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.

CRH stimulation improves 18F-FDG-PET detection of pituitary adenomas in Cushing's disease.

OBJECTIVE: In MRI-negative cases Cushing's disease (CD), surgeons perform a more extensive exploration of the pituitary gland, with fewer instances of hormonal remission. 18F-fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) has a limited role in detecting adenomas that cause CD (corticotropinomas). Our previous work demonstrated corticotropin-releasing hormone (CRH) stimulation leads to delayed, selective glucose uptake in corticotropinomas. Here, we prospectively evaluated the utility of CRH stimulation in improving 18F-FDG-PET detection of adenomas in CD. METHODS: Subjects with a likely diagnosis of CD (n = 27, 20 females) each underwent two 18F-FDG-PET studies [without and with ovine-CRH (oCRH) stimulation] on a high-resolution PET platform. Standardized-uptake-values (SUV) in the sella were calculated. Two blinded neuroradiologists independently read 18F-FDG-PET images qualitatively. Adenomas were histopathologically confirmed, analyzed for mutations in the USP8 gene and for glycolytic pathway proteins. RESULTS: The mean-SUV of adenomas was significantly increased from baseline (3.6 ± 1.5) with oCRH administration (3.9 ± 1.7; one-tailed p = 0.003). Neuroradiologists agreed that adenomas were visible on 21 scans, not visible on 26 scans (disagreed about 7, kappa = 0.7). oCRH-stimulation led to the detection of additional adenomas (n = 6) not visible on baseline-PET study. Of the MRI-negative adenomas (n = 5), two were detected on PET imaging (one only after oCRH-stimulation). USP8 mutations or glycolytic pathway proteins were not associated with SUV in corticotropinomas. CONCLUSIONS: The results of the current study suggest that oCRH-stimulation may lead to increased 18F-FDG uptake, and increased rate of detection of corticotropinomas in CD. These results also suggest that some MRI invisible adenomas may be detectable by oCRH-stimulated FDG-PET imaging. CLINICAL TRIAL INFORMATION: 18F-FDG-PET imaging with and without CRH stimulation was performed under the clinical trial NIH ID 12-N-0007 (clinicaltrials.gov identifier NCT01459237). The transsphenoidal surgeries and post-operative care was performed under the clinical trial NIH ID 03-N-0164 (clinicaltrials.gov identifier NCT00060541).

Earlier post-operative hypocortisolemia may predict durable remission from Cushing's disease.

CONTEXT: Achievement of hypocortisolemia following transsphenoidal surgery (TSS) for Cushing's disease (CD) is associated with successful adenoma resection. However, up to one-third of these patients recur. OBJECTIVE: We assessed whether delay in reaching post-operative cortisol nadir may delineate patients at risk of recurrence for CD following TSS. METHODS: A retrospective review of 257 patients who received 291 TSS procedures for CD at NIH, between 2003 and 2016. Early biochemical remission (serum cortisol nadir <5 µg/dL) was confirmed with endocrinological and clinical follow-up. Recurrence was detected by laboratory testing, clinical stigmata or medication dependence during a median follow-up of 11 months. RESULTS: Of the 268 unique admissions, remission was recorded in 241 instances. Recurrence was observed in 9% of these cases with cortisol nadir ≤5 µg/dL and 6% of cases with cortisol nadir ≤2 µg/dL. The timing of hypocortisolemia was critical in detecting late recurrences. Morning POD-1 cortisol <3.3 µg/dL was 100% sensitive in predicting durable remission and morning POD-3 cortisol ≥18.5 µg/dL was 98.6% specific in predicting remote recurrence. AUROC analysis revealed that hypocortisolemia ≤5 µg/dL before 15 h (post-operative) had 95% sensitivity and an NPV of 0.98 for durable remission. Serum cortisol level ≤2 µg/dL, when achieved before 21 h, improved sensitivity to 100%. CONCLUSIONS: In our cohort, early, profound hypocortisolemia could be used as a clinical prediction tool for durable remission. Achievement of hypocortisolemia ≤2 µg/dL before 21 post-operative hours appeared to accurately predict durable remission in the intermediate term.

Potential utility of FLAIR in MRI-negative Cushing's disease.

OBJECTIVE Accurate presurgical localization of microadenomas in Cushing's disease (CD) leads to improved remission rates and decreased adverse events. Volumetric gradient recalled echo (3D-GRE) MRI detects pituitary microadenomas in CD in up to 50%-80% cases as a focus of hypointensity due to delayed contrast wash-in. The authors have previously reported that postcontrast FLAIR imaging may be useful in detecting otherwise MRI-negative pituitary microadenomas as foci of hyperintensity. This reflects theoretically complementary imaging of microadenomas due to delayed contrast washout. The authors report on the diagnostic accuracy and clinical utility of FLAIR imaging in the detection of microadenomas in patients with CD. METHODS The authors prospectively analyzed imaging findings in 23 patients (24 tumors) with biochemically proven CD who underwent transsphenoidal surgery for CD. Preoperatively, the patients underwent pituitary MRI with postcontrast FLAIR and postcontrast 3D-GRE sequences. RESULTS Postcontrast FLAIR hyperintensity was detected in macroadenomas, and in 3D-GRE-positive or -negative microadenomas. Overall, 3D-GRE was superior in detecting surgically and histopathologically confirmed, location-concordant microadenomas. Of 24 pituitary adenomas, 18 (75%; sensitivity 82%, positive predictive value 95%) were found on 3D-GRE, and 13 (50% [1 was false positive]; sensitivity 55%, positive predictive value 92%) were correctly identified on FLAIR. The stand-alone specificity of 3D-GRE and FLAIR was similar (50%). These results confirm the superiority of 3D-GRE as a stand-alone imaging modality. The authors then tested the utility of FLAIR as a complementary tool to 3D-GRE imaging. All 5 patients with negative 3D-GRE MRI displayed a distinct focus of FLAIR enhancement. Four of those 5 cases (80%) had location-concordant positive histopathological results and achieved postsurgical biochemical remission. The remaining patient was not cured, because resection did not include the region of FLAIR hyperintensity. CONCLUSIONS This study suggests that delayed microadenoma contrast washout may be detected as FLAIR hyperintensity in otherwise MRI-negative CD cases. The authors propose adding postcontrast FLAIR sequences to complement 3D-GRE for surgical planning in patients with CD. Clinical trial registration no.: NIH protocol 03-N-0164, NCT00060541 (clinicaltrials.gov).

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.

Different imaging characteristics of concurrent pituitary adenomas in a patient with Cushing's disease.

We report a patient with Cushing's disease (CD) and two pituitary adenomas that demonstrated different imaging characteristics and therefore suggest an alternative imaging strategy for these patients. A 42-year-old woman presented with signs and symptoms of CD. Biochemical evaluation confirmed hypercortisolemia and suggested CD. On pituitary MRI with spoiled gradient recalled acquisition in the steady-state and T1-weighted spin echo protocols, a 5mm hypoenhancing region typical for a pituitary adenoma was identified on the left. However, after surgical resection the patient remained hypercortisolemic and pathology revealed a non-functional adenoma. At early repeat surgical exploration a 10mm adenoma was found in the right side of the gland. Postoperatively the patient became hypocortisolemic and pathology demonstrated an adrenocorticotropic hormone (ACTH)-staining adenoma. On review of the initial MRI this tumor corresponded to a region of contrast retention best visualized on delayed fluid attenuated inversion recovery (FLAIR) imaging. While the incidentaloma in this case demonstrated classical imaging characteristics of a pituitary adenoma the larger ACTH-secreting tumor was best appreciated by contrast retention. This suggests a role for delayed postcontrast FLAIR imaging in the preoperative evaluation of CD. ACTH-secreting tumors causing CD cause significant morbidity. Due to their small size, a pituitary adenoma is frequently not identified on imaging despite endocrinologic testing suggesting CD. Regardless of improvements in MRI, many tumors are only identified at surgical exploration.

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.

Divergent effects of a combined hormonal oral contraceptive on insulin sensitivity in lean versus obese women.

OBJECTIVE: To evaluate the effects of a commonly used combined hormonal oral contraceptive (OC) on carbohydrate metabolism in obese as compared with lean women. DESIGN: 6-month prospective study. SETTING: Clinical research center at an academic medical center. PATIENT(S): Premenopausal nondiabetic women with body mass index <25 kg/m(2) (n = 15) or >30 kg/m(2) (n = 14). INTERVENTION(S): Ethinyl estradiol (35 µg) and norgestimate (0.18/0.215/0.25 mg) for 6 cycles. MAIN OUTCOME MEASURE(S): Insulin sensitivity by frequent sampling intravenous glucose tolerance test; other indices of insulin sensitivity (homeostatic model assessment of insulin sensitivity index [ISI HOMA], the Matsuda index); fasting lipid panel. RESULT(S): Insulin sensitivity changed from 6.62 ± 3.69 min(-1)/mIU/L (baseline) to 8.23 ± 3.30 min(-1)/mIU/L (6 months) in lean women, and from 4.36 ± 2.32 to 3.82 ± 2.32 min(-1)/mIU/L in obese women. Divergent effects on insulin sensitivity were also observed with ISI HOMA and the Matsuda index. Low-density lipoprotein increased by approximately 20 mg/dL in both the lean and obese groups. CONCLUSION(S): Lean and obese women exhibit differential changes in insulin sensitivity when given 6 months of a commonly used oral contraceptive. The mechanisms of these differences and whether these divergent effects persist in the long term require further investigation.

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.

Long-term effect of metformin on metabolic parameters in the polycystic ovary syndrome.

Insulin resistance is a central feature of the PCOS and may increase cardiovascular risk. Owing to insulin resistance, the metabolic syndrome is more prevalent in women with PCOS compared with unaffected women. Metformin improves the metabolic profile in PCOS in short-term studies. In this study, we evaluated the long-term effect of metformin on metabolic parameters in women with PCOS during routine care without a controlled diet.We performed a retrospective medical chart review of 70 women with PCOS receiving metformin from an academic endocrine clinic. Metabolic risk factors were compared before and after metformin treatment. Time trends of these metabolic parameters were also analysed. After a mean follow-up of 36.1 months with metformin treatment, improvements were observed for BMI (-1.09 +/- 3.48 kg/m2, p = 0.0117), diastolic blood pressure (-2.69 +/- 10.35 mmHg, p = 0.0378), and HDL cholesterol (+5.82 +/- 11.02 mg/dL, p <0.0001).The prevalence of metabolic syndrome decreased from 34.3% at baseline to 21.4% (p = 0.0495). The course of BMI reduction during metformin treatment was significantly more pronounced in women with PCOS with metabolic syndrome at baseline, compared with those without the metabolic syndrome (p = 0.0369 for interaction). In conclusion, metformin improved the metabolic profile of women with PCOS over 36.1 months, particularly in HDL cholesterol, diastolic blood pressure and BMI.

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.