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Department of Public Health and Clinical Medicine, Umeå University Hospital (E.R., S.S., M.E., O.J., T.O.), Umeå, Sweden 90185; and Department of Medical Sciences, University of Edinburgh (R.A., D.E.W.L., B.R.W.), Western General Hospital, Edinburgh, United Kingdom EH4 2XU
Address all correspondence and requests for reprints to: Prof. Brian R. Walker, University of Edinburgh, Endocrinology Unit, Western General Hospital, Edinburgh, United Kingdom EH4 2XU. E-mail address: . b.walker{at}ed.ac.uk
Abstract
Cushing’s syndrome and the metabolic syndrome share clinical similarities. Reports of alterations in the hypothalamic-pituitary-adrenal (HPA) axis are inconsistent, however, in the metabolic syndrome. Recent data highlight the importance of adipose 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which regenerates cortisol from cortisone and, when overexpressed in fat, produces central obesity and glucose intolerance. Here we assessed the HPA axis and 11ß-HSD1 activity in women with moderate obesity and insulin resistance.
Forty women were divided into tertiles according to body mass index (BMI; median, 22.0, 27.5, and 31.4, respectively). Serum cortisol levels were measured after iv CRH, low dose dexamethasone suppression, and oral cortisone administration. Urinary cortisol metabolites were measured in a 24-h sample. A sc abdominal fat biopsy was obtained in 14 participants for determination of 11ß-HSD type 1 activity in vitro.
Higher BMI was associated with higher total cortisol metabolite excretion (r = 0.49; P < 0.01), mainly due to increased 5
- and, to a lesser extent, 5ß-tetrahydrocortisol excretion, but no difference in plasma cortisol basally, after dexamethasone, or after CRH, and only a small increase in the ACTH response to CRH. Hepatic 11ß-HSD1 conversion of oral cortisone to cortisol was impaired in obese women (area under the curve, 147,736 ± 28,528, 115,903 ± 26,032, and 90,460 ± 18,590 nmol/liter·min; P < 0.001). However, 11ß-HSD activity in adipose tissue was positively correlated with BMI (r = 0.55; P < 0.05).
In obese females increased reactivation of glucocorticoids in fat may contribute to the characteristics of the metabolic syndrome. Increased inactivation of cortisol in liver may be responsible for compensatory activation of the HPA axis. These alterations in cortisol metabolism may be a basis for novel therapeutic strategies to reduce obesity-related complications.
INCREASED TISSUE exposure to glucocorticoids may influence fat mass and fat distribution, as is clearly evident in patients with Cushing’s syndrome who accumulate abdominal fat. Idiopathic obesity is a component of the metabolic syndrome (also called the insulin resistance syndrome or syndrome X, associated with increased risk of cardiovascular disease), which shares other features in common with Cushing’s syndrome, including insulin resistance and hypertension. More subtle abnormalities of cortisol activity have therefore been sought in patients with idiopathic obesity.
The cortisol production rate is consistently increased in obese subjects. However, the hypothesis that this can be accounted for by primary activation of the hypothalamic-pituitary-adrenal (HPA) axis is not uniformly supported by published data. Circulating levels of cortisol are normal or even low during the morning peak of the diurnal rhythm (1, 2, 3, 4, 5) and may be modestly elevated in the evening trough (6). Feedback regulation of the HPA axis does not seem to differ between lean and obese subjects after standard doses (usually 1 mg overnight) of dexamethasone (7), although recent intriguing data suggest subtle abnormalities (8) and an impairment of nocturnal suppression with endogenous cortisol (9). Feedforward regulation of the HPA axis is more difficult to test. A link has been proposed between responsiveness to stress and hypercortisolemia in obese men (6). In response to CRH, increased ACTH reactivity has been reported in both sexes (10, 11), and increased cortisol responses have been found in women (8, 12, 13), with obesity. However, we have been unable to detect alterations in ACTH or cortisol reactivity to CRH in male obese subjects (3). Discrepant results may reflect earlier studies having been limited to morbidly obese subjects. It is thus not clear whether overweight/moderate obesity per se is associated with alterations in the HPA axis drive in females and, if so, whether this is linked only to central obesity.
An alternative, but not exclusive, hypothesis is that an increased cortisol production rate in obesity reflects normal HPA axis function compensating for changes in peripheral cortisol metabolism. Metabolic clearance rates of cortisol, measured by isotope dilution, are increased in obesity (14). Recent data confirm that obesity is associated with increased cortisol metabolite excretion in urine in men and women (3, 4, 7, 15) and suggest that thisresults from a combination of increased excretion of A ring reduced (especially 5-reduced) cortisol metabolites (15, 16) together with impaired hepatic regeneration of cortisol from cortisone, at least in men (3, 7). The combination of increased cortisol inactivation and impaired liver regeneration of cortisol might lead to a compensatory activation of the HPA axis, via a decrease in the negative feedback signal, to maintain circulating cortisol levels.
A further crucial control of cortisol activity is exerted in peripheral tissues by tissue-specific prereceptor metabolism, determining access of cortisol to corticosteroid receptors. The key enzyme in adipose tissue is 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which regenerates active cortisol from inactive cortisone (17). In mice, transgenic knockout of 11ß-HSD1 results in protection from the hyperglycemia of high fat feeding (18), whereas overexpression using the adipose-specific aP2 enhancer-promoter results in an approximately 3-fold increase in intraadipose 11ß-HSD1 activity, an approximately 2-fold increase in intraadipose glucocorticoid levels, and dramatic central obesity and insulin resistance (19). These changes occur independently of circulating glucocorticoid concentrations, because these are modestly elevated in the knockout mouse and normal in the transgenic overexpressing mouse. In male leptin-resistant Zucker obese rats (20) and in men with idiopathic obesity (3), we have reported that 11ß-HSD1 activity is increased in adipose tissue. An increased tissue-specific exposure to glucocorticoids may thus contribute to Cushingoid features in obese subjects. However, in rats and perhaps in humans, regulation of 11ß-HSD1 is gender specific (21, 22). It is therefore not known whether alterations in tissue-specific glucocorticoid exposure may contribute to obesity in women.
In the current study we examined peripheral cortisol metabolism and regulation of the HPA axis in women with contrasting body mass indices.
Subjects and Methods
Subjects
Subjects were recruited from a population-based study in northern Sweden, the WHO-conducted MONICA Project (23). From an original random sample of 2815 women and men, 41 Caucasian women living in the health care districts of Umeå or Skellefteå, not using contraceptive pills or hormone replacement therapy, were selected representing a wide range of body mass indices (BMI) and fasting plasma insulin levels. Diabetes mellitus and thyroid dysfunction were excluded by routine laboratory tests, and 1 subject was excluded because of type 2 diabetes. None of the others had clinical features of endocrine, hepatic, or renal disease. Seven women were smokers. One woman was receiving inhaled steroid therapy for bronchial asthma, but the dose used (budesonide, <400 µg/24 h) was not considered to influence test results (24). Four women were taking medication with acetylsalicylic acid after suspected transient ischemic attacks (n = 2), for arthralgia, and for migraine, respectively. Five women had hypertension, treated with ß-blockers, angiotension-converting enzyme inhibitors, or diuretics; this was not discontinued during the study. Twenty-four women were postmenopausal. In the 16 pre- and perimenopausal women glucocorticoid tests were performed in the follicular phase of the menstrual cycle (5–10 d after starting menstruation). The studies were approved by the ethics committee of Umeå University Hospital, and written informed consent was obtained from all individuals.
Clinical protocol
Subjects attended the out-patient clinic after an overnight fast. Anthropometric measurements included height to the nearest centimeter, weight to the nearest 200 g, and waist (at the level of the umbilicus) and hip (maximum circumference over the buttocks) circumferences measured to the nearest 0.5 cm. Blood pressure was measured in the supine position with a mercury sphygmomanometer. Body composition was estimated by bioelectrical impedance analysis (BIA 101F, Akern-RJL System bioelectrical impedance instrument, EL.Dot, Fredriksvaerk, Denmark) (25).
A hyperinsulinemic euglycemic clamp was used to measure insulin sensitivity (26). Catheters were inserted into an antecubital vein of the right arm (for infusion of insulin and glucose) and in a dorsal vein of the left hand, which was heated (for sampling of arterialized blood). Human insulin (Actrapid, NovoNordisk, Malmö, Sweden) was infused in a priming dose for the first 10 min and then as a continuous infusion of 56 mU/m2·min for 110 min. The resulting mean ± SD plasma insulin concentration during the steady state period, i.e. the second hour of the clamp, was calculated as the mean of insulin levels at 60, 90, and 120 min. Euglycemia was achieved by infusion of 20% glucose solution, and the mean glucose level during the same period was calculated from the mean of the 60, 90, and 120 min plasma glucose levels. Insulin sensitivity was assessed by the M/I insulin sensitivity index, i.e. the amount of glucose infused during the second hour of the clamp (M value in milligrams of glucose per kilograms of body weight per minute) divided by mean plasma insulin concentration (in milliunits per liter) multiplied by 100.
The following tests were performed in random order, with test days separated by at least 24 h. 1) A CRH test (1 µg CRH/kg body weight; Ferring Pharmaceuticals Ltd., Malmö, Sweden) was performed in the afternoon during fasting from 0930 h. The subject lay supine, a catheter was inserted in an antecubital vein at 1230 h, and at 1300 h CRH was injected iv. Samples for ACTH and cortisol were drawn on six occasions from 1245 h until 1500 h. 2) Subjects took dexamethasone (3.5 µg/kg body weight from a 35 µg /ml suspension) orally at 2300 h. After an overnight fast a catheter was placed in an antecubital vein at 0800 h, and blood was taken for serum cortisol determination. Subjects then took oral 25 mg cortisone acetate (Cortone, MSD, Sollentuna, Sweden) with water. Serum cortisol samples were taken during the following 4 h. 3) On another occasion, subjects collected a 24-h urine sample for measurement of cortisol metabolites.
A subgroup of subjects (n = 14, selected at random according to their availability at a later date) attended the out-patient clinic after an overnight fast. After local anesthesia with prilocain (10 mg/ml Citanest, Astra USA, Inc., Södertälje, Sweden) in the skin area to the right of the umbilicus, approximately 1.5 cm3 sc fat were excised through a 2- to 3-cm incision.
Laboratory methods
Blood glucose was measured at the bedside in duplicate with a glucose dehydrogenase oxidation technique (Hemocue AB, Ängelholm, Sweden). Serum insulin was analyzed using a microparticle enzyme immunoassay (Abbott Scandinavia AB, Stockholm, Sweden) with no cross-reactivity with proinsulin or C peptide.
Blood samples for cortisol determination were taken in tubes containing an inert polyester gel, and serum was stored at -20 C until assayed with a commercial RIA (Orion Diagnostica, Espoo, Finland). Samples for ACTH determination were taken in prechilled EDTA test tubes containing 225 kallikrein inhibiting units aprotinin/ml blood and centrifuged immediately, and plasma was stored at -70 C until assayed with a commercial RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA).
Urine aliquots were stored without preservative at -20 C until assayed. Cortisol and its metabolites were measured by gas chromatography and electron impact mass spectrometry after Sep-Pak C18 extraction, hydrolysis with ß-glucuronidase, and formation of methoxime-trimethylsilyl derivative, as previously described (27). Epi-cortisol and epi-tetrahydrocortisol were used as internal standards, which were added to samples before extraction. Peaks of interest were quantified by the ratio of (area under the peak)/(area under neighboring internal standard peak). Ratios were compared against standard curves for each steroid included in every assay batch.
The fat biopsies were snap-frozen in liquid nitrogen and stored at -70 C until assayed. After thawing, the fat was homogenized in Krebs buffer at pH 7.4, and 750 µg/ml protein was incubated at 37 C with 2 mM NADP and 100 nM [1,2,6,7-3H4]cortisol for 30 h, with samples withdrawn at 3, 6, 20, and 30 h for separation of cortisol and cortisone by HPLC with on-line liquid scintillation detection (20). 11ß-HSD1 activity was measured in the dehydrogenase direction (i.e. cortisol to cortisone), rather than reductase (cortisone to cortisol), because this is the preferred reaction when the enzyme is liberated from its intracellular environment (28) and driven with excess cofactor. This activity is proportional to total 11ß-HSD1 protein present in the incubation (20). Under these conditions, there was no evidence of conversion of cortisol to other metabolites, such as 5-reduced cortisol.
Statistics
Data are given as the mean ± SD or, if not normally distributed, as medians with the interquartile range, unless otherwise stated. Variables were naturally log-transformed to obtain normal distribution where necessary before statistical analysis. Areas under the curve were estimated according to the trapezoid rule.
Subjects were divided into tertiles according to their BMI, using cut-offs of 23.8 and 29.7 kg/m2, respectively. One-way ANOVA followed by Tukey’s B post hoc test were used to test differences between groups. For correlation analysis, Pearson correlation coefficients and partial correlations were calculated. Pharmacokinetic analysis was performed using the Kinetica software package (Innaphase, Champs-sur-Marne, France). The volume of distribution and clearance were determined by noncompartmental analysis, and the appearance rate constant was determined in a two-compartment model. P < 0.05 was considered to indicate statistical significance.
Results
The clinical data of the women divided into BMI tertiles are shown in Table 1
. As expected, insulin sensitivity deteriorated with increasing obesity (Table 1).
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Basal ACTH levels at 1300 h did not differ between groups of women with different BMI (Fig. 1A). The peak in plasma ACTH occurred 30 min after the injection of CRH in all groups, and there was a trend toward higher ACTH response in the two higher BMI tertiles (P = 0.06 for ACTH levels at 30 min). The increase in ACTH levels 30 min after the injection of CRH correlated with fat mass; this was also significant after adjustment for age and insulin sensitivity (Table 2).
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) or dexamethasone (Fig. 2) did not differ between groups with contrasting BMI. The incremental cortisol response at 30 min after CRH was weakly associated with waist circumference, and this became nonsignificant after adjustment for age and insulin sensitivity.
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) and correlated positively with all indexes of obesity (Table 3). When adjusted for lean body mass, all correlations remained significant (data not shown).
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Levels of serum cortisol after oral administration of cortisone were lower with increasing BMI and other indices of obesity (Fig. 2 and Table 4). Pharmacokinetic analysis attributed this to a combination of increased clearance, increased volume of distribution, and, to a lesser extent, decreased rate of appearance of cortisol (Table 4).
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-tetrahydrocortisol (5-THF) and 5ß-THF in the two higher BMI tertiles, whereas tetrahydrocortisone (THE) excretion did not differ significantly between groups (Fig. 3 and Table 3). As a result, the ratio of (5-THF + 5ß-THF)/THE, which reflects the balance of 11ß-HSD activities, was increased in more obese women. The ratio of 5-THF/5ß-THF was also higher with increasing BMI, but this was not independent of age and insulin sensitivity. Urinary cortisol and cortisone excretion were not influenced by differences in BMI.
The subgroup of women (n = 14) who underwent a sc fat biopsy did not differ in age, tobacco use, systolic blood pressuren or insulin sensitivity (data not shown), but were somewhat leaner than the rest of the participants (median BMI 24.8 vs. 28.9; P < 0.05). In correlation analysis, in vitro 11ß-HSD1 activity in sc fat increased significantly with increasing obesity (Fig. 4), independently of age and insulin sensitivity.
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This study shows that women with a moderate degree of obesity have minimal changes in dynamic responsiveness of the HPA axis, but substantial changes in peripheral metabolism of cortisol. These changes are tissue specific, with increased inactivation of cortisol in the liver and increased regeneration of cortisol in adipose tissue. As a result, they may explain the paradoxical lowering of basal circulating cortisol levels in conjunction with Cushingoid features in obese females.
In adipose tissue, 11ß-HSD1 activity was increased in obese women, as previously reported in males (3, 29). The importance of this finding is thrown into sharp focus by the recent report of the phenotype of mice with adipose-specific transgenic overexpression of 11ß-HSD1 (19). These mice have an approximately 200% elevation in 11ß-HSD1 activity in fat, which causes marked central obesity and glucose intolerance. In the women studied here, an increase in BMI of 5.5 kg/m2 between lowest and middle tertiles was associated with an increase in 11ß-HSD1 activity of 65%. In the previous study of men (3) in which more obese men were better represented among those who volunteered for adipose biopsy, an increase in BMI of 9.8 kg/m2 was associated with an increase in adipose 11ß-HSD1 activity of 345%. Thus, these differences are within the magnitude that has been demonstrated in mice to have an important causal influence on obesity and its associated metabolic manifestations.
In contrast with findings in adipose biopsies, generation of serum cortisol after oral administration of cortisone was impaired in obesity, as shown previously in men and interpreted as reflecting impaired hepatic 11ß-HSD1 activity (3, 7). We have extended previous interpretation with the addition of pharmacokinetic analysis. This adds further evidence that the volume of distribution and the rate of clearance of cortisol are increased in obesity. The increased volume of distribution reflects the fact that glucocorticoids distribute in adipose tissue. The increased rate of clearance confirms previous findings using isotope tracer (14). We attribute this not only to impaired hepatic conversion of cortisone to cortisol by 11ß-HSD1 (which may, in fact, be fully compensated for in women by enhanced reactivation in adipose tissue; see below), but also to increased A ring reduction of cortisol, reflected in increased urinary excretion of tetrahydrocortisols. This is most obvious for 5-THF, suggesting that up-regulation of 5-reductase is important in increased clearance of cortisol (15, 16), but excretion of 5ß-THF is also increased. Compared with differences in volume of distribution and clearance, the decrease in the calculated rate of appearance of cortisol from cortisone in obese women was modest and indeed was not statistically significant. This may reflect less precise measurement of the appearance rate, because it is based on relatively few data points for plasma cortisol during the appearance phase and is theoretically susceptible to differences in gastrointestinal absorption of cortisone. It remains likely that there is impaired hepatic conversion of cortisone to cortisol by 11ß-HSD1 given the trends for an inverse relationship between the rate of appearance and indices of obesity in Table 4, and corroborative evidence in rodent obesity (20). However, these findings suggest that more direct measurements are required to quantify the extent of down-regulation of hepatic 11ß-HSD1 activity in human obesity and its influence on intrahepatic cortisol concentrations.
Direct comparisons have shown that urinary cortisol metabolite excretion differs between sexes, with women having lower excretion of total cortisol metabolites (15, 21, 30), higher (5-THF + 5ß-THF)/THE ratio, and higher 5-THF/5ß-THF ratios (15). These gender-related differences in cortisol metabolism may relate to the higher proportion of fat mass in women than men. Although impaired hepatic 11ß-HSD1 has been a consistent finding now in three studies of obesity (here and in Refs. 3 and 7), the ratio of (5-THF + 5ß-THF)/THE has been highly inconsistent, showing positive (15), negative (3, 7, 16) and neutral (4) relationships with obesity in men. This ratio indicates the balance of all 11ß-HSD activities in all tissues. The positive relationship with obesity in women suggests that the increased adipose regeneration of cortisol has a more potent influence than the decreased hepatic regeneration of cortisol. This balance between liver and fat may differ in these subjects from some previous cohorts because of the higher proportion of body fat in relation to BMI in women than men. This is important because it indicates that 11ß-HSD1 activity in adipose tissue can indeed make a significant contribution to the circulating cortisol pool. Intriguingly, the (5-THF + 5ß-THF)/THE ratio was no more strongly related to central than peripheral fat. Although central adipose stromal cells in culture display higher 11ß-HSD1 activity than cells from sc adipose (31), no such regional difference has been observed in freshly isolated adipose tissue in rodents (20), and the increase in 11ß-HSD1 activity reported here and previously (3, 29) is described in sc tissue. It remains to be determined whether 11ß-HSD1 has an especially important role in visceral fat, or whether regional differences in the effects of 11ß-HSD1 are entirely dependent on differences in the expression of glucocorticoid receptors (32).
Compared with the differences in peripheral cortisol metabolism, the changes in dynamic responses of the HPA axis in obese women in this study were modest. Basal serum cortisol concentrations did not differ in obese women, although in previous studies with larger numbers of subjects an inverse relationship between BMI and serum cortisol was observed in both men and women (1, 2, 5). There were no significant associations between anthropometric or metabolic variables and postdexamethasone serum cortisol levels, although we found a trend for lower levels among the most obese women. This differs from the increased feedback sensitivity to dexamethasone we recently found in obese men (3). Data are highly conflicting regarding feedback sensitivity in earlier studies, with increased, unaltered, and decreased feedback function all reported (1, 7, 8). An association between obesity and serum dexamethasone levels has been reported in females (33), and consequently, the use of weight-adjusted doses in this study might have influenced the results. In addition, the choice of a synthetic exclusive glucocorticoid receptor agonist may not be appropriate. Low doses of hydrocortisone were recently shown to inhibit nighttime levels of ACTH in lean, but not in moderately obese, males (9). This suggests that mineralocorticoid receptor dysfunction and/or central changes in 11ß-HSD1 (34) in obesity can lead to a subtle feedback insensitivity.
We did find evidence for increased ACTH responsiveness to CRH in obese women. However, in correlation analysis, this difference was only apparent in relation to total fat mass and not to other indices of obesity. We also found a weak positive relationship between CRH-induced cortisol response and waist circumference, but this did not persist after correction for age and insulin sensitivity and was not apparent in comparing tertiles of BMI. Previous literature is highly inconsistent regarding ACTH responses to CRH (10, 11, 35, 36) and cortisol responses to ACTH (8, 12, 13, 37, 38) in obesity. These discrepancies may reflect differences in selection criteria between studies; our study group was a population-based sample with BMI ranging from normal weight to moderate obesity in contrast with some earlier study populations recruited from obesity units with more pronounced obesity. Alternatively, these results may reflect a true discrepancy between enhanced ACTH response to CRH combined with adrenocortical resistance to ACTH. The latter could reflect the action of cytokines, notably TNF- and IL-6, to inhibit ACTH-induced steroidogenesis (39), especially because circulating proinflammatory cytokine levels are higher in obesity. To these possible explanations, the current study adds another, involving cortisol metabolism. We hypothesize that increased A ring reductase activity is responsible for increased clearance of cortisol (15) and that compensatory activation of the HPA axis is responsible for increased total cortisol metabolite excretion. A discrepancy in the apparent response of cortisol and ACTH to CRH may reflect the substantial increase in the clearance rate of cortisol. Whatever the subtleties of these differences, however, the net result is that differences in the HPA do not result in major differences in circulating cortisol concentrations in obesity.
In conclusion, we have found tissue-specific alterations in cortisol metabolism in overweight females. This includes enhanced inactivation of cortisol by A ring reductases, decreased hepatic conversion of cortisone to cortisol by 11ß-HSD1, but increased adipose tissue 11ß-HSD1 activity of sufficient magnitude to substantially enhance local glucocorticoid action. In association with altered peripheral metabolism, we found compensatory activation of the HPA axis but this appears insufficient to increase plasma cortisol levels. Up-regulation of adipose 11ß-HSD1 therefore appears to be a key contributor to obesity and metabolic dysfunction in both men and women, which may explain the clinical similarities between Cushing’s syndrome and the metabolic syndrome and is an exciting target for possible future treatments aiming to reduce glucocorticoid effects in fat.
Acknowledgments
We are grateful to Inger Arnesjö, Maria Backlund, Margareta Hedbäck, Else-Britt Lundström, Cecilia Nordenson, Cecilia Mattsson, and Jill Campbell for excellent technical assistance, and to Hans Stenlund for advice about statistical matters.
Footnotes
This work was supported by the Swedish Heart and Lung Foundation, the Swedish Medical Research Council (Grant 71p-11769, to T.O.), the Medical Faculty of Umeå University, the Northern County Councils Cooperation Committee (Visare Norr), and the Heart and Lung Association in Kramfors-Sollefteå.
B.R.W. is a British Heart Foundation Senior Research Fellow.
Abbreviations: BMI, Body mass index; HPA, hypothalamic-pituitary-adrenal; 11ß-HSD1, 11ß-hydroxysteroid dehydrogenase type 1; THE, tetrahydrocortisone; THF, tetrahydrocortisol.
Received January 29, 2002.
Accepted March 28, 2002.
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B. Mariniello, V. Ronconi, S. Rilli, P. Bernante, M. Boscaro, F. Mantero, and G. Giacchetti Adipose tissue 11{beta}-hydroxysteroid dehydrogenase type 1 expression in obesity and Cushing's syndrome Eur. J. Endocrinol., September 1, 2006; 155(3): 435 - 441. [Abstract] [Full Text] [PDF]
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V. S. Densmore, N. M. Morton, J. J. Mullins, and J. R. Seckl 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Induction in the Arcuate Nucleus by High-Fat Feeding: A Novel Constraint to Hyperphagia? Endocrinology, September 1, 2006; 147(9): 4486 - 4495. [Abstract] [Full Text] [PDF]
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A. Gambineri, V. Vicennati, S. Genghini, F. Tomassoni, U. Pagotto, R. Pasquali, and B. R. Walker Genetic Variation in 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Predicts Adrenal Hyperandrogenism among Lean Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2295 - 2302. [Abstract] [Full Text] [PDF]
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M. E. Trujillo, M.-J. Lee, S. Sullivan, J. Feng, S. H. Schneider, A. S. Greenberg, and S. K. Fried Tumor Necrosis Factor {alpha} and Glucocorticoid Synergistically Increase Leptin Production in Human Adipose Tissue: Role for p38 Mitogen-Activated Protein Kinase J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1484 - 1490. [Abstract] [Full Text] [PDF]
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S. K. Paulsen, S. B. Pedersen, J. O. L. Jorgensen, S. Fisker, J. S. Christiansen, A. Flyvbjerg, and B. Richelsen Growth Hormone (GH) Substitution in GH-Deficient Patients Inhibits 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression in Adipose Tissue J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1093 - 1098. [Abstract] [Full Text] [PDF]
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K. M Oltmanns, B. Dodt, B. Schultes, H. H Raspe, U. Schweiger, J. Born, H. L Fehm, and A. Peters Cortisol correlates with metabolic disturbances in a population study of type 2 diabetic patients Eur. J. Endocrinol., February 1, 2006; 154(2): 325 - 331. [Abstract] [Full Text] [PDF]
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