Peripheral Metabolism Of Cortisol Research Articles

Alteration in glucocorticoids secretion and metabolism in patients affected by cystic fibrosis.

Cystic fibrosis (CF) is an inherited syndrome associated with a mutation in a cystic fibrosis transmembrane conductance regulator gene, composed of exocrine gland dysfunction involving multiple systems that may result in chronic respiratory infections, pancreatic enzyme deficiency, and developmental disorders. Our study describes for the first time the urinary profile of glucocorticoid metabolites and the activity of the enzymes involved in the development and metabolism of cortisol in patients with CF, using a gas chromatography/mass spectrometry method. Data were obtained from 25 affected patients and 70 sex- and age- matched healthy volunteers. We have shown a general decrease in the activity of enzymes involved in the peripheral metabolism of cortisol, such as 11β-hydroxysteroid dehydrogenase type 2, 5α- and 5β-reductases. In contrast, the activity of 11β-hydroxysteroid dehydrogenase type 1, the enzyme that converts cortisone to cortisol, increased. Furthermore, our study found a significant decrease in glucocorticoid excretion in patients with CF. This may suggest adrenal insufficiency or dysregulation of the HPA axis and the development of peripheral mechanisms to counteract cortisol degradation in the case of reduced synthesis of glucocorticoids by the adrenal glands. Furthermore, the activity of 5α-reductase seems to be enhanced only through the backdoor pathway, especially when we taking into consideration 11β-hydroxyandrosterone/11β-hydroxyetiocholanolone ratio which has been shown to be the best differential marker for enzyme activity. CF impairs nutritional effects and energetic balance in patients; thus, our findings suggest the existence of adaptive mechanisms due to limited secretion of adrenal steroids and subsequent diminished amounts of their metabolites in urine. On the other hand, local control of cortisol availability is maintained by enhanced 11βHSD1 activity and its recovery from cortisone in organs and tissues which need this. Steroid hormone dysregulation might be another important factor in the course of CF that should be taken into account when planning an effective and comprehensive therapy.

The nonhuman primate hypothalamo-pituitary-adrenal axis is an orchestrator of programming-aging interactions: role of nutrition.

Developmental programming alters life-course multi-organ function and significantly affects life-course health. Recently, interest has developed in how programming may influence the rate of aging. This review describes interactions of nutrition and programming-aging interactions in hypothalamo-pituitary-adrenal (HPA) development and function from fetal development to old age. A full picture of these interactions requires data on levels of HPA activity relating to the hypothalamic, adrenal cortical, circulating blood, and peripheral cortisol metabolism. Data are provided from studies on our baboon, nonhuman primate model both across the normal life course and in offspring of maternal baboons who were moderately undernourished by a global 30% diet reduction during pregnancy and lactation. Sex differences in offspring outcomes in response to similar challenges are described. The data clearly show programming of increased HPA axis activity by moderate maternal undernutrition. Increased postnatal circulating cortisol concentrations are related to accelerated aging of the brain and cardiovascular systems. Future studies should address peripheral cortisol production and the influence of aging advantage in females. These data support the view that the HPA is an orchestrator of interactions of programming-aging mechanisms.

Pituitary-adrenal axis and peripheral cortisol metabolism in obese patients.

A close relationship between adiposity and increased cortisol levels is well established in patients with endogenous hypercortisolism. Nevertheless, hypothalamic-pituitary-adrenal (HPA) axis regulation in overweight subjects is still a matter of concern. We studied free cortisol (urinary free cortisol, UFC and late night salivary cortisol, LNSC), pituitary feedback (serum cortisol after 1 mg dexamethasone suppression test, 1 mg DST) and peripheral cortisol metabolism (urinary cortisol to cortisone ratio, F/Eratio) in a large series of overweight subjects without Cushing's Syndrome. We considered 234 patients divided in 5 BMI classes, matched for age and gender (BMI ≤ 25 kg/m2n = 38; 25-30 n = 58; 30-35 n = 52; 35-40 n = 52; >40 n = 34). UFC, LNSC and urinary F/Eratio were assessed with LC-MS. We collected 183 LNSC, 176 UFC, 152 1 mg DST and 64 F/Eratio tests. UFC levels were higher in lean subjects, and they decreased according to the BMI classes (p = 0.022). Non-suppressed cortisol levels (>50 nmol/L) after 1 mg DST were observed especially in patients with normal weight or mild obesity. Patients with BMI ≥ 35 kg/m2 revealed a reduced F/Eratio (0.39 vs. 0.61, p = 0.006). The specificity of tests (false positive results) was higher considering 1 mg DST or UFC in obese patients, on the contrary impaired cortisol rhythm (LNSC above normality) was observed in 47 subjects, irrespective of weight. Overweight and obese subjects are characterised by an original regulation of HPA axis (reduced UFC levels, increased suppression after 1 mg DST) and peripheral cortisol metabolism (reduced F/Eratio), suggesting an effort to counteract hypercortisolism.

Maternal Glucocorticoid Metabolism Across Pregnancy: A Potential Mechanism Underlying Fetal Glucocorticoid Exposure

Across pregnancy, maternal serum cortisol levels increase up to 3-fold. It is not known whether maternal peripheral cortisol metabolism and clearance change across pregnancy or influence fetal cortisol exposure and development. The primary study objective was to compare maternal urinary glucocorticoid metabolites, as markers of cortisol metabolism and clearance, between the second and third trimester of pregnancy. Secondary objectives were to test associations of total maternal urinary glucocorticoid excretion, with maternal serum cortisol levels and offspring birth weight z score. A total of 151 women with singleton pregnancies, recruited from prenatal clinic at the Pittsburgh site of the Measurement of Maternal Stress (MOMS) study, had 24-hour urine collections during both the second and third trimesters. Between the second and third trimester, total urinary glucocorticoid excretion increased (ratio of geometric means [RGM] 1.37, 95% CI 1.22-1.52, P < .001), and there was an increase in calculated 5β-reductase compared to 5α-reductase activity (RGM 3.41, 95% CI 3.04-3.83, P < .001). During the third trimester total urinary glucocorticoid excretion and serum cortisol were negatively correlated (r = -0.179, P = .029). Mean total urinary glucocorticoid excretion across both trimesters and offspring birth weight z score were positively associated (β = 0.314, P = .001). The estimated activity of maternal enzymes responsible for cortisol metabolism change between the second and third trimester of pregnancy. Additionally, maternal peripheral metabolism and clearance of cortisol may serve as a novel mechanism affecting fetal cortisol exposure and growth.

Microsomal pre-receptor cortisol production is inhibited by resveratrol and epigallocatechin gallate through different mechanisms.

Local activation of cortisol in hormone target tissues is a major determinant of glucocorticoid effect. Disorders in this peripheral cortisol metabolism play an important role in the development of metabolic diseases, such as obesity or type 2 diabetes mellitus. Hence, dietary factors influencing the activity of the involved enzymes can have major impacts on the risk of the above diseases. Resveratrol and epigallocatechin gallate (EGCG), two natural polyphenols found in several nutriments and in green tea, respectively, are well-known for their antiobesity and antidiabetic activities. EGCG has been shown to interfere with microsomal cortisol production through decreasing the luminal NADPH:NADP+ ratio. The aim of this study was to clarify if resveratrol also induces such a redox shift or causes any direct enzyme inhibition that influences local cortisol production. Cortisone-cortisol conversions and changes in NADPH levels were monitored in rat liver microsomal vesicles. Cortisol production was inhibited by resveratrol in a concentration dependent manner while the intrinsic reducing and oxidizing capacity as well as the NADPH level inside the ER-derived vesicles remained unaffected. Activity measurements performed in permeabilized microsomes confirmed that resveratrol, unlike EGCG, inhibits 11β-hydroxysteroid dehydrogenase type 1 directly. Long-term moderation of pre-receptor cortisol production likely contributes to the beneficial health effects of both polyphenols. © 2018 BioFactors, 45(2):236-243, 2019.

Clinical Outcomes of Minimized Hydrocortisone Dosage of 100 Mg/Day on Lower Occurrence of Hyperglycemia in Septic Shock Patients.

The current international guideline recommended 200 mg/day of hydrocortisone intravenously to treat septic shock. However, a subsequent study on cortisol metabolism actually showed an increase in cortisol level during sepsis. Hence, the smaller hydrocortisone dose of 100 mg/day might be sufficient and reduce steroid-associated complications. We aimed to compare the clinical outcomes of minimized hydrocortisone dose of 100 mg to the currently recommended dose in the treatment of septic shock patients. A double-blinded randomized controlled trial included 80 septic shock patients with hemodynamic instability despite fluid and vasopressive therapy. Participants were divided equally into two groups to treat with 100 mg/day or 200 mg/day of hydrocortisone, then stepwise down titrated and discontinued on day 8. The outcome of interest was the hyperglycemic rate. Vital status, time to shock reversal, superinfection and gastrointestinal bleeding rates were also compared. Patients with 100 mg hydrocortisone had significantly lower hyperglycemic rate compared with 200 mg, 63.9% versus 86.5% (the adjusted hazard ratio [HR], 0.08; 95% confidence interval [CI], 0.02-0.41, P = 0.002). Time to shock reversal was shorter in patients with 100 mg hydrocortisone, 2 days vs. 4 days, P = 0.031. The 28-day mortality rate when adjusted for Simplified Acute Physiology Score II showed no significant difference (HR, 0.68; 95% CI, 0.37-1.24, P = 0.209). The reinfection and gastrointestinal bleeding rates were comparable between groups. Minimized daily hydrocortisone dosage of 100 mg could lower the occurrence of hyperglycemia without increasing mortality in septic shock, compared with the currently recommended dosage of 200 mg/day.

The influence of combined oral contraceptives containing drospirenone on hypothalamic-pituitary-adrenocortical axis activity and glucocorticoid receptor expression and function in women with polycystic ovary syndrome.

Most women with PCOS have increased adrenal androgen production, enhanced peripheral metabolism of cortisol and elevation in urinary excretion of its metabolites. Increased cortisol clearance in PCOS is followed by a compensatory overdrive of the hypothalamic-pituitary-adrenocortical (HPA) axis. We hypothesized that oral contraceptives containing ethinylestradiol and drospirenone (EE-DRSP) could modulate glucocorticoid receptor (GR) expression and function and thus affect HPA axis activity in PCOS patients. We analyzed 12 women with PCOS (age 24.17±4.88 years; body mass index 22.05±3.97 kg/m²) treated for 12 months with EE-DRSP and 20 BMI matched controls. In all subjects testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), cortisol (basal and after dexamethasone), concentrations of GR protein, phospo-GR211 protein, number of GR per cell (B(max) and its equilibrium dissociation constant (K(D)) were measured. Before treatment, increased concentrations of testosterone and DHEAS (p<0.001, respectively), unaltered basal cortisol and an increased sensitivity (p<0.05) of the HPA axis to dexamethasone were observed in PCOS women in comparison to controls. After treatment, testosterone (p<0.01), DHEAS (p<0.05) and cortisol suppression after dexamethasone (p<0.01) were decreased in PCOS women. There were no changes in GR protein concentration, GR phosphorylation nor in the receptor functional parameters B(max) and K(D) in women with PCOS before and after the therapy, and in comparison to controls. Prolonged treatment with EE-DRSP in PCOS women decreased serum androgens and increased cortisol in the presence of decreased sensitivity of the HPA axis and did not exert changes in GR expression and function.

The R453Q and D151A polymorphisms of Hexose-6-Phosphate Dehydrogenase Gene (H6PD) influence the polycystic ovary syndrome (PCOS) and obesity

Hexose-6-phosphate dehydrogenase (H6PDH) influences 11β-hydroxysteroid dehydrogenase activity, a key enzyme in the peripheral metabolism of cortisol that modulates insulin sensitivity in adipose tissue. To study the associations of R453Q and D151A polymorphisms in the H6PDH gene (H6PD) with polycystic ovary syndrome (PCOS) and their influence on clinical and metabolic variables, we genotyped 237 patients with PCOS and 135 control women for the R453Q (rs6688832) and D151A (rs34603401) variants in H6PD. The R453Q genotypes were distributed differently in patients and controls (χ2=9.55, P=0.002). Genotypes of D151A were distributed evenly in women with PCOS and controls, but showed a different distribution in non-obese and obese women (χ2=3.95, P=0.047), especially within the PCOS subgroup (χ2=4.65, P=0.031). A backward stepwise likelihood ratio logistic regression model (Nagelkerke's R2=0.490; χ2=164; P<0.0001) retained free testosterone (OR=1.13; 95% CI: 1.10–1.17) and H6PD Q453 alleles (OR=0.46; 95% CI: 0.27–0.79) as statistically significant predictors for PCOS, whereas homeostasis model assessment of insulin resistance and the H6PD D151A variant were excluded by the model. Both H6PD variants were associated with several phenotypic variables, including fasting insulin, homeostasis model assessment of insulin resistance and androstenedione levels. In summary, the R453Q and D151A variants of the H6PD gene are associated with PCOS and obesity, respectively, and may contribute to the PCOS phenotype by influencing obesity, insulin resistance and hyperandrogenism.

Apparent mineralocorticoid excess syndrome: report of one family with three affected children

The syndrome of apparent mineralocorticoid excess (AME) is an autosomal recessive disorder characterized by hypertension, hypokalemia, low renin, and hypoaldosteronism. It is caused by deficiency of 11β-hydroxysteroid dehydrogenase, which results in a defect of the peripheral metabolism of cortisol to cortisone. As a consequence, the serum cortisol half-life (T½) is prolonged, ACTH is suppressed, and serum cortisol concentration is normal. The hormonal diagnosis of the disorder is made by the increased ratio of urine-free cortisol to cortisone. In patients with AME, this ratio is 5-18, while in normal individuals it is <0.5. These studies suggest that an abnormality in cortisol action or metabolism results in cortisol behaving as a potent mineralocorticoid and causing the syndrome of AME. We report three siblings - two female and one male - with the syndrome of apparent mineralocorticoid excess who presented with hypertension, hypokalemia, low renin, and low aldosterone levels. The finding of abnormally high ratios of 24-h urine-free cortisol to cortisone in our three patients (case 1, 8.4; case 2, 25; and case 3, 7.5) confirmed the diagnosis of apparent mineralocorticoid excess syndrome in these children. They were treated with oral potassium supplements. The addition of spironolactone resulted in a decrease in blood pressure, rise in serum potassium and a gradual increase in plasma renin activity in all three. In this study, the genetic testing of those three siblings with the typical clinical features of AME has detected missense mutation c.662C>T (p.Arg208Cys) in exon 3 of the HSD11B2 gene in the homozygous state.

Evaluation of Hepatic 11 β-Hydroxysteroid Dehydrogenase Activity by Cortisone Acetate Test in Young Adults With Diabetes Mellitus Type 1

Cortisone acetate test was performed in twelve young adult patients with diabetes mellitus type 1, after dexamethasone administration to suppress endogenous cortisol production. Previous screening revealed that all of the subjects had peak cortisol responses in the range from subnormal to normal, as determined by a low-dose Synacthen test. The aim was to find out whether these patients would exhibit different conversion of cortisone to cortisol by 11beta-hydroxysteroid dehydrogenase. Using multifactorial ANOVA the following significant relationships were obtained between cortisol or cortisol/cortisone ratio measured during the test and other parameters examined a) before dexamethasone suppression and b) during the test: a) Cortisol at 120(th) minute negatively correlated with daily insulin dose and positively with basal aldosterone. Cortisol/cortisone ratio at 60(th), 120(th), 180(th), and 240(th) minute negatively correlated with basal aldosterone/plasma renin activity ratio, urinary free cortisol/24 hours and positively with basal dehydroepindrosterone sulphate. b) Cortisol at 120(th) minute negatively correlated with suppressed basal serum glycemia; cortisol/cortisone ratio during the whole test negatively correlated with supressed basal ACTH. The examination of peripheral metabolism of cortisol using cortisone acetate test in patients with diabetes mellitus type 1 showed adaptive changes of 11beta-hydroxysteroid dehydrogenace activity associated with altered cortisol tissue supply.

Increased 5α-Reductase Activity and Adrenocortical Drive in Women with Polycystic Ovary Syndrome

ABSTRACT Context Polycystic Ovary Syndrome (PCOS) is characterized by hyperandrogenism, anovulation and susceptibility to the metabolic syndrome. Altered peripheral cortisol metabolism has been reported in PCOS but also in simple obesity. Objective To describe cortisol metabolism and metabolic characteristics of a large PCOS cohort and to delineate the effect of obesity by comparison to BMI-matched controls. Design Observational, cross-sectional study. Setting Outpatient clinics of two secondary/tertiary care centres Patients or Other Participants 178 PCOS patients fulfilling Rotterdam criteria and 100 BMI-matched controls. Intervention 24-h urine collection for steroid metabolite excretion, fasting blood samples followed by an OGTT. Main Outcome Measures Urinary steroid metabolites including glucocorticoids and androgens and the ratios reflecting enzymatic activities involved in peripheral cortisol and androgen metabolism, 5α-reductase and 11β-hydroxysteroid dehydrogenase type 1 and 2. Circulating levels of glucose, insulin, DHEA, DHEAS and testosterone, calculation of HOMA. Results Total androgen metabolites were higher in PCOS compared to BMI-matched controls (4105 ± 2047 vs. 2532 ± 1610 μg/24h for the non-obese, 5547 ± 2911 vs. 2468 ± 1794 μg/24hr for the obese, both p &amp;lt; 0.001). Total glucocorticoid metabolites were higher in obese PCOS vs. controls (10786 ± 3852 vs. 8834 ± 4487 μg/24hr, p = 0.001). 5α-reductase activity correlated with BMI, insulin levels and HOMA. Both obese and non-obese PCOS patients had higher 5α-reductase activity than controls (all p &amp;lt; 0.05). 11β-hydroxysteroid dehydrogenase activities did not differ between PCOS and controls. Conclusions PCOS is associated with enhanced androgen and cortisol metabolite excretion and increased 5α-reductase activity that cannot be explained by obesity alone. Increased adrenal corticosteroid production represents an important pathogenic pathway in PCOS.

Inhibition of cortisol metabolism by 17α,20β-P: Mechanism mediating semelparity in salmon?

In vitro experiments were conducted to test the hypothesis that 17α,20β-dihydroxy-4-prengnen-3-one (17,20-P) regulates cortisol metabolism in Pacific salmon. In both rainbow trout and coho salmon, cortisol metabolism was significantly higher in the kidney compared to the liver. The rainbow trout kidney converted cortisol primarily into an unidentified water-soluble metabolite with a molecular mass of 354. The coho salmon kidney converted cortisol primarily into cortisol-21-sulfate. High physiological concentrations of 17,20-P had no effect on cortisol metabolism by the rainbow trout kidney, but almost completely inhibited the production of cortisol-21-sulfate by the coho salmon kidney. This was accompanied by a coincident increase in the production several neutral cortisol metabolites, including cortisone. Cortisone was also found to inhibit renal sulfotransferase (SULT) activity suggesting that there could be a local positive feedback mechanism initiated by the rise in 17,20-P that quickly reduces SULT activity as follows: the pre-spawning rise in 17,20-P inhibits SULT, cortisol is metabolized to cortisone instead of cortisol-21-sulfate, cortisone further inhibits SULT, more cortisone is produced, and so on. If SULT normally acts as a gatekeeper enzyme to protect the cell from cortisol excess, this mechanism would rapidly remove enzymatic protection and expose tissues to high local concentrations of cortisol. In addition, the inhibition of peripheral cortisol metabolism by 17,20-P could increase circulating concentrations of the corticosteroid. These events could be a part of the mechanism that leads to the symptoms of cortisol excess associated with the post-spawning mortality of semelparous Pacific salmon.

Increased clearance of cortisol by 5β-reductase in a subgroup of women with adrenal hyperandrogenism in polycystic ovary syndrome

Increased peripheral metabolism of cortisol may explain compensatory ACTH-dependent adrenal steroidogenesis and hence hyperandrogenism in polycystic ovary syndrome (PCOS). Previous studies have described an increased 5alpha-reduction of cortisol or impaired regeneration of cortisol by 11beta-HSD1 in PCOS. However, these observations may be confounded by obesity. Moreover, the relationship between alterations in cortisol metabolism and the extent of adrenal androgen hyper-secretion in response to ACTH has not been established. This study aimed to examine the association between cortisol metabolism and ACTH-dependent adrenal hyperandrogenism in PCOS, independently of obesity. We compared 90 PCOS women (age 18-45 yr) stratified by adrenal androgen responses to ACTH1-24 and 45 controls matched for age and body weight. PCOS women were stratified as normal responders (NR), intermediate responders (IR), and high responders (HR) to 250 microg ACTH1-24: NR (no.=27) had androstenedione and DHEA responses within 2 SD of the mean in controls; IR (no.=43) had DHEA responses >2 SD above controls; HR (no.=20) had both androstenedione and DHEA responses >2 SD above controls. All groups were similar for age, body weight, and body fat distribution. Basal testosterone, androstenedione, and 5alpha-dihydrotestosterone plasma levels were similarly elevated among the 3 groups of PCOS compared with controls, whereas basal DHEA-S was higher in HR (2.8+/-1.2 microg/ml) and IR (2.4+/-1.1 microg/ml) than in NR (1.8+/-0.8 microg/ml) and controls (1.7+/-0.6 microg/ml). The HR group had the lowest basal plasma cortisol levels (101+/-36 ng/ml vs IR 135+/-42 ng/ml, NR 144+/-48 ng/ml, and controls 165+/-48 ng/ml; all p<0.01), but the greatest cortisol response to ACTH1-24 (Delta(60-0)cortisol 173+/-60 ng/ml vs IR 136+/-51 ng/ml, NR 114+/-50 ng/ml, and controls 127+/-50 ng/ml; all p<0.01), and the highest urinary excretion of total and 5beta-reduced cortisol metabolites (eg 5beta-tetrahydrocortisol/ cortisol ratio 25.2+/-15.3 vs IR 18.8+/-10.7, NR 19.7+/-11.4, and controls 17.2+/-13.7; all p<0.05). There were no differences in urinary excretion of 5alpha-reduced cortisol metabolites or in 5alpha-dihydrotestosterone/testosterone ratio between groups. Adrenal androgen excess in PCOS is associated with increased inactivation of cortisol by 5beta-reductase that may lower cortisol blood levels and stimulate ACTH-dependent steroidogenesis.

The adrenal and polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders characterized by androgen excess, oligo-ovulation and polycystic ovaries. Although ovaries are the main source of increased androgens in the syndrome, between 20 and 30% of patients with PCOS have adrenal androgen (AA) excess, detectable primarily by elevated dehydroepiandrosterone sulfate (DHEAS) levels. Patients with PCOS demonstrate a generalized hypersecretion of adrenocortical products, basally and in response to ACTH stimulation. The mechanisms of these abnormalities are unclear although AA excess in PCOS is likely a complex trait, modulated by both intrinsic and acquired factors. To date, no specific genetic defects have been identified. The production of AAs in response to ACTH appears to be closely related to altered factors regulating glucose-mediated glucose disposal, increased peripheral metabolism of cortisol, and to a less extent to the effects of extra-adrenal androgens, insulin resistance, hyperinsulinemia or obesity. Finally, DHEAS levels and the response of AAs to ACTH are relatively constant over time and are closely correlated between PCOS patients and their siblings suggesting that this abnormality is an inherited trait in PCOS.

Modulation of glucocorticoid metabolism by the growth hormone – IGF‐1 axis

The growth hormone-insulin-like growth factor 1 (GH-IGF-1) axis plays an important role in modulating the peripheral metabolism of glucocorticoids mainly through its effect on the isoenzyme 11 beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) which, in vivo, functions as a reductase catalysing the conversion of cortisone to cortisol. Several in vivo and ex vivo studies have shown that the GH-IGF-I system inhibits the expression and activity of 11beta-HSD1 in adipose tissues and the liver resulting in reduced local regeneration of cortisol. This interaction has clinically significant implications as it may at least partly explain the phenotypes of acromegaly and adult GH deficiency and the effects that treatment of these conditions has on body composition. In addition, by accelerating the peripheral metabolism of cortisol, GH therapy may precipitate adrenal insufficiency in susceptible hypopituitary patients, and endocrinologists should be mindful of this phenomenon when starting hypopituitary patients on GH replacement therapy.

The Hypothalamic‐Pituitary‐Adrenal Axis Activity in Obesity and the Metabolic Syndrome

A hypothetical role of glucocorticoids in human obesity has been suggested since the abdominal obesity phenotype and syndromes of endogenous or exogenous hypercortisolism share several clinical, metabolic, and cardiovascular similarities. An emerging body of evidence indicates that both neuroendocrine dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis as well as peripheral alterations of cortisol metabolism may play a role in the pathophysiology of abdominal obesity. Major alterations of the HPA axis in vivo may be identified in different ways. They include evaluation of hormone concentrations: (a) in basal conditions, in blood, urine, or saliva samples; (b) during dynamic studies following stimulation with different neuropeptides or psychological stress challenges, or suppression with inhibiting agents of the HPA axis at different levels; and (c) after mixed meals or meals containing different nutrient compositions. In addition, alteration of peripheral cortisol metabolism can be detected by direct measurement of cortisol metabolites in urine, although this is a matter of more complex investigation. Alterations of the HPA axis in abdominal obesity are associated with insulin resistance, which suggests a direct responsibility of these hormonal alterations in the susceptibility of affected patients to develop both metabolic and cardiovascular diseases. According to available data, no single marker probably has the power to detect subtle alterations of the HPA axis in conditions, such as the abdominal obesity and the metabolic syndrome. On the contrary, they indicate the need for multiple parameters. At present, evaluation of urinary free cortisol, particularly during the night-time, and salivary-free cortisol appear to be promising for these purposes, whereas dynamic tests should be reserved for specific clinical settings, involving well-characterized patients.

Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates.

Androgen excess in women with polycystic ovary syndrome (PCOS) may be ovarian and/or adrenal in origin, and one proposed contributing mechanism is altered cortisol metabolism. Increased peripheral metabolism of cortisol may occur by enhanced inactivation of cortisol by 5alpha-reductase (5alpha-R) or impaired reactivation of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) resulting in decreased negative feedback suppression of ACTH secretion maintaining normal plasma cortisol concentrations at the expense of androgen excess. We have tested whether any enzyme dysregulation was related to circulating insulin or androgen concentrations in women with PCOS and have sought to clarify their relationship with obesity. First, to avoid obesity-related effects on cortisol metabolism, 18 lean women with PCOS were compared with 19 lean controls who were closely matched for body mass index (BMI). Second, the impact of obesity was studied in a cross-section of 42 PCOS women of a broad range of BMI. We measured 24-h urinary excretion of steroid metabolites by gas chromatography/mass spectrometry and fasting metabolic and hormone profiles. Urinary excretion of androgens [androsterone (P = 0.003), etiocholanolone (P = 0.02), and C19 steroid sulfates (P = 0.009)], cortisone metabolites [tetrahydrocortisone (THE) (P = 0.02), alpha-cortolone (P < 0.001), beta-cortol + beta-cortolone (P < 0.001), cortolones (P < 0.001), and E metabolites (P < 0.001)], and TCM (P = 0.002) were raised in lean PCOS subjects when compared with controls. A significantly higher 5alpha-tetrahydrocortisol (5alpha-THF)/5beta-THF ratio (P = 0.04) and a significantly lower alpha-THF + THF + alpha-cortol/THE + cortolones ratio (P = 0.01) were found in lean PCOS women compared with lean controls, indicating both enhanced 5alpha-R and reduced 11beta-HSD1 activities. A decreased THE/cortolones ratio (P = 0.03) was also found in lean PCOS women compared with lean controls, indicating increased 20 alpha/beta-HSD activity. In the group of 42 PCOS subjects, measures of 5alpha/5beta reduction were positively correlated with the homeostasis model insulin resistance index (HOMA-R): alpha-THF/THF and HOMA-R (r = 0.34; P = 0.03), androsterone/etiocholanolone and HOMA-R (r = 0.32; P = 0.04), and total 5alpha /total 5beta and HOMA-R (r = 0.37; P = 0.02). A positive correlation was also found between measures of 5alpha-R and BMI (r = 0.37; P = 0.02). No correlation was found between measures of 11beta-HSD1 activity and indices of insulin sensitivity or BMI. We have demonstrated that there is an increased production rate of cortisol and androgens as measured in vivo in lean PCOS women. Insulin seems to enhance 5alpha reduction of steroids in PCOS but was not associated with the elevated cortisol production rate. The changes in 5alpha-R, 11beta-HSD1, and 20alpha/beta-HSD enzyme activities observed in PCOS may contribute to the increased production rates of cortisol and androgens, supporting the concept of a widespread dysregulation of steroid metabolism. This dysregulation does not seem to be the primary cause of PCOS because no correlation was found between serum androgen levels or urinary excretion of androgens with measurements of either 5alpha-R or 11beta-HSD1 activities.

Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity.

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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates cortisol from cortisone and, when overexpressed in fat, produces central obesity and glucose intolerance. Here we assessed the HPA axis and 11beta-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 11beta-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 5alpha- and, to a lesser extent, 5beta-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 11beta-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, 11beta-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.

Tissue-Specific Changes in Peripheral Cortisol Metabolism in Obese Women: Increased Adipose 11 -Hydroxysteroid Dehydrogenase Type 1 Activity

Tissue-Specific Changes in Peripheral Cortisol Metabolism in Obese Women: Increased Adipose 11 -Hydroxysteroid Dehydrogenase Type 1 Activity

Serum cortisol/cortisone ratio after Synacthen stimulation

Objectives: 11β-Hydroxysteroid dehydrogenase (11β-HSD) enzymes interconvert active cortisol and inactive cortisone. There is growing evidence that local tissue concentrations of cortisol are generally modulated by site specific different 11β-HSD actions. While 11β-HSD type 2 unidirectionally inactivates cortisol, type 1 isoform acts bidirectionally. 11β-HSD type 1 is mainly localized in the liver and may thus restore circulating biologically inactive cortisone to active cortisol thereby modulating systemic glucocorticoid action; such a mechanism might be of importance in stressful situations. To study this hypothesis we investigated the influence of exogenous ACTH on serum cortisol/cortisone ratio. Design and Methods: Paired serum samples that were submitted for routine analysis of cortisol before and 1 h after stimulation with 250 μg ACTH (1–24) (Synacthen) were collected prospectively if the routine tests indicated normal adrenal function; 40 patients were included in the study, 29 patients were female, 11 male, median age was 31 yr (range 14–70). Serum cortisol and cortisone were determined using LC-ESI/MS/MS with an online sample extraction system and tri-deuterated cortisol as the internal standard. Results: While mean serum cortisol increased by 109% (mean basal concentration 373 nmol/L (SD 151 nmol/L), stimulated 781 nmol/L (SD 194 nmol/L)), mean serum cortisone significantly decreased after ACTH administration by 31% ( p < 0.001, paired t-test for differences). Mean serum cortisone was 70 nmol/L (SD 16 nmol/L) before and 48 nmol (SD 16 nmol/L) after ACTH administration; decrease in serum cortisone was observed in 34 (85%) of the patients. The ratio of serum cortisol/cortisone increased in all subjects (mean 5.4 (SD 1.9) before ACTH, and 16.2 (SD 6.2) after ACTH; p < 0.001). Conclusions: The data of our observational study suggest a modulation of peripheral metabolism of cortisol by ACTH with a stimulation of systemic 11β-HSD type 1 activity, leading to restoration of inactive cortisone to biologically active cortisol.