. RESULTS: Switching to PAS-LAR treatment significantly improved QoL without altering IGF-1 levels. QoL did not correlate with GH or IGF-1 levels, but sKlotho correlated with the observed improvements in QoL by the AcroQoL global (r = -0.35, p = 0.012) and physical subdimension (r = -0.34, p = 0.017), and with PASQ headache (r = 0.28, p = 0.048), osteoarthralgia (r = 0.46, p = 0.00080) and soft tissue swelling score (r = 0.29, p = 0.041). Parallel changes in serum sKlotho and IGF-1 (r = 0.31, p = 0.023) suggest sKlotho and IGF-1 to be similarly dependent on GH. Comparing the PAS-LAR combination therapy and the monotherapy group we did not observe a significant difference in improvement of QoL. CONCLUSIONS: Patients experienced improved QoL during PAS-LAR, either as monotherapy or in combination with PEGV. Soluble Klotho concentrations appear to be a useful marker of QoL in acromegaly patients but the underlying mechanisms remain to be investigated.

Peroxisome proliferator-activated receptor gamma (PPAR) agonism reduces the insulin-stimulated increase in circulating interleukin-6 in GH replaced GH-deficient adults.

CONTEXT: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists modify cardiovascular risk factors and inflammatory markers in patients with type 2 diabetes. GH treatment in GH-deficient (GHD) patients may cause insulin resistance and exerts ambiguous effects on inflammatory markers. OBJECTIVE: To investigate circulating markers of inflammation and endothelial function in GH replaced GHD patients before and after 12 weeks administration of either pioglitazone 30 mg/day (N = 10) or placebo (N = 10) in a randomized double-blind parallel design. METHODS: Circulating levels of interleukins (ILs)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, high sensitivity C-reactive protein, vascular cell adhesion molecule-I, and osteoprotegerin (OPG) were measured in the basal state and after a 2.5 h hyperinsulinaemic euglycaemic clamp. RESULTS: Insulin sensitivity improved in the group receiving PPARgamma agonist (P = 0.03). Serum IL-6 levels increased by 114 +/- 31% (mean +/- SE) in the entire group (N = 20) following the hyperinsulinaemic euglycaemic clamp (P = 0.01) performed at study start. Twelve weeks of PPARgamma agonist treatment significantly abrogated this insulin-stimulated increment in IL-6 levels compared to placebo (P = 0.01). Furthermore PPARgamma agonist treatment significantly lowered basal IL-4 levels (P < 0.05). CONCLUSIONS: (i) IL-6 levels increase during a hyperinsulinaemic clamp in GH replaced patients (ii) This increase in IL-6 is abrogated by PPARgamma agonist treatment (iii) we hypothesize that PPARgamma agonist-induced improvement of insulin sensitivity may obviate a compensatory rise in IL-6.

Redundancy in regulation of lipid accumulation in skeletal muscle during prolonged fasting in obese men.

Fasting in human subjects shifts skeletal muscle metabolism toward lipid utilization and accumulation, including intramyocellular lipid (IMCL) deposition. Growth hormone (GH) secretion amplifies during fasting and promotes lipolysis and lipid oxidation, but it is unknown to which degree lipid deposition and metabolism in skeletal muscle during fasting depends on GH action. To test this, we studied nine obese but otherwise healthy men thrice: (a) in the postabsorptive state ("CTRL"), (b) during 72-hr fasting ("FAST"), and (c) during 72-hr fasting and treatment with a GH antagonist (GHA) ("FAST + GHA"). IMCL was assessed by magnetic resonance spectroscopy (MRS) and blood samples were drawn for plasma metabolomics assessment while muscle biopsies were obtained for measurements of regulators of substrate metabolism. Prolonged fasting was associated with elevated GH levels and a pronounced GHA-independent increase in circulating medium- and long-chain fatty acids, glycerol, and ketone bodies indicating increased supply of lipid intermediates to skeletal muscle. Additionally, fasting was associated with a release of short-, medium-, and long-chain acylcarnitines to the circulation from an increased ß-oxidation. This was consistent with a ≈55%-60% decrease in pyruvate dehydrogenase (PDHa) activity. Opposite, IMCL content increased ≈75% with prolonged fasting without an effect of GHA. We suggest that prolonged fasting increases lipid uptake in skeletal muscle and saturates lipid oxidation, both favoring IMCL deposition. This occurs without a detectable effect of GHA on skeletal muscle lipid metabolism.

Peroxisome proliferator-activated receptor gamma agonism modifies the effects of growth hormone on lipolysis and insulin sensitivity.

CONTEXT: Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists such as thiazolidinediones (TZDs) improve insulin sensitivity in type 2 diabetes mellitus (T2DM) through effects on fat metabolism whereas GH stimulates lipolysis and induces insulin resistance. OBJECTIVE: To evaluate the impact of TZDs on fat metabolism and insulin sensitivity in subjects exposed to stable GH levels. DESIGN: A randomized, placebo-controlled, double-blind parallel-group study including 20 GH-deficient patients on continued GH replacement therapy. The patients were studied before and after 12 weeks. INTERVENTION: Patients received either pioglitazone 30 mg (N = 10) or placebo (N = 10) once daily for 12 weeks. RESULTS: Adiponectin levels almost doubled during pioglitazone treatment (P = 0.0001). Pioglitazone significantly decreased basal free fatty acid (FFA) levels (P = 0.02) and lipid oxidation (P = 0.02). Basal glucose oxidation rate (P = 0.004) and insulin sensitivity (P = 0.03) improved in the patients who received pioglitazone treatment. The change in insulin-stimulated adiponectin level after pioglitazone treatment was positively correlated to the change in insulin-stimulated total glucose disposal (R = 0.69, P = 0.04). CONCLUSION: The impact of GH on lipolysis and insulin sensitivity can be modified by administration of TZDs.

Fasting in healthy subjects is associated with intrahepatic accumulation of lipids as assessed by 1H-magnetic resonance spectroscopy.

The impact of fasting on IHL (intrahepatic lipid) content in human subjects has not been investigated previously, but results indicate that it may change rapidly in response to metabolic cues. The aim of the present study was to measure IHL content after fasting and to correlate this with circulating lipid intermediates. A total of eight healthy non-obese young males were studied before and after 12 or 36 h of fasting. IHL content was assessed by (1)H-magnetic resonance spectroscopy, and blood samples were drawn after the fasting period. IHL content increased significantly after the 36 h fasting period [median increase 156% (range, 4-252%); P<0.05]. Furthermore, a significant positive correlation between this increase and 3-hydroxybutyrate concentration was detected (P=0.03). No significant change in IHL content was demonstrated after the 12 h fasting period. The baseline median inter-individual variation in IHLs was 0.51% (range, 0.25-0.72%). The coefficient of variation of IHL measurements was 11.6%; 25-30% of the variation was of analytical origin and the remaining 70-75% was attributed to repositioning. In conclusion, IHL content increases in healthy male subjects during fasting, which demonstrates that nutritional status should be accounted for when assessing IHLs in clinical studies. Moreover, the increase in IHLs was positively correlated with the concentration of 3-hydroxybutyrate.

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.

Growth Hormone Research Society perspective on biomarkers of GH action in children and adults.

OBJECTIVE: The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly. PARTICIPANTS: GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry. EVIDENCE: Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs. CONSENSUS PROCESS: Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process. CONCLUSIONS: The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly.

The impact of pegvisomant treatment on substrate metabolism and insulin sensitivity in patients with acromegaly.

CONTEXT: Pegvisomant is a specific GH receptor antagonist that is able to normalize serum IGF-I concentrations in most patients with acromegaly. The impact of pegvisomant on insulin sensitivity and substrate metabolism is less well described. PATIENTS AND METHODS: We assessed basal and insulin-stimulated (euglycemic clamp) substrate metabolism in seven patients with active acromegaly before and after 4-wk pegvisomant treatment (15 mg/d) in an open design. RESULTS: After pegvisomant, IGF-I decreased, whereas GH increased (IGF-I, 621 +/- 82 vs. 247 +/- 33 microg/liter, P = 0.02; GH, 5.3 +/- 1.5 vs. 10.8 +/- 3.3 microg/liter, P = 0.02). Basal serum insulin and plasma glucose levels decreased after treatment (insulin, 54 +/- 5.9 vs. 42 +/- 5.3 pmol/liter, P = 0.001; glucose, 5.7 +/- 0.1 vs. 5.3 +/- 0.0 mmol/liter, not significant), whereas palmitate kinetics were unaltered. During the clamp, the glucose infusion rate increased after pegvisomant (3.1 +/- 0.5 vs. 4.4 +/- 0.6 mg/kg.min, P = 0.02), whereas the suppression of endogenous glucose production tended to increase (0.7 +/- 0.0 vs. 0.5 +/- 0.1 mg/kg.min, not significant). Total resting energy expenditure decreased after pegvisomant treatment (1703 +/- 109 vs. 1563 +/- 101 kcal/24 h, P = 0.03), but the rate of lipid oxidation did not change significantly. CONCLUSIONS: 1) Pegvisomant treatment for 4 wk improves peripheral and hepatic insulin sensitivity in acromegaly. 2) This is associated with a decrease in resting energy expenditure, whereas free fatty acid metabolism is unaltered. 3) The data support the important direct effects of GH on glucose metabolism and add additional benefits to pegvisomant treatment for acromegaly.