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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 0·1). Leptin correlated to kilogram fat mass in both women (r = 0·55, 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. (Less)

OBJECTIVE: Previous studies have shown possible neuroendocrine effects of GH. In the present study we investigated the incidence of mental disorders and the prevalence of mental distress and cognitive dysfunction in hypopituitary women with untreated GH deficiency compared to population-based controls.DESIGN AND PATIENTS: Thirty-three hypopituitary women with a median age of 64 years (range 39--77 years) were investigated cross-sectionally, without any change in hormone substitutions. Twenty-nine of the patients had been operated for a pituitary tumour, 25 had received radiotherapy and 15 had visual dysfunction. The patients were with a very high probability GH deficient, as 29 had subnormal IGF-I levels and the other four were GH deficient as assessed by an insulin tolerance test. The patients were compared with 33 controls matched for sex, age, smoking habits, educational level and residence.MEASUREMENTS: The incidence of mental disorders was calculated from the date of diagnosed hypopituitarism to the time of the present investigation. Mental well-being was assessed by three self-rating questionnaires: the Symptom Checklist-90 (SCL-90), the Interview Schedule for Social Interaction (ISSI) and the social network concept. The subjects were examined with neuropsychological tests of vocabulary (SRB:1 vocabulary test), perceptual speed (WAIS-R Digit Symbol), spatial ability (WAIS-R Block Design), verbal memory (Cronholm--Molander verbal memory test), spatial learning (Austin Maze Test) and reaction time (APT Two-way Reaction Time and APT Inhibition).RESULTS: The hypopituitary women had a higher incidence of mental disorders than the controls; Incidence Rate Ratio 4.5 (95% CI 1.0--21). The Global Severity Index, i.e. the average score of all 90 questions of the SCL-90, was higher in patients (P = 0.001), and the patients had significantly more symptoms of somatization, anxiety, depression, obsession--compulsion, hostility--irritability, phobic and psychotic symptoms (all P less-than-or-equal 0.04). Moreover, 14 patients compared to four controls were classified as possible cases of mental distress according to the SCL-90 (P = 0.006). The patients experienced lower availability of both social attachment (P = 0.02) and integration (P = 0.001), but there were no group differences in the adequacy of these dimensions or in emotional support. The patients had lower scores in four of seven neuropsychological tests (all P less-than-or-equal 0.04).CONCLUSIONS: The hypopituitary women had a higher incidence of mental disorders, more symptoms of mental distress and increased prevalence of cognitive dysfunction. The impaired results in the patients could possibly be explained by several factors, such as transfrontal surgery, radiotherapy, visual dysfunction and unphysiological hormone substitution. Moreover, it is probable that GH deficiency contributed, but placebo-controlled double-blind studies are warranted to investigate whether the psychological dysfunction is reversible on GH substitution. (Less)

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 mug/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. (Less)

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.

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.

Growth hormone (GH) has insulin-antagonistic effects, and GH secretion is augmented during fasting and hypoglycemia. In the present study, 10 patients aged 21 to 28 years with childhood-onset GH deficiency (GHD) were studied during a 24-hour fast and a hypoglycemic glucose clamp before and after 9 months of GH replacement. During the 24-hour fast, blood glucose, serum insulin, and serum free fatty acid (FFA) levels were measured. In the hypoglycemic clamp, the counterregulatory hormones (plasma catecholamines, serum glucagon, and serum cortisol), serum insulin-like growth factor (IGF) binding protein-1 (IGFBP-1), serum FFA, and glucose uptake were measured. The GH dose was adjusted to the response of serum IGF-I, and the median GH dose was 0.14 IU/kg/wk (range, 0.08 to 0.19). At the end of the study, serum IGF-I levels were normalized in all but one patient, in whom serum IGF-I was above the normal range. Nine months of GH treatment did not cause any significant changes in the blood glucose level, insulin to glucose ratio, or serum FFA level during the 24-hour fast, and none of the patients experienced hypoglycemia either before or after GH treatment. However, GH therapy resulted in increased insulin resistance during hypoglycemia, without changes in the counterregulatory hormonal responses, serum IGFBP-1, or serum FFA.

OBJECTIVE Many GH deficient (GHD) patients have impaired glucose tolerance and GH substitution in these patients has caused deleterious effects on glucose tolerance with hyperinsulinaemia. This further impairment of glucose tolerance might be due to an unphysiologically high dose of GH. Whether such a deterioration can be avoided by an optimal GH replacement dose is not known. In most previous studies, the GH dose was calculated according to body weight or body surface area and not adjusted according to the serum IGF-I response. DESIGN The study was of open design and investigations were performed before the start of GH substitution and after nine months of treatment. The GH dose was adjusted according to the response in serum IGF-I, and in patients with sub-normal serum IGF-I levels (all but two) we aimed for a serum IGF-I level in the middle of the normal range. The median GH dose at the end of the study was 0.14 IU/kg/week. PATIENTS Ten patients, eight males and two females, with childhood onset GHD were examined. Their median age was 27 years (range 21–28). MEASUREMENTS Overnight and 24-h fasting levels of glucose, insulin and IGFBP-1 were measured. Directly after the 24-h fast an oral glucose tolerance test (OGTT), with measurements of glucose, insulin and IGFBP-1 was performed. An intravenous glucose tolerance test (IVGTT) was performed after overnight fasting. Body composition was measured with bioimpedance analysis (BIA) and quality of life was assessed using a self-rating questionnaire, Qol-AGHDA. RESULTS After GH treatment, there were no significant changes in glucose tolerance, measured by overnight and 24-h fasting levels of glucose, insulin and IGFBP-1, an oral glucose tolerance test (after 24-h fasting) and an intravenous glucose tolerance test (after overnight fasting). Percentage fat mass and BMI correlated negatively with both the 24 h fasting IGFBP-1 levels and the IGFBP-1 responses after the OGTT. All patients decreased their percentage of fat mass measured by BIA [median −2.9%; range −1.0–(−6.6); P = 0.005]. The administered GH dose correlated negatively with the relative change in whole body resistance (r = −0.66; P = 0.04). All, but one of the patients improved their quality of life score after GH therapy. CONCLUSIONS In a group of young patients with childhood onset GH deficiency, 9 months of treatment with a low GH dose (median 0.14 IU/kg/week) caused no significant deterioration of glucose tolerance. The strong negative associations between BMI or percentage fat mass and IGFBP-1 suggest that serum IGFBP-1 is more closely related than insulin to body composition in GH deficient patients. It is important to consider which critical endpoints should determine the GH dose. We would suggest that, apart for normalizing the serum IGF-I level, another main endpoint should be normalization of, or at least avoidance of any deterioration in glucose tolerance.

Specific causes of death, survival, and recurrence rates were assessed in a cohort of 60 patients who had undergone surgery for craniopharyngioma between 1951 and 1988. Compared to the general population, the standardized mortality ratio (SMR) was increased [5.55; 95% confidence interval (CI), 3.68-8.22], and it was higher among females (SMR, 11.4) than males (SMR, 4.79). The risk of cardio- and cerebrovascular mortality (SMR, 3.21; 95% CI, 1.29-6.61) was also enhanced. The cumulative survival rates 10 and 15 yr after the initial operation were 68% (95% CI 54-78) and 59% (95% CI 30-63), respectively. A multivariate survival analysis adjusting for age showed a protective effect of radiotherapy (hazard ratio, 0.3; 95% CI, 0.1-0.8) and an increased risk of death after recurrence (hazard ratio, 4.4; 95% CI, 1.4-14), but no obvious effect of radicality at surgery. However, when patients who had died within 6 months after surgery were excluded, no significant protective effect of radiotherapy remained. The cumulative frequency of recurrence after 10 yr was 33% (95% CI, 22-48%), and that after 15 yr was 40% (95% CI, 28-56%). The incidence of recurrence did not differ significantly with respect to age, radicality at surgery, or postoperative radiotherapy. The determinants for long term outcome in patients with craniopharyngioma are interrelated in a complex way, which calls for strict selection criteria in follow-up studies and the use of multivariate statistical models.

OBJECTIVE An increased prevalence of atherosclerosis has been shown among patients with hypopituitarism. The aim of the present study was to assess whether patients with hypopituitarism experience increased cardiovascular, in particular cerebrovascular, mortality. DESIGN AND PATIENTS Retrospective cohort study of mortality, 1952–1992, in 344 patients, of whom 130 were female, receiving conventional hormone replacement for hypopituitarism following neurosurgery for pituitary tumours. The general population in the catchment area of southern Sweden from which the patients were recruited constituted the reference population. Expected mortality was obtained from cause, sex, calendar year, and 5-year age-specific death rates for the area. RESULTS Increased mortality from cerebrovascular disease (standardized mortality ratio (SMR) 3.39; 95% CI 2.27–4.99) was the main contributor to the increased overall cardiovascular mortality (SMR 1.75; 95% CI 1.40–2.19). The increase in mortality from cardiac diseases was much smaller (SMR 1.41; 95% CI 1.04–1.88). The risk for cerebrovascular death was higher in women (SMR 4.91) than in men (SMR 2.64). The relative risk for cerebrovascular death was independent of the time interval since diagnosis of pituitary insufficiency, but was greater in subjects diagnosed at an earlier age (

Objectives: To examine the risk of developing adrenal carcinomas and clinically overt hypersecreting tumours during short-term follow-up in patients with adrenal incidentalomas. Design: 229 (98 males and 131 females) patients with adrenal incidentalomas were investigated in a prospective follow-up study (median time 25 months; range 3–108 months). The patients were registered between January 1996 and July 2001 and followed until December 2004. Twenty-seven Swedish hospitals contributed with follow-up results. Methods: Diagnostic procedures were undertaken according to a protocol including reinvestigation with computed tomography scans after 3–6 months, 15–18 months and 27–30 months, as well as hormonal evaluation at baseline and after 27–30 months of follow-up. Operation was recommended when the incidentaloma size increased or if there was a suspicion of a hypersecreting tumour. Results: The median age at diagnosis of the 229 patients included in the follow-up study was 64 years (range 28–84 years) and the median size of the adrenal incidentalomas when discovered was 2.5 cm (range 1–8 cm). During the follow-up period, an increase in incidentaloma size of ≥0.5 cm was reported in 17 (7.4%) and of ≥1.0 cm was reported in 12 (5.2%) of the 229 patients. A decrease in size was seen in 12 patients (5.2%). A hypersecreting tumour was found in 2% of the hormonally investigated patients: Cushing’s syndrome (n = 2) and phaeochromocytoma (n = 1). Eleven patients underwent adrenalectomy, but no cases of primary adrenal malignancy were observed. Conclusions: Patients with adrenal incidentaloma had a low risk of developing malignancy or hormonal hypersecretion during a short-term follow-up period.

BACKGROUND: Reduced life expectancy has been shown in patients with hypopituitarism, mainly caused by cardiovascular diseases. A major cause of hypopituitarism is pituitary adenomas, and radiotherapy may be employed as a treatment modality to reduce the post-operative regrowth rate of these tumours. Recently, we showed that in patients with craniopharyngiomas, tumour regrowth foreshadowed a fourfold risk increase for death. For patients with pituitary adenomas, the impact of regrowth on life expectancy is, however, not known. OBJECTIVE: To assess the impact of a reoperation due to a regrowth of a pituitary macroadenoma on mortality, taking into account other candidate prognostic factors. DESIGN AND PATIENTS: In 281 patients with operated and irradiated macroadenomas, excluding acromegaly and Cushing's disease, 35 patients had a regrowth (median follow-up 16.6 years). Possible risk factors for tumour regrowth were investigated by Cox regression models. RESULTS: For tumour regrowth, age, calendar time at primary surgery, gender and extension of tumour growth had no statistically significant impact. For younger patients, the proportion of regrowths was higher, but after age-stratified Cox regression analysis only regrowth was shown to have a significant impact on mortality, with a more than doubled mortality risk for patients with tumour regrowth as compared with the non-regrowing tumour patients (hazard ratio=2.24, P

Summary OBJECTIVE Adult survivors of childhood acute lymphoblastic leukaemia (ALL) often exhibit GH deficiency (GHD), due to prophylactic cranial radiotherapy (CRT). It is not known whether the observed risk for adiposity in these patients is associated with impaired insulin sensitivity and whether the insulin sensitivity is affected by GH replacement therapy. SUBJECTS AND DESIGN Eleven patients with GHD (median age 29 years), previously given prophylactic CRT for ALL, and 11 sex-, age- and body mass index (BMI)-matched controls were investigated with bioimpedance analysis (BIA) and analysis of serum leptin, serum free fatty acids (FFA) and serum insulin. Insulin sensitivity was measured by a euglycaemic–hyperinsulinaemic clamp technique (IS-clamp). Moreover, the effects of 12 months of individually titrated GH treatment (median dose 0·5 mg/day) on these parameters were investigated. RESULTS At baseline, the patients had lower fat free mass (FFM) (P = 0·003), higher percentage fat mass (FM) (P = 0·05), serum insulin (P = 0·02) and serum leptin/kg FM (P = 0·01) than controls. The patients had a tendency towards impaired IS-clamp (P = 0·06), which disappeared after correction for body composition (IS-clamp/kg FFM; P > 0·5). In the patients, time since CRT was positively correlated with percentage FM (r = 0·70, P = 0·02), and there was an independent negative association between serum FFA and IS-clamp (P = 0·05). Twelve months of GH treatment increased serum IGF-I (P = 0·003) and FFM (P = 0·02) and decreased percentage FM (P = 0·03), but no significant changes were seen in serum leptin/kg FM, serum FFA, FFA-clamp, serum insulin or IS-clamp (all, P ≥ 0·2). CONCLUSIONS Young adult survivors of childhood ALL with GHD had increased fat mass, hyperleptinaemia and impaired insulin sensitivity, which could be a consequence of radiation-induced impairment of GH secretion or mediated by other hypothalamic dysfunctions, such as leptin resistance or other unknown factors, affected by CRT. Twelve months of individualized GH replacement therapy led to positive effects on body composition, but the hyperleptinaemia, hyperinsulinaemia and the impaired insulin sensitivity remained unchanged.

Vascular mortality, especially cerebrovascular disease (CVD), are the most pronounced cause of mortality in women with hypopituitarism. In a cohort of 342 patients operated and irradiated for pituitary tumors, 31 died from CVD (CVD patients) between 1952 and 1996. The study assessed whether the radiation regimens and duration of symptoms of hypopituitarism before operation differed between the 31 CVD patients and the 62 matched patients from the same cohort who had not died from CVD (control patients). Furthermore, the infarction/hemorrhage ratio, type of clinical stroke syndrome, and time to death after stroke were investigated in the CVD patients and in matched controls from the general population who had died from CVD (population controls). No significant differences in maximum or centrally absorbed dose, maximum or central biological equivalent dose, field size, or number of fraction were recorded between CVD and control patients. A significant difference in the duration of symptoms of hypopituitarism before operation was recorded, but only in women (P = 0.01). There were no significant differences in the infarction/hemorrhage ratio (P > 0.3) of lacunar or posterior circulation syndrome compared with middle cerebral artery syndrome with cortical features (P = 0.22) or the proportion of patients who died within the first month after stroke onset (60% vs. 59%, respectively) between CVD patients and population controls. In conclusion, no significant effect on CVD deaths could be detected for any radiation parameter. A long history of unsubstituted pituitary insufficiency may be a contributing factor to the very high CVD mortality among women. There were no indications of significant differences in type of stroke, clinical stroke syndromes, or stroke fatality between the CVD patients and the population controls.

Bulow B, Ahren B (Lund University, Lund, Sweden) on behalf of the Swedish Research Council Study Group of Endocrine Abdominal Tumours. Adrenal incidentaloma - experience of a standardized diagnostic programme in the Swedish prospective study. J Intern Med 2002; 252: 239-246. OBJECTIVE: To report the 5-year experience of a diagnostic programme for adrenal incidentaloma with special emphasis to diagnose hormonally active and malignant lesions. DESIGN: A prospective study in which new cases of adrenal incidentalomas in Sweden have been evaluated by a standardized diagnostic protocol between January 1996 and July 2001. SETTING: Thirty-three different Swedish hospitals have contributed with cases. SUBJECTS: A total of 381 patients (217 females, 164 males) with adrenal incidentalomas were studied. INTERVENTIONS: Diagnostic procedures were undertaken according to a standardized programme. Operation was recommended if the incidentaloma had a size of more than 3-4 cm or if there was a suspicion of a hypersecreting tumour. MAIN OUTCOME MEASURES: The size of the incidentaloma, clinical characteristics of the patients and results of biochemical diagnostic tests were registered. RESULTS: The median age of the patients was 64 years (18-84 years), and the median size of the incidentalomas was 3 cm (1-20 cm). A total of 85(22%) patients were operated. Twenty of thesepatients were diagnosed with a benign hypersecreting tumour and 14 with a malignant tumour. Fourteen of 15 operated patients with diagnosed pheochromocytoma had elevated 24-h urinary noradrenaline and all of the patients operated because of a biochemical suspicion of aldosterone or cortisol hypersecretion (n = 6) were found to have adrenal adenomas. Of the 14 operated patients with malignant diseases, 10 were adrenal carcinomas (median size 10 cm; range 4-16 cm). In a multiple logistic regression model, incidentaloma size was significantly associated with the risk of a malignant tumour (P = 0.009), and there was a tendency of an association between age/male sex and the risk of a malignancy (both, P = 0.07). CONCLUSION: In this Swedish multicentre study of 381 cases with adrenal incidentalomas, 5% had benign hypersecreting tumours and nearly 4% had malignant tumours. The results of the biochemical diagnostic tests used had a high compatibility with the histological diagnosis found at operation in the patients with hypersecreting tumours. Tumour size, male gender and high age were predictive for the risk of a malignant tumour. A follow-up of the patients is warranted in order to establish whether there are undiscovered cases of malignant or hypersecreting tumours amongst the nonoperated patients.

Previous studies have shown possible neuroendocrine effects of GH. In the present study we investigated the incidence of mental disorders and the prevalence of mental distress and cognitive dysfunction in hypopituitary women with untreated GH deficiency compared to population-based controls.Thirty-three hypopituitary women with a median age of 64 years (range 39--77 years) were investigated cross-sectionally, without any change in hormone substitutions. Twenty-nine of the patients had been operated for a pituitary tumour, 25 had received radiotherapy and 15 had visual dysfunction. The patients were with a very high probability GH deficient, as 29 had subnormal IGF-I levels and the other four were GH deficient as assessed by an insulin tolerance test. The patients were compared with 33 controls matched for sex, age, smoking habits, educational level and residence.The incidence of mental disorders was calculated from the date of diagnosed hypopituitarism to the time of the present investigation. Mental well-being was assessed by three self-rating questionnaires: the Symptom Checklist-90 (SCL-90), the Interview Schedule for Social Interaction (ISSI) and the social network concept. The subjects were examined with neuropsychological tests of vocabulary (SRB:1 vocabulary test), perceptual speed (WAIS-R Digit Symbol), spatial ability (WAIS-R Block Design), verbal memory (Cronholm--Molander verbal memory test), spatial learning (Austin Maze Test) and reaction time (APT Two-way Reaction Time and APT Inhibition).The hypopituitary women had a higher incidence of mental disorders than the controls; Incidence Rate Ratio 4.5 (95% CI 1.0--21). The Global Severity Index, i.e. the average score of all 90 questions of the SCL-90, was higher in patients (P = 0.001), and the patients had significantly more symptoms of somatization, anxiety, depression, obsession--compulsion, hostility--irritability, phobic and psychotic symptoms (all P less-than-or-equal 0.04). Moreover, 14 patients compared to four controls were classified as possible cases of mental distress according to the SCL-90 (P = 0.006). The patients experienced lower availability of both social attachment (P = 0.02) and integration (P = 0.001), but there were no group differences in the adequacy of these dimensions or in emotional support. The patients had lower scores in four of seven neuropsychological tests (all P less-than-or-equal 0.04).The hypopituitary women had a higher incidence of mental disorders, more symptoms of mental distress and increased prevalence of cognitive dysfunction. The impaired results in the patients could possibly be explained by several factors, such as transfrontal surgery, radiotherapy, visual dysfunction and unphysiological hormone substitution. Moreover, it is probable that GH deficiency contributed, but placebo-controlled double-blind studies are warranted to investigate whether the psychological dysfunction is reversible on GH substitution.

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 TNF alpha 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, TNF alpha 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 greater than or equal to 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 TNF alpha and TNF alpha 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 TNF alpha. 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.

thereafter allocate observation time to the latter category. Tomlinson and colleagues emphasise that a drawback with the previous cohort studies is that they compare small numbers of patients. We think that they have misunderstood this issue. They have based their analyses on 181 dead patients (18% of the cohort), whereas the analysis in one of the Swedish cohorts 3 was based on 188 (55%) dead patients. Thus, the statistical power was similar in the two studies. The discrepancy in proportion of diseased patients is due to differences in calendar year for start of observation and length of follow-up. Moreover, we are surprised that Tomlinson and colleagues discuss their finding that patients with craniopharyngioma have an especially poor survival prognosis without mentioning the original finding made in one of the Swedish cohorts.