Primary aldosteronism: functional histopathology and long-term follow-up after unilateral adrenalectomy.

OBJECTIVES: To investigate the long-term outcome after unilateral adrenalectomy in patients with primary aldosteronism (PA) and to establish the role of functional pathology for the final diagnosis of aldosterone-producing adenoma (APA) or hyperplasia. DESIGN: A single-centre, retrospective cohort study in a hospital setting. PATIENTS: Consecutive patients with PA, n = 120, who underwent unilateral adrenalectomy between 1985 and 2010. Preoperative and postoperative data were analysed. To indicate the site of aldosterone secretion in the resected adrenal, we added functional methods to routine histopathology, using in situ hybridization and immunohistochemistry to detect the presence of enzymes needed for aldosterone (CYP11B2) and cortisol (CYP11B1, CYP17A1) synthesis. RESULTS: The median follow-up was 5 years and the cure rate of PA 91%. Hypertension was improved in 97% and normalized in 38%. Functional histopathology changed the final diagnosis from APA to hyperplasia in 6 cases (7%). Five of these had no expression of or staining for aldosterone synthase in the adenoma, but only in nodules in the adjacent cortex. All except one APA patient were cured of PA. They had lower preoperative serum potassium and higher 24-h urinary aldosterone than patients with hyperplasia. Among patients with hyperplasia 16 of 26 were cured. CONCLUSIONS: Most patients were cured of PA by unilateral adrenalectomy. Almost all noncured benefitted from the operation as the blood pressure improved. Functional histopathology proved helpful in the distinction between APA and hyperplasia, and we recommend that functional histopathology should be added to routine histopathology to improve the diagnostic evaluation and aid in tailoring the follow-up.

Voice characteristics in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) is an autosomal recessive inherited disorder resulting in lack of cortisol and often aldosterone and overproduction of androgens. Raised levels of androgens can lead to increased mass in the laryngeal tissues, which may lower the fundamental frequency (F0) of the voice. DESIGN/PATIENTS: A follow-up study of voice characteristics in 38 women with CAH and 24 age-matched controls between 18 and 63 years of age using subjective self-ratings of voice symptoms and acoustic and perceptual analyses. The results were correlated to mutation and treatment. MEASUREMENTS: The subjects rated degree of hoarseness, dark voice, voice problems and vocal fatigue on visual analogue scales. Audio recordings were made of a standard reading passage in a sound treated booth. Acoustic analyses were made of the subjects' mean, minimum and maximum F0 in the habitual speech range. Three voice clinicians made perceptual evaluations of dark voice in terms of timbre. RESULTS: Women with CAH rated higher values than controls with regard to the statement 'my voice is a problem in my daily life'. They spoke with significantly lower mean, lower minimum and lower maximum F0, as well as darker voice quality as compared with the controls. Affected voice symptoms were associated with a late diagnosis or problems with medication. CONCLUSION: The voices in women with CAH can be virilized because of late diagnosis or suboptimal treatment with glucocorticoids. These voice problems may need referral for voice assessment and should be considered when treating CAH.

Increased liver enzymes in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

The aims were assessing liver function tests (LFT) in women with congenital adrenal hyperplasia (CAH) on glucocorticoids. Sixty-one women with genetically verified CAH due to 21-hydroxylase deficiency, aged 18-63 years were compared to 61 controls. Serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT), anthropometry and fat mass (dual energy X-ray absorptiometry) were measured. ALT and GGT were higher in the entire patient group (p=0.01 and 0.002); AST, GGT and ALP in patients > or =30 years (p=0.007-0.045); all LFT in salt-wasting (p<0.001-0.042); GGT in simple virilizing (p=0.008); ALT, GGT and ALP in Null/Null genotype (p=0.018-0.040); ALT and GGT in I2splice genotype (p<0.001 and 0.011). Using a recently proposed cut-off level for ALT (>0.317 microkat/L), 54% of patients vs 23% of controls had elevated levels (p=0.028). In patients, GGT and ALP correlated with waist circumference and with total body and trunk fat (r=0.274-0.406, p=0.001-0.043). However, ALT, GGT and ALP were increased even in non-obese patients (waist circumference < or =88 cm and body mass index <30 kg/m(2)) (p=0.012-0.045) mainly attributed to the patients > or =30 years who also demonstrated elevated insulin levels and HOMA-indices. In conclusion, compared with controls, women with CAH have higher LFT, in particular patients > or =30 years and those with severe forms, probably reflecting a higher lifetime glucocorticoid exposure. LFT were positively correlated to measurements of body fat. These women might have increased frequency of NAFLD. The finding of higher LFT also in non-obese patients suggests that not only central obesity but also glucocorticoids per se may influence.

Type of mutation and surgical procedure affect long-term quality of life for women with congenital adrenal hyperplasia.

CONTEXT: In congenital adrenal hyperplasia (CAH) caused by different mutations, feminizing surgery is mostly performed in childhood, and many patients are lost to follow-up. OBJECTIVE/PATIENTS: A follow-up study on 62 CAH women aged 18-63 yr and 62 age-matched controls to correlate findings of both operative method and mutation was performed. DESIGN: Semistructured interviews were performed in cases and controls, as well as a gynecological examination in the cases. The results were correlated with disease-causing mutations and earlier surgical procedures if performed. SETTING: The study was conducted at university hospital referral clinics. MAIN OUTCOME MEASURES: Gynecological examination in all cases correlated to previous surgery (n = 49), type of mutation, and questionnaire responses. RESULTS: Half of the CAH women claimed that the disease affected their sex life. The women were less satisfied with their genitals, whether operated or not. Clitoris size and functions were affected by the surgical method. Five women had a clinically evident vaginal stenosis on examination. However, almost half of patients experienced a narrow vagina. The overall psychosexual aspects of life were affected in these patients with later sexual debut, fewer pregnancies and children, and an increased incidence of homosexuality. These quality of life factors were correlated to the severity of the mutations. CONCLUSIONS: The overall quality of life in adult women with CAH is affected both by the type of mutation and operative procedure. Indications for clitoroplasty should be restrictive. Medical, surgical, and psychological treatment should be centralized.

Fracture incidence in GH-deficient patients on complete hormone replacement including GH.

UNLABELLED: Fracture risk in GHD patients is not definitely established. Studying fracture incidence in 832 patients on GH therapy and 2581 matched population controls, we recorded a doubled fracture risk in CO GHD women, but a significantly lower fracture risk in AO GHD men. INTRODUCTION: The objective of this study was to evaluate fracture incidence in patients with confirmed growth hormone deficiency (GHD) on replacement therapy (including growth hormone [GH]) compared with population controls, while also taking potential confounders and effect modifiers into account. MATERIALS AND METHODS: Eight hundred thirty-two patients with GHD and 2581 matched population controls answered a questionnaire about fractures and other background information. Incidence rate ratio (IRR) and 95% CI for first fracture were estimated. The median time on GH therapy for childhood onset (CO) GHD men and women was 15 and 12 yr, respectively, and 6 and 5 yr for adult onset (AO) GHD men and women, respectively. RESULTS: A more than doubled risk (IRR, 2.29; 95% CI, 1.23-4.28) for nonosteoporotic fractures was recorded in women with CO GHD, whereas no risk increase was observed among CO GHD men (IRR, 0.61) and AO GHD women (IRR, 1.08). A significantly decreased incidence of fractures (IRR, 0.54; 95% CI, 0.34-0.86) was recorded in AO GHD men. CONCLUSIONS: Increased fracture risk in CO GHD women can most likely be explained by interaction between oral estrogen and the GH-IGF-I axis. The adequate substitution rate of testosterone (90%) and GH (94%) may have resulted in significantly lower fracture risk in AO GHD men.

Metabolic profile and body composition in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

CONTEXT: The chronic, often supraphysiological glucocorticoid doses used in congenital adrenal hyperplasia (CAH) might increase morbidity in cardiovascular disease and diabetes. OBJECTIVE: Our aim was to assess risk factors for cardiovascular disease and diabetes in CAH women. SUBJECTS, METHODS, AND DESIGN: We compared 61 women, 18-63 yr, with CAH due to 21-hydroxylase deficiency with 61 age- and sex- matched controls. Twenty-seven were younger than 30 yr, and 34 were 30 yr or older. Anthropometry, fat and lean mass measured by dual-energy x-ray absorptiometry, serum lipids, insulin, and adrenocortical steroids were studied. MAIN OUTCOME MEASURE: Body composition and cardiovascular risk factors were the main outcome measures. RESULTS: Younger patients and controls had similar waist to hip ratio, lean and fat mass, and insulin. Older patients had higher waist to hip ratio, lean mass, and insulin than controls. Fat mass was similar to controls but higher than in younger patients. Lipid profiles were slightly more favorable in older patients than controls. Gestational diabetes was more common in patients (21% of pregnancies vs. 0, P < 0.026). Few older patients had hypertension, cardiovascular disease, or diabetes. Despite moderate glucocorticoid doses, most patients had suppressed androgens. CONCLUSIONS: No clear evidence of unfavorable cardiovascular risk factors were found. Increased fat mass and higher insulin levels were, however, found in patients older than 30 yr. High frequency of gestational diabetes is a risk marker for future diabetes. Lifelong follow-up, lifestyle modifications, and attempts to adjust and reduce the glucocorticoid doses seem important.

Fractures and bone mineral density in adult women with 21-hydroxylase deficiency.

CONTEXT: Patients with classical congenital adrenal hyperplasia (CAH) receive lifelong, often supraphysiological, glucocorticoid therapy. Pharmacological doses of glucocorticoids are an established risk factor for osteoporosis. OBJECTIVE: Our objective was to evaluate bone mineral density (BMD), fracture prevalence, and markers of bone metabolism in adult females with CAH. DESIGN: This was a cross-sectional observational study. SETTING: Tertiary care referral centers were used in this study. PARTICIPANTS: We studied 61 women, aged 18-63 yr, with genetically verified CAH due to 21-hydroxylase deficiency. They were patients with salt wasting (n = 27), simple virilizing (n = 28), and nonclassical 21-hydroxylase deficiency (n = 6). A total of 61 age-matched women were controls. MAIN OUTCOME MEASURES: History of fractures was recorded. Total body, lumbar spine, and femoral neck BMD were measured by dual-energy x-ray absorptiometry. The World Health Organization criteria for osteopenia and osteoporosis were used. Serum marker of bone resorption, beta-C telopeptide was studied. RESULTS: The mean glucocorticoid dose in hydrocortisone equivalents was 16.9 +/- 0.9 mg/m2. Patients had lower BMD than controls at all measured sites (P < 0.001). In patients younger than 30 yr old, 48% were osteopenic vs. 12% in controls (P < 0.009). In patients 30 yr or older, 73% were osteopenic or osteoporotic vs. 21% in controls (P < 0.001). BMD was similar in the two classical forms and had no obvious relationship to genotypes. beta-C-telopeptide was decreased in older patients. More fractures were reported in patients than controls (P < 0.001). The number of vertebrae and wrist fractures almost reached significance (P = 0.058). CONCLUSIONS: Women with CAH have low BMD and increased fracture risk. BMD should be monitored, adequate prophylaxis and treatment instituted, and glucocorticoid doses optimized from puberty.

Nonfatal stroke, cardiac disease, and diabetes mellitus in hypopituitary patients on hormone replacement including growth hormone.

CONTEXT: The impact of long-term GH replacement on cerebrovascular and cardiovascular diseases and diabetes mellitus in hypopituitary patients is unknown. OBJECTIVE: The incidence of nonfatal stroke and cardiac events, and prevalence of type 2 diabetes mellitus (T2D) and cardioprotective medication were compared between cohorts of GH-deficient (GHD) patients and population controls. DESIGN AND PARTICIPANTS: The incidence of nonfatal stroke and cardiac events was estimated retrospectively from questionnaires in 750 GHD patients and 2314 matched population controls. A prevalence of T2D and cardioprotective medication was recorded at the distribution of questionnaires. Time since first pituitary deficiency to start of GH therapy was 4 and 2 yr, and time on GH therapy was 6 yr for GHD women and men, respectively. RESULTS: Lifelong incidence of nonfatal stroke was tripled in GHD women and doubled in GHD men, but a decline was seen in both genders during periods after first pituitary hormone deficiency and GHD, during which most patients had GH therapy. The lifelong incidence of nonfatal cardiac events declined in GHD men during first pituitary hormone deficiency and GHD periods. GHD women had a higher prevalence of T2D and lipid-lowering medication, whereas GHD men had a higher prevalence of antihypertensive medication. CONCLUSIONS: The declined risks of nonfatal stroke in both genders and of nonfatal cardiac events in GHD men during periods on GH replacement may be caused by prescription of cardioprotective drugs and 6-yr GH replacement. GHD women had an increased prevalence of T2D, partly attributed to higher body mass index and lower physical activity.

Eating behavior and gastric emptying in adults with Prader-Willi syndrome.

BACKGROUND/AIMS: Prader-Willi syndrome (PWS) is a complex genetic disorder characterized by distinctive physical, behavioral and psychiatric features. One cardinal symptom is excessive eating, often leading to extreme obesity. The etiology of the hyperphagia is unknown, but eating behaviors and gastrointestinal motility could play a pivotal role. In this pilot study, we therefore sought to give a closer description of the two. METHODS: 12 PWS adults, 6 men and 6 women, 17-37 years of age with a median BMI of 34.9 were evaluated. Computerized monitoring of eating behavior and assessment of gastric emptying using paracetamol absorption were analyzed. Gastric emptying rate was compared to the rate in normal and obese controls. RESULTS: Eating behavior pattern was nonhomogeneous in the PWS patients, but they experienced both hunger and satiation. In PWS gastric emptying was similar to lean subjects (p > 0.05), but longer than in obese subjects (p < 0.05). CONCLUSIONS: Despite obesity, this group of adults with PWS did not display overeating in the test situation and gastric emptying rate was normal. Numbers are small, but the results are important for the treatment of obesity in this special group of patients.

Adrenal incidentaloma - follow-up results from a Swedish prospective study.

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 > or =0.5 cm was reported in 17 (7.4%) and of > or =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.

Expression and growth dependency of the insulin-like growth factor I receptor in craniopharyngioma cells: a novel therapeutic approach.

Craniopharyngioma is a rare benign intracranial epithelial tumor that, however, often recurs and sometimes kills the affected patients, one-third of which are children. In many cases, the patients acquire growth hormone deficiency and postoperatively need substitution. Generally, growth hormone promotes local release of insulin-like growth factor I (IGF-I), which in turn activates the IGF-I receptor (IGF-IR) if present. Together, these circumstances raise the question whether IGF-IR may be involved in craniopharyngioma growth. To address this issue, we analyzed phenotypically well-characterized primary low-passage craniopharyngioma cell lines from nine different patients for IGF-IR expression and IGF-I dependency. Two of the cell lines showed no/very low expression of the receptor and was independent on IGF-I, whereas five cell lines exhibited a strong expression and was clearly contingent on IGF-I. The two remaining cell lines had low receptor expression and IGF-I dependency. Upon treatment with an IGF-IR inhibitor, cells with high IGF-IR expression responded promptly with decreased Akt phosphorylation followed by growth arrest. These responses were not seen in cells with no/very low receptor expression. Growth of cell lines with low IGF-IR expression was only slightly affected by IGF-IR inhibition. Taken together, our data suggest that IGF-IR may be involved in the growth of a subset of craniopharyngiomas and points to the possibility of the involvement of IGF-IR inhibitors as a treatment modality to obtain complete tumor-free conditions before growth hormone substitution.

Growth hormone induced lipolysis during short- and long-term administration in adult Prader-Willi patients.

Prader-Willi syndrome (PWS) is a complex genetic disease, clinically characterised by short stature, abnormal body composition, with more body fat than lean body mass, hyperphagia and obesity. Partial growth hormone (GH) deficiency is common, and GH treatment to PWS children and adults has shown beneficial effects on body composition. In this study, we have evaluated indices of GH's lipolytic effect in 6 PWS adults analysing glycerol, lactate and glucose in dialysate from microdialysis in subcutaneous abdominal adipose tissue. The patients were four men and two women, 19-37 years old; all hypogonadal. BMI was 24.2-49.1, mean 35.9 kg/m(2). All had normal serum insulin levels. They received GH therapy (Genotropin Pfizer) during 12 months and doses were individually titrated to normal serum IGF-I for age. Immediately before treatment start and at 12 months, 30-36 h after the last GH injection, sampling of dialysate was carried out at night (11 p.m. to 7 a.m.), as well as after intravenously injection of a standardised GH dose (0.8 mg). At baseline individual mean night time glycerol and lactate were similar to levels in adults without PWS (160.7-278.1 micromol/L and 0.80-3.99 mmol/L, respectively), and did not change with 12 months GH treatment. Glucose levels were normal, except in a patient with diabetes, and did not change during the study. Compared to baseline the immediate effect of GH injection resulted in a significant increase in glycerol levels after 12 months. In conclusion, night time lipolytic response in this small group of PWS adults seemed normal and did not change after 12 months GH treatment. On the other hand short-term GH induced lipolysis increased, indicating normal lipolytic response in PWS.

Metabolic profile and body composition in adults with Prader-Willi syndrome and severe obesity.

Previous investigations of adults with the Prader-Willi syndrome (PWS) are few and have demonstrated severe obesity with increased morbidity and mortality in cardiovascular disease. It is, thus, important to identify risk factors and, if possible, start prevention. We studied the clinical, genetic, endocrinological, and metabolic findings in 19 adult PWS patients (10 men; mean age, 25 yr). The PWS karyotype was demonstrated in 13 patients. The mean body mass index was 35.6 kg/m(2), and total body fat was increased. Two thirds were biochemically hypogonadal. Fifty percent had severe GH deficiency (GHD). Four were hypertensive. One patient had heart failure and diabetes. Impaired glucose tolerance was seen in 4 patients, elevated homeostasis model assessment index in 9 patients, and modest dyslipidemia in 7. IGF-binding protein-1 correlated negatively with insulin levels. Four patients had osteoporosis, and 11 had osteopenia. There was no significant difference between the group with the PWS karyotype and the group without the karyotype in age, body mass index, waist/hip ratio, percent body fat, insulin values, homeostasis model assessment index, or lipid profile, except for lipoprotein(a), which was significantly higher in the group with the negative karyotype. IGF-I and lumbar spine bone mineral density were significantly lower in patients with genetic alteration, indicating a more severe GHD. The risk factors found in this study predicting cardiovascular disease are interpreted as secondary to GHD. These findings point to the importance of evaluating treatment of GHD in adults with PWS.

Diurnal profiles of testosterone and pituitary hormones suggest different mechanisms for menstrual disturbances in endurance athletes.

The aim of this study was to evaluate the diurnal pattern of testosterone and pituitary hormones in endurance female athletes with different types of menstrual disorder. Age- and body mass index-matched groups of endurance athletes with amenorrhea (n = 10) and oligomenorrhea (n = 6), regularly cycling athletes (n = 8), and sedentary controls (n = 8) were compared with respect to 24-h hormonal profiles of testosterone, LH, prolactin (PRL), GH, insulin, IGF binding protein 1 (IGFBP-1), and cortisol. The 24-h hormone profiles in amenorrheic athletes were characterized by decreased LH pulsatility and peak amplitude of PRL and increased baseline levels of GH and cortisol. However, oligomenorrheic athletes displayed a significantly different pattern with higher diurnal testosterone secretion than all other groups. Furthermore, LH, PRL, GH, and cortisol secretions were comparable with regularly menstruating subjects. In the combined group of athletes with menstrual disturbances, diurnal secretions of testosterone, LH, and PRL were positively, whereas cortisol was negatively correlated with the number of menstruations the last year. Although this could be explained by a gradual inhibition of the hypothalamic-pituitary-gonadal axis, our results indicate that the symptoms of amenorrhea and oligomenorrhea may reflect two hormonally distinct conditions. Thus, amenorrheic athletes displayed a hormonal pattern in agreement with hypothalamic inhibition due to energy deficiency, whereas oligomenorrheic athletes demonstrated increased diurnal secretion of testosterone, suggesting a different mechanism, e.g. essential hyperandrogenism.

Postoperative differentiation between unilateral adrenal adenoma and bilateral adrenal hyperplasia in primary aldosteronism by mRNA expression of the gene CYP11B2.

OBJECTIVE: Primary aldosteronism (PA) is characterized by hypertension, hypokalemia and suppressed renin-angiotensin system caused by autonomous aldosterone production. The aim of this study was to localize mRNA expression of the genes coding for steroidogenic enzymes in adrenals from a group of patients with PA and relate this to clinical work-up, histopathology and outcome of adrenalectomy. DESIGN: This was a retrospective study of 27 patients subjected to adrenalectomy for PA. METHODS: Clinical data were collected and follow-up of all patients was performed. Paraffin-embedded specimens were analyzed by the in situ hybridization technique, with oligonucleotide probes coding for the steroidogenic enzyme genes. RESULTS: The resected adrenals had the histopathologic diagnosis of adenoma (11), adenoma and/or hyperplasia (15) or hyperplasia (1). CYP11B2 expression (indicating aldosterone production) was found in a dominant adrenal nodule from 22 patients. Fourteen of these had additional CYP11B2 expression in the zona glomerulosa. All 22 patients were cured of PA by adrenalectomy. One of these patients, who had additional high expression of CYP11B2 in the zona glomerulosa, was initially cured, but the condition had recurred at follow-up. Two patients had a mass shown on computed tomography without CYP11B2 but with CYP11B1 and CYP17 expression (indicating cortisol production). Instead their adrenals contained small nodules with CYP11B2 expression. These patients were not cured. CONCLUSIONS: Clinical data, endocrinologic evaluation and histopathology in combination with mRNA in situ hybridization of steroidogenic enzyme genes provide improved opportunities for correct subclassification postoperatively of patients with primary aldosteronism. At present, the in situ hybridization method is of special value for analysis of cases not cured by adrenalectomy.

The growth hormone-insulin-like growth factor axis in adult patients with Prader Willi syndrome.

OBJECTIVE: Prader Willi syndrome (PWS) is a genetic disorder characterised by short stature, extreme obesity, body composition abnormalities and behavioural problems. Hypothalamic dysfunction with low growth hormone (GH) secretion and low levels of GH-related growth factors is common. However, the interpretation is difficult because of the concomitant obesity, which in itself has important effects on the GH-IGF-I-system. We therefore analysed free and total IGF-I, total IGF-II and their binding proteins in obese PWS adults before and during 12 months GH treatment. Seventeen adults, 9 men and 8 women, 17-32 years of age with a mean BMI of 35+/-2.3 kg/m(2) participated. All had clinical PWS. They were randomized to treatment with placebo or GH (Genotropin, Pharmacia) 0.8 IU (0.26 mg) for one month, and then 1.6 IU (0.53 mg) for 5 months. Subsequently GH doses were individually titrated to normal levels for age. Overnight fasting levels of free and total IGF-I, total IGF-II, GH-binding protein (GHBP) and IGF-binding proteins (IGFBP)-1, -2 and -3 were measured by RIA at baseline and after 6 and 12 months GH treatment. Mean levels+/-SEM of free IGF-I were 1.02+/-0.12 microg/L as compared to a reference value of 0.95+/-0.15 microg/L, while mean total IGF-I was 128+/-15 microg/L (212+/-14 microg/L) and total IGF-II was 704+/-45 microg/L (825+/-34 microg/L). Mean IGFBP-2 158+/-24 microg/L (764+/-72 microg/L) and GHBP 2.65 nmol/L (1.71+/-0.3 1nmol/L). IGFBP-1 and IGFBP-3 levels were normal. Both free and total IGF-I increased significantly during GH treatment, while IGF- and GH-binding proteins as well as total IGF-II remained unchanged. CONCLUSION: Low total IGF-I and, in relation to the obesity, low free IGF-I, low total IGF-II and non-suppressed IGFBP-1 are consistent with the concept that PWS patients have a partial GH deficiency, which can be corrected by GH replacement.

Peptides associated with hyperphagia in adults with Prader-Willi syndrome before and during GH treatment.

UNLABELLED: Prader-Willi syndrome (PWS) is a complex genetic disorder characterised by mild mental retardation and distinct physical, behavioural, and psychiatric features. One of the cardinal symptoms is excessive eating, which--if left untreated--leads to extreme obesity. In the present study we have examined circulating levels of peptides with documented association to hyperphagia in young adults with PWS. Since growth hormone (GH) is often used nowadays to correct GH insufficiency during childhood PWS, we also studied the impact of GH administration on the peptides. Seventeen adults, 9 men and 8 women, 17-32 years of age with a mean BMI of 35+/-3.2 kg/m(2) participated. All had clinical PWS (Holm's criteria). Genetic testing was performed in all patients and in 11 the diagnosis was confirmed. They were randomized to treatment with either placebo or GH (Genotropin, Pharmacia Corporation) for 6 months. Subsequently all received open label treatment to provide all subjects with 12 months active GH treatment. Doses were individually titrated. Weight, BMI, oxytocin (baseline only), leptin, Neuropeptide Y (NPY), and ghrelin were evaluated at baseline and after 6 and 12 months. At baseline plasma mean oxytocin was within and serum ghrelin just above the normal range (14.7+/-1.2 pmol/L and 0.87+/-0.12 microg/L, respectively). Serum leptin levels were high above and plasma NPY levels within the lower normal range (47.8+/-29.1 microg/L and 13+/-1 pmol/L, respectively). Results were independent of genotype. No changes in mean BMI, ghrelin, leptin or NPY were seen following GH treatment. CONCLUSION: Leptin levels were in general high reflecting obesity and as a consequence NPY levels were low. In simple obesity oxytocin levels are high, while ghrelin levels are suppressed. In view of the adiposity oxytocin circulated in abnormally low and ghrelin in abnormally high concentrations in our patients. GH treatment of PWS patients did not change ghrelin, leptin or NPY. We suggest that both oxytocin and ghrelin are involved in the pathogenesis of hyperphagia seen in PWS.

Transsphenoidal surgery in Cushing disease: 10 years of experience in 34 consecutive cases.

OBJECT: Cushing disease is a rare disorder. Because of their small size the adrenocorticotropic hormone (ACTH)-producing tumors are often not detectable on neuroimaging studies. To obtain a cure with transsphenoidal surgery (TSS) may therefore be difficult. In this report the authors present 10 years of experience in the treatment of patients with Cushing disease who were followed up with the same protocol and treated by the same surgeon. METHODS: Thirty-four patients, 26 of them female and eight of them male (mean age 40 years, range 13-74 years) were studied. All had obvious clinical signs and symptoms of Cushing syndrome. Magnetic resonance (MR) imaging was performed in all patients, and inferior petrosal sinus (IPS) sampling was done in 14. In 12 patients MR imaging indicated a pituitary tumor; 10 were microadenomas and two were macroadenomas. In six patients with no visible tumor, the results of IPS sampling supported the diagnosis. All patients underwent TSS; the mean follow-up duration was 6 +/- 0.5 years. Selective adenomectomy was performed in 32 and hemihypophysectomy in the other two patients. A cure was obtained in 31 patients (91%) after one TSS and in two more patients after further TSS; one patient was not cured despite two TSSs and one underwent bilateral adrenalectomy. Disease recurrence was seen in two patients after 3 years, and they were successfully treated with stereotactic gamma knife surgery. Half of the patients had an ACTH deficiency postoperatively, whereas one third had other pituitary hormone insufficiencies. There were no serious complications attributable to the surgical intervention. CONCLUSIONS: Transsphenoidal surgery with selective adenomectomy is an effective and safe treatment for Cushing disease. In the patients presented in this study, the surgical outcome seemed to depend on careful preoperative evaluation and the surgeon's experience. For optimal results in this rare disease the authors therefore suggest that the endocrinological, radiological, and surgical procedures be coordinated in a specialized center.

Gamma knife radiosurgery for craniopharyngiomas: long-term results in the first Swedish patients.

OBJECT: The purpose of this study was to assess the long-term treatment efficacy and morbidity of patients who undergo gamma knife radiosurgery (GKS) for craniopharyngioma. METHODS: Twenty-one consecutive Swedish patients were evaluated retrospectively: 11 children (< or = 15 years) and 10 adults. The time from diagnosis to the most recent follow-up imaging study was 6.3 to 34.3 years (mean 18.2 years, median 16.8 years). Tumor volumes and morbidity from GKS or other treatments were assessed at the time of the most recent imaging study or at the time of a subsequent new treatment. The observation period ranged from 0.5 to 29 years (mean 7.5 years, median 3.5 years). The prescription dose ranged from less than 3 Gy to 25 Gy. The mean tumor volume was 7.8 cm3 (range 0.4-33 cm3). There were 22 tumors in 21 patients treated with GKS. Five of these tumors were reduced in size, three were unchanged, and 14 increased. Tumor progression correlated with a low dose to the tumor margin. Eleven (85%) of 13 tumors that received a dose of less than 6 Gy to the margin increased in size, whereas only three (33%) of nine tumors that received 6 Gy increased. This difference was statistically significant (p = 0.01). In five of six patients tumors that became smaller after GKS there were no recurrences within a mean follow-up period of 12 years. Nine (82%) of 11 tumors in children ultimately increased after GKS, compared with five (50%) of 10 in adults. In eight patients there was a deterioration of visual function. In all except one this could be related to a volume increase but radiation-induced damage could not be excluded as a factor in any of them. Four patients developed pituitary deficiencies. CONCLUSIONS: Gamma knife radiosurgery is effective in controlling growth of craniopharyngiomas with a minimum dose of 6 Gy. The findings also suggest that other stereotactic techniques, such as cyst aspiration and intracystic treatment, are only of value in reducing tumor volume in preparation for safe GKS.

Somatropin therapy in adults with Prader-Willi syndrome.

Prader-Willi syndrome is a complex genetic disorder with a characteristic cognitive, behavioral, and endocrinologic phenotype. Obesity, partial growth hormone (GH) secretion, and hypogonadism are common. Results of several somatropin (GH therapy) studies in children with Prader-Willi syndrome have shown improvement in growth, body composition, physical strength, and agility. GH deficiency in adults without Prader-Willi syndrome is associated with abdominal obesity, insulin resistance, and an unfavorable lipid profile, and the partial state of GH deficiency seen in Prader-Willi syndrome thus renders these patients exposed to a lifelong risk of metabolic diseases. The nongrowth effects of somatropin in children with Prader-Willi syndrome have directed interest towards adults in preventing long-term consequences of GH deficiency, but the potential impact of somatropin therapy in adults with Prader-Willi syndrome is not known in detail. To date, only one study has been published. In this study, 17 patients (9 men and 8 women) with a mean age of 25 years and a mean body mass index of 35 +/- 3.2 kg/m2 were examined. Eleven had the Prader-Willi syndrome genotype. They were treated with somatropin (Genotropin) for 12 months after an initial placebo-controlled period of 6 months. Compared with placebo, somatropin increased insulin-like growth factor-1 levels (p < 0.01) and decreased body fat (p = 0.04). During the 12-month period with somatropin therapy, the mean reduction in body fat was 2.5% (p < 0.01), concomitant with a mean increase in lean body mass of 2.2kg (p < 0.05). Lipid profiles were normal in most patients before treatment and did not change. The oral glucose tolerance test was impaired in one patient at study start and in five patients at 12 months. No patients developed diabetes mellitus. Furthermore, insulin levels remained unchanged, and estimation of insulin resistance by homeostasis model assessment did not disclose any change. Transient adverse effects attributed to water retention occurred in three patients. In conclusion, the one published study of somatropin therapy in adults with Prader-Willi syndrome showed beneficial effects on body composition without pronounced adverse effects. However, further studies are required to establish the definite role and optimal dosage of somatropin, as well as long-term effects, in adults with Prader-Willi syndrome.