(Patho)physiology of cross‐sex hormone administration to transsexual people: the potential impact of male–female genetic differences

There is a limited body of knowledge of desired and undesired effects of cross‐sex hormones in transsexual people. Little attention has been given to the fact that chromosomal configurations, 46,XY in male‐to‐female transsexuals subjects (MtoF) and 46,XX in female‐to‐male transsexual subjects (FtoM), obviously, remain unchanged. These differences in their genomes cause sex differences in the functions of cells. This study reviews sex differences in metabolism/cardiovascular pathology, immune mechanisms, bone (patho)physiology and brain functions and examines whether they are, maybe partially, determined by genetic mechanisms rather than by (cross‐sex) hormones. There do not appear to be major genetic impacts on the changes in bone physiology. Also immune functions are rather unaffected and the evidence for an increase of autoimmune disease in MtoF is preliminary. Brain functions of transsexuals may have differed from controls before cross‐sex hormones; they do undergo shifts upon cross‐sex hormone treatment, but there is no evidence for changes in sex‐specific brain disease. The prevalence of cardiovascular disease is higher in MtoF receiving oestrogens than in FtoM receiving androgens. While type of oestrogen and route of administration might be significant, it is reasonable to speculate that nonhormonal/genetic factors play a role.     

Ghrelin and leptin levels in young adults with cystic fibrosis: relationship with body fat.

BACKGROUND: Ghrelin and leptin are hormones implicated in energy balance coordination and body weight regulation. There are conflicting data regarding the levels and role of leptin while ghrelin has not been studied in CF. The aim of this study was to investigate fasting serum ghrelin and leptin levels in CF adolescents as compared to healthy controls and analyze their association with body fat. METHODS: Fourteen CF adolescents having pancreatic insufficiency and twenty healthy adolescents were enrolled in the study. Diabetic patients were excluded. In all participants' height, weight, body mass index (BMI) and body fat % (BF %) were estimated. Ghrelin and leptin levels were determined after an overnight fast. RESULTS: Weight, BMI and BF% were significantly lower in CF adolescents than those of controls. Fasting leptin levels in CF were significantly higher in CF patients (p=0.030), compared to controls and significantly lower in CF males as compared to CF females (p=0.01). Fasting ghrelin levels were significantly lower in CF males as compared to male controls (p<0.001) and comparable in females. CONCLUSIONS: As the overall clinical outcome of CF patients is related to the nutritional status and body weight, the role of ghrelin and leptin in these patients needs to be elucidated.     

Men and women,so different,so similar: observations from cross‐sex hormone treatment of transsexual subjects

Sexual differentiation in mammals is largely driven by the presence of androgen in males and their absence in females. The presence of androgens induces a number of irreversible changes in males: prenatally, the genital differentiation; during puberty, the development of secondary sex characteristics – the larger facial bones, hand, feet and height in males. A large number of metabolic variables are influenced by sex hormones and consequently show difference between men and women, and this helps to explain differences in pathologies, such as cardiovascular disease, bone fractures and auto immune disease. There is some recent evidence that some sex differences in brain functions are not mediated by sex hormones, but by‐products of genes located on the X and Y chromosomes. This communication reviews the results of administration of cross‐sex hormone treatment to transsexual persons transitioning to the other sex. Natal males are treated with anti‐androgens+oestrogens and natal females with testosterone. This provides a unique opportunity to study which metabolic functions are not irreversibly sex‐differentiated but are determined by the prevailing milieu of sex steroids. The insights gained with these studies should lead to a better appreciation of the role of sex steroids in cardiovascular disease and diabetes mellitus which presently do not receive due attention.     

Testosterone decreases adiponectin levels in female to male transsexuals

Aim:To evaluate the effect of testosterone(T)on adiponectin serum levels in transsexual female patients.Methods:We measured adiponectin,leptin,luteinizing hormone and follicle stimulating hormone,T,estradiol,lipid profile,biochemical parameters and body composition in 16 transsexual female patients at baseline and after 6 months of Ttreatment(100mg Testoviron Depot/10 days,i.m.).Results:Adiponectin levels were 16.9±7.3 mg/mL at baselineand 13.5±7.4 mg/mL at month 6 of T treatment(P<0.05).Leptin and high-density lipoprotein cholesterol decreasedsignificantly,whereas body mass index,waist circumference and lean body mass increased significantly after 6months of T treatment.No changes in insulin or Homeostasis Model Assessment were detected.Conclusion:T cansignificantly reduce adiponectin serum levels in transsexual female patients.(Asian JAndro12006 Nov;8:725-729)     

Adipose tissue cytokines, insulin sensitivity, inflammation, and cardiovascular outcomes in end-stage renal disease patients.

From an evolutionary perspective, Darwinian selection has favored insulin-resistant individuals, ie, those with a trait ensuring brain functioning in situations of extreme fuel deprivation. The ability to mount a powerful inflammatory response to infection was another survival advantage in our ancestors, and we now have solid evidence showing that these 2 traits, insulin resistance and inflammation (as measured by serum C-reactive protein [CRP]), are associated in modern human beings. In an analysis of 192 nondiabetic hemodialysis patients, leptin and adiponectin were related in an opposite fashion with insulin sensitivity in end-stage renal disease (ESRD) and interacted in determining insulin resistance in these patients. The risk of insulin resistance was about 6 times higher in ESRD patients with an unfavorable combination of the 2 adipokines (high leptin and low adiponectin) than in those with a favorable combination (low leptin and high adiponectin). Low adiponectin but not high leptin predicted incident cardiovascular events in this cohort. Neither leptin nor adiponectin were associated with CRP in a cross-sectional analysis, but they were linked in an opposite fashion to CRP in a longitudinal study in 21 patients with acute inflammation secondary to infection. High sympathetic activity predicts adverse cardiovascular outcomes in ESRD. Of note, we found that the risk for cardiovascular events is more than 3 times higher in patients with high sympathetic activity and low adiponectin than in those with high adiponectin and low sympathetic activity. The adipocyte hormones leptin and adiponectin are associated in an opposite fashion to insulin sensitivity and inflammation in ESRD patients. Relatively lower plasma adiponectin levels are associated with a higher rate of incident cardiovascular events. Finally, low adiponectin and high norepinephrine seem to be interacting factors in the dismal cardiovascular outcomes with ESRD.     

B-type natriuretic Peptide modulates ghrelin, hunger, and satiety in healthy men

Chronic heart failure is accompanied by anorexia and increased release of B-type natriuretic peptide (BNP) from ventricular cardiomyocytes. The pathophysiological mechanisms linking heart failure and appetite regulation remain unknown. In this study, we investigated the impact of intravenous BNP administration on appetite-regulating hormones and subjective ratings of hunger and satiety in 10 healthy volunteers. Participants received in a randomized, placebo-controlled, crossover, single-blinded study (subject) placebo once and 3.0 pmol/kg/min human BNP-32 once administered as a continuous infusion during 4 h. Circulating concentrations of appetite-regulating peptides were measured hourly. Subjective ratings of hunger and satiety were evaluated by visual analog scales. BNP inhibited the fasting-induced increase in total and acylated ghrelin concentrations over time (P = 0.043 and P = 0.038, respectively). In addition, BNP decreased the subjective rating of hunger (P = 0.009) and increased the feeling of satiety (P = 0.012) when compared with placebo. There were no significant changes in circulating peptide YY, glucagon-like peptide 1, oxyntomodulin, pancreatic polypeptide, leptin, and adiponectin concentrations. In summary, our results demonstrate that BNP exerts anorectic effects and reduces ghrelin concentrations in men. These data, taken together with the known cardiovascular properties of ghrelin, support the existence of a heart-gut-brain axis, which could be therapeutically targeted in patients with heart failure and obesity.     

Ghrelin, glucose homeostasis, and carotid intima media thickness in kidney transplantation

BACKGROUND: Abnormalities in glucose homeostasis (AGH) frequently occur in kidney transplantation and favor vascular lesions. The purpose of this study was to analyze whether C-reactive protein (CRP), adiponectin, and ghrelin are markers of AGH and indicators of carotid atherosclerosis in kidney transplant patients with fasting plasma glucose below 126 mg/dL. METHODS: This was a cross-sectional study of 85 kidney transplant patients (59 men; mean age: 52.4 +/- 11.6 years; median posttransplant follow-up 31 (range 3-61) months). All patients underwent an oral glucose tolerance test. Abnormalities in glucose homeostasis were diagnosed following American Diabetes Association criteria. CRP, adiponectin, and ghrelin levels were determined. Doppler ultrasound of the carotid artery was performed to determine intima media thickness (IMT) and atheromatous plaque. RESULTS: A total of 50.5% of patients had AGH (12.9% were diagnosed with new-onset diabetes mellitus after transplantation and 37.7% had impaired glucose tolerance or impaired fasting glucose), whereas 49.4% were normoglycemic. Patients with AGH were older (P=0.002), had greater carotid IMT (P=0.022), and lower ghrelin concentrations (P=0.017) than normoglycemic patients. Logistic regression analyses showed ghrelin to be an independent marker for AGH (P=0.012) and AGH to be related to greater IMT (P=0.041). No differences in adiponectin or CRP were found in relation to AGH or atherosclerosis; however, there was a positive correlation between adiponectin levels and prednisone dose (r=0.240; P=0.044). CONCLUSIONS: A total of 50.5% of the study patients had abnormalities in glucose homeostasis. Patients with AGH had a higher percentage of preclinical atherosclerosis (greater carotid IMT). Ghrelin is an independent marker for abnormalities in glucose homeostasis.     

The Effect of Biliopancreatic Diversion with Pylorus-Preserving Sleeve Gastrectomy and Duodenal Switch on Fasting Serum Ghrelin, Leptin and Adiponectin Levels: Is there a Hormonal Contribution to the Weight-Reducing Effect of this Procedure?

Background: Ghrelin is a peptide hormone with orexigenic properties, primarily produced by the stomach. Different changes in fasting ghrelin levels have been reported following bariatric surgery. In this study, we investigate the hypothesis that because ghrelin is mainly produced by the fundus of the stomach, biliopancreatic diversion with sleeve gastrectomy with total resection of the gastric fundus and duodenal switch (BPD-DS) will cause substantial decrease in circulating ghrelin levels. Methods: Serum fasting ghrelin, leptin and adiponectin concentrations were measured by ELISA in 13 patients with morbid obesity who achieved weight loss by BPD-DS, before the operation and 18 months after. Results: After BPD-DS, BMI decreased significantly, from 59.15±15.82 kg/m² to 32.91±6.46 kg/m² (P=0.001). Serum fasting ghrelin level decreased from 1.44±0.77 ng/ml to 0.99±0.35 ng/ml (P=0.019). Serum leptin level decreased from 1.81±0.38 ng/ml to 1.65±0.32 ng/ml, (P=0.196), and adiponectin level increased from 37.85±11.24 μg/ml to 39.84±16.27 μg/ml (P=0.422). Conclusions: BPD-DS is associated with markedly suppressed ghrelin levels, possibly contributing to the longlasting weight-reducing effect of the procedure. Leptin levels decreased and adiponectin increased, as expected, after weight loss. Sleeve gastrectomy with resection of the gastric fundus seems to be the main cause of the postoperative reduction in ghrelin levels.     

Ghrelin and leptin elevation in postoperative intra-abdominal sepsis

BACKGROUND: Both ghrelin and leptin are important signals in the regulation of food intake and energy balance. Leptin concentrations are elevated in the majority of obese individuals, and its levels usually correlate with adiposity and body mass index. Ghrelin as a new growth hormone (GH)-releasing peptide was discovered in 1999. Ghrelin stimulates food intake and exhibits gastroprotective properties. Many other regulatory effects of both ghrelin and leptin involving cardiovascular, gastrointestinal, renal, and endocrine systems were revealed. New experimental studies show both hormones as new acute phase reactants in animal models of inflammatory reaction. The aim of this study was to characterize the levels of circulating ghrelin and leptin in relation to systemic inflammatory response. We used a postoperative bacterial sepsis after large abdominal surgery as a model of cytokine network hyperstimulation. PATIENTS AND METHODS:The prospective study was performed on 25 surgical patients with proven postoperative intra-abdominal sepsis after large abdominal surgery. Plasma levels of ghrelin (RIA), leptin, TNF-alpha, IL-1beta, sIL-2R, IL-6 (ELISA analysis), CRP and alpha1-antitrypsin (nephelometric analysis) were analyzed. RESULTS: Authors demonstrate statistically significant elevation of plasma ghrelin (492.3+/-70.6 ng/l) and leptin (31.6+/-12.2 microg/l) compared with the control group (336.5+/-46,1, p<0.01 for ghrelin, 3.5+/-1.2 microg/l, p<0.001 for leptin). The regression coefficient was the highest for ghrelin and IL-6 (r=0,44, p<0.05), and for ghrelin and TNF (r=0.43, p<0.05) in the sepsis group. In regard to leptin, the regression coefficient was the highest for IL-6 and leptin (r=0.53, p<0.05) and for leptin and CRP (r=0.51, p<0.05). There was no significant correlation between ghrelin and IL-1beta, ghrelin and sIL-2R, and leptin and IL-1beta. CONCLUSIONS: During postoperative intra-abdominal sepsis, both ghrelin and leptin plasma levels are elevated and positively correlate with both inflammatory cytokines (TNF-alpha, IL-6) and main APP member (CRP). It supports experimental finding that TNF-alpha and IL-6 can be important regulatory factors of their synthesis. This hormonal reaction is not specific to sepsis--the significant increase of both ghrelin and leptin occurs during an uncomplicated postoperative response, although in a lesser extent than was shown in sepsis.     

Associations between plasma ghrelin levels and body composition in end-stage renal disease: a longitudinal study.

BACKGROUND: Ghrelin is a newly detected orexigenic gastric hormone that stimulates food intake. Increased levels of ghrelin are often found in disease states associated with wasting. Wasting is a common phenomenon in end-stage renal disease (ESRD) patients in whom elevated ghrelin levels have been reported. However, no data are available on the relationship between body composition and plasma ghrelin levels in this patient group. METHODS: The study population consisted of 108 (71 males) ESRD patients aged 53+/-12 years. Body composition, nutritional status (subjective global assessment), estimated protein intake (nPNA), plasma ghrelin, plasma insulin and serum leptin were evaluated close to the start of dialysis treatment. Twelve healthy subjects (nine males, 44+/-6 years) served as the control group. A longitudinal evaluation of changes in plasma ghrelin and body composition was performed in 52 of the patients after 12 months of dialysis treatment. RESULTS: Markedly elevated plasma ghrelin levels (843+/-485 vs 443+/-302 pg/ml; P<0.01) were observed in ESRD patients compared with controls. Basal plasma ghrelin levels correlated significantly with plasma insulin (R = -0.32; P<0.05), body mass index (R = -0.24; P<0.05), log serum leptin levels (R = -0.23; P<0.05) and truncal fat mass (R = -0.25; P<0.05). The longitudinal analysis of body composition demonstrated that whereas fat mass increased (23.7+/-8.6 to 25.3+/-9.9 kg; P<0.05) and plasma ghrelin levels decreased (855+/-429 to 693+/-408 pg/ml; P<0.05) significantly in peritoneal dialysis patients, no significant changes in either body composition or plasma ghrelin levels were found in patients treated by haemodialysis. CONCLUSION: Markedly elevated plasma ghrelin levels are found in advanced renal failure and correlate with fat mass, plasma insulin and serum leptin levels. Changes in plasma ghrelin during 12 months of peritoneal dialysis treatment are associated with changes in body composition.     

Obesity in patients with Bardet–Biedl syndrome: influence of appetite-regulating hormones

Background

Bardet-Biedl syndrome (BBS) is a genetic disorder with obesity as one of the major phenotypic criterion, which is proposed to be of neuroendocrine origin. Therefore, disturbances in appetite-regulating hormones have been considered as causative factors. Acyl ghrelin is an orexigenic hormone, whereas its desacylated form, obestatin, and leptin have the opposite functions. Ghrelin is negatively regulated in relation to nutritional status. The aim of this study was to evaluate the impact of hormone alterations on obesity development in BBS patients.

Methods

Total and acylated ghrelin, obestatin, leptin and adiponectin were measured in eight children with BBS. The results were analyzed in relation to auxological parameters [body mass index (BMI), height].

Results

The mean BMI was significantly increased in BBS patients compared to the controls. Plasma levels of acylated ghrelin, total ghrelin and obestatin were slightly elevated in BBS patients compared to controls, as was the acyl/total ghrelin ratio. Leptin levels were significantly elevated in BBS patients.

Conclusion

BBS patients lack the negative regulatory mechanisms of appetite-regulating hormones with respect to nutritional status and exhibit resistance to anorexigenic leptin. This results in a shift towards the orexigenic effects of this self-regulating system. These alterations may in part be responsible for the disturbed appetite regulation in BBS patients.     

Fasting Plasma Ghrelin Levels Increase Progressively after Biliopancreatic Diversion: One-year Follow-up

Background: The role of ghrelin in weight control after surgery is not clear. We examined plasma ghrelin and leptin levels in patients with morbid obesity undergoing biliopancreatic diversion (BPD) of Scopinaro. Methods: 30 adult patients (27 females, 3 males), undergoing elective BPD were recruited from the Hospital Surgery Service. Fasting blood samples for biochemical determinations were drawn before surgery and 1, 3 and 12 months after BPD. Human plasma ghrelin was measured by RIA. Results: During the study period, weight, BMI and serum leptin levels decreased significantly at all sample points compared to preoperative values. Ghrelin plasma levels increased during the study, with statistical significance at 3 months and 1 year after surgery compared with preoperative levels. While leptin changes correlated with changes in BMI, no correlation was found between ghrelin and leptin or BMI changes. Conclusion: Plasma ghrelin levels could be decreased in obese patients as a compensatory mechanism to their nutritional state, but our results do not support the postulated beneficial role of ghrelin in the 1-year weight loss after BPD. They rather suggest that weight loss somehow stimulates ghrelin secretion, even in the absence of part of the stomach.     

Leptin, adiponectin, and ghrelin dysregulation in chronic kidney disease.

In the past 10 years, 3 new metabolic compounds, leptin, adiponectin, and ghrelin, involved in energy metabolism, body composition, and appetite regulation, have been discovered. We have assessed their characteristics in 46 patients with stage 3 to 4 chronic kidney disease to evaluate the role of decreased renal function in the abnormal handling reported in more severe end-stage renal disease patients. In addition to the usual correlations with body mass index and body fat mass, the results show unexpected positive correlations between leptin and insulin, leptin and adiponectin, a weak inverse relationship between adiponectin and glomerular filtration rate, and no influence of C-reactive protein on either leptin or adiponectin in these noninflamed patients. Serum ghrelin was inversely correlated with body mass index and with glomerular filtration rate as measured by inulin clearance. Thus, ghrelin and leptin, 2 antagonist signals for energy balance, both seem to increase when glomerular filtration rate is reduced, potentially neutralizing their respective biologic effects in severe renal insufficiency.     

Effect of bariatric surgery on endogenous sex hormones and sex hormone-binding globulin levels: a systematic review and meta-analysis

BackgroundMost studies have shown beneficial effect of bariatric surgery (BS) on serum levels of sex hormones.ObjectiveA systematic review and meta-analysis was conducted to examine the magnitude of possible changes in levels of sex hormones following BS.SettingsElectronic databases were searched, including PubMed, Scopus, Web of Science, and Embase, for relevant studies.MethodsThe heterogeneity of the studies was examined by χ² tests and the degree of heterogeneity was estimated using I² statistic.ResultsThe results of pooled analyses revealed that BS caused a significant increase in luteinizing hormone (LH), follicular stimulating hormone (FSH), total testosterone (TT), and sex hormone binding globulin (SHBG) levels and conversely, decreased dehydroepiandrosterone (DHEA) and estradiol (E2) levels in males. For females, BS significantly increased LH, FSH, and SHBG levels and conversely, decreased androstenedione (AE), E2 and TT levels. Additionally, the level of progesterone (P), prolactin (PRL), free testosterone (FT) and dehydroepiandrosterone sulfate (DHEA-S) showed no significant changes in patients who had undergone BS.ConclusionBS changed most sex hormones levels including LH, FSH, TT, SHBG, AE, DHEA, and E2. It seems that BS is able to exert substantial impacts on sex hormones levels and as well as sexual function, however, larger, and more precise trials are required to specifically focus on these claims.     

Protein-energy wasting modifies the association of ghrelin with inflammation, leptin, and mortality in hemodialysis patients

Ghrelin abnormalities contribute to anorexia, inflammation, and cardiovascular risk in hemodialysis patients, leading to worse outcome. However, ghrelin levels are influenced by the nutritional status of the individual. We hypothesized that the consequences of ghrelin alterations in hemodialysis patients are context sensitive and dependent on the presence of protein-energy wasting (PEW). In this cross-sectional study of 217 prevalent hemodialysis patients followed for 31 months, we measured ghrelin, leptin, PEW (subjective global assessment), and C-reactive protein (an index of inflammation). Compared to patients in the middle and upper tertile of ghrelin levels, those in the lowest tertile were older, had higher leptin levels and body mass index, and presented an increased mortality risk that persisted after adjustment for age, gender, and dialysis vintage. This risk was lost after correction for comorbidities. Patients with PEW and low ghrelin values had abnormally high C-reactive protein and leptin by multivariate analysis of variance, and the highest mortality risk compared to non-PEW with high ghrelin from all-cause and cardiovascular-related mortality (adjusted hazard ratios of 3.34 and 3.54, respectively). Low ghrelin values in protein-energy wasted hemodialysis patients were linked to a markedly increased cardiovascular mortality risk. Thus, since these patients were more anorectic, our results provide a clinical scenario where ghrelin therapies may be particularly useful.     

Plasma Ghrelin Levels Are Associated with Coronary Microvascular and Endothelial Dysfunction in Peritoneal Dialysis Patients

Cardiovascular (CV) disease is the main cause of death in peritoneal dialysis (PD) patients, and endothelial dysfunction (ED) is an early sign of vascular pathology. Ghrelin, a gastric peptide with CV actions, has been shown to inhibit proatherogenic changes in experimental models. However, another peptide hormone, leptin, may mediate deleterious effects on the CV system. The aim of this study is to evaluate the relationship between plasma ghrelin and leptin levels, and their association with coronary microvascular and endothelial functions in PD patients. Twenty-four (14 females and 10 males; mean age 44 ± 12 yr) nondiabetic PD patients, between 18 and 70 years of age, were enrolled. In addition to demographic, clinical, and laboratory parameters, plasma concentrations of ghrelin and leptin were evaluated. Endothelial functions of the coronary arteries were determined by coronary flow reserve (CFR) measurement using transthoracic Doppler echocardiography (TTDE). A CFR value of < 2 was used as an evidence for ED. When the study group was divided according to CFR measurements as CFR < 2 and ≥ 2, there were no significant differences considering age, gender, etiology of renal disease, body mass index (BMI), duration of dialysis, PD modality, PD solution type, history of peritonitis, mean arterial pressure, ejection fraction, and biochemical parameters between the two subgroups. Plasma ghrelin levels (129.4 ± 82.1 pg/mL) in patients with CFR ≥ 2 were significantly higher than those in patients with CFR< 2 (63.3 ± 35.8 pg/mL) (p = 0.03). However, no significant differences in plasma leptin levels were found between these groups [31.39 ± 37.81 ng/mL vs. 63.95 ± 72.83 ng/mL (p = 0.28)]. No correlation existed between plasma ghrelin levels and age, BMI, duration of dialysis, mean arterial pressure, ejection fraction, plasma leptin levels, and biochemical parameters. Decreased plasma ghrelin levels may contribute to the development of atherosclerosis in PD patients by causing ED.     

Serum Ghrelin, Leptin and Adiponectin Levels before and after Weight Loss: Comparison of Three Methods of Treatment – A Prospective Study

Background: Ghrelin is a peptide hormone with orexigenic properties, primarily produced by the stomach. Leptin and adiponectin are the two adiposity products that participate in body weight control. Leptin always decreases and adiponectin increases after weight loss. Different changes in fasting ghrelin levels have been reported following bariatric surgery. In this study, we compare the changes in fasting ghrelin, leptin and adiponectin levels in 3 groups of patients who achieved weight loss by either diet, MacLean vertical banded gastroplasty (VBG) or biliopancreatic diversion with duodenal switch (BPD-DS). Methods: Serum fasting ghrelin, leptin and adiponectin concentration was measured in 40 obese patients who achieved weight loss by either diet (n=14), VBG (n=13) or BPD-DS (n=13), before and after weight loss. The follow-up period was 18 months for BPD-DS and VBG and 6 months for diet. Serum ghrelin level was measured by ELISA. Results: BMI was significantly decreased in all 3 groups: 9.2±2.4% (P<0.01) following diet, 38.47±7.26% (P<0.01) after VBG, and 42.88±9.09% after BPD-DS (P<0.01). Serum fasting ghrelin level increased after diet (110.45±117.84%, P=0.002) and VBG (65.48±92.93%, P=0.001),but decreased after BPD-DS (−21.63±28.63%, P=0.019). Leptin concentration decreased and adiponectin increased in all groups. Conclusions: Unlike after diet or gastric restrictive surgery, BPD-DS is associated with markedly suppressed ghrelin levels, possibly contributing to the weight-reducing effect of this operation. Sleeve gastrectomy seems to be the main cause of this reduction.     

The rat arcuate nucleus integrates peripheral signals provided by leptin,insulin, and a ghrelin mimetic

The hypothalamic circuits controlling food intake and body weight receive and integrate information from circulating satiety signals such as leptin and insulin and also from ghrelin, the only known circulating hormone that stimulates appetite following systemic injection. Activation of arcuate neurons by ghrelin and ghrelin mimetics (the growth hormone secretagogues) is augmented in 48-h-fasted rats compared with fed rats, as reflected by a greater number of cells expressing Fos protein in response to administration of the same maximally effective dose. Here we sought to determine whether this increased responsiveness in fasting might reflect or be influenced by low levels of circulating satiety factors such as leptin or insulin. Chronic central infusion of insulin or leptin during a 48-h fast suppressed the threefold increase in the Fos response to intravenous injection of a maximally effective dose of growth hormone-releasing peptide (GHRP)-6, a synthetic growth hormone secretagogue. This appears to be a direct central action of insulin and leptin because the marked decrease in plasma levels of insulin, leptin, and glucose during fasting were unaffected by central administration of either hormone. Furthermore, the GHRP-6-induced Fos response was twofold greater in obese leptin- and insulin-resistant Zucker rats compared with lean controls. These data provide evidence that the ghrelin-sensitive circuits in the hypothalamus are dynamically regulated by central insulin and leptin action.     

Five new cases of breast cancer in transsexual persons

Cross‐sex hormone treatment of transsexual people may be associated with the induction and growth stimulation of hormone‐related malignancies. We report here five cases of breast cancer, three in female‐to‐male (FtoM) transsexual subjects and two in male‐to‐female (MtoF) transsexual subjects. In the general population the incidence of breast cancer increases with age and with duration of exposure to sex hormones. This pattern was not recognised in these five transsexual subjects. Tumours occurred at a relatively young age (respectively, 48, 41, 41, 52 and 46 years old) and mostly after a relatively short span of time of cross‐sex hormone treatment (9, 9–10 but in one after 30 years). Occurrence of breast cancer was rare. As has been reported earlier, breast tumours may occur in residual mammary tissue after breast ablation in FtoM transsexual people. For adequate treatment and decisions on further cross‐sex hormone treatment it is important to have information on the staging and histology of the breast tumour (type, grade and receptor status), with an upcoming role for the androgen receptor status, especially in FtoM transsexual subjects with breast cancer who receive testosterone administration. This information should be taken into account when considering further cross‐sex hormone treatment.     

Effects of neonatal castration and androgenization on sexual dimorphism in bone, leptin and corticosterone secretion

This study investigated the role of neonatal sex steroids in rats on sexual dimorphism in bone, as well as on leptin and corticosterone concentrations throughout the lifespan. Castration of males and androgenization of females were used as models to investigate the role of sex steroids shortly after birth. Newborn Wistar rats were divided into four groups, two male groups and two female groups. Male pups were cryoanesthetized and submitted to castration or sham-operation procedures within 24 h after birth. Female pups received a subcutaneous dose of testosterone propionate (100 μg) or vehicle. Rats were euthanized at 20, 40, or 120 postnatal days. Body weight was also measured at 20, 40, and 120 days of age, and blood samples and femurs were collected. The length and thickness of the femurs were measured and the areal bone mineral density (areal BMD) was determined by dual-energy X-ray absorptiometry (DEXA). Biomechanical three-point bending testing was used to evaluate bone breaking strength, energy to fracture, and extrinsic stiffness. Blood samples were submitted to a biochemical assay to estimate calcium, phosphorus, alkaline phosphatase, leptin, and corticosterone levels. Weight gain, areal BMD and bone biomechanical properties increased rapidly with respect to age in all groups. In control animals, skeletal sexual dimorphism, leptin concentration, and dimorphic corticosterone concentration patterns were evident after puberty. However, androgen treatment induced changes in growth, areal BMD, and bone mass properties in neonatal animals. In addition, neonatally-castrated males had bone development and mechanical properties similar to those of control females. These results suggest that the exposure to neonatal androgens may represent at least one covariate that mediates dimorphic variation in leptin and corticosterone secretions. The study indicates that manipulation of the androgen environment during the critical period of sexual differentiation of the brain causes long-lasting changes in bone development, as well as serum leptin and corticosterone concentrations. In addition, this study provides useful models for the investigation of bone disorders induced by hypothalamic hypogonadism.