Hypopituitary Subjects Research Articles

Sheehan syndrome: Cardiovascular and metabolic comorbidities.

Sheehan syndrome (SS) caused by postpartum hemorrhage leads to partial or complete pituitary hormone deficiency. In addition to lipid and glucose abnormalities, patients with SS have increased body fat, insulin resistance (IR), coagulation abnormalities, increased leptin concentration, low-grade inflammation, and endothelial dysfunction that predispose them to cardiovascular diseases. Untreated growth hormone (GH) deficiency, hypogonadism, and excess glucocorticoid use are considered risk factors for these abnormalities. Compared to other hypopituitary subjects, patients with SS are younger and have a longer duration of disease and severe GH deficiency. Replacement with GH in addition to standard hormone replacement improves their cardiometabolic profile.

Growth Hormone Cut-Off Post Glucagon Stimulation Test in an Indian Cohort of Overweight/Obese Hypopituitary Patients for the Diagnosis of Adult Growth Hormone Deficiency.

Obesity has been associated with reduced growth hormone (GH) secretion, which might lead to the over diagnosis of adult GH deficiency (GHD) in overweight (OW)/obese hypopituitary patients. Currently, there are no body mass index (BMI)-specific peak GH cut-offs for the glucagon stimulation test (GST) for assessing adult GHD in India, given the BMI cut-offs vary for Asians. The study's main objective was to determine a peak GH cut-off level for the diagnosis of adult GHD in overweight (OW)/obese individuals utilizing the GST. Forty OW/obese subjects were studied in two groups of 20 each. The first group included 20 OW/obese hypopituitary adults and the second group included 20 control subjects. The intervention consisted of a 3 h GST. The main outcome measured was the peak GH level on GST. The mean age of control subjects was lower (33.15 ± 7.67 v/s. 42.10 ± 13.70 years; P = 0.017) in comparison with hypopituitary adults. The mean BMI (27.93 ± 1.63 v/s. 25.81 ± 1.66 kg/m2; P < 0.001), mean IGF1 (272.81 ± 38.57 v/s. 163.75 ± 42.42; P < 0.001, and mean HOMA IR (11.8 ± 9.7 v/s. 6.02 ± 3.14; P = 0.02) was greater in OW/obese controls. The mean GH peak was significantly higher in control subjects (5.41 ± 3.59 ng/mL v/s. 1.49 ± 1.25 ng/mL; P < 0.001) compared to hypopituitary subjects. ROC curve analysis demonstrated a GH cut-off of 3.3 ng/mL with a moderate sensitivity of 70% and high specificity of 95%, with an AUC of 0.838 (P < 0.001; 95% confidence interval [CI] of 0.710-0.965) for the diagnosis of GHD in overweight/obese hypopituitary adults. This study demonstrates that a cut-off of 3.3 ng/mL would diagnose GHD in Indian overweight/obese hypopituitary adults.

Ghrelin Does Not Directly Stimulate Secretion of Glucagon-like Peptide-1.

The gastrointestinal hormone ghrelin stimulates growth hormone secretion and appetite, but recent studies indicate that ghrelin also stimulates the secretion of the appetite-inhibiting and insulinotropic hormone glucagon-like peptide-1 (GLP-1). To investigate the putative effect of ghrelin on GLP-1 secretion in vivo and in vitro. A randomized placebo-controlled crossover study was performed in eight hypopituitary subjects. Ghrelin or saline was infused intravenously (1 pmol/min × kg) after collection of baseline sample (0 min), and blood was subsequently collected at time 30, 60, 90, and 120 minutes. Mouse small intestine was perfused (n = 6) and GLP-1 output from perfused mouse small intestine was investigated in response to vascular ghrelin administration in the presence and absence of a simultaneous luminal glucose stimulus. Ghrelin receptor expression was quantified in human (n = 11) and mouse L-cells (n = 3) by RNA sequencing and RT-qPCR, respectively. Ghrelin did not affect GLP-1 secretion in humans (area under the curve [AUC; 0-120 min]: ghrelin infusion = 1.37 ± 0.05 min × nmol vs. saline infusion = 1.40 ± 0.06 min × nmol [P = 0.63]), but induced peripheral insulin resistance. Likewise, ghrelin did not stimulate GLP-1 secretion from the perfused mouse small intestine model (mean outputs during baseline/ghrelin infusion = 19.3 ± 1.6/25.5 ± 2.0 fmol/min, n = 6, P = 0.16), whereas glucose-dependent insulinotropic polypeptide administration, used as a positive control, doubled GLP-1 secretion (P < 0.001). Intraluminal glucose increased GLP-1 secretion by 4-fold (P < 0.001), which was not potentiated by ghrelin. Finally, gene expression of the ghrelin receptor was undetectable in mouse L-cells and marginal in human L-cells. Ghrelin does not interact directly with the L-cell and does not directly affect GLP-1 secretion.

Oxytocin alterations and neurocognitive domains in patients with hypopituitarism.

Oxytocin is a hypothalamus derived, posterior pituitary stored nonapeptide which has gained recent interest as an important neuropsychiatric and metabolic hormone beyond its classic role in lactation and parturition. Hypopituitarism is a heterogenous disorder of derangement in one or more anterior or posterior pituitary hormones. Diagnosis of deficiency and hormone replacement exists to address all relevant axes except for oxytocin. Our study aims to define derangements in oxytocin in a unique population of patients with hypopituitarism and correlate levels with measures of emotional health and quality of life. A cross-sectional, single day study was completed to measure plasma oxytocin levels in a diverse population of patients with hypopituitarism compared to controls. Subjects also completed depression, quality of life and stress-related questionnaires, and emotion recognition tasks. Thirty-eight subjects completed the study, 18 with hypopituitarism (9 with diabetes insipidus) and 20 controls. After controlling for differences in age, weight and gender, plasma oxytocin levels were highest in subjects with diabetes insipidus compared to control [mean, IQR: 44.3pg/ml (29.8-78.2) vs. 20.6 (17-31.3), p = 0.032]. Amongst hypopituitary subjects, those with duration of disease greater than 1year had higher oxytocin levels. No significant differences were observed for psychosocial measures including emotion recognition tasks. Plasma oxytocin levels were found higher in patients with hypopituitarism compared to controls and highest in those with diabetes insipidus. Longer duration of hypopituitarism was also associated with higher plasma levels of oxytocin. Further study is needed to better define oxytocin deficiency and investigate response to treatment.

Low-dose hydrocortisone replacement is associated with improved arterial stiffness index and blood pressure dynamics in severely adrenocorticotrophin-deficient hypopituitary male patients.

Increased cardiovascular and cerebrovascular morbidity and mortality in hypopituitary subjects may be linked to inappropriate glucocorticoid exposure; however, the pathophysiology remains unclear. We aimed to examine the effect of three commonly prescribed hydrocortisone (HC) regimens on vascular risk factors. An open crossover study randomising ten hypopituitary men with severe adrenocorticotrophic hormone deficiency to three HC dose regimens: dose A (20mg mane and 10mg tarde), dose B (10mg mane and 10mg tarde) and dose C (10mg mane and 5mg tarde). Following 6 weeks on each regimen, participants underwent 24-h serum cortisol sampling, 24-h ambulatory blood pressure (BP) measurements, calculation of the Ambulatory Arterial Stiffness Index (AASI), oral glucose tolerance testing and fasting serum osteoprotegerin (OPG) sampling. There were no differences in 24-h BP between dose regimens and controls; however, low-dose HC replacement (dose C) was associated with the lowest AASI, indicating a less stiff arterial tree (P<0.05) compared with the other dose regimens. Loss of the physiologic nocturnal BP dip was more common in higher HC replacement regimens, although only significant for dose B compared with dose C (P=0.03). Twenty per cent of patients had abnormal glucose tolerance, but this was unrelated to dose regimen. OPG correlated strongly with 24-h BP in those on dose A only (r=0.65, P=0.04). Currently prescribed HC replacement doses do not result in significant differences in absolute BP levels or improvements in insulin sensitivity. However, lower HC doses may result in lower arterial stiffness and a more physiological nocturnal BP dip. Long-term studies are required to confirm these findings and evaluate their impact on vascular morbidity in this patient group.

Effects of GH replacement therapy on thyroid volume and nodule development in GH deficient adults: a retrospective cohort study.

Despite the well-known effects of GH/IGF1 signaling on the thyroid, few data are available on the risk of developing nodular goiter in hypopituitary subjects during GH replacement therapy (GHRT). We aimed to define the effects of GH therapy on thyroid volume (TV) and nodular growth. The records of 96 subjects (47 males and 49 females, median age 48 years) with GH deficit (GHD) were investigated. Seventy also had central hypothyroidism (CH). At the time of our retrospective evaluation, median treatment duration was 5 years. Pre-treatment TV was smaller in GHD patients than in healthy subjects (P=0.030). During GH treatment, TV significantly increased (P=0.016 for the entire group and P=0.014 in euthyroid GHD patients). Before starting GH therapy, 17 patients harbored thyroid nodules. During GH therapy, nodule size increased slightly in seven patients, and new thyroid nodules occurred in nine patients. Among the 79 patients without pre-existing thyroid nodules, 17 developed one or more nodules. There was no difference in the prevalence of CH in GHD patients with or without thyroid nodules (P=0.915; P=0.841, when patients with pre-therapy nodular goiter were excluded), the main predictor for nodule development being serum IGF1 (P=0.038). GHRT is associated with TV's increase in GHD patients. Thyroid nodules developed in 27% of patients, mainly in relation to pre-therapy IGF1 levels, independently of normal or impaired TSH stimulation.

The diagnosis of GH deficiency in obese patients: a reappraisal with GHRH plus arginine testing after pharmacological blockade of lipolysis

The diagnosis of GH deficiency (GHD) in obese patients is complicated by the reduced GH secretion associated with overweight. A GH response to GHRH+arginine lower than 4.2 microg/l is currently considered indicative of GHD in obesity. The aim of the study was to investigate the effect of acute pharmacological blockade of lipolysis on the GH response to GHRH+arginine in obese patients. Two groups of patients were studied: 12 obese patients with proven GHD and 14 patients with essential obesity. On separate occasions, two tests were carried out in each patient: GHRH+arginine and GHRH+arginine preceded by acipimox. The mean GH peak after GHRH+arginine was significantly lower in hypopituitary patients than in subjects with essential obesity. Acipimox significantly increased the mean GH response in patients with essential obesity, but not in hypopituitary subjects. All hypopituitary patients and 7/14 patients with essential obesity displayed GH peaks lower than 4.2 microg/l after GHRH+arginine: the GH response to the test increased after acipimox pretreatment in five of these seven essentially obese subjects. After acipimox administration, free fatty acids (FFAs) significantly fell in both groups with comparable mean absolute decreases. All IGF1 values were normal in both groups of subjects. Our study has demonstrated that the acipimox-induced acute reduction of circulating FFA levels increases mean somatotropin response to GHRH+arginine in patients with essential obesity, whereas it has no effect in hypopituitary subjects. The current criterion for the diagnosis of GHD in obese patients may be misleading. Indeed, subjects affected by third degree obesity, like most of our patients, may be erroneously classified as really GH-deficient and started on an expensive unjustified treatment. It appears therefore that the current criteria for the diagnosis of GHD in obesity should be reconsidered in the light of further studies also taking into account different body mass index groups.

High Prevalence of Abnormal Circadian Blood Pressure Regulation and Impaired Glucose Tolerance in Adults with Hypopituitarism

Patients with hypopituitarism have an increased mortality from cardiovascular events. Reduced nocturnal blood pressure decline (non-dipping) and impaired glucose tolerance are considered as cardiovascular risk factors. To evaluate the role of these risk factors in patients with hypopituitarism we determined the 24-hour blood pressure regulation and glucose tolerance status in hypopituitary patients with and without growth hormone (GH) deficiency. Sixty-one hypopituitary subjects 5 +/- 3 years after brain surgery because of macroadenoma, 61 patients with type 2 diabetes mellitus (T2DM), and 20 healthy controls were included. Forty-four hypopituitary patients were GH deficient and 28 of these on GH treatment. Non-dipping was observed in 41 % (n = 7) of hypopituitary subjects with normal GH release, in 46 % (n = 13) of patients on GH therapy, and in 69 % (n = 11) of untreated GH deficient patients. Untreated GH deficient patients had a higher systolic night/day ratio (1.00 +/- 0.03) compared to non GH deficient (0.92 +/- 0.02; p < 0.02) and GH treated hypopituitary patients (0.93 +/- 0.01; p < 0.02). The rate of non-dipping in hypopituitarism was comparable to that in T2DM. Pathologic glucose tolerance was diagnosed in 30 % of the hypopituitary patients. The prevalence of non-dipping was independent of glucose metabolism in hypopituitary patients. All controls had normal night time blood pressure fall and glucose metabolism. The high prevalence of nocturnal non-dipping and glucose intolerance detected in this cohort might contribute to the increased cardiovascular risk of hypopituitary patients.

Endothelial Function and Coagulant Factors in Growth Hormone-Treated Hypopituitary Adults Receiving Desmopressin

Although GH deficiency may underlie the increased cardiovascular risk in adult hypopituitarism, other coexisting hormonal deficiencies and/or unphysiological hormone replacement may contribute. L-Deamino-8-D-arginine (DDAVP), when administered parenterally, potentiates hemostasis by increasing plasma procoagulant factors. We investigated whether chronic intranasal DDAVP therapy influences clotting factors (plasma fibrinogen, factor VIII, and von Willebrand factor antigen) and endothelial function (flow-mediated dilation of the brachial artery) in 30 GH-treated hypopituitary subjects, including both DDAVP-treated subjects (group A) (mean age, 46 +/- 11 yr) and vasopressin-sufficient subjects (group B) (mean age, 47 +/- 16 yr). Fifteen healthy controls (group C) (mean age, 48 +/- 12 yr) were also studied. All hypopituitary patients were receiving stable GH replacement (median duration, 19 months). Comparing the three groups, concentrations of fibrinogen (mean +/- SD) (A, 3.3 +/- 1.0 g/liter vs. B, 3.5 +/- 0.9 vs. C, 2.6 +/- 0.8, P < 0.05), factor VIII (A, 130% +/- 30% vs. B, 128% +/- 30% vs. C, 104% +/- 35%, P < 0.05) and von Willebrand factor antigen (A, 124% +/- 35% vs. B, 134% +/- 45% vs. C, 93% +/- 36%, P < 0.05) were higher in hypopituitary subjects, compared with controls. However, there were no differences in clotting factors between groups A and B. Flow-mediated dilation did not differ significantly between the two hypopituitary groups (A, 5.9% +/- 2.0% vs. B, 4.7% +/- 1.6%) and was similar to that in the control group (C, 5.7% +/- 2.1%). In conclusion, although endothelium-dependent vasodilation is intact in GH-treated hypopituitary adults, elevated concentrations of hemostatic markers suggest the persistence of a prothrombotic tendency and endothelial dysfunction. Intranasal DDAVP does not appear to influence this proatherogenic profile in hypopituitary adults with vasopressin deficiency.

Effects of short- and long-term growth hormone replacement on lipoprotein composition and on very–low-density lipoprotein and low-density lipoprotein apolipoprotein B100 kinetics in growth hormone–deficient hypopituitary subjects

In this study, we concurrently examined the effects of 8 and 40 weeks of growth hormone replacement (GHR) on lipids, lipoprotein composition, low-density lipoprotein (LDL) size, very–low-density lipoprotein (VLDL) apolipoprotein (apo)B kinetics and LDL apoB kinetics. Eight weeks of GHR did not alter lipid profiles. Forty weeks of GHR increased high-density lipoprotein-cholesterol (HDL-C) concentration (P =.01), nonsignificantly reduced LDL-C (P =.06), and reduced the HDL/LDL-C ratio (P =.04). Forty weeks of GHR increased HDL free cholesterol (P =.03), total cholesterol (P =.01), and cholesterol ester (P <.01) concentrations. No other significant changes in VLDL, LDL, or HDL composition or LDL size were noted at any time. Eight weeks of GHR reduced VLDL apoB absolute secretion rate (ASR, P =.03), with nonsignificant reductions in fractional secretion rate (FSR, P =.09) and pool size (P =.09). After 40 weeks of GHR, the VLDL apoB ASR, FSR, and pool size were not significantly different from baseline. Forty weeks of GHR increased both LDL apoB FSR (P =.02) and LDL apoB ASR (P =.04), with a small decrease in pool size. Thus, GHR may have important antiatherogenic effects; HDL-C increased, LDL-C was nonsignificantly reduced, the total/HDL-C ratio was reduced, VLDL apoB production was reduced, and LDL apoB turnover was increased. Copyright 2003, Elsevier Science (USA). All rights reserved.

Pulsatile, nyctohemeral and entropic characteristics of GH secretion in adult GH‐deficient patients: selectively decreased pulsatile release and increased secretory disorderliness with preservation of diurnal timing and gender distinctions

The present clinical investigation uses a high-precision GH immunofluorometric assay to examine the postulate that principally the amplitude mode of GH secretory control is disrupted in adults with GH deficiency. To this end, we investigated GH secretory dynamics in a cohort of 19 adult GH-deficient (GHD) patients and 19 age-, gender- and body mass index-matched controls. GHD was established by blunted (< 7 mU/l) GH release during insulin-induced hypoglycaemia. Twenty-four-hour serum GH concentration profiles obtained by 10-min sampling were analysed by deconvolution, cosinor analysis and approximate entropy to appraise pulsatile, diurnally rhythmic, and pattern-dependent GH secretion, respectively. Deconvolution analysis revealed that pulsatile GH release was decreased by threefold, due to amplitude-specific damping, detectable GH secretory burst frequency was paradoxically increased by twofold, but basal non-pulsatile GH release was fully preserved. GH half-life in patients and controls was similar, thus excluding major kinetic differences. The acrophase (time of maximum) of the 24-h GH rhythm was unchanged. The regularity of the GH release process, as measured by ApEn, was decreased profoundly in GHD patients (P < 10(-8)). The changes in GH secretion were similar in irradiated and nonirradiated patients. Daily GH secretion was also comparable in male and female GHD patients, but plasma IGF-I concentrations were higher in male than female patients (P = 0.031). Furthermore, the gender-specific GH ApEn difference, evident in controls, was still demonstrable in patients (P = 0.017). The ratio of plasma IGF-I and pulsatile GH production was increased threefold in patients (P = 0.004), pointing to increased sensitivity to GH in GH deficiency and/or non-GH-dependent IGF-I production. The present detailed analyses of daily GH secretory dynamics in patients with (moderate) GH deficiency document an amplitude-specific decrease in pulsatile GH secretion, which is partly compensated for by increased GH pulse frequency. The remarkably disorderly patterns of GH secretion in patients identify other major alterations in GH neuroregulation in such individuals, reflecting withdrawal of expected GH and/or IGF-I repression of pulsatile GH secretion. Preservation of the nyctohemeral timing of GH release and the gender contrast in GH ApEn in GHD patients would also be consistent with partial retention of central neuroregulation and GH/IGF-I feedback-dependent control in hypopituitary subjects.

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.

Sexual dimorphism in 11 beta hydroxysteroid dehydrogenase activity and its relation to fat distribution and insulin sensitivity; a study in hypopituitary subjects.

Sexual dimorphism of 11 beta hydroxysteroid dehydrogenase activity (11 beta HSD) as measured by the urinary 11-OH/11-oxo cortisol metabolite ratio has been documented in healthy subjects. Since body composition, fat distribution and insulin sensitivity vary between the sexes we have investigated whether these factors may account for the observed difference. Studies were performed in ACTH deficient hypopituitary subjects to eliminate the effect of feedback modulation of cortisol secretion. 44 hypopituitary patients, (m:f, 32:12), median age 51 years, median weight 86 kg, on hydrocortisone and other replacement therapy as appropriate were studied. Urine 11-OH/11-oxo cortisol metabolites and serum and urine cortisone (E) and cortisol (F) were measured in relation to total cortisol metabolites and cortisol binding globulin; fat distribution was assessed by Dual Energy X-ray absorptiometry (DXA), and insulin sensitivity by homeostatic model of assessment. Cortisol bioavailability (total urine cortisol metabolites, urine free cortisol and cortisol binding globulin) was similar in both sexes. The 11-OH/11-oxo ratio was lower in females than males (median; 0.99 vs 1.3, P < 0.03) while thyroid status was similar. Females had higher percentage fat (median 47.7 vs 34.9, P < 0.01); total fat (median 39.5 vs 34.9 kg, P < 0.01), android fat (median 9.1 vs 6.6 kg, P < 0.01); gynoid fat (median; 9.9 vs 6.8 kg, P < 0.05) and lower insulin sensitivity (median 15.3 vs 30.6, P < 0.01). In all subjects, the 11-OH/11-oxo ratio was inversely related to body weight (P < 0.01), % fat (P < 0.05), total fat (P < 0.01), android fat (P < 0.01), gynoid fat, (P < 0.01) and directly correlated to insulin sensitivity, P < 0.01. Stepwise regression analysis showed gynoid fat to be the most important factor determining the 11-OH/11-oxo ratio. In 24 subjects (f:m, 8:16) on exogenous sex steroid therapy insulin sensitivity was similar but the sexual dimorphism of the 11-OH/11-oxo ratio remained unchanged (median; 1.0 vs 1.7, P < 0.05). The urine and serum F and E and their ratio (F/E) were similar in these groups. These data confirm the presence of sexual dimorphism in 11 beta-hydroxysteroid dehydrogenase activity in hypopituitary patients as described in normal individuals. This is the first in vivo evidence that this dimorphism is related to body composition. Our findings suggest that sexual dimorphism may be determined by the activity of type 1 and not type 2 11 beta-hydroxysteroid dehydrogenase.

5 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.

Intense sympathetic nerve activity in adults with hypopituitarism and untreated growth hormone deficiency.

Perturbations in the sympathetic nervous system may be anticipated in adults with hypopituitarism and untreated GH deficiency, because the syndrome is associated with both peripheral and central factors known to modulate sympathetic traffic. The higher prevalence of hypertension and increased cardiovascular morbidity/mortality reported in GH-deficient patients may suggest increased activity of the sympathetic nervous system. We recorded muscle sympathetic nerve activity (MSNA) in 10 hypopituitary adults with adequate hormonal replacement therapy except GH and in 10 healthy controls matched for age, gender, and body mass index to test whether hormonal aberrations in hypopituitarism and untreated GH deficiency are associated with an increase in sympathetic nerve traffic. Blood samples for insulin-like growth factor I, free T4, and TSH were taken after an overnight fast, followed by an oral glucose tolerance test. Direct intraneural recordings of MSNA were performed with a tungsten microelectrode from the peroneal nerve. The hypopituitary subjects had markedly increased MSNA (54 +/- 4 bursts/min vs. 34 +/- 4 in controls; P < 0.002), which was not related to abdominal obesity or altered glucose metabolism. When assessed for the whole study group, MSNA was inversely correlated to serum insulin-like growth factor I (r = -0.59; P < 0.006) and TSH (r = -0.46; P < 0.04). MSNA was positively correlated to diastolic blood pressure (r = 0.80; P < 0.0005) in patients, but not in controls. The intense sympathetic discharge is suggested to be of central origin and may be an important underlying mechanism for the secondary hypertension and increased cardiovascular morbidity/mortality in this patient group.

Reperti RM in pazienti con deficit di GH

MR is able to depict anatomic details of the abnormality in hypothalamic-pituitary region. We report the results in 30 prepurbertal, hypopituitary subjects, aged 6 months-14 years. We analyzed: the MR patterns and their distribution in the patients; the prevalence of “birth traumas” in this group; the prognostic value and the ability to relate to clinical and hormonal data of the MR features

Overnight metabolic fuel deficiency in patients treated conventionally for hypopituitarism.

Hormone replacement in hypopituitary adults attempts to reproduce normal physiology. Conventional regimens fail to mimic normal hormone profiles over 24 hours. To investigate the metabolic consequences of conventional hormone replacement in hypopituitary adults by measuring circulating levels of the major fuels, glucose, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate (3-OHB) over 24 hours in hypopituitary subjects and controls. Ten GH and adrenocorticotrophin deficient hypopituitary adults on conventional replacement and 13 controls matched for age, sex and body mass index were studied. The patients received replacement with hydrocortisone twice daily (at 0730 and 1730 h; mean (range) daily dose 22 (10-30) mg/24 h) but not with GH. Other hormones were replaced as clinically necessary. Circulating glucose, NEFA, glycerol and 3-OHB levels were measured over 24 hours together with concentrations of cortisol (total and free), GH and insulin, and urinary free cortisol. Levels of glucose, NEFA and 3-OHB were lower in patients than controls (mean +/- SEM) (4.3 +/- 0.1 vs 5.3 +/- 0.1 mmol/l, P = 0.0001; 291 +/- 46 vs 448 +/- 48 mumol/l, P = 0.015; 78 +/- 8 vs 136 +/- 24 mumol/l, P = 0.035, respectively) before breakfast. This decrease in glucose, NEFA and 3-OHB was observed in the patient group throughout the night, from midnight to breakfast. For NEFA, the decrease persisted throughout the 24 hours. Glycerol did not differ significantly in patients and controls. Integrated levels of total and free plasma cortisol, and 24-hour urine cortisol excretion, were normal in patients but total and free plasma cortisol concentrations overnight were markedly decreased (overnight area under the curve (AUC) of total cortisol: 440 +/- 154 vs 1593 +/- 267 nmol/l h, P = 0.0024; overnight AUC of free cortisol: 24 +/- 8 vs 161 +/- 26 nmol/l h, P = 0.0001). GH levels were low throughout the whole 24 hours in the patient group (24-hour AUC: 10.6 +/- 5.1 vs 74.6 +/- 19.6 mU/l h, P = 0.008). Hypopituitary adults on conventional hormone replacement regimens have low concentrations of metabolic fuels, glucose, non-esterified fatty acids and 3-hydroxybutyrate throughout the night, possibly related to GH deficiency or to decreased overnight circulating cortisol levels. This overnight fuel deficiency may underlie the mechanism for the non-specific symptoms, such as fatigue and headache in the early morning, which are frequent in this group of patients.

Low density lipoprotein particle size in hypopituitary adults receiving conventional hormone replacement therapy.

Adults receiving conventional replacement therapy for hypopituitarism are known to have increased cardiovascular mortality. The aim of this study was to assess the lipid profiles of 30 hypopituitary adults compared with 2 case control groups, 1 matched for age, sex, and body mass index (BMI) and the second matched for age and sex only with a BMI representative of the general population. Fasting lipids, lipoproteins, and apoproteins (Apo) were determined by routine methods. Low density lipoprotein (LDL) particle size was determined by nondenaturing gradient gel electrophoresis. LDL size was significantly smaller in the hypopituitary group (25.9 +/- 0.1 nm) than in the BMI-matched (26.2 +/- 0.1 nm; P < 0.05) and standard control (26.3 +/- 0.1 nm; P < 0.01) groups. High density lipoprotein cholesterol levels in the hypopituitary group were significantly lower than those in the BMI-matched control group (1.13 +/- 0.06 vs. 1.34 +/- 0.06 mmol/L; P < 0.05) and the standard control group (1.38 +/- 0.06 mmol/L; P < 0.005). Apo A1 levels were also lower compared with those in the BMI-matched (122 +/- 6 vs. 137 +/- 4 mg/dL; P < 0.05) and the standard (143 +/- 4 mg/dL; P < 0.005) control groups. There was a trend toward higher triglyceride levels when the hypopituitary subjects were compared with the standard control group [1.4 (95% CI, 1.3-2.2) vs. 1.0 (95% CI, 0.9-1.4) mmol/L; P = 0.06]. These differences were more marked in the female subjects studied. No significant differences were noted in total cholesterol, LDL cholesterol, or Apo B levels. We conclude that hypopituitary patients receiving conventional replacement therapy have an atherogenic lipid profile characterized by small dense LDL, decreased high density lipoprotein cholesterol, and increased triglyceride levels, which may contribute to the excess cardiovascular mortality in this group.

Literature Reviews: Pediatric Endocrinology: The Growth-Hormone-Releasing Activity of Hexarelin, a New Synthetic Hexapeptide, in Short Normal and Obese Children and in Hypopituitary Subjects Loche S, Cambiaso P, Carta D, et al. J Clin Endocrinol Metab. 1995;80:674-678

Literature Reviews: Pediatric Endocrinology: The Growth-Hormone-Releasing Activity of Hexarelin, a New Synthetic Hexapeptide, in Short Normal and Obese Children and in Hypopituitary Subjects Loche S, Cambiaso P, Carta D, et al. J Clin Endocrinol Metab. 1995;80:674-678

Evaluation and application of a highly sensitive assay for serum growth hormone (GH) in the study of adult GH deficiency.

Previous work from our laboratory addressing the diagnosis of GH deficiency in adults showed that RIA measurement of the 24-h integrated GH concentration (IGHC) was unable to discriminate between hypopituitary and age-, sex-, and body mass index-matched normal subjects because of the occurrence of undetectable levels (< 200 ng/L) within both groups. In contrast, full separation was achieved using stimulation by the insulin tolerance test (ITT). The data showed no significant relationship between IGHC and insulin-like growth factor-I (IGF-I) within either group. To determine whether limited sensitivity obscured diagnostic and physiological information, we assessed and modified a commercially available enzyme-linked immunosorbent assay (Elegance GH ELISA, Bioclone Australia) to achieve a high sensitivity (1 ng/L) and applied it to the study of IGHC and the relationship to IGF-I in a study group of 30 normal and 19 subjects with severe organic hypopituitarism. Using this assay, the IGHCs from all subjects were detectable and correlated significantly with detectable values obtained by RIA (n = 24; r = 0.80; P = 0.0001). Mean IGHC in normal subjects was significantly higher than that in hypopituitary subjects (852 +/- 131 vs. 97 +/- 28 ng/L), but the IGHCs from the two groups were not completely separate. Twenty-six percent of hypopituitary subjects had IGHC values within the normal range (111-3454 ng/L). IGHC decreased with age in normal subjects. Age stratification improved the separation, but an overlap remained in the young (< 50 yr old) and old (> 50 yr old) groups. Measurement of 12-h nocturnal IGHC levels improved the separation between hypopituitary and normal subjects in the young subjects only. IGHC was significantly related to IGF-I in hypopituitary (r = 0.59; P = 0.0084) and normal subjects (r = 0.55; P = 0.0017) and in the combined groups (r = 0.64; P = 0.0001). The data show that a sensitive ELISA reliably quantifies IGHC in normal and hypopituitary subjects. IGHCs in hypopituitary patients are lower, but not clearly separated from values in normal counterparts despite their having unequivocally impaired GH responses to ITT. We conclude that 1) IGHC in normal subjects can be reliably defined by sensitive ELISAs; 2) the diagnostic utility of the IGHC does not match the reliability or simplicity of an ITT, and 3) GH is a significant regulator of IGF-I in both normal and reduced states of GH secretion.