CONTEXT It is well established that clinical features of acromegaly concern the teeth and the jaw, but less is known about the degree of oral and maxillofacial pathologies. PATIENTS 28 acromegalics (13 females, 15 males) with a mean age 49±11 (mean±SD) years (range 31-70) were included in the study. 32% had active disease, 68% were well-controlled under the somatostatin analogue octreotide, the dopamine agonist cabergoline, and the GH receptor antagonist pegvisomant, or were cured after pituitary surgery and/or radiation. METHODS All subjects undergone intensive and complex examinations of a plaster model and facial arch with articulator, an intra-oral bracket-pen registration, analysis of a digital picture, panoramic and lateral radiographs with cephalometry in comparison with a reference group (n=201). RESULTS 42% had a diastema mediale (0.9±1.1 mm). Overbite and overjet (vertical overbite) correlated with the disease duration (r²=0.2237; p=0.011 respectively r²=0.3364; p=0.015). 96% had an asymmetric movement of the mandible. 57% had a prognathism. The protrusion of the mandible correlated significantly with the disease duration (r²=0.1784; p=0.028). The degree of the mandibular prognathism (SNB-angle) was higher in the acromegalic group (84°±7° vs. 81°±3°, p<0.05). The ANB-angle indicates the relation between maxilla and mandible and was negative in the acromegalic group and positive in the controls (-0.3°±5.0° vs. 1.6°±2.1°, p=<0.05) and correlated negative with the disease duration (r²=0.2553; p=0.0061). The mandibular angle was significantly greater in the acromegalic group (126°±9° acromegalic group vs. 121°±7°control group, p=0.003). The length of the mandible correlated with the disease duration (r²=0.2801; p=0.0038). 86% had an asymmetric face. The high of the midface was in the acromegalic group higher (6.1±0.7 vs. 5.5±0.4 cm, p=0.0009) as well as the lower bony high of the face (9.5±1.0 acromegalics vs. 6.9±0.5 cm controls, p=0.0009). The high of the lower bony face correlated with as well with the disease duration (r²=0.3224; p=0.0016). CONCLUSIONS Patients with acromegaly suffer not only from cardiovascular, metabolic and neoplastic complications, but also from dental and jaw disorders. The high incidence of these manifestations and its relation to the disease duration requires a carefully work-up of oral and maxillofacial examinations in close collaboration with endocrinologists, dentists and dental surgeons.

CONTEXT:Serum calcitonin (hCT) measurement may be useful for detecting medullary thyroid carcinoma (MTC), but the routine use of hCT after pentagastrin stimulation to screen patients with nodular thyroid disease remains controversial. PATIENTS:A total of 1007 patients (567 females and 440 males) with nodular thyroid disease and a mean age of 55+/-14 (mean+/-S.D.) years were included in the study. All patients did not have impaired renal function, bacterial infection, alcohol and drug abuse, pseudohypoparathyroidism, or proton-pump inhibitor therapy. Individuals referred with known elevation of hCT, Graves' disease, or autoimmune thyroid disease were not considered or included in this investigation. METHODS:Serum hCT levels were determined under basal conditions, and when basal values were >or=10 and <100 pg/ml, testing was repeated after pentagastrin stimulation. Patients with basal or stimulated levels >100 pg/ml were referred for surgery. RESULTS:hCT levels >10 pg/ml were increased in 17 patients (1.7%). One patient had a basal hCT level of 4400 pg/ml with a histological confirmation of a MTC. In this patient, pentagastrin test was not performed. Sixteen patients with basal hCT between 10 and 100 pg/ml underwent pentagastrin-stimulated hCT measurement. Of 16 patients, 4 had stimulated hCT>100 pg/ml. Of 17 patients with hCT>10 pg/ml, 2 had MTC, and of 17 patients, 3 had C-cell hyperplasia. In total, two patients (0.20%) had a histologically verified MTC. CONCLUSIONS:Basal hCT measurement together with pentagastrin-stimulated hCT measurement in cases of basal hCT>10 pg/ml detects MTC in 0.20% of patients with nodular thyroid disease. Whether this high incidence of MTC has major implications or not has to be discussed, but it should be considered as a useful and recommended tool for early detection of MTC and to save patients' life.

CONTEXTData on cardiovascular risk in acromegaly are scanty and lack a clear correlation to epidemiological data.OBJECTIVEOur aim was an evaluation of cardiovascular risk factors in patients with active acromegaly, a calculation of the Framingham risk score (FRS) compared with age- and gender-matched controls of the general population, and an evaluation of the effect of IGF-I normalization.DESIGN AND SETTINGWe conducted a retrospective, comparative study at a university referral center.PATIENTSA total of 133 patients with acromegaly (65 men, aged 45-74 yr) from the German Pegvisomant Observational Study were matched to 665 controls from the general population.MAIN OUTCOME MEASURESRisk factors were measured at baseline and after 12 months of treatment with pegvisomant (n=62).RESULTSPatients with acromegaly had increased prevalence of hypertension, mean systolic and diastolic blood pressure (BP), history of diabetes mellitus and glycosylated hemoglobin (all P<0.001) and decreased high-density lipoprotein, low-density lipoprotein, and total cholesterol (all P<0.001). FRS was significantly higher in patients with acromegaly compared with controls (P<0.001). At 12 months, systolic BP (P=0.04) and glycosylated hemoglobin (P=0.02) as well as FRS (P=0.005) decreased significantly. IGF-I was normalized in 62% (41 of 62). In these patients, glucose and systolic and diastolic BP was significantly lower than in partially controlled patients.SUMMARYWe found an increased prevalence of cardiovascular risk factors in acromegalic patients compared with controls. Control of acromegaly led to a significant decrease of FRS, implying a reduced risk for coronary heart disease. This was most significant in those patients who completely normalized their IGF-I levels.CONCLUSIONDisease control is important to reduce the likelihood for development of coronary heart disease.

It is well established, that the increased mortality in patients with acromegaly is due to cardiac diseases. Cardiomyopathy is the predominant cardiac alteration in patients with acromegaly. There are less data about coronary heart disease or coronary calcifications. Electron beam computed tomography (EBCT) is the standard imaging modality for identification of coronary artery calcifications (CAC) and can determine the extent and severity of coronary atherosclerosis. Coronary risk was evaluated by the Framingham risk score (FRS). The prospective study included 30 patients with acromegaly (mean age 53+/-14 year; 16 females, 14 males; BMI 28.1+/-3.6 kg/m (2); mean+/-SD), 12 patients had active disease (IGF-1 751+/-338 microg/L; GH 25.6+/-36.4 microg/L), 9 were well-controlled (IGF-1 157+/-58 microg/L; GH 1.8+/-1.1 microg/L) under somatostatin analogue octreotide (n=5), dopamine agonists (n=2), and the GH receptor antagonist pegvisomant (n=2; GH levels were not determined in this subgroup) and 9 were cured IGF-1 (148+/-57 microg/L; GH 0.5+/-0.2 microg/L). Increased left ventricular muscle mass index (LVMI >132 g/m (2)) was focused in 53%, hypercholesterinemia in 63%, hypertension in 43%, diabetes mellitus/impaired glucose tolerance in 27%, and smokers in 53% (pack per year 9+/-15 yr). For quantification of CAC the EBCT was used and the Agatston calcium score was determined. Results were composed to established age and sex adjusted percentile distribution of CAC. CAC was present in 53%, high CAC score (75 (th) percentile) in 37% and were categorized as cardiovascular high risk patients. FRS was related to the CAC score (p=0.008, r (2)=0.22) and the disease duration (p=0.002, r (2)=0.29). The CAC score correlated with LVMI (p=0.02, r (2)=0.17), the disease duration of acromegaly (p=0.004, r (2)=0.36), and the FRS (p=0.008, r (2)=0.22). Patients with a high CAC score had a longer disease duration of 9.6+/-4.7 versus 5.4+/-2.8 years with CAC<75 (th) percentile (p=0.02). In summary, the disease duration and consequently the accompanying metabolic disorders appear to influence the degree of CAC in patients with acromegaly. The observations underline the importance of early and sufficient treatment of acromegaly in high risk patients.

OBJECTIVES:Sleep apnoea has been consistently reported to occur in acromegaly. In uncontrolled patients, the severity of sleep apnoea influences physical activity in the daytime. We investigated the influence of disease activity on tongue volume and sleep apnoea treated with the GH receptor antagonist pegvisomant in poorly controlled patients with acromegaly under octreotide.DESIGN AND METHODS:A total of 12 patients with active acromegaly (six females; six males; mean age 57+/-15 years; body mass index 29.4+/-4.2 kg/m(2); mean+/-S.D.) were treated with pegvisomant (13.5+/-5.0 mg/die) for 6 months. Tongue volume was examined by magnetic resonance imaging, and sleep apnoea was characterized by polysomnography before and after 6 months of treatment with pegvisomant. The mandibular length was determined by lateral X-ray films.RESULTS:IGF1 levels decreased after 6 months in all patients (407+/-114 to 199+/-23 microg/l; P=0.0001). The tongue volume decreased (105+/-33 to 83+/-33 ml; P=0.007) as well as the apnoea-hypnoea index (23+/-22 to 18+/-18/h; P=0.0066). The mandibular length correlated with the initial tongue volume (r(2)=0.6072, P=0.0028).CONCLUSION:In conclusion, successful treatment with pegvisomant can decrease tongue volume, which has benefits for coexisting sleep disordered breathing.

INTRODUCTION:We determined the prevalence of anterior pituitary dysfunction in a multi-centre screening program across five German endocrine centres in patients rehabilitating from TBI (GCS<13).PATIENTS & METHODS:246 patients (39+/-14 yrs; 133 males, 12+/-8 months after TBI) underwent a series of baseline endocrine tests with central assessment of TSH, free T4, prolactin, LH, FSH, testosterone (m), estradiol (f), cortisol, GH, and IGF-I. If IGF-I was <-2 SDS dynamic testing was performed. GHD was defined according to BMI-dependent cut-off values for GH response to GHRH+arginine of <4.2, <8.0 and <11.5 ng/ml in obese, overweight and lean subjects, respectively, or <3 micro g/l in ITT. Hypocortisolism was suggested when basal cortisol was <200 nmol/l and confirmed by ITT (peak<500 nmol/l).RESULTS:In TBI patients some degree of impaired pituitary function was shown in 21% (n=52/246). Total, multiple and isolated deficits were present in 1%, 2% and 18%, respectively. 19% had an IGF-I of <-1 SDS, 9% of <-2 SDS. In 5% GHD was confirmed. 9% had hypogonadism. 4% had hypocortisolism and 1% of patients had confirmed ACTH-deficiency. 12% had TSH-deficiency.SUMMARY:In summary, in this large series carried out on an unselected group of TBI survivors we have found hypopituitarism in every fifth patient with predominantly secondary hypogonadism and hypothyreosis. Regarding somatotrope insufficiency IGF-I is decreased in 50% of GHD patients.CONCLUSION:These findings strongly suggest that patients who suffer head trauma should routinely undergo endocrine evaluation.

Testosterone pellets seem to be an androgen formulation with a long biological action and a strong pharmacodynamic efficacy. We performed this investigation to establish detailed data about the pharmacokinetics, the efficacy and side-effects of subcutaneously implanted testosterone (T) pellets in a single center between 1994 and 2005. In an open-label, non-randomized study, 6 T-pellets, each containing 200mg of fused crystalline T, were implanted in the subdermal fat tissue of the lower abdominal wall of 100 hypogonadal men over 5 years. All patients (mean age 39.7±13.4 yr; BMI 28.1±5.6kg/m2; T <4.7 nmol/l; mean±SD) suffered from primary (n=34) or secondary hypogonadism (n=66). Blood samples for determination of T, hemoglobin, PSA, lipid parameters and bone mineral density (BMD) at the lumber spine 2–4 were obtained over 5 years. T kinetics was revealed over 7 months after implantation. The pharmacokinetic study in 100 hypogonadal men revealed an initial short-lived burst release of T with a peak concentration of 25.5±8.9 nmol/l after 2 months which was followed by a decline after 4 months (14.7±6.7 nmol/l), 5 months (11.8±5.8 nmol/l), 6 months (7.8±3.2 nmol/l) and 7 months (5.5±3.0 nmol/l). After a period of 5 years hemoglobin (14.6±1.6 to 15.1±1.3g/dl; p=0.03) and BMD of the lumbar spine 2–4 (1090±175 to 1263±203g/cm2; p=0.003) increased. PSA (1.12±1.0 to 0.76±0.64 ng/ml; p=0.16), total cholesterol, HDL, LDL and triglycerides did not changes. The only side-effects observed during 1100 implantations in the total group were 20 local infections (1.8%) and the extrusion of 82 pellets.

Sleep apnoea has been consistently reported to occur in acromegaly. In poorly controlled patients, the severity of sleep apnoea may influence physical activity in the daytime. To address this issue, we investigated the influence of disease activity on tongue volume and sleep apnoea treated with the GH-receptor antagonist pegvisomant in poorly controlled patients with acromegaly under octreotide. 14 patients with active acromegaly (9 females; 5 males; mean age 55±14yrs; BMI 28.0±4.9kg/m2; mean±SD) were treated with pegvisomant (13.5±5.0mg/die) over 6 months. Tongue volume was examined by magnet resonance imaging and sleep apnoea was characterized by polysomnography before and after 6 months treatment with pegvisomant. The initial tongue volume was significantly higher in patients with acromegaly (142±48ml) in comparison to the BMI and age-matched healthy control group (97±5ml, p=0.02). Results of 7/14 were present. IGF-1 levels reduced after 6 months (361±161 to 212±71µg/L; p=0.04). The tongue volume decreased significantly (142±48 to 105±25ml; p=0.017) whereas the apnoea-hypnoea-index (AHI) only decreased as a tendency (26±26 to 22±26 /h; p=0.14). In conclusion, successful treatment with pegvisomant can decrease tongue volume, which may have benefits for coexisting sleep disordered breathing.

OBJECTIVE Patients with traumatic brain injury (TBI) are at moderate risk of GH deficiency (GHD), requiring a diagnostic test with high specificity. The GHRH + arginine (GHRH + ARG) test has been recommended as a reliable alternative to the insulin-tolerance test (ITT) as a standard test with a cutoff level of 9 ng/ml. However, it has recently been questioned for its low specificity in obese subjects, and now BMI-dependent cut-off levels are available. In this study, we compared the ITT and GHRH + ARG test in patients with TBI. DESIGN A cross-sectional study METHODS We performed an ITT and a GHRH + ARG test in 21 patients with TBI (6 women, 15 men; mean age 40.2 +/- 12.1 years; BMI 30.7 +/- 6.2). The number of patients classified discordantly as GH deficient by the ITT and the GHRH + ARG test with both classical and BMI-dependent cut-off levels was assessed. RESULTS Using the GHRH + ARG test with the classical cut-off ( 3 ng/ml), and one patient as GH sufficient who had a blunted GH response to ITT (discordance rate 61.9%). All patients discordantly classified as GH deficient by the GHRH + ARG test had a BMI of >or= 28. With the BMI-dependent cut-offs (4.2, 8.0, and 11.5 ng/ml in obese, overweight, and lean subjects respectively), only 3 of the 21 patients were discordantly classified (discordance rate 14.3%). CONCLUSIONS Our results discourage the use of a cut-off level of 9 ng/ml for the GHRH + ARG test in obese subjects. The diagnostic reliability of this test is improved with the BMI-dependent cut-offs.

Although hypopituitarism is a known complication of traumatic head injury, it may be under-recognized due to its subtle clinical manifestations. To address this issue, we determine the prevalence of neuroendocrine abnormalities in patients rehabilitating from severe traumatic brain injury (Glasgow Coma Scale < or = 8). 76 patients (mean age 39 +/- 14 yr; range 18-65; 53 males and 23 females; BMI 25.8 +/- 4.2 kg/m2; mean +/- SD) with a severe traumatic brain injury, an average of 22 +/- 10 months before this study (median, 20 months), underwent a series of standard endocrine tests, including TSH, free T4, T4, T3, prolactin, testosterone (males), estradiol (females), cortisol, ACTH, GH, and IGF-I. All subjects also underwent GH response to GHRH + arginine. Growth hormone deficiency (GHD) was defined as a GH response < 9 microg/L to GHRH + arginine and was confirmed by ITT (< 3 microg/L). Pituitary deficiency was shown in 24% of the patients (18/76). 8% (n = 6) had GHD (GH-peak range [GHRH + arginine]: 2.8-6.3 microg/L; GH-peak range [ITT]: 1.5-2.2 microg/L; IGF-I range: 62-174 microg/L). 17% (n = 13) had hypogonadism (total testosterone < 9.5 nmol/L and low gonadotropins in 12 males; low estradiol, and low gonadotropins in 1 female). Total testosterone levels did not correlate with BMI or age. 2 males with hypogonadism also showed a mild hyperprolactinemia (33 and 41 ng/ml). 3% (n = 2) patients had partial ACTH-deficiency (cortisol-peak [ITT] 392 and 417 nmol/L) and 3% (n = 2) had TSH-deficiency. In summary, we have found hypopituitarism in one-fourth of patients with predominantly secondary hypogonadism and GHD. These findings strongly suggest that patients who suffer head trauma must routinely include neuroendocrine evaluations.

BACKGROUND:Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and chronic anovulation. The genetic background of the insulin resistance frequently associated with PCOS is unclear.OBJECTIVES:To examine the influe nce of the Pro12Ala polymorphism of the peroxisome proliferator activated receptor gamma (PPARgamma), which is thought to play a role in the regulation of insulin sensitivity, on endocrine and metabolic parameters in PCOS patients.METHODS:PPARgamma alleles were analysed in 102 PCOS patients (age 27 +/- 5.3 years) and 104 age matched control women. PCOS was defined by the NIH-criteria as the presence of chronic oligo- or anovulation and hyperandrogenism. Family history and clinical parameters were evaluated by personal interview and physical examination, parameters of insulin resistance [homeostasis model assessment (HOMA) and Matsuda-index] were evaluated with a glucose tolerance test.RESULTS:Seventy-nine (77.5%) PCOS patients were carriers of the wild-type PPARgamma allele (Pro/Pro), while 23 (22.5%) had at least one Ala allele (X/Ala), with an equal distribution in controls. X/Ala PCOS women were more insulin-sensitive, evidenced by lower fasting insulin, HOMA index and insulin secretion. Differences in insulin resistance did not depend on body mass index. The genotype had no influence on lipid status, leptin, adiponectin, ghrelin, or family history of type 2 diabetes. A significantly lower proportion of Pro/Ala patients had hirsutism and they had on average lower hirsutism scores than Pro/Pro patients. No relationship was found between the Pro/Ala polymorphism and other signs of hyperandrogenism.CONCLUSION:The Pro12Ala polymorphism of the PPARgamma gene is associated with increased insulin sensitivity and lower hirsutism scores in PCOS women.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterised by menstrual irregularities and hyperandrogenism, affecting approximately 5% of premenopausal women. An association of PCOS with peripheral insulin resistance (IR) as the cause of its predisposition to develop a metabolic syndrome (MS) has been established. Therefore, early screening for metabolic parameters is of great importance regarding the prevention of cardiovascular diseases (CVD). In 259 PCOS women (age 27±5.9 years) cardiovascular risk factors were evaluated by physical examination, blood testing and a personal interview. MS was defined according to the NCEP ATP III criteria. The 10-year estimated CVD risk was determined by the Framingham score and projected to the age of 60. In PCOS patients 34.7% were smokers and 47% exercised frequently. Obesity was found in 49.6%, waist-circumference >88cm in 55.6%, IR in 58.8%, impaired glucose tolerance in 6.2%, type 2 diabetes mellitus (DM) in 3.5%, increased total cholesterol in 52.6%, LDL cholesterol ≥ 115mg/dl in 59.5%, low HDL in 48.3%, elevated triglycerides in 24.2% and an increased sensitive CRP in 46.4% of PCOS subjects. MS was present in 33.6% of PCOS patients. Family history of obesity was found in 71.1%, DM in 50.0%, apoplexy in 42.7%, peripheral vascular disease in 29.7% and coronary heart disease in 47.9% of affected women. The average calculated risk at the age of 60 to suffer an acute coronary event in the next ten years was 12.9%, provided that no additional risk factors develop. In conclusion, a third of our PCOS cohort fulfilled the ATP III criteria of MS before the age of 30. It is unclear whether the high incidence of cardiovascular risk factors also leads to greater expectation of morbidity and mortality.

Polycystic ovary syndrome (PCOS), which affects about one million women in Germany, is associated with insulin resistance and a high incidence of obesity. Leptin, the product of the ob gene, is involved in the regulation of energy balance and obesity and circulates in both, free and bound forms. The soluble leptin receptor (sOB-R) is the most important leptin binding protein, thus influencing free leptin levels in humans. We assessed the association of metabolic or endocrine parameters and leptin or sOB-R levels in 52 PCOS women (28±5.8 years). Leptin and sOB-R levels were measured using ELISA kits (dsl, Sinsheim, Germany). In addition, endocrine parameters (testosterone, free andogen index –FAI-, androstendione, LH/FSH ratio) were evaluated and a 3-h glucose tolerance test (OGTT) was performed to assess indices of insulin resistance (HOMA-IR, fasting insulin, AUC-insulin). Body fat was measured using a bio-impedance analyser. In PCOS patients no correlation was found between leptin or sOB-R and endocrine features or indices of insulin resistance. However, as expected, body fat, BMI, waist and hip circumference were positively correlated with leptin levels (r=0.76, 0.74, 0.62 and 0.72, respectively). A better inverse correlation of leptin and sOB-R was found in lean women than in the entire PCOS cohort (r=0.66 and 0.37, respectively). In a subgroup analysis of lean, overweight and obese patients significant differences were found in: leptin (20.8±19.4 vs. 37.2±25.2 vs. 68.5±21.4 ng/ml, p<0.001), sOB-R (9.4±3.6 vs. 9.8±4.4 vs. 7.0±3.2 ng/ml, p=0.046) and HOMA-IR (1.2±0.5 vs. 2.3±0.8 vs. 6.0±3.5). In conclusion, in PCOS women obesity and insulin resistance are associated with high leptin and low sOB-R levels, suggesting that the decrease in sOB-R, by increasing the degree of unbound leptin, might be a compensatory mechanism of leptin resistance in obesity.

Abdominal obesity and insulin resistance are central findings in the metabolic syndrome. The metabolic syndrome leads to similar symptoms of growth hormone deficiency (GHD), such as increased body fat mass and decreased lean body mass, disorders of glucose and lipid metabolism. The aim of the present study was to evaluate parameters of GH/IGF-1 axis in patients with the metabolic syndrome and its correlation with characteristic parameters of the metabolic syndrome, such as BMI, waist circumference, abdominal fat mass, fasting plasma glucose (FPG) and glucose disposal rate (GDR). The study group consisted of 25 males with the metabolic syndrome (age 55±5 yr, BMI 33.4±2.8kg/m2, FPG 121±24mg/dL; mean±S.D.). The mean IGF-1 level was 140+47µg/L and GH peaks after GHRH plus arginine (GHRH/ARG) ranged from 1.2 to 15.9µg/L (6.1±3.5µg/L) and were below 5µg/L in 10 males. 24h-GH-secretion correlated with IGF-1 levels (p=<0.0001, r2=0.6). 22/25 (88%) showed a GH response <9µg/L. IGF-1 (p=0.003, r2=0.34) and the mean 24h-GH-secretion (p=0.01, r2=0.32) correlated with the GH peak after GHRH/ARG. The BMI correlated with GH peak after GHRH/ARG (p=0.01, r2=0.21), with the mean 24h-GH-secretion (p=0.02, r2=0.24) and with the IGF-1 levels (p=0.001, r2=0.27). Furthermore, waist circumference correlated with GH peak after GHRH/ARG (p=0.01, r2=0.21), with the mean 24h-GH-secretion (p=0.02, r2=0.25) and with the IGF-1 (p=0.02, r2=0.21). We have seen a trend of correlation between IGF-1 and the abdominal fat mass (p=0.059, r2=0.15). Moreover, we have seen a weak but not significant correlation between GDR and GH peak after GHRH/ARG (p=0.06, r2=0.54). The mean 24h-cortisol-secretion was 224±54 nmol/l and did not correlate with the GH peak after GHRH/ARG (p=0.54, r2=0.1). In conclusion, GH/IGF-1 axis is blunted in patients with the metabolic syndrome. BMI and waist circumference are strong parameters correlating with a diminished somatotropic function. Obesity decreases GH secretion and consequently shares many symptoms of untreated GHD.

Although hypopituitarism is a known complication of traumatic head injury, it may be underrecognized due to its subtle clinical manifestations. To address this issue, we determine the prevalence of neuroendocrine abnormalities in patients rehabilitating from severe traumatic brain injury (Glasgow Coma Score ≤8).

Little is known about the impact of estrogen replacement therapy for bone formation, glucose metabolism and hormonal parameters on males with aromatase deficiency. Transdermal estrogen (TE) replacement was initiated at 100 mu g/week in months 0 - 3, 50 mu g/week in months 3 - 6, 25 mu g/week in months 6-12, 75 mu g/week in months 12-24, and 25 mu g/week in months 24-36 to substitute for the deficiency in a 27-year-old homozygous male with a mutation on the CYP19 gene. Estradiol levels increased from < 10 at baseline to 45,12, 27 and 17 pg/ml (normal range 10-50) after 6,12, 24 and 36 months, and inversely correlated to LH and FSH levels. Testosterone levels changed from 31.2 nmol/l at baseline to 3.8, 22.1, 7.1 and 22.0 nmol/l (9.5 - 30) after 6, 12, 24 and 36 months, respectively, and correlated closely to basal and stimulated LH and FSH levels at 100 mu g GnRH. Bone maturation progressed, and metacarpal and phalangeal epiphysis closed after 12 months. Spongiosa-hydroxyapatite of the radius assessed by quantitative computed tomography changed from 52 to 83, 51, 69 and 71 Mg/cm(3) (120 - 160); bone mineral density of the lumbar spine assessed by dual energy X-ray-absorptiometry (normal value > 1.150) increased from 0.971 (T-Score -2.24) to 1.043 (-1.64), 1.065 (1.46), 1.128 (-0.93) g/cm(2) and 1.021 (-1.82) after 6, 12, 24 and 36 months of TE, respectively. Osteocalcin as a bone formation parameter and aminoterminal collagen type I telopeptide as a bone resorption parameter increased during high-dose estrogen supplementation, and then decreased during the lower doses. Lipoprotein (a) increased from 20mg/dl at baseline to 60 and 62 mg/dl after 6 and 12 months, and then decreased to 24 and 25 mg/dl after 24 and 36 months, respectively, while total cholesterol, HDL, LDL and triglycerides did not change. AUC glucose decreased continuously after oral glucose load, and HOMA IR reached its lowest value the 75 mu g weekly estradiol dose. This study confirms the role of estrogens in achieving bone mineralization and maturation in human males. Additionally, estradiol has dual negative feedback sites that on the hypothalamus to decrease GnRH pulse frequency, and on the pituitary to decrease responsiveness to GnRH. The improvement in glucose metabolism after estrogen replacement therapy suggests a probable role of sex steroids in insulin sensitivity. The optimal weekly dose of transdermal estrogen replacement for normalizing estrogen levels and maintain bone mass in adult males with aromatase deficiency may be 50 - 75 mu g spread over two doses.

Adiponectin is a recently discovered adipocytokine that correlates negatively with body mass index and body fat. In patients with GH deficiency, treatment with recombinant human growth hormone (rhGH) reduces body fat mass and thus may also have a favorable effect in patients with metabolic syndrome, and would also be expected to increase adiponectin levels. However, due to its diabetogenic effect, rhGH treatment also bears an increased risk for the development of type 2 diabetes mellitus. We conducted a 18-month randomized, double-blind, placebo-controlled study to assess the effect of rhGH in combination with metformin (MGH) in 14 obese men (7 MGH; 7 Metformin+Placebo, 54 +/- 2 years, BMI 33.0 +/- 1.2 kg/m(2)) with mildly elevated fasting plasma glucose (FPG) at screening (6.1-8.0 mmol/l). All patients received metformin (850 mg twice daily) for treatment of type 2 diabetes mellitus/impaired glucose tolerance, either alone or in combination with rhGH (daily dose 9.5 mug/kg body weight). Glucose disposal rate (GDR) was measured using the euglycemic hyperinsulinemic clamp technique, and body composition was measured by DEXA at 0 and 18 months. After 18 months, the mean adiponectin concentration increased by 32 +/- 11 % (p = 0.018) in the MGH group and did not change in the MP group (- 10 +/- 13 %; p = n. s.). The difference in relative changes in adiponectin levels between the two groups after 18 months was statistically significant (p = 0.026). Improvement in insulin sensitivity (GDR) correlated positively with adiponectin levels (r = 0.73; p = 0.004). In conclusion, the additional administration of rhGH increased adiponectin levels in patients with metabolic syndrome, indicating its potential role in adiponectin-associated insulin sensitivity alterations.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterised by chronic anovulation and hyperandrogenism. The majority of PCOS patients show an increased insulin resistance as well as obesity and develop the sequelae of the metabolic syndrome in later years. The adipocyte-derived hormone leptin is thought to regulate body weight. Ghrelin, a peptide produced by the endocrine cells of the stomach, is also implicated as an important regulator of energy homeostasis. The aim of our study was to evaluate whether therapy with metformin modulates serum concentrations of leptin and ghrelin in PCOS patients. To this end ghrelin and leptin levels were measured in 50 PCOS women (age 27±5.5 years) before and after 6 months metformin treatment using RIA kits (LINCO Research Inc., St. Charles, MO, USA). In addition, endocrine parameters were measured and a glucose tolerance test was performed to assess insulin and glucose levels. Insulin resistance and beta-cell function were evaluated by the homeostasis model assessment test (HOMA). Body fat was measured using the Body FAT Watcher (NAIS Wellnesslife GmbH, Düsseldorf, Germany). Women taking contraceptive pills were excluded from the study. During metformin treatment HOMA-IR (4.4±3.7 to 2.2±1.3) and testosterone (2.9±1.0 to 2.0±0.7 nmol/l) decreased significantly. No significant changes were found in: BMI (31.0±7.5 to 29.8±6.8kg/m2), body fat (38.1±8.5 to 36.0±7.7%), glucose at 120 minutes (110.0±37.9 to 100.2±27.6mg/dl) or HOMA-beta (260.0±169.8 to 210.0±152.6%). Leptin decreased significantly from 36.7±23.1 to 28.8±15.6 ng/ml (p=0.0454) after 6 months metformin therapy. Ghrelin showed an inverse effect, increasing from 40.4±32.7 to 95.8±60.1 pg/ml during the study period (p<0.0001). In conclusion, the amelioration of insulin resistance in metformin treated PCOS patients correlates with an increase in fasting ghrelin and a decrease in leptin concentrations.

Besides the high prevalence of cardiac diseases in patients with acromegaly, it is currently discussed whether these patients may have an increased risk of cancer, e.g. thyroid malignancies. High serum levels of IGF-1 and GH as well as auto-/paracrine IGF-1 secretion seem to be the predominant factors of complications. Consequently, 80% of patients with acromegaly have goiter and 60% have nodules. While positive effects of IGF-1 on thyroid proliferation are well known, the role of GH on thyroid tumorigenesis is not clear.