Papers by Lynnette Nieman
Pituitary, 2015
Cushing's disease is a rare disorder characterized by overproduction of ACTH from a pituitary... more Cushing's disease is a rare disorder characterized by overproduction of ACTH from a pituitary adenoma leading to hypercortisolemia that in turn leads to increased morbidity and mortality. Here we review the comorbidities associated with Cushing's disease and their impact on quality of life and mortality. Recent evidence suggests that correction of hypercortisolemia may not lead to complete resolution of comorbidities associated with this condition. In particular, increased cardiovascular risk may persist despite long-term remission of hypercortisolemia. This may be related to persistence of visceral adiposity, adverse adipokine profile, glucose intolerance, hypertension, dyslipidemia, atherosclerosis and a procoagulant phenotype. Prior prolonged exposure to glucocorticoids also may have irreversible effects on the central nervous system, leading to persistent cognitive and mood alterations. Osteoporosis and fractures, especially vertebral fractures, can further add to morbid...
The Lancet Diabetes & Endocrinology
DeckerMed Family Medicine
Cushing syndrome is a condition with protean manifestations that are caused by chronic exposure t... more Cushing syndrome is a condition with protean manifestations that are caused by chronic exposure to excess glucocorticoids. Treatment with supraphysiologic doses of glucocorticoids is the most common cause. Pathologic hypercortisolism may result from autonomous adrenal production or as a result of the action of excessive adrenocorticotropic hormone (ACTH) production by a tumor, which stimulates adrenal cortisol production. Primary adrenal forms include unilateral adenoma or carcinoma or, rarely, bilateral hyperplasia and/or nodules. This chapter covers the epidemiology, etiology, pathophysiology, and diagnosis of Cushing syndrome. Clinical manifestations, physical examination findings, and laboratory tests, including tests of the blood and other body fluids, imaging studies, and biopsy, are discussed. The differential diagnosis, treatment options, complications, and prognosis are described. Tables outline clinical features and causes of Cushing syndrome, abnormalities associated with...
Journal of the Endocrine Society
Background: Cyclical Cushing’s syndrome (CCS) is characterized by alternating periods of endogeno... more Background: Cyclical Cushing’s syndrome (CCS) is characterized by alternating periods of endogenous hypercortisolism and eucortisolism. A literature survey of 60 adult patients with CCS found 15 to have ectopic ACTH secretion (EAS) (1). The duration and frequency of hypercortisolemia are unpredictable, creating a diagnostic challenge. Objective: Describe biochemical and clinical characteristics of patients with CCS due to occult or histologically proven ectopic ACTH-secreting neuroendocrine tumor (NET). Methods: We conducted a retrospective medical record review of 12 adults with EAS admitted to our institution. Inclusion required 1) evidence of ectopic ACTH tumor from biochemical testing (CRH stimulation, 8 mg dexamethasone suppression [DST], and/or inferior petrosal sinus sampling [IPSS]) or pathology results and 2) cycles of hypercortisolism (Hi-F) to eucortisolism (Eu-F) off medical treatment. Results: Average age on admission was 61 (46-79) years; 58% were women. All 12 had bio...
European Journal of Endocrinology
This manuscript is part of a commissioned series of urgent clinical guidance documents on the man... more This manuscript is part of a commissioned series of urgent clinical guidance documents on the management of endocrine conditions in the time of COVID-19. This clinical guidance document underwent expedited open peer review by Jérôme Bertherat
30th Annual Meeting North American Skull Base Society
Journal of the Endocrine Society
Abstract Background: Ectopic ACTH Syndrome (EAS) is caused by over production of ACTH from non-pi... more Abstract Background: Ectopic ACTH Syndrome (EAS) is caused by over production of ACTH from non-pituitary neuroendocrine tumors (NET). Tumor localization is challenging; lesions are often < 1 cm in diameter or slow growing so that they are not seen on thin-cut CT or FDG-PET. The use of functional imaging such as 68Ga-DOTATATE PET/CT (DOTATATE) and 6 mCi Octreoscan (OCT) takes advantage of somatostatin receptor expression on these NETs [1-3]. Here, we studied the type 2 somatostatin receptor (SSTR2) expression in ectopic ACTH-producing tumors by immunohistochemistry (IHC) and correlated it with DOTATATE and OCT findings. Methods: All 17 patients (pts) had anatomic and functional imaging and histologic confirmation of EAS. IHC of tumors included evaluation of ACTH, SSTR2 and Ki67; pancreatic tissue islets were the positive SSTR2 control. An experienced research pathologist scored positive staining by the distribution of staining throughout the tumor (diffuse or patchy/focal), the % of cells that were positive (as 1 – 30%, >30-<60% or >60%), and staining intensity (as 1-3). We correlated the IHC findings with imaging (positive or negative in tumor site) and aggressiveness markers in the area of greatest IHC staining, defined as the Ki67 index (<3%, >3-20%, or >20% positive), mitotic count in 10-25 high power fields (HPF), or presence of tumor necrosis or metastasis. Results: The median age at diagnosis was 50 ± 12 years, 65% were females (n:11/17), median tumor size 9 mm (range 4-67 mm). Tumor was identified by DOTATATE in 13/16 pts and by OCT in 3/17. All 17 resected tumors stained for ACTH. Tumor type and location included 11 pulmonary NETs (64%), and 1 each of pulmonary tumorlets, appendiceal NET, ovarian teratoma, mediastinal NET, pheocromocytoma and a NET in a lymph node with unknown primary. Ten tumors had 3+ SSTR2 staining in >75% cells; DOTATATE was positive for all, OCT detected only 3. Four tumors had 0 – 1% of SSTR2 positive cells; DOTATATE was positive in 2 and OCT in none. Three tumors had <10, <25 and 50% staining and 1-2+ intensity; DOTATATE detected 1 and OCT none. Both scans were negative in a mediastinal NET with necrosis, Ki67 >20%, 25 mitoses/10 HPF and <1% SSTR2+ cells, and a metastatic ovarian teratoma with Ki67 21%, mitotic count 21/10HPF and <25% SSTR2+ cells. Conclusions: Most EAS tumors in our cohort were small, expressed SSTR2, and lacked markers of aggressiveness. Strong SSTR2 expression correlated with positive 68Ga-DOTATATE findings in 100% of cases but only 33% of OCT cases. Negative or limited SSTR2 receptor distribution was associated with 43% rate of DOTATATE positivity. Further investigation is needed into expression of other SSTRs to understand this finding. We speculate that positive imaging is a complex reflection of tumor size, SSTR expression, and malignancy potential.
Journal of the Endocrine Society
Abstract Abnormalities of hypothalamic-pituitary-adrenal (HPA) axis are frequent accompaniments o... more Abstract Abnormalities of hypothalamic-pituitary-adrenal (HPA) axis are frequent accompaniments of mood and anxiety disorders. Adolescence (and puberty) are associated with both an increased onset of mood/anxiety disorders, as well as the emergence of sex differences in the risk for these conditions (i.e., a 2-fold increased life-time risk in women compared with men). Finally, sex differences in HPA axis response to a range of stressors are documented in both rodents and humans. We employed the awakening cortisol response (ACR) to evaluate the HPA axis in a sample of normally-developing pre and post pubertal children. We studied 66 prepubertal children (25 girls, 41 boys) and 29 post pubertal children (14 girls,15 boys). Pubertal stage (PS) was assessed by a trained clinician: in boys based on testicular volume (TV) using the Prader orchidometer; in girls based on breast development. All children (and 1st degree relatives) were free of any past/current psychiatric disorder (as determined by structured diagnostic interview); all children were medically well, medication free, had a BMI within the 15th -85th percentile, normal bone age, and normal IQs. Pre and post pubertal children were selected for awakening cortisol response (ACR) analysis from a larger longitudinal study. The first visit was selected for prepubertal children. Post pubertal children were selected during their most recent visit at PS V. There was no overlap in these groups of children. ACR studies were performed on the morning of outpatient clinic visits. Salivary cortisol was measured by chemiluminescent enzyme immunoassay on Siemens Immullite1000 analyzer. The ACR area under the curve (AUC) and individual time points (0, 30, 45 and 60 minutes) were analyzed by ANOVAs. In the AUC cortisol there was a significant main effect of sex (F1,94=7.5; p=0.007) but no main or interactive effects of PS (p=0.3 and p=0.2, respectively). Similarly, the individual timepoints showed significant main effects of sex (ANOVA-R: F1,91=7.4, p=0.008) and time (F3,89=19, p<.001), but no main effects of PS, nor any between-subjects interactive effects. (p=ns, all comparisons). In summary, we found no effects of pubertal stage on the ACR and that sex differences in the ACR occurred independently of pubertal stage. Therefore, our preliminary findings suggest that sex differences in HPA axis appear prior to gonadarche. These findings are analogous to previous adult data from our group (Roca, et al. 2005) in which sex differences in HPA axis responsivity were observed in adult men and women during both eugonadal and GnRH agonist-induced hypogonadal conditions.
Journal of the Endocrine Society
Journal of the Endocrine Society
Abstract Background: Increased tissue cortisol availability and enhanced glucocorticoid action ha... more Abstract Background: Increased tissue cortisol availability and enhanced glucocorticoid action have been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes. Objective: To test the hypothesis that blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance in overweight/obese subjects with glucose intolerance. Design: We conducted a randomized, placebo-controlled, double-blind, crossover trial of mifepristone (50 mg orally, every six hr) in overweight/obese subjects (BMI 25-37 kg/m2), with abnormal glucose tolerance (n=16, women=7). Participants (age:56 ± 8 yr) had prediabetes (n=12) or mild type 2 DM (n=4, A1c < 7%) on diet control or stable dose of metformin for 3 months (n=2). Mifepristone or placebo treatment for one week was followed by a 6-8-week washout and crossover to the other arm. At baseline, and after each treatment period, insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test (FSIVGTT) and an oral glucose tolerance test (OGTT). Whole body glucose disposal index of insulin sensitivity (SI) was derived using a Minimal model analysis. Adipose tissue-SI, which reflects insulin-induced free fatty acid (FFA) suppression, was estimated by the log-linear slope of FFA levels during the FSIVGTT. Matsuda index, oral glucose insulin sensitivity index (OGIS, ml/min/m2), and hepatic insulin resistance index (HIRI, mg/dL×µU/mL×105) were derived from OGTT. Adipo-IR, a surrogate measure of adipocyte insulin resistance, was calculated by multiplying fasting concentrations of FFA and insulin (mmol×pmol/L). Comparison of various post-treatment parameters was performed using crossover ANOVA. This analysis takes into account specific treatment arm, treatment order, and treatment effects. Thus, we explicitly tested for carryover effects in our crossover study. Results: GR blockade did not affect body weight (p=0.56) or fasting glucose (p=0.67), but significantly decreased fasting insulin levels when compared with placebo [mean (95%CI): -40.7 (-68.53 to -12.91), p=0.007]. Mifepristone administration for one week did not alter whole body glucose disposal indices of insulin sensitivity (FSIVGTT-Si: p=0.52, Matsuda Index: p=0.74; and OGIS: p=0.75). However, GR blockade reduced HIRI [-19.80 (-40.76 to 1.15), p=0.05], Adipo-IR [-15.54 (-31.47 to 0.37), p=0.04], and improved Adipose-SI [-19.75 (-31.41 to -8.08), p=0.003]. Conclusions: In patients with abnormal glucose tolerance, short-term GR blockade improved hepatic and adipose tissue insulin sensitivity without significantly altering whole-body insulin sensitivity. These findings suggest that GR may be a therapeutic target in insulin-resistant states. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.
Journal of the Endocrine Society
Journal of the Endocrine Society
Journal of the Endocrine Society
Endocrinology and Metabolism
Cushing's syndrome, a potentially lethal disorder characterized by endogenous hypercortisolism, m... more Cushing's syndrome, a potentially lethal disorder characterized by endogenous hypercortisolism, may be difficult to recognize, especially when it is mild and the presenting features are common in the general population. However, there is a need to identify the condition at an early stage, as it tends to progress, accruing additional morbidity and increasing mortality rates. Once a clinical suspicion is raised, screening tests involve timed measurement of urine, serum or salivary cortisol at baseline or after administration of dexamethasone, 1 mg. Each test has caveats, so that the choice of tests must be individualized for each patient. Once the diagnosis is established, and the cause is determined, surgical resection of abnormal tumor/tissue is the optimal treatment. When this cannot be achieved, medical treatment (or bilateral adrenalectomy) must be used to normalize cortisol production. Recent updates in screening for and treating Cushing's syndrome are reviewed here.
Journal of Neurosurgery
OBJECTIVEAccurate presurgical localization of microadenomas in Cushing’s disease (CD) leads to im... more OBJECTIVEAccurate 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.METHODSThe 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 sequence...
The Journal of Clinical Endocrinology & Metabolism
Context: Perioperative increases in adrenocorticotropic hormone (ACTH) and cortisol mimic results... more 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).
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Papers by Lynnette Nieman