Diabetes mellitus secondary to treatment with immune checkpoint inhibitors.

Cancer immunotherapy has been one of the highlights in the advancement of cancer care. Certain immune checkpoint inhibitors bind to PD-1 on T cells and mediate an antitumour immune response. Given that immune checkpoint inhibitors are becoming part of standard care, a new class of adverse events-immune-related adverse events-has emerged. Among them is endocrine toxicity, most commonly targeting the thyroid, pituitary, or adrenal glands. New-onset diabetes mellitus has been reported in fewer than 1% of patients. We present a patient with type 1 diabetes mellitus secondary to immunotherapy, together with an overview of the associated literature. Patients who develop type 1 diabetes mellitus experience a rapid course, and diabetic ketoacidosis is commonly the presenting symptom. Insulin is currently the treatment of choice; oral antidiabetics or corticosteroids do not assist in management. Several predictive factors are under investigation, but physician awareness and prompt management are key to a positive outcome.

The ongoing challenge of discrepant growth hormone and insulin-like growth factor I results in the evaluation of treated acromegalic patients: a systematic review and meta-analysis.

OBJECTIVE: Growth hormone (GH) and insulin-like growth factor I (IGF-I) are the principal biomarkers used to assess disease activity in acromegaly, and any discrepancy between them renders interpretation of results inconclusive. Purpose of this study was to assess the frequency of this discrepancy and identify parameters that might affect its occurrence. DESIGN: A systematic review of MEDLINE and Scopus was performed (1987-2013) followed by a meta-analysis to address the frequency of discrepant results between GH and IGF-I levels. Meta-regression and subgroup analyses were performed assessing the effects of the year of publication, the different types of GH testing and GH assays used, as well as the impact of treatment with somatostatin analogues (SSAs) on the occurrence of this discrepancy. RESULTS: The analysis retrieved 39 eligible studies totalling 7071 patients. The pooled discordance rate between GH and IGF-I was 25·7% (95% CI: 22·3-29·4), and the predominant format was that of elevated IGF-I with normal GH levels (15·3%, 95% CI: 12·5-18·7). No significant correlation between the discordance rate and the year of publication was shown; whereas, the use of ultrasensitive GH assays resulted in higher discordance rates (30·7%, 95% CI: 25·9-35·9 vs 19·8%, 95% CI: 14·1-27·2, P = 0·04) as did treatment with SSAs (32·5%, 95% CI: 27·8-37·4) vs (21·6%, 95% CI: 17·8-25·6, P = 0·001). CONCLUSIONS: Discrepancy between GH and IGF-I results is encountered in a quarter of treated patients with acromegaly, especially when using ultrasensitive GH assays or in patients receiving SSAs, a fact that the clinician should take into consideration when making clinical decisions.

Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis.

OBJECTIVE: Somatic mutations in the GNAS1 gene, which encodes the alpha-subunit of G stimulatory proteins (gsp), are frequently detected in somatotroph pituitary tumors and have been associated to specific clinical and histopathological characteristics. However, the question whether the presence of a somatic gsp mutation affects the response to somatostatin analog treatment remains unresolved. DESIGN: Following a literature search, we performed a meta-analysis, including 8 eligible studies, in order to estimate the effect of gsp mutation on the percent reduction of growth hormone (GH) levels during an acute octreotide suppression test (OST). A total of 310 patients with acromegaly [126 gsp (+) and 184 gsp (-)] were included in the analysis. RESULTS: The presence of the gsp mutation was related with a greater reduction in GH levels on OST [Weighted Mean Difference (WMD): 9.08 % (95 % CI, 2.73, 15.42); p = 0.005; random effects model]. There was significant heterogeneity for this effect estimate (I(2) = 58 %, p value for heterogeneity = 0.02). A sensitivity analysis after exclusion of a study with different methodology of OST provided similar estimates [WMD: 6.93 % (95 % CI, 1.40, 12.46); p = 0.01], albeit with no significant heterogeneity (I(2) = 35 %, p value for heterogeneity = 0.16). CONCLUSIONS: The present meta-analysis suggests a role for gsp mutation as a prognostic factor of treatment response to somatostatin analogs.

Incidence of pituitary incidentalomas in patients with adrenal adenomas.

With the advent of modern imaging modalities, endocrine incidentalomas are increasingly being discovered. We aimed to investigate the presence of pituitary incidentalomas (PI) in patients with adrenal incidentalomas (AI), and identify potential metabolic correlates in this cohort. 26 patients (18 females) with AI discovered on abdominal computerized tomography were studied. All patients underwent pituitary magnetic resonance imaging (MRI) and endocrine investigations to evaluate functional adrenal pathology, anterior pituitary hormonal status, insulin-resistance indices and presence of metabolic syndrome. Pituitary MRI revealed a microadenoma and a 4×5 mm cyst in 1 patient respectively, and an empty sella in 4 (2 partial) patients. Overall, 6/26 (23%) patients with an AI had evidence of pituitary imaging pathology but only 8% had a PI; none had any evidence of abnormalities in pituitary function. Subclinical hypercortisolism was the only hyperfunctional status detected in 4 patients with AI but was unrelated to the pituitary findings. No abnormality of insulin secretion and action was found between patients with or without pituitary pathology. In the present study 23% of patients with AI had some alteration in pituitary morphology, and 2 a PI without accompanying pituitary hormonal deficit or metabolic derangement. Further studies are required to address this issue and identify a potential pathogenetic mechanism.

The increase in thyroid cancer incidence is not only due to papillary microcarcinomas: a 40-year study in 1 778 patients.

AIM: Thyroid cancer incidence has been increased over the last decades. The aims of the present study were: (a) to identify a changing trend in thyroid cancer in Northern Greece, (b) to examine patients' and tumoral characteristics and (c) to investigate the increase of papillary microcarcinomas and that of invasive or larger cancers. PATIENTS AND METHODS: We retrospectively analyzed the records of 1 778 patients who were diagnosed with thyroid cancer between January 1971 and December 2010. The study period was divided into 4 decades: 1971-1980, 1981-1990, 1991-2000, 2001-2010. Patients were separated into 2 groups: in Group A we have included papillary thyroid microcarcinomas (PTM) and in Group B all cancers with diameter >10 mm as well as invasive cancers ≤10 mm. RESULTS: Patients diagnosed with thyroid cancer increased substantially per decade. The relative frequency of papillary thyroid cancer cases increased (from 60% up to 84.6% in the last decade) and follicular cancers decreased (from 40% down to 11.6%). During the study period, cancer size declined. Frequency of PTM (Group A) increased from 0% up to 19.3% in the last decade, but cancers of this group represent only a minority of total cancers. CONCLUSIONS: The increase of thyroid cancer in this cohort was mainly due to tumors larger than 1 cm and also to smaller in size but invasive thyroid tumors. This increase outnumbers the increase in papillary thyroid microcarcinomas.

Long-term outcome of primary endocrine non-Hodgkin lymphomas: does the site make the difference?

AIM: Primary lymphomas of endocrine glands are extremely rare. Our study adds more data to the few published series regarding the incidence, clinical characteristics, management and overall survival (OS) by comparing the various diffuse large B-cell endocrine lymphomas. Moreover, it contributes to a better understanding of these neoplasms and provides concepts for future research. METHODS: We retrospectively evaluated the clinical profile and the patterns of outcome among patients who were treated in our center with the diagnosis of aggressive, B-cell, primary endocrine lymphoma. RESULTS: Between May 1980 and December 2011, 450 patients were diagnosed as primary extranodal non-Hodgkin lymphomas. Among them, 18 cases (4%) were primary testicular lymphoma (PTL), 8 cases (2%) were primary thyroid lymphoma (PTHL) and 4 cases (1%) were primary adrenal lymphoma (PAL). The therapeutic approaches employed were variable, including mainly chemotherapy in combination with radiotherapy and surgery. The median OS for the patients with PTL and PAL was 27 and 6 months, respectively. Better outcome was observed in patients with PTHL for whom the median OS has not been reached yet, whereas the PAL group had the worst prognosis. CONCLUSIONS: The discrepancies in the outcome among endocrine lymphomas could be partly attributed to their biologic variability, which might be determined by the initial site involved. We conclude that treatment decisions should be made according to a multi-disciplinary approach to avoid unnecessary surgery. Existing treatment strategies for PTL and PAL fail to provide long-term survival, rendering the application of novel therapeutic approaches essential.

Calcitonin stimulation tests for the early diagnosis and follow-up of patients with C cell disease: a descriptive analysis.

BACKGROUND/AIM: Residual or recurrent medullary thyroid carcinoma (MTC) after thyroidectomy is diagnosed by elevated serum calcitonin (CT) levels. However, in minimal residual MTC or C-cell hyperplasia (CCH), where imaging studies are often negative, basal CT levels are frequently normal and CT stimulation tests are required. We aimed to compare CT stimulation tests with calcium, pentagastrin and their combination in identifying minimal residual MTC and CCH. MATERIAL AND METHODS: We studied 10 post-thyroidectomy patients with MTC and 20 first-degree relatives of the patients who had no clinically apparent MTC. We performed 54 combined (calcium plus pentagastrin) stimulation tests, 35 calcium stimulation tests and 26 pentagastrin stimulation tests. RESULTS: Basal CT levels were abnormal (≥500 pg/ml) in 4 patients with apparent metastatic disease (Group 1A) and in 2 patients with minimal residual disease (Group 1B) but were normal (0-300 pg/ml) in 4 patients with no residual disease (Group 1C) and in the relatives (Group 2). In Groups 1A, 1B and 1C, maximal elevation in CT levels was greater after the combined stimulation test than after calcium or pentagastrin tests. The combined stimulation test induced the greatest increases (920, 700 and 706 pg/ml, respectively) in 3 relatives (Group 2); CCH was confirmed histologically in these patients. Side-effects were mild, short-lasting and of similar intensity and duration during all tests. CONCLUSIONS: Patients with subclinical MTC (minimal residual or recurrent MTC) or their relatives (with CCH) usually have normal basal CT levels and stimulation tests are necessary. Combined test represents the most sensitive and safe stimulation test for the diagnosis of subclinical hypercalcitonemia.

Height, whole Body Surface Area, gender, working outdoors, and sunbathing in previous summer are important determinants of serum 25-hydroxyvitamin D levels.

OBJECTIVE: To investigate if serum 25-hydroxyvitamin D (25(OH)D) is related to the whole Body Surface Area (BSA), and to several other anthropometric and environmental factors. MATERIALS/METHODS: Serum 25(OH)D was determined in 489 apparently healthy subjects (346 women and 143 men, mean age 43.9 years) in April and May. From all subjects the following data were available: height, body weight, waist to hip ratio, BSA, BMI, environment of work (indoors vs. outdoors), habit of regularly sunbathing during previous summer(s), fear of sun, dwelling in city or village, and skin color. RESULTS: Approximately 43% of the participants had serum 25(OH)D levels between 10 and 20 ng/ml, 44% had values between 20.1 and 30 ng/ml, whereas about 5% had values below 10 ng/ml and only 9% had values above 30 ng/ml. There was a significant positive relationship between 25(OH)D, height and BSA, which was more pronounced for BSA in obese subjects even after adjustment for work outdoors and sunbathing during previous summer(s). Outdoor workers and sunbathers had higher 25(OH)D compared to indoor workers and non-sunbathers respectively. Men when compared to women had higher 25(OH)D regardless of BMI and this difference was apparently due to the fact that men were taller, had greater BSA, and worked more often outdoors. CONCLUSIONS: Height, whole BSA, gender, working outdoors and sunbathing in previous summer(s) proved to be significant determinants of serum 25(OH)D. Vitamin D status is higher in taller individuals with greater BSA, and in men when compared to women.

Hypophysitis superimposed on a non-functioning pituitary adenoma: diagnostic clinical, endocrine, and radiologic features.

Pituitary adenomas are common neoplasms requiring medical and/or surgical treatment when associated with hormonal hypersecretion. Treatment of non-functioning pituitary adenomas is necessary when symptoms of mass effect or hormonal deficits occur. However, therapeutic options, including surgical resection and/or radiotherapy, can be associated with significant complications. Hence, it is important to consider disorders that could present in a similar manner to pituitary adenomas, for which surgery is not the indicated therapeutic approach. We describe herein a 38-yr-old woman who presented with a pituitary lesion that was considered to be a non-functioning pituitary adenoma. Due to lack of hormonal deficits and/or compression of adjacent structures, we opted for conservative management and followup with consecutive magnetic resonance imaging. Fifteen months after initial diagnosis, considerable enlargement of the lesion was noted, extending mainly superiorly and indenting the optic chiasm. Repeated endocrine investigation revealed partial anterior pituitary insufficiency. The patient underwent trans-sphenoidal resection of the pituitary lesion; histology revealed a null cell pituitary adenoma and lymphocytic hypophysitis (LYH) of the non-neoplastic adenohypophysial gland. Post-operatively, complete anterior and partial posterior pituitary insufficiency developed. This case illustrates the effects of new-onset LYH in a patient with a pre-existing non-functioning pituitary adenoma. Being aware of this rare possibility is important, as enlargement of the pituitary lesion may not be caused by expansion of the preexisting tumor, but by the onset of LYH of the nonneoplastic pituitary tissue.

Effects of thyroxine withdrawal in biochemical parameters and cardiac function and structure in patients with differentiated thyroid cancer.

AIM: Patients with differentiated thyroid carcinoma (DTC) are closely monitored during the first decade after diagnosis. At intervals of 1-2 years withdrawal of suppressive doses of T(4) is recommended in order to check thyroglobulin (Tg) levels under increased TSH. T(4) therapy is usually withdrawn for 5 weeks (during the first 3 weeks patients receive treatment with T(3) instead of T(4), and the last 2 weeks stop all medication). There are a few reported studies looking into the effects of T(4) withdrawal in athyreotic patients in terms of biochemical parameters and ultrasound indices. We studied patients with DTC at two time points: during suppressive T(4) treatment and at the end of the T(4) withdrawal protocol in order to identify acute changes that become apparent after 5 weeks of treatment modification. METHODS: Hormonal and biochemical parameters were measured as well as ultrasound indices of cardiac function and structure. RESULTS: Statistically significant increases were found in total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol and triglycerides with T(4) withdrawal. Creatine phosphokinase showed a striking increase with treatment withdrawal. In addition, liver enzymes, total protein and albumin concentrations increased. Creatinine levels increased significantly and sodium decreased on stopping T(4) treatment. The ultrasound indices of cardiac function and structure did not show significant changes. CONCLUSIONS: Acute hypothyroidism following T(4) withdrawal in DTC patients leads to important biochemical changes without significant alterations in cardiac function and structure. These changes may adversely affect patients, especially older patients or those with other chronic diseases.

Somatostatin receptor expression in vivo and response to somatostatin analog therapy with or without other antineoplastic treatments in advanced medullary thyroid carcinoma.

The long-term treatment of metastatic medullary thyroid carcinoma (MTC) with somatostatin (SST) analogs was evaluated in 22 patients with persistant or relapsed disease and with in vivo positive SST receptor (SSTR) tumors. After surgical intervention all patients but one, initially or at a later time, had persistenly (15) or after relapse (7) elevated serum calcitonin (CT, 252-69482 pg/ml) and carcinoembryonic antigen (CEA, 8-1130 ng/ml) concentrations; also, all of them showed positive uptake in 111In-pentetreotide scanning. Daily doses of 0.4-1.0 mg octreotide subcutaneously, or monthly doses of 20-30 mg long-acting octreotide (LAR) intramuscularly for 3-21 months were administered. Systemic chemotherapy (Ch) with or without external radiotherapy (eRT) was given to 13 patients simultaneously. A beneficial effect on pre-existing diarrhea was observed in 8 patients (subjective partial remmission, sPR 36.4%); 10 other patients showed stable disease, while in 4 a worsening of pre-existing diarrhea was observed. CT and CEA concentrations decreased more than 25% in 4 out of 22 patients (18%) and 11 patients showed a decrease of less than 25% (biological SD). No objective response in tumour growth was demonstrated. Patients (10 survivors in group B) treated with Ch+eRT plus Octerotide showed higher sR (92.5%), lower mortality (23.1%), longer mean time to death (130 months) and longer mean total survival (mts) time (145 months) in comparison to group A patients who had 66.7% sR, 33.3% mortality, only 88.5 months mean time to death and 101 months mts-time. Long-term octreotide and octreotide-LAR treatment offers a subjective and biological partial remission in one third and in one fourth of the MTC patients respectively, but it does not improve the natural course of the tumor. It remains to be answered if these drugs, combined with other antineoplastic therapies, have a synergistic effect relating to treatment response and to patient survival and mortality.

Hypopituitarsim is associated with triglyceride enrichment of very low-density lipoprotein.

The dyslipidemia associated with hypopituitarism may contribute to increased vascular mortality. The atherogenic potential of lipoproteins is determined not only by concentration but also by their composition. We therefore studied very low-density lipoprotein composition and apolipoprotein B kinetics in 16 hypopituitary subjects and 16 controls. Hypopituitarism was associated with reduced high-density lipoprotein cholesterol (0.98[0.82-1.18] vs. 1.35[1.15-1.41] mmol/liter, P < 0.001) and increased triglyceride concentrations (1.64[1.09-2.77] vs. 1.12[0.66-1.67] mmol/liter, P = 0.01). Total (P = 0.76) and low-density lipoprotein cholesterol (P = 0.56) concentrations were similar. Very low-density lipoprotein- triglyceride was significantly increased (1.48[1.02-2.55] vs. 0.9[0.31-2.30] mmol/liter, P = 0.004), but very low-density lipoprotein cholesterol levels were similar (P = 0.93). The molar ratios of very low-density lipoprotein-triglyceride:apolipoprotein B (6193[4283-9566] vs. 3599[3188-6854], P = 0.005) and very low-density lipoprotein-triglyceride:cholesterol (2.8[1.98-3.78] vs. 1.6[1.44-2.80], P < 0.003) were significantly increased; very low-density lipoprotein-cholesterol:apolipoprotein B molar ratios (P = 0.93) were similar. Very low-density lipoprotein apolipoprotein B fractional synthetic rate (a measure of apolipoprotein B catabolism, P = 0.42) and pool size (P = 0.63) were similar. The very low-density lipoprotein apolipoprotein B absolute synthetic rate (a measure of apolipoprotein B synthesis) tended to be higher in hypopituitarism (17.7[2.91-19.50] vs. 26.6[19.64-28.05] mg/kg per day, P = 0.24) but failed to reach statistical significance. The absolute synthetic rate, and hence very low-density lipoprotein production, correlated with very low-density lipoprotein triglyceride:apolipoprotein B ratio (P = 0.02, Rs = 0.63), suggesting that triglyceride enrichment of very low-density lipoprotein is important in the mechanism underlying very low-density lipoprotein overproduction in hypopituitarism. Because triglyceride-enriched lipoproteins are proatherogenic, this may contribute to the vascular mortality observed in hypopituitarism. The reasons for these observations are unknown; GH deficiency or routine endocrine replacement may be important.

Effects of 7 years of growth hormone replacement therapy in hypopituitary adults.

Short-term studies of GH replacement in adult hypopituitarism have usually demonstrated beneficial effects on body composition and circulating lipids, with neutral or occasionally adverse effects on glucose tolerance. Fasting hyperinsulinemia has been reported. GH effects on cardiac function have been variable. The effects of long-term GH therapy, taking into account the consequences of increasing age, are not fully known. Thirty-three hypopituitary, initially middle-aged adults were studied over a 7-yr period; 12 patients took GH therapy (mean, 0.7 mg daily) continuously (group A); 11 took GH for only 6-18 months, a minimum of 5 yr previously (group B); and 10 patients never received GH therapy (group C). Other pituitary replacement was maintained. Effects on anthropometry, body composition (by bioimpedance analysis, total body potassium, and dual energy x-ray absorptiometry), circulating lipids, glucose and insulin concentrations, cardiac 2-dimensional and Doppler echocardiography, and exercise tolerance were assessed before and after the treatment period. Continuous GH therapy had no significant effect on body weight, but it prevented the increase in waist circumference and waist to hip ratio that occurred in the patients without GH substitution (waist to hip ratio, group A, 0.87+/-0.08 at baseline, 0.85+/-0.09 at 7 yr; group B, 0.89+/-0.11 at baseline, 0.94+/-0.11 at 7 yr; P < 0.005 for GH effect; group C, 0.87+/-0.10 at baseline, 0.92+/-0.10 at 7 yr; P < 0.005 for GH effect). A GH-induced decrease in subscapular skinfold thickness was also observed. By bioimpedance analysis, GH therapy caused an increase in total body water and fat-free mass, and a decrease in the percent body fat. Although changes occurred with time in all groups, no significant additional GH therapy effects were observed on glucose tolerance, insulin concentrations, lipid levels, cardiac dimensions, echocardiographic diastolic function, or exercise tolerance. In conclusion, prolonged GH substitution in middle-aged hypopituitary adults causes a sustained improvement in body composition. Other benefits, e.g. on lipid levels and exercise tolerance, were not apparent at 7 yr when comparisons were made with GH-untreated hypopituitary controls. Potentially adverse effects on glucose tolerance and insulinemia did not develop with prolonged GH therapy.

Effects of growth hormone treatment on very-low density lipoprotein apolipoprotein B100 turnover in adult hypopituitarism.

Adult hypopituitarism is associated with hyperlipidemia, mainly due to an increase of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels. Recent studies have shown that such patients exhibit increased hepatic secretion of VLDL apolipoprotein B100 (VLDL apo B100). To examine the effects of growth hormone (GH) replacement on VLDL apo B100 turnover, 13 GH-deficient hypopituitary patients (8 women and 5 men; aged 47 +/- 3 years, mean +/- SEM; body mass index [BMI], 30 +/- 2 kg/m2) entered a double-blind placebo-controlled study for 6 months (GH 0.125 IU/kg/wk for 4 weeks, and then 0.25 IU/kg/wk). GH was subsequently used in all patients for a further 6 months. A 6-hour [1-13C] leucine infusion was administered at baseline and at 6 months. The secretion rate of VLDL apo B100 was derived by kinetic analysis following quantitation of isotopic enrichment by gas chromatography/mass spectrometry. The GH-treated group (6 patients) demonstrated a similar fractional secretion rate (FSR) for VLDL apo B100 at 0 and 6 months. The pool size and absolute secretion rate (ASR) also were unaffected significantly by GH therapy. No significant changes were observed in the placebo group (7 patients). Treatment with GH for 6 months caused an increase in the high-density lipoprotein (HDL) cholesterol concentration (13 patients, 1.27 +/- 0.13 v 1.16 +/- 0.10 mmol/L, respectively, P = .05), whereas total cholesterol and triglyceride concentrations did not change. Nonesterified fatty acids (NEFAs) increased during GH therapy (471 +/- 43 micromol/L at 6 months v 349 +/- 49 micromol/L at baseline, P < .0005). The data suggest that GH does not affect VLDL apo B100 turnover in a significant way.

The effects of growth hormone replacement therapy on overnight metabolic fuels in hypopituitary patients.

OBJECTIVE: Hypopituitary adults on conventional replacement have low concentrations of metabolic fuels throughout the night, possibly related to GH deficiency or to decreased cortisol levels overnight. We investigated whether GH replacement corrects the overnight fuel deficiency. DESIGN: We measured circulating levels of metabolic fuels: glucose, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate (3-OHB) and insulin concentrations over 24 h (from 0730 h to 0700 h) in hypopituitary adults before and after GH treatment in a randomized double-blind placebo-controlled trial of 3 months' duration. PATIENTS: Thirteen hypopituitary patients, 8 women and 5 men, were studied. RESULTS: Six patients (4 women and 2 men) received GH and 7 patients (4 women and 3 men) were allocated to receive placebo. There was no difference in fasting (0730 h), area under the curve (AUC) between 2400 h and 0700 h (overnight) and AUC over 24 h for plasma glucose, 3-OHB, glycerol and insulin concentrations as a result of GH treatment. Fasting and overnight AUC for NEFA were significantly higher on GH treatment ((mean +/- SEM) 243 +/- 29 vs. 446 +/- 90 micromol/l, P = 0.03, 1522 +/- 208 vs. 2167 +/- 123 micromol/l H, P = 0.046, respectively), but AUC over 24 h was not affected significantly. No significant changes in any fuel were seen in the placebo group. The changes in fasting, overnight and 24 h AUC for glucose, 3-OHB, glycerol and insulin levels with GH and with placebo for 3 months were similar. The changes in fasting and overnight AUC for NEFA before and after 3 months were significantly different in the group treated with GH vs. the group treated with placebo (median (lower-upper quartile) 104 (90-276) vs. -89 (-98 to 26) micromol/l, P = 0.002; 633 (263-967) vs. -895 (-1379 to -494) micromol/l h, P = 0.002, respectively), but the changes in 24-h AUC for NEFA were not significant between the two groups. CONCLUSIONS: GH replacement in hypopituitary adults increases fasting and overnight (between 2400 h and 0700 h) non-esterified fatty acid concentrations, consistent with the known lipolytic effect of GH. GH did not influence the concentrations of other metabolic fuels or insulin.

Long-term effects of growth hormone therapy on intermediary metabolism and insulin sensitivity in hypopituitary adults.

Experience with growth hormone (GH) therapy in adult hypopituitarism has been gained for more than 10 years. Most of the data on GH therapy derive from studies with a duration of 2 years or less, but longer term information is required if patients are to be treated with GH replacement therapy for many years. We have studied patients after 4 years of treatment. At the end of this time, body mass index was unchanged but short-term benefits in body composition (decreased percentage body fat and increased fat-free mass) which had been evident at 2 years were still apparent. Fasting plasma glucose and the plasma glucose area under the curve during an oral glucose tolerance test were similar before and after 4 years of therapy, although fasting insulin levels were increased in comparison with baseline. Total cholesterol and low density lipoprotein cholesterol concentrations were lower at 4 years than at the outset but high density lipoprotein cholesterol and triglyceride levels were unchanged. The available evidence therefore suggests that concerns regarding glucose intolerance in patients receiving long-term GH therapy have not been substantiated. The beneficial effects on body composition, and on total and low density lipoprotein cholesterol levels, persisted over the 4 years of study.

Very-low-density lipoprotein apolipoprotein B100 kinetics in adult hypopituitarism.

Hypopituitarism is associated with hyperlipidemia, the mechanisms of which are not fully known. One possible mechanism is an increased hepatic secretion of very-low-density lipoprotein (VLDL) apolipoprotein B100 (apo B100). To investigate this, 13 hypopituitary patients (seven women and six men; age, 46 +/- 3 years [mean +/- SEM]; body mass index [BMI], 29 +/- 2 kg/m2) and 13 matched controls (seven women and six men; age, 43 +/- 3 years; BMI, 28 +/- 2 kg/m2) were investigated in a stable-isotope study. [1-(13)C]leucine (1 mg/kg body weight) was administered, followed by a continuous 6-hour infusion of [1-(13)C]leucine (at a rate of 1 mg/kg/h). Patients had a similar fractional secretion rate (FSR) of VLDL apo B100 versus controls (0.37 +/- 0.05 v 0.38 +/- 0.06 pools/h, respectively), but they had a significantly larger pool size (3.4 +/- 0.3 v 1.9 +/- 0.3 mg/kg) and higher absolute secretion rate ([ASR] 27.8 +/- 2.9 v 16.0 +/- 2.5 mg/kg/d). The increase in hepatic VLDL production may explain the lipid abnormalities found in hypopituitarism. Fasting circulating nonesterified fatty acids (NEFAs) were decreased in the patients (284 +/- 26 v 664 +/- 92 micromol/L, P < .001) despite the increase in VLDL secretion. An inverse relationship was observed between the NEFA level and VLDL apo B100 FSR in the patients (r(s) = -.85, P < .005).

The circadian rhythm of leptin is preserved in growth hormone deficient hypopituitary adults.

OBJECTIVE: Leptin acts as a satiety factor in regulating food intake and body homeostasis, but its regulation is not well defined. Specific leptin receptors have been found in the brain and it has been hypothesized that leptin production by adipose tissue is under neuroendocrine control. A circadian rhythm has been demonstrated with highest leptin levels between midnight and early morning hours. The possibility that hypopituitarism (or pituitary surgery +/- radiotherapy) abolishes this leptin rhythm was investigated by measuring serum leptin levels during a 24-h period in patients with impaired pituitary function. PATIENTS AND DESIGN: Circulating leptin levels were measured hourly over 24-h in 14 hypopituitary patients (8 women and 6 men) using a sensitive and specific radioimmunoassay. Hypopituitarism was the consequence of pituitary tumors treated surgically and/or with radiotherapy. All patients were GH deficient and were receiving conventional replacement with cortisol (n = 13), thyroxine (n = 12) and desmopressin (n = 4) but not with GH. RESULTS: A significant diurnal variation in circulating leptin concentrations was observed in 13 of the 14 patients. The mean (+/- SEM) leptin levels for 8 women were 51.9 (+/- 10.7) ng/ml and for 6 men 11.0 (+/- 2.0) micrograms/l. The overall lowest leptin levels (29.3 +/- 7.9 ng/ml) were observed at 0830 h after overnight fasting, rising gradually to maximum levels (43.0 +/- 9.8 ng/ml) at 0200 h declining thereafter towards fasting values. The mean (+/- SEM) magnitude of circadian variation in absolute leptin levels from the calculated mean level for each patient was 5.6 (+/- 1.2) ng/ml (8.4 +/- 1.4 for women and 1.9 +/- 0.3 for men). The mean (+/- SEM) of the ratio of the amplitude versus mean leptin levels over 24 h for each individual patient was 0.18 (+/- 0.02) (0.19 +/- 0.03 for women and 0.18 +/- 0.02 for men). CONCLUSIONS: A circadian rhythm for leptin is generally present in hypopituitary patients who had undergone pituitary surgery and/or radiotherapy, with the highest serum leptin levels being obtained between midnight and early morning hours. Although some patients had some residual pituitary activity, intact hypothalamic-pituitary function is not essential for leptin's circadian rhythm.

How much, and by what mechanisms, does growth hormone replacement improve the quality of life in GH-deficient adults?

The majority of studies (but not all) have demonstrated that adults with hypopituitarism of both childhood and adult onset have a diminished quality of life (QOL) in comparison with the normal population. Reductions in physical and mental energy, dissatisfaction with body image and poor memory have been reported most consistently. A specific role for growth hormone (GH) deficiency, as opposed to multiple pituitary hormone deficiency, has been observed for the memory deficit, which extends to both short- and long-term memory. Comparisons with normal siblings have confirmed the reduced QOL, although differences have been small. There is less consensus for a reduction in QOL when hypopituitary subjects are compared with patients with other chronic diseases, with studies supporting (in comparison with diabetics) and refuting (in comparison with patients following mastoid surgery) the reduction in QOL. GH replacement in adults has improved QOL, particularly in the domains of energy level and self-esteem, and memory has improved. The social impact of these changes may be considerable, with patients requiring fewer days' sick leave. A major placebo effect is present, however, and neutral results as well as positive have been reported in placebo-controlled trials. Where a positive effect has been observed, it has been more likely to occur in patients with a low QOL at the outset. It is otherwise impossible to predict at the outset those who will benefit from GH replacement. GH treatment has effects on body composition, exercise capacity, muscle strength, total body water and intermediary metabolism which would be expected to improve QOL. Replacement therapy also has side-effects, and it is the variable balance of the positive and negative effects, coupled with the difficulties of measuring QOL, which have led to the disparate results in the literature. There is probably also a true inter-individual variation, although the mechanisms of this are currently unknown.