Detailed assessment of hypothalamic damage in craniopharyngioma patients with obesity.

BACKGROUND/OBJECTIVES: Hypothalamic obesity (HO) occurs in 50% of patients with the pituitary tumor craniopharyngioma (CP). Attempts have been made to predict the risk of HO based on hypothalamic (HT) damage on magnetic resonance imaging (MRI), but none have included volumetry. We performed qualitative and quantitative volumetric analyses of HT damage. The results were explored in relation to feeding related peptides and body fat. SUBJECTS/METHODS: A cross-sectional study of childhood onset CPs involving 3 Tesla MRI, was performed at median 22 years after first operation; 41 CPs, median age 35 (range: 17-56), of whom 23 had HT damage, were compared to 32 controls. After exclusions, 35 patients and 31 controls remained in the MRI study. Main outcome measures were the relation of metabolic parameters to HT volume and qualitative analyses of HT damage. RESULTS: Metabolic parameters scored persistently very high in vascular risk particularly among HT damaged patients. Patients had smaller HT volumes compared to controls 769 (35-1168) mm3 vs. 879 (775-1086) mm3; P < 0.001. HT volume correlated negatively with fat mass and leptin among CP patients (rs = -0.67; P < .001; rs = -0.53; P = 0.001), and explained 39% of the variation in fat mass. For every 100 mm3 increase in HT volume fat mass decreased by 2.7 kg (95% CI: 1.5-3.9; P < 0.001). Qualitative assessments revealed HT damage in three out of six patients with normal volumetry, but HT damage according to operation records. CONCLUSIONS: A decrease in HT volume was associated with an increase in fat mass and leptin. We present a method with a high inter-rater reliability (0.94) that can be applied by nonradiologists for the assessment of HT damage. The method may be valuable in the risk assessment of diseases involving the HT.

Microstructural white matter alterations and hippocampal volumes are associated with cognitive deficits in craniopharyngioma.

CONTEXT: Patients with craniopharyngioma (CP) and hypothalamic lesions (HL) have cognitive deficits. Which neural pathways are affected is unknown. OBJECTIVE: To determine whether there is a relationship between microstructural white matter (WM) alterations detected with diffusion tensor imaging (DTI) and cognition in adults with childhood-onset CP. DESIGN: A cross-sectional study with a median follow-up time of 22 (6-49) years after operation. SETTING: The South Medical Region of Sweden (2.5 million inhabitants). PARTICIPANTS: Included were 41 patients (24 women, ≥17 years) surgically treated for childhood-onset CP between 1958-2010 and 32 controls with similar age and gender distributions. HL was found in 23 patients. MAIN OUTCOME MEASURES: Subjects performed cognitive tests and magnetic resonance imaging, and images were analyzed using DTI of uncinate fasciculus, fornix, cingulum, hippocampus and hypothalamus as well as hippocampal volumetry. RESULTS: Right uncinate fasciculus was significantly altered (P ≤ 0.01). Microstructural WM alterations in left ventral cingulum were significantly associated with worse performance in visual episodic memory, explaining approximately 50% of the variation. Alterations in dorsal cingulum were associated with worse performance in immediate, delayed recall and recognition, explaining 26-38% of the variation, and with visuospatial ability and executive function, explaining 19-29%. Patients who had smaller hippocampal volume had worse general knowledge (P = 0.028), and microstructural WM alterations in hippocampus were associated with a decline in general knowledge and episodic visual memory. CONCLUSIONS: A structure to function relationship is suggested between microstructural WM alterations in cingulum and in hippocampus with cognitive deficits in CP.

GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults.

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.

Moderate dose cranial radiotherapy causes central adrenal insufficiency in long-term survivors of childhood leukaemia.

Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy. The survival rate in the Scandinavian countries is now around 85 %. ALL patients treated with cranial radiotherapy (CRT) are at risk for growth hormone deficiency (GHD), but little is known about other pituitary insufficiencies, e.g. ACTH. Adult ALL patients (median age at study 25 years), treated with 24 Gy (18-30) of CRT during childhood were investigated. We performed an insulin tolerance test (ITT) to evaluate cortisol secretion. We measured basal serum ACTH and cortisol levels before and after 5 years of GH therapy. 14 out of 37 (38 %) ALL patients had a subnormal cortisol response to an ITT (257-478 nmol/L) while there was no significant difference in basal cortisol levels between 44 patients and controls (P > 0.3). Female, but not male ALL patients had significantly lower ACTH levels compared to controls (P = 0.03). After 5 years of GH therapy only male ALL patients had significantly lowered basal plasma cortisol (P = 0.02). ALL survivors, treated with a moderate dose CRT, have a central adrenal insufficiency 20 years after diagnosis. An increased awareness of the risk for an adrenal insufficiency is of importance and life-long surveillance of the entire hypothalamic-pituitary axis is recommended in these patients.

Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality.

CONTEXT: Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. OBJECTIVE: To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. DESIGN AND METHODS: All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. MAIN OUTCOME MEASURES: Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. RESULTS: An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. CONCLUSION: Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease.

Bone loss after childhood acute lymphoblastic leukaemia: an observational study with and without GH therapy.

OBJECTIVE: Bone mineral density (BMD) in survivors of acute lymphoblastic leukaemia (ALL) seems to vary with time, type of treatments and GH status. We aimed to evaluate BMD in ALL patients with GH deficiency (GHD), with and without GH therapy. DESIGN: Case-control study. METHODS: We examined 44 (21 women) GHD patients (median 25 years) treated with cranial radiotherapy (18-24 Gy) and chemotherapy and matched population controls for BMD with dual-energy X-ray absorptiometry. For 5 and 8 years, two subgroups with (0.5 mg/day) (n=16) and without GH therapy (n=13) and matched controls were followed respectively. RESULTS: At baseline, no significant differences in BMD or Z-scores at femoral neck and L2-L4 were recorded (all P>0.3). After another 8 years with GHD, the Z-scores at femoral neck had significantly decreased compared with baseline (0.0 to -0.5; P<0.03) and became lower at the femoral neck (P=0.05), and at L2-L4 (P<0.03), compared with controls. After 5 years of GH therapy, only female ALL patients had a significantly lower femoral neck Z-scores (P=0.03). The female ALL patients reached an IGF1 level of -0.7 s.d. and male patients reached the level of +0.05 s.d. CONCLUSIONS: On average, 25 years after diagnosis, GH-deficient ALL patients experienced a significant decrease in Z-scores at femoral neck, and if Z-scores continue to decrease, there could be a premature risk for osteoporosis. GH therapy was not shown to have a clear beneficial effect on BMD. Whether higher GH doses, particularly in women, will improve Z-scores needs further investigation.

Physiological restitution after night-call duty in anaesthesiologists: impact on metabolic factors.

BACKGROUND: Several studies have shown impaired mental well-being and performance in physicians work on call, but knowledge of the physiological effects is scarce. The aims of the present study were to investigate if there was a metabolic stress response in the restitutional phase after night-call duty, indicating potential negative health effects, and determine whether there were differences between physician specialities. METHODS: Anaesthesiologists (n = 19) were compared with paediatricians/ear, nose and throat (ENT) surgeons (n = 18). On an ordinary workday, 1 and 3 days after work on night call, blood samples were taken for analysis of glucose, thyroid-stimulating hormone (TSH), free thyroxine, testosterone, insulin growth factor-1 (IGF-1), high- and low-density lipoprotein cholesterol (HDL and LDL), triglycerids (TG) and insulin. Saliva cortisol was sampled on an ordinary working day, a day including 16-h night call, the third day following, and for anaesthesiologists also on a day off work. RESULTS: TSH differed significantly between days in both groups, with a 26% lower level 1 day after on-call duty (P < 0.001). A 48% cortisol rise in the morning preceding night duty was found for paediatricians/ENT surgeons (P < 0.01). CONCLUSION: The significant dip in TSH level 24 h after night-call duty indicates a metabolic effect of working on night call and should be studied further. However, the levels were within the normal range and the overall results do not imply any serious metabolic changes and only minor differences were seen between specialist groups.

Risk for severe hypoglycaemia with unawareness in GH-deficient patients during the insulin tolerance test.

OBJECTIVE: The insulin tolerance test (ITT) has been suggested as the gold standard for diagnosing GH deficiency (GHD). The ITT is, however, potentially hazardous. Glucose monitoring during the ITT varies between centres and there is surprisingly little information on the actual level of blood glucose nadir and the duration of hypoglycaemia in patients undergoing the ITT. The aim of the present study was to closely monitor the blood glucose level and to register the presence of symptoms and signs of hypoglycaemia during the ITT. DESIGN AND PATIENTS: Sixteen patients (seven women), aged 22-59 years were consecutively recruited for an ITT, and showed GHD (peak GH < 3 microg/l). RESULTS: In five (31%) of the patients unawareness of hypoglycaemia was recorded, the median nadir blood glucose level was 1.4 mmol/l (range 1.1-1.9) and the duration of blood glucose < 2.2 mmol/l was 25 min (range 20-33). The remaining 11 patients were symptomatic, and tiredness (n=6) and dizziness (n=3) were the most frequent symptoms. In these symptomatic patients the median nadir blood glucose level was 1.3 mmol/l (range 1.0-1.6) and the duration of blood glucose < 2.2 mmol/l was 25 min (range 15-30). CONCLUSIONS: In patients with GHD subjected to the ITT, symptoms of hypoglycaemia were scarce and a third showed unawareness. Close blood glucose monitoring is recommended at the ITT as low nadir blood glucose levels and long duration of hypoglycaemia may be present irrespective of symptoms of hypoglycaemia. Recommendations for intervention with intravenous glucose, at unacceptable low blood glucose levels or at prolonged hypoglycaemia, are warranted.

The gender differences in growth hormone-binding protein and leptin persist in 80-year-old men and women and is not caused by sex hormones.

OBJECTIVE: Leptin and growth hormone-binding protein (GHBP) both show gender differences that might be explained by sex hormones. To study the potential relevance of oestradiol and testosterone, we have examined 80-year-old subjects in whom oestradiol is higher in men than in women. The interrelationships between leptin, insulin, GHBP and fat mass in this age group were also investigated. DESIGN AND SUBJECTS: Ninety-four subjects (55 females and 39 males), all 80 years old, were investigated in a community-based study. None of the investigated subjects was being treated for diabetes mellitus and none of the women had oestrogen replacement. METHODS: Levels of testosterone, oestradiol, SHBG, IGF-I, GHBP, glucose, insulin and leptin were analysed. Body composition was measured with bioimpedance analysis (BIA). RESULTS: As in younger age groups, serum leptin, the ratio leptin/kilogram fat mass and serum GHBP were higher in the women (all, P< or =0.007), although serum oestradiol was higher in the men (P<0.001). There were no significant associations between sex hormones and leptin or GHBP either in women or in men (all, r<0.13, P>0.1). Leptin correlated to kilogram fat mass in both women (r=0.55, P<0.001) and men (r=0.47, P=0.003), but in contrast, there were no significant correlations between GHBP and fat mass and GHBP and IGF-I, either in women or in men (all, r<0.24, P>0.2). Insulin and leptin were significantly associated with GHBP, both in women (r=0.48, P<0.001 and r=0.43, P=0.001, respectively) and in men (r=0.40, P=0.01 and r=0.34, P=0.03, respectively). CONCLUSIONS: Although the 80-year-old men had higher oestradiol levels than the women, the women had higher levels of leptin and GHBP. There were no correlations between sex hormones and leptin and GHBP, which indicates that the gender differences are not caused by sex hormones in old age. In contrast to studies in younger subjects, GHBP did not correlate to fat mass in the investigated 80-year-old men and women. In the older subjects investigated, as in younger subjects, GHBP was significantly correlated with leptin and insulin.

Increased leptin and tumour necrosis factor alpha per unit fat mass in hypopituitary women without growth hormone treatment.

BACKGROUND: The adipocyte products, leptin and tumour necrosis factor (TNF)alpha, are associated with atherosclerotic diseases and may be factors contributing to the enhanced cardiovascular risk in hypopituitary patients with growth hormone (GH) deficiency. OBJECTIVE: To investigate whether leptin and TNFalpha are increased in a group of hypopituitary women previously found to have increased cardiovascular morbidity, and to compare them with matched individuals of the same sex and age and with similar body composition. DESIGN AND PATIENTS: Thirty-three GH-deficient women with a median age of 64 years (range 39-77 years) were investigated cross-sectionally. The patients were compared with 33 controls matched for sex, age, smoking habits, educational level and residence. METHODS: Body composition was measured by bioimpedance analysis. Fasting concentrations of leptin, TNFalpha and insulin were analysed in patients and controls. RESULTS: There was no significant difference in body mass index or fat mass between patients and controls (both P > or =0.4). Serum leptin did not differ significantly between patients and controls. However, when serum leptin concentrations were expressed per kilogram fat mass, the patients had significantly greater concentrations (P=0.01). Serum TNFalpha and TNFalpha per kilogram fat mass were also significantly greater in the patients (both P=0.001). In contrast, serum insulin did not differ significantly between patients and controls. In the patients, serum leptin concentrations correlated positively with kilogram fat mass (r=0.54, P=0.002). Leptin concentration per kilogram fat mass was positively correlated with insulin (r=0.40, P=0.03). CONCLUSIONS: In contrast to serum concentrations of TNFalpha, serum leptin did not differ from that in controls, implying that leptin is not a major contributor to the previously found increase in cardiovascular morbidity in the hypopituitary women investigated. However, the patients had increased leptin concentrations per unit fat mass, indicating an altered adipocyte secretory function in this group.

Plasma levels of persistent organohalogens and hormone levels in adult male humans.

In this study the authors assessed the possible relationship between high dietary exposure to persistent organohalogens (OHS) through fatty fish from the Baltic Sea and hormone levels in adult men. Blood samples were drawn from 110 men who consumed varying amounts of fish (i.e., 0-32 meals per month) for analysis of plasma levels of 18 polychlorinated biphenyl (PCB) congeners, 5 hydroxy-PCBs, 1,1,1-trichloro-2,2-bis(4-chlorophenyl)-ethane (p,p'-DDT), 1,1-dichloro-2,2-bis(4-chlorophenyl)-ethene (p,p'-DDE), hexachlorobenzene, and 2,2',4,4'-tetrabromodiphenyl ether. In addition, plasma levels of follicle-stimulating hormone, luteinizing hormone, prolactin, plasma thyrotropin, free and total T3, free and total T4, and free testosterone were analyzed. The authors adjusted for age, and the only significant associations that remained were negative correlations between 2,2',4,4'-tetrabromodiphenyl ether and plasma thyrotropin (p < .001), and between pentachlorophenol and follicle-stimulating hormone (p = .04). The authors expected that there would be some significant correlations that resulted from pure chance. High consumption of organohalogen-polluted fish did not appear to affect plasma concentrations of pituitary, thyroid, or testosterone hormone levels in male adults.

Plasma concentrations of persistent organochlorines in relation to thyrotropin and thyroid hormone levels in women.

OBJECTIVES: There is a concern that persistent organohalogen toxicants, such as polychlorinated biphenyls (PCBs), might display endocrine-disrupting effects in exposed populations. In this study the correlations between PCBs and thyrotropin (TSH) and thyroid hormone concentrations in plasma were assessed in adult women. METHODS: The study group consisted of 182 fishermen's wives from the Swedish east coast, with a median age of 42 years (range 23-62) and a median current consumption of contaminated fatty fish from the Baltic Sea of two meals per month (range 0-12). TSH, free (FT3) and total (TT3) triiodothyronine and free (FT4) and total (TT4) thyroxin in plasma were analyzed by immunofluorometric assays, and 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) in plasma was analyzed by gas chromatography with electron capture detection. Twenty other PCB and two hydroxy-PCB congeners were analyzed in subgroups of the women. Plasma lipid analyses were performed with enzymatic techniques. RESULTS: The CB-153 concentration in plasma (range 16-776 ng/g lipid) was negatively correlated with the TT3 concentrations (range 1.0-3.0 nmol/l, rs = -0.29, P < 0.001). This association remained after age adjustment. CONCLUSIONS: The present study gives some support for the notion that dietary exposure to persistent organochlorine compounds (POCs) might weakly affect peripheral thyroid hormone concentrations in adult women.

Incidence of a second tumor in hypopituitary patients operated for pituitary tumors.

Recently, an association between increased blood levels of insulin-like growth factor I (IGF-I) and increased risks of prostate, breast, lung, and colorectal cancers has been suggested. As today adults with GH deficiency are subjected to GH substitution, there is a pressing need for baseline tumor incidence data. The aim of the study was to assess the risk for a second tumor in a cohort of 328 patients with hypopituitarism treated for a pituitary tumor from 1958--1992. The patients were receiving conventional hormone treatment, but without GH substitution. The overall tumor incidence [standardized incidence ratio (SIR)] was lower than expected (0.85), but the 95% confidence interval (CI) did not exclude unity (0.59--1.21). Only two prostate cancers occurred (SIR, 0.34; 95% CI, 0.04--1.24). Two brain tumors (SIR, 1.96; 95% CI, 0.24--7.08) and two endocrine tumors (part of multiple endocrine neoplasm syndromes; SIR, 4.00; 95% CI, 0.48--14.5) had occurred. When excluding brain and endocrine tumors, the overall SIR decreased to 0.77, but did still not differ significantly from unity (0.52--1.13). Thus, a tendency for a decreased overall tumor risk, although not statistically significant, was noted, especially when excluding brain and endocrine tumors. This tendency was more emphasized for prostate cancer, but low numbers hamper a firm conclusion. These results may serve as a baseline for tumor risk among adult patients with pituitary insufficiency supplemented with GH.

Is there an increase in second brain tumours after surgery and irradiation for a pituitary tumour?

OBJECTIVE: To assess the incidence of second brain tumours in patients operated and irradiated for pituitary tumours. DESIGN AND PATIENTS: The study base consisted of a consecutive series of 325 patients operated and irradiated for pituitary tumours, excluding patients with acromegaly and Cushing's disease. Comparison was made with the general population from the same catchment area as the patients. The follow-up period started in 1958 and on an individual basis patients were followed from the onset of postoperative irradiation until December 1995, or until date of death, emigration or a second brain tumour diagnosis, whichever occurred first. RESULTS: Three brain tumours (two astrocytomas and one meningioma) were observed, compared with 1-13 expected (standardized incidence ratios (SIR) 2.7; 95% confidence interval (CI) 0.6-7.8). CONCLUSION: The present study gives no firm support for an increased incidence of a second brain tumour in patients operated and irradiated for pituitary tumours. A crude meta-analysis of the present and previously published cohort studies of patients with irradiated pituitary tumours gives an SIR of 6.1 (95% CI 3.16-10.69). Thus, the results of the meta-analysis are in favour of an increased risk for second brain tumours. A genetic trait that predisposes to both pituitary tumours and brain tumours is an alternative causal factor. There is no definite proof that cranial irradiation per se is the causal factor. This question cannot be fully answered until sufficient cohort studies of nonirradiated pituitary tumour patients have been carried out.

Low individualized growth hormone (GH) dose increased renal and cardiac growth in young adults with childhood onset GH deficiency.

OBJECTIVE: In childhood onset GH deficiency (GHD) a reduction in left ventricular mass (LV-mass) and impairment of systolic function as well an impairment in glomerular filtration rate (GFR) has been shown. The aim of the present study was to assess if a low GH dose resulted in an improvement in morphological and functional parameters of these organs. DESIGN AND PATIENTS: Eleven patients with childhood onset GHD were investigated before and after 10 months of GH treatment at a dose of 1.5 IU/day (range 1-2), corresponding to 0.02 IU/kg/day or 7 microg/ kg/day. The GH dose resulted in a serum IGF-I level in the normal range in all but one patient. MEASUREMENTS: Doppler echocardiography of the heart and ultrasound examination of the kidneys was performed. Glomerular filtration rate (GFR) was estimated with iohexol clearance and urinary proteinuria was measured with 24-h urinary samples collected for analyses of albumin, alpha-1-microglobulin, IgG and albumin/creatinine clearance ratio. Body composition was measured by bioelectric impedance analysis. RESULTS: L V-mass index increased significantly after GH treatment (P = 0.04), and there was a clear trend for a positive correlation between the increase in serum IGF-I and the increase in LV-mass index, although it did not reach significance (r= 0.57, P = 0.07). GH treatment did not increase cardiac fractional shortening. Kidney length increased significantly (P = 0.02) with an average increase of 1 cm (range - 0.5-1.5 cm). No significant changes in median GFR or serum creatinine were recorded. Three patients with subnormal GFR before GH treatment normalized after 10 months of treatment. Urine analysis showed no abnormalities before or after GH treatment. A significant decrease in percentage fat mass was recorded (P = 0.03). CONCLUSION: A low individualized GH dose to adults with childhood onset GHD resulted in an increase in LV-mass index and kidney length. Re-establishing GH treatment with a low dose in this patient group can lead to a further somatic maturation of these organs, probably not accomplished previously.

Effects of lead on the endocrine system in lead smelter workers.

In this study of the effects of lead on the endocrine system, 77 secondary lead-smelter workers (i.e., 62 active and 15 retired) were compared with 26 referents. Lead concentrations were determined in plasma with inductively coupled plasma mass spectrometry (i.e., index of recent exposure), in blood with atomic absorption spectrophotometry, and in fingerbone with K x-ray fluorescence technique (i.e., index of long-term exposure). In addition, pituitary hormones were determined in serum by fluoroimmunoassay, and thyroid hormones and testosterone in serum were determined with radioimmunoassay. Nine lead workers and 11 referents were challenged with gonadotrophin-releasing hormone and thyrotrophin-releasing hormone, followed by measurements of stimulated pituitary hormone levels in serum. Median levels of lead in plasma were 0.14 microg/dl (range = 0.04-3.7 microg/dl) in active lead workers, 0.08 microg/dl (range = 0.05-0.4 microg/dl) in retired lead workers, and 0.03 microg/dl (range = 0.02-0.04 microg/dl) in referents (1 microg/dl = 48.3 nmol/l). Corresponding blood lead concentrations were 33.2 microg/dl (range = 8.3-93.2 microg/dl), 18.6 microg/dl (range = 10.4-49.7 microg/dl), and 4.1 microg/dl (range 0.8-6.2 microg/dl), respectively. Respective bone lead levels were 21 microg/gm (range = -13 to 99 microg/gm), 55 microg/gm (range = 3-88 microg/gm), and 2 microg/gm (range = -21 to 14 microg/gm). Concentrations of basal serum hormone (i.e., free thyroid hormones, thyrotrophin, sex hormone binding globulin, and testosterone) were similar in the 3 groups. There were no significant associations between the hormones mentioned herein and blood plasma, blood lead, and bone lead levels. In the challenge test, stimulated follicle-stimulating hormone levels were significantly lower in lead workers (p = .014) than in referents, indicating an effect of lead at the pituitary level. Also, there was a tendency toward lower basal stimulated follicle-stimulating hormone concentrations in lead workers (p = .08). This effect, however, was not associated with blood plasma level, blood lead level, or bone lead level. In conclusion, a moderate exposure to lead was associated with only minor changes in the male endocrine function, particularly affecting the hypothalamic-pituitary axis. Given that sperm parameters were not studied, the authors could not draw conclusions about fertility consequences.

The negative association between serum free testosterone and leptin is dependent on insulin-like growth factor-binding protein 1 in healthy young and middle-aged men.

OBJECTIVE: Previous studies have shown that serum levels of testosterone correlate negatively with leptin and positively with insulin-like growth factor binding protein 1 (IGFBP-1). The present study examined whether these associations are linked. DESIGN AND PATIENTS: The association between serum levels of IGFBP-1, free testosterone and insulin on one hand and leptin on the other hand were investigated in 38 healthy men with a median age of 48 years (range 23-62 years). RESULTS: Univariate analyses revealed that serum levels of leptin correlated negatively with serum free testosterone (r = - 0.42, P = 0.008) and with serum IGFBP-1 (r = - 0. 45, P = 0.005) and positively with body mass index (BMI; r = 0.46, P = 0.003) and serum insulin (r = 0.45, P = 0.004). Serum free testosterone correlated with IGFBP-1 (r = 0.42, P = 0.008) but not with serum insulin (r = - 0.08, ns). The correlations between leptin and free testosterone and between leptin and IGFBP-1 remained significant after adjustement for the influences of BMI and insulin. Forward stepwise multiple regression when BMI, insulin, testosterone and IGFBP-1 were entered in a model as independent variables and leptin as the dependent variable showed that BMI and IGFBP-1 were independent predictors of circulating leptin. These two parameters yielded an r 2 of 0.38, thereby together explaining approximately 40% of serum leptin. CONCLUSION: Serum levels of free testosterone and IGFBP-1 correlate negatively with serum leptin in healthy nonobese men but this influence is dependent on the influence of IGFBP-1. The study therefore suggests an important impact of IGFBP-1 on the regulation of circulating leptin in young and middle-aged men.

Hypopituitary females have a high incidence of cardiovascular morbidity and an increased prevalence of cardiovascular risk factors.

We recently reported that female patients with hypopituitarism receiving controlled thyroid and steroid hormone substitution, but without GH replacement, had a more than 2-fold increase in cardiovascular mortality compared to the general population. In the present study we investigated the incidence of cardiovascular disease as well as the prevalence of cardiovascular risk factors in 33 females with hypopituitarism for 6-46 yr (median, 18) compared to those in 33 control subjects recruited from the general population in the same geographical area and matched for sex, age, smoking habits, educational level, and residence location. The patients were with a very high probability GH deficient, as 29 had subnormal serum insulin-like growth factor I levels, and the other 4 were GH deficient, as assessed by an insulin tolerance test. The incidence of cardiovascular disease was significantly higher among the hypopituitary patients (incidence ratio, 3.7; 95% confidence interval, 1.2-11.3), and the consumption of cardioactive drugs was also significantly higher (P = 0.002). Hypopituitary patients had a lower degree of physical exercise during their spare time (P = 0.02), a higher waist/hip ratio (P = 0.01), lower high density lipoprotein cholesterol (P = 0.002), and higher low density/high density lipoprotein ratio (P = 0.009). Furthermore, the patients had a significantly increased left atrium size (P = 0.05), but no difference was observed for other cardiac measures. In the patients, serum insulin-like growth factor I levels significantly correlated with left ventricular mass index (r = 0.48; P = 0.006), suggesting that GH has a strong impact on cardiac size. More episodes of bradycardia (P = 0.05), but no increased occurrence of extrasystolies, were encountered in the patients during 24-h continuous electrocardiogram monitoring. Carotid artery intima-media thickness and plaque numbers did not differ between patients and controls. In conclusion, hypopituitary females exhibit an increased incidence of cardiovascular disease, higher cardioactive drug consumption, and an increased prevalence of cardiovascular risk factors. The increased cardiovascular morbidity could not be ascribed to inadequate estrogen or thyroid hormone treatment, and unsubstituted GH deficiency is probably an important contributing factor.