Mifepristone Improves Adipose Tissue Insulin Sensitivity in Insulin Resistant Individuals.

BACKGROUND: Increased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance. METHODS: We conducted a randomized, double-blinded, placebo-controlled, crossover study in overweight/obese individuals (n = 16, 44% female) with prediabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 h) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT [primary outcome: insulin sensitivity index (SI)] and OGTT [Matsuda index (MI) and oral glucose insulin sensitivity index (OGIS)]. Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT. RESULTS: Mifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7 ±â€…32.9 vs 42.8 ±â€…23.9; P = 0.002) and reduced adipo-IR (49.9 ±â€…45.9 vs 65.5 ±â€…43.8; P = 0.004), and HIRI (50.2 ±â€…38.7 vs 70.0 ±â€…44.3; P = 0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or ß-cell glucose sensitivity. CONCLUSION: Short-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism.

AN INDIVIDUALIZED APPROACH TO THE EVALUATION OF CUSHING SYNDROME.

Cushing syndrome (CS) is caused by chronic exposure to excess glucocorticoids. Early recognition and treatment of hypercortisolemia can lead to decreased morbidity and mortality. The diagnosis of CS and thereafter, establishing the cause can often be difficult, especially in patients with mild and cyclic hypercortisolism. Surgical excision of the cause of excess glucocorticoids is the optimal treatment for CS. Medical therapy (steroidogenesis inhibitors, medications that decrease adrenocorticotropic hormone [ACTH] levels or glucocorticoid antagonists) and pituitary radiotherapy may be needed as adjunctive treatment modalities in patients with residual, recurrent or metastatic disease, in preparation for surgery, or when surgery is contraindicated. A multidisciplinary team approach, individualized treatment plan and long-term follow-up are important for optimal management of hypercortisolemia and the comorbidities associated with CS. ABBREVIATIONS: ACTH = adrenocorticotropic hormone; BIPSS = bilateral inferior petrosal sinus sampling; CBG = corticosteroid-binding globulin; CD = Cushing disease; CRH = corticotropin-releasing hormone; CS = Cushing syndrome; Dex = dexamethasone; DST = dexamethasone suppression test; EAS = ectopic ACTH syndrome; FDA = U.S. Food & Drug Administration; HDDST = high-dose DST; IPS/P = inferior petrosal sinus to peripheral; MRI = magnetic resonance imaging; NET = neuroendocrine tumor; PET = positron emission tomography; UFC = urinary free cortisol.

Normalized Early Postoperative Cortisol and ACTH Values Predict Nonremission After Surgery for Cushing Disease.

Context: Perioperative increases in adrenocorticotropic hormone (ACTH) and cortisol mimic results of corticotropin-releasing hormone (CRH) stimulation testing. This phenomenon may help identify patients with residual adenoma after transsphenoidal surgery (TSS) for Cushing disease (CD). Objective: To predict nonremission after TSS for CD. Design: Retrospective case-control study of patients treated at a single center from December 2003 until July 2016. Early and medium-term remission were assessed at 10 days and 11 months. Patients and Setting: Two hundred and ninety-one consecutive TSS cases from 257 patients with biochemical evidence of CD seen at a clinical center. Interventions: Normalized early postoperative values (NEPVs) for cortisol and ACTH were calculated as immediate postoperative cortisol or ACTH levels minus preoperative post-CRH-stimulation test levels. Main Outcome Measures: Prediction of early nonremission was evaluated using logistic regression. Prediction of medium-term remission was assessed using Cox regression. Predictive ability was quantified by area under the receiver operating characteristic curve (AUROC). Results: NEPVs for cortisol and ACTH predicted early nonremission [adjusted odds ratio (OR): 1.1; 95% confidence interval (CI): 1.0, 1.1; P = 0.016 and adjusted OR: 1.0; 95% CI: 1.0, 1.0; P = 0.048, respectively]. AUROC for NEPV of cortisol was 0.78 (95% CI: 0.61, 0.95); for NEPV of ACTH, it was 0.80 (95% CI: 0.61, 0.98). NEPVs for cortisol and ACTH predicted medium-term nonremission [hazard ratio (HR): 1.1; 95% CI: 1.0, 1.1; P = 0.023 and HR: 1.0; 95% CI: 1.0, 1.0; P = 0.025, respectively]. Conclusions: NEPVs for cortisol and ACTH predicted nonremission after TSS for CD.

Cushing's syndrome: epidemiology and developments in disease management.

Cushing's syndrome is a rare disorder resulting from prolonged exposure to excess glucocorticoids. Early diagnosis and treatment of Cushing's syndrome is associated with a decrease in morbidity and mortality. Clinical presentation can be highly variable, and establishing the diagnosis can often be difficult. Surgery (resection of the pituitary or ectopic source of adrenocorticotropic hormone, or unilateral or bilateral adrenalectomy) remains the optimal treatment in all forms of Cushing's syndrome, but may not always lead to remission. Medical therapy (steroidogenesis inhibitors, agents that decrease adrenocorticotropic hormone levels or glucocorticoid receptor antagonists) and pituitary radiotherapy may be needed as an adjunct. A multidisciplinary approach, long-term follow-up, and treatment modalities customized to each individual are essential for optimal control of hypercortisolemia and management of comorbidities.

Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing's syndrome, adrenal insufficiency, and congenital adrenal hyperplasia.

The hypothalamic-pituitary-adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing's syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing's syndrome). Endogenous Cushing's syndrome can be subdivided into ACTH-dependent and ACTH-independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing's syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long-term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control.

Cushing's syndrome: all variants, detection, and treatment.

Diagnosis of Cushing's syndrome involves a step-wise approach and establishing the cause can be challenging. Several pathogenic mechanisms have been proposed for glucocorticoid-induced hypertension, including a functional mineralocorticoid excess state, upregulation of the renin angiotensin system, and deleterious effects of cortisol on the vasculature. Surgical excision of the cause of excess glucocorticoids remains the optimal treatment. Antiglucocorticoid and antihypertensive agents and steroidogenesis inhibitors can be used as adjunctive treatment modalities in preparation for surgery and in cases where surgery is contraindicated or has not led to cure.

Changes in glucose tolerance with metformin treatment in polycystic ovary syndrome: a retrospective analysis.

OBJECTIVE: To determine whether treatment with metformin would prevent progression to glucose intolerance and type 2 diabetes in women with polycystic ovary syndrome (PCOS). METHODS: We conducted a retrospective review of medical records of women treated for PCOS during a 5-year period. Eligibility criteria included exclusion of diabetes at baseline by an oral glucose tolerance test, treatment with metformin, and a repeated oral glucose tolerance test after at least 1 year of metformin therapy. Fifty women with PCOS fulfilled the eligibility criteria. RESULTS: At baseline, 11 women (22%) had impaired glucose tolerance (IGT), and 39 (78%) had normal glucose tolerance (NGT). After treatment with metformin, IGT persisted in 5 (45%) of the 11 women who had IGT at baseline, whereas 6 (55%) had reversion to NGT. During a mean treatment period of 43.3 months, 2 (5%) of the 39 women with baseline NGT had conversion to IGT, resulting in an annual conversion rate from NGT to IGT of 1.4%. In comparison with the 16% to 19% annual conversion rate reported in the literature, metformin treatment in this study resulted in an 11-fold decrease in the annual conversion rate from NGT to IGT (P = 0.01). None of the 50 women developed diabetes. CONCLUSION: The findings of this retrospective study suggest that long-term treatment with metformin delays or prevents the development of IGT and type 2 diabetes in women with PCOS.

Is metformin a primary ovulatory agent in patients with polycystic ovary syndrome?

Insulin resistance is an important pathophysiological feature of the polycystic ovary syndrome (PCOS). Insulin resistance and its compensatory hyperinsulinemia contribute to the anovulation, hyperandrogenism, infertility and early pregnancy loss suffered by women with PCOS. Current evidence supports the role of metformin in the treatment of anovulation in PCOS, both in monotherapy and concomitantly with clomiphene in clomiphene-resistant patients. In addition, novel evidence suggests that insulin sensitizers may also play a role in reducing the risk of early pregnancy loss. The insulin-sensitizing agents available commercially include metformin, rosiglitazone and pioglitazone. Compared with the thiozolidinediones, metformin is the agent that has been most frequently studied in PCOS, and has the most favorable pregnancy safety profile. In conclusion, there is strong evidence supporting the use of metformin as a primary ovulatory agent in women with PCOS.

Prevention of diabetes and cardiovascular disease in women with PCOS: treatment with insulin sensitizers.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in United States, affecting 6-10% of females in the reproductive age group. Recent studies have shown that insulin resistance plays an important role in the pathogenesis of PCOS. Traditionally, management of PCOS consisted mainly of ovulation induction, treatment of acne and hirsutism, and prevention of endometrial cancer. However, with mounting evidence showing that PCOS is associated with dysmetabolic syndrome and an increased risk for developing diabetes and heart disease, this can no longer be our sole focus. Current data support a strong recommendation that women with PCOS should undergo comprehensive evaluation for diabetes and recognized cardiovascular risk factors and receive appropriate treatment as needed. Lifestyle modifications remain the first-line therapy for all obese women with PCOS. However, many obese women with PCOS find weight loss difficult to achieve and maintain, and this is not an option for lean women with PCOS. For these reasons, insulin-sensitizing drugs are proving to be a promising and unique therapeutic option for chronic treatment of PCOS.