ADRENAL GLAND DISORDERS AND DISORDERS OF FEMALE REPRODUCTION
, Head, Section on Reproductive Medicine
Smita Baid, MD, Clinical Associate
Bhaskar Gundabolu, MD, Clinical Associate
Eric Levens, MD, Clinical Associate
John Lindsay, MD, Clinical Associate
Qingxiang Wei, BS, Technician
Wendy Blocker, RNP, Research Nurse
Matthew Wade, BS, Predoctoral Fellow
Over the past decade, our group has made important contributions to the differential diagnosis of hypercortisolism. We established the corticotropin-releasing hormone (CRH) test and inferior petrosal sinus sampling (IPSS) as major diagnostic tools in the identification of pituitary adenomas causing Cushing’s syndrome. However, the detection of Cushing’s syndrome remains difficult, as does localization of ectopic ACTH-producing tumors (Newell-Price et al., Lancet 2006;3;367:1605). We also evaluate the pathophysiology of and potential new treatments for fibroids in women. This reproductive disorder is common, poorly understood, and lacks optimal medical treatments.
Investigation of Adrenal Gland Disorders
Localization of ectopic ACTH-secreting tumors
Imaging studies are the cornerstone for tumor localization in patients with Cushing’s syndrome caused by ectopic ACTH secretion (EAS). Despite routine use of computed tomography (CT) and magnetic resonance imaging (MRI), tumors remain occult in up to 50 percent of patients with EAS. Up to half of these patients do not respond to medical therapy for hypercortisolism and must undergo bilateral adrenalectomy with life-long replacement therapy. Thus, there is a need for improved imaging techniques to identify ACTH-secreting tumors.
Nuclear medicine techniques enable in vivo imaging of pathophysiological processes; among these techniques, positron emission tomography (PET) studies are finding increasing use in oncology. We previously evaluated the utility of [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) or [111In-DTPA-D-Phe]-pentetreotide optical coherence tomography (OCT) at higher-than-standard doses of radionuclide (18 mCi; H-OCT) and found that FDG-PET did not detect tumors that were occult on CT/MRI; H-OCT rarely identified a lesion. Thus, conventional modalities of CT and MRI should be used in Cushing’s syndrome patients, as FDG-PET does not provide additional information. H-OCT may be useful and needs more investigation. We are now evaluating the utility of [18F]- L-3,4-dihydroxyphenylalanine (18F-DOPA) PET to identify tumors associated with Cushing’s syndrome. This compound is a precursor of serotonin production in neuroendocrine tumors and thus is a good candidate for PET examination in that most occult ACTH-secreting tumors are neuroendocrine.
Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK. Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab 2005;90:4955-62.
Performance of screening tests for Cushing’s syndrome in obese patients
Recent data suggest that Cushing’s syndrome is more common than suspected in populations with a common feature of the disorder such as diabetes or hypertension. Calls for increased screening in these populations may, however, result in false positive diagnoses. As weight gain and obesity are nearly universal features of Cushing’s syndrome, we hypothesized that screening might be indicated but recognized that results would yield poor specificity. We therefore conducted a study in a weight loss clinic and enrolled individuals with at least two additional signs or symptoms of Cushing’s syndrome. Preliminary analysis suggests a high rate (nearly 20 percent) of false-positive screening in patients found to be normal on subsequent confirmatory testing. If confirmed after further study, these results suggest that current recommendations for screening may need revision.
We compared the performance of two techniques, RIA and LC-MS/MS, for measuring salivary cortisol. We studied 261 obese subjects (186 female) with at least two additional features—beyond diabetes and hypertension—of Cushing’s syndrome and 60 healthy volunteers (30 female), who provided split bedtime salivary samples for cortisol measurement. Using laboratory-provided normative ranges, RIA gave a lower specificity than LC-MS/MS in obese subjects but not in healthy volunteers. Among subjects with at least one abnormal result, both RIA and LC-MS/MS values were abnormal in 44 percent of obese and 75 percent of healthy volunteers. We did not diagnose Cushing’s syndrome in any subject. Thus, salivary cortisol levels should not be the sole test for diagnosing Cushing’s syndrome if laboratory-provided reference ranges are used for diagnostic interpretation.
Evaluation of ACTH assays in Cushing’s syndrome
Measurement of plasma ACTH levels by RIA is used to identify adrenal causes of Cushing’s syndrome and to distinguish ectopic Cushing’s syndrome from Cushing’s disease. We wished to determine whether diagnostic criteria developed with RIA would also be applicable to immunoradiometric (IRMA) or immunochemiluminescent (ICMA) assays. To compare diagnostic utility, we measured ACTH by RIA, IRMA, and/or ICMA assay in samples obtained during basal sampling, following CRH testing and during IPSS. While lower, IRMA results correlated highly with RIA and showed similar sensitivity and specificity for the diagnosis of adrenal Cushing’s syndrome and for the diagnosis of Cushing’s disease during CRH testing. IRMA, ICMA, and RIA showed similar sensitivity and specificity during IPSS. The data thus support the use of ACTH immunometric assays, which are more available than RIA and offer similar diagnostic utility.
Baid SK, Sinaii N, Wade M, Rubino D, Nieman LK. Radioimmunoassay and tandem mass spectrometry measurement of bedtime salivary cortisol levels: a comparison of assays to establish hypercortisolism. J Clin Endocrinol Metab 2007;92:3102-7.
Leong GM, Abad V, Charmandari E, Reynolds JC, Hill S, Chrousos GP, Nieman LK. Effects of child- and adolescent-onset endogenous Cushing syndrome on bone mass, body composition, and growth: a 7-year prospective study into young adulthood. J Bone Miner Res 2007;22:110-8.
Lindsay JR, Shanmugam VK, Oldfield EH, Remaley AT, Nieman LK. A comparison of immunometric and radioimmunoassay measurement of ACTH for the differential diagnosis of Cushing’s syndrome. J Endocrinol Invest 2006;29:983-8.
Disorders of Female Reproduction
CDB-2914 as a potential therapeutic agent for fibroids
We have investigated the effect of single doses of the progestin receptor modulator CDB-2914 on the menstrual cycle in women and showed that doses of 100 or 200 mg retard folliculogenesis and precipitate menses in, respectively, the follicular and luteal phases. Ongoing studies are evaluating whether the agent may shrink fibroid size. We are also using gene arrays to evaluate the pathophysiology of leiomyomata.
COLLABORATORS
Alicia Armstrong, MD, Program in Reproductive and Adult Endocrinology, NICHD, Bethesda, MD
Diana Blithe, PhD, Contraception and Reproductive Health Branch, NICHD, Bethesda, MD
Jorge Carrasquillo, MD, Nuclear Medicine, NIH Clinical Center, Bethesda, MD
Richard Chang, MD, Diagnostic Radiology, NIH Clinical Center, Bethesda, MD
Clara Chen, MD, Nuclear Medicine Department, NIH Clinical Center, Bethesda, MD
Catherine Chow, MD, Diagnostic Radiology, NIH Clinical Center, Bethesda, MD
Arthur Frank, MD, George Washington University Weight Management Program, Washington, DC
Ahmed Gharib, MD, Office of the Scientific Director, NHLBI, Bethesda, MD
Mark Gladwin, MD, Pulmonary and Vascular Medicine Branch, NHLBI, Bethesda, MD
Deloris Koziol, PhD, Biostatistics and Clinical Epidemiology Service, NIH Clinical Center, Bethesda, MD
Maria Merino, MD, Laboratory of Pathology, NCI, Bethesda, MD
Tonja Nansel, PhD, Prevention Research Branch, NICHD, Bethesda, MD
Edward H. Oldfield, MD, Surgical Neurology Branch, NINDS, Bethesda, MD
Karel Pacak, MD, Program in Reproductive and Adult Endocrinology, NICHD, Bethesda, MD
Nicholas Patronas, MD, Diagnostic Radiology, NIH Clinical Center, Bethesda, MD
Ahalya Premkumar, MD, Diagnostic Radiology, NIH Clinical Center, Bethesda, MD
James C. Reynolds, MD, Nuclear Medicine, NIH Clinical Center, Bethesda, MD
Domenica Rubino, MD, George Washington University Weight Management Program, Washington, DC
Ninet Sinaii, PhD, MPH, Office of the Deputy Director for Clinical Care, NIH Clinical Center, Bethesda, MD
Bob Wesley, PhD, Biostatistics and Clinical Epidemiology Service, NIH Clinical Center, Bethesda, MD
For further information, contact niemanl@mail.nih.gov.
