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Investigation of Adrenal Gland Disorders and Disorders of Female Reproduction

Lynnette Nieman, MD
  • Lynnette Nieman, MD, Head, Section on Reproductive Endocrinology
  • Smita Abraham, MD, Staff Clinician
  • Qingxiang Wei, BS, Technician
  • Marina Zemskova, MD, Clinical Fellow
  • Nicola M. Neary, MD, Clinical Fellow
  • Susmeeta T. Sharma, MD, Clinical Fellow
  • Ozan Suer, Clinical Research Training Program Student
  • Aleta Hong, BA, Postbaccalaureate Trainee

Over the past decade, we have made major contributions to the differential diagnosis of hypercortisolism. We established the corticotropin releasing hormone (CRH) test and inferior petrosal sinus sampling (IPS) 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 the localization of ectopic ACTH-producing tumors. We also evaluate the pathophysiology and potential new treatments for fibroids in women. This reproductive disorder is common, poorly understood, and lacks optimal medical treatments.

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 adrenocorticotropin hormone (ACTH) secretion (EAS). Despite routine use of computed tomography (CT) and magnetic resonance imaging (MRI), tumors remain occult in up to 50% of patients with EAS. Up to half of the EAS patients do not respond to medical therapy of 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 permit 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) PET or [111In-DTPA-D-Phe]-pentetreotide (OCT) at higher-than-standard doses of radionuclide (18 mCi; H-OCT) in patients with EAS (thus, including those in whom we subsequently found a tumor, as well as those who were occult). We 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 these patients. 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 in any patient presenting with EAS. This compound is a precursor for serotonin production in neuroendocrine tumors and is therefore a good candidate for PET examination, given that most occult ACTH-secreting tumors are neuroendocrine.

Evaluation of the 1 µg Cortrosyn stimulation test. We tested 60 individuals in the morning and afternoon. Twenty-five volunteers (19 at 1600 h) had a subnormal cortisol response (peak cortisol 10.4-17.5 µg/dl), using a criterion <18 µg/dl (497 nmol/l), for a specificity of 58% (confidence interval [CI] 45-71%). Afternoon testing had a significant impact on failure rates (odds ratio 6.98, CI 2.17-22.43), while gender and age did not. The stock solution contained 1 µg ACTH, but after administration through tubing it contained only 0.5-0.8 µg. The high rate of abnormal results, especially in the afternoon, and loss of ACTH through tubing suggest that morning testing and minimal tubing should be adopted to avoid an inappropriate diagnosis of adrenal insufficiency.

Evaluation of screening tests for the diagnosis of Cushing's syndrome in overweight and obese individuals. With the epidemic of obesity, the diagnosis of Cushing's syndrome is being considered in more patients, few of whom will have the disorder. To evaluate whether wide-spread screening should be done, we studied 369 subjects with a 24-h urine cortisol, and/or late-night salivary cortisol, and/or 1 mg dexamethasone suppression test (DST). Abnormal tests were repeated and/or a dexamethasone-CRH test was performed. In addition to obesity, subjects had a mean of five to six features of Cushing's syndrome. None was found to have Cushing's syndrome. Test specificities to exclude Cushing's syndrome for subjects who completed three tests were: urine cortisol, 96% (95% CI, 93-98%]; DST, 90% (95% CI, 87-93%); salivary cortisol, 84% by RIA (95% CI, 79-89%) and 92% by liquid chromatography–tandem mass spectrometry (95% CI, 88-95%). The combined specificity (both tests normal) for all combinations of two tests was 84 to 90%, with overlapping CIs. These data do not support widespread screening of overweight and obese subjects for Cushing's syndrome; test results for such patients may be falsely abnormal.

Evaluation of an optimal magnetic resonance imaging (MRI) protocol for the detection of corticotrope tumors. While detection of pituitary tumors with MRI may reduce diagnostic costs and improve surgical outcomes for patients with Cushing's disease, the optimal T1-weighted spin-echo (SE) MRI protocol remains unknown. We examined the MRI parameters in 21 patients with Cushing's disease whose initial pituitary MRI study gave a false negative result and in whom a lesion was subsequently identified at the NIH. Scan parameters that differed between the NIH and externally performed scans were: TR (400 ms vs. 492 ± 19 ms, P = 0.0002); TE (10.3 ± 0.5 vs. 17.2 ± 1.2 ms, P = 0.0003); FOV (12 x 12 cm vs.17 ± 0.6 x 18 ± 0.7 cm, P < 0.0001). Thus, not all 'T1-weighted SE' scans are equally accurate. The MRI technique, particularly FOV and TR/TE value, influences the results.

Disorders of female reproduction

We investigated whether the endometrium of women with endometriosis is abnormal and whether such abnormality might account for the decreased fertility rates associated with this condition. We recently demonstrated lower levels of progesterone-dependent markers of implantation in the luteal-phase endometrium of women with endometriosis than in that of healthy volunteers. In addition, a placebo-controlled, randomized trial of raloxifene in women with endometriosis showed an earlier return of pain in individuals treated with the agent than in untreated individuals, despite its anti-endometrial effects in healthy control women.

We investigated the early luteal effects of a single dose of the progesterone (P) receptor modulator CDB-2914 (10, 50, or 100 mg) or placebo given after ovulation and within two days of the LH surge in 56 cycling women. CDB-2914 caused a significant dose-dependent decrease in endometrial thickness, an increase in glandular progesterone receptors, and a decrease in peripheral node addressins. Estradiol and P levels and menstrual cycle timing were not altered. The alteration in endometrial thickness and P-dependent markers of implantation in the absence of changes in hormone levels and cycle length suggests that CDB-2914 may have contraceptive properties.

Additional Funding

  • Some of these projects received external funding from two CRADAs executed with HRA-Pharma, Paris France, under a cooperative research and development agreement.
  • Part of this work received funding from a Bench-to-Bedside award.


  • Baid SK, Rubino D, Sinaii N, Ramsey S, Frank A, Nieman LK. Specificity of screening tests for Cushing's syndrome in an overweight and obese population. J Clin Endocrinol Metab. 2009 94:3857-3864.
  • Chowdhury IN, Sinaii N, Oldfield EH, Patronas N, Nieman LK. A change in pituitary MRI protocol detects ACTH-secreting tumors in patients with previously negative results. Clin Endocrinol (Oxf). 2010 72:502-506.
  • Zemskova MS, Gundabolu B, Sinaii N, Chen CC, Carrasquillo JA, Whatley M, Chowdhury I, Gharib AM, Nieman LK. Utility of various functional and anatomic imaging modalities for detection of ectopic adrenocorticotropin-secreting tumors. J Clin Endocrinol Metab. 2010 95:1207-19.
  • Stratton P, Levens ED, Hartog B, Piquion J, Wei Q, Merino M, Nieman LK. Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914. Fertil Steril. 2010 93:2035-41.
  • Wei Q, St Clair JB, Fu T, Stratton P, Nieman LK. Reduced expression of biomarkers associated with the implantation window in women with endometriosis. Fertil Steril. 2009 91:1686-91.


  • Alicia Armstrong, MD, Program on Reproductive and Adult Endocrinology, NICHD, Bethesda, MD
  • Diana Blithe, PhD, Contraception and Reproductive Health Branch, NICHD, Bethesda, MD
  • Jorge A. Carrasquillo, MD, Memorial Sloan-Kettering Cancer Center, New York, NY
  • Richard Chang, MD, Diagnostic Radiology, Clinical Center, NIH, Bethesda, MD
  • Clara Chen, MD, Nuclear Medicine Department, Clinical Center, NIH, Bethesda, MD
  • Ahmed Gharib, MD, Office of the Scientific Director, NHLBI, Bethesda, MD
  • Deloris Koziol, PhD, Biostatistics and Clinical Epidemiology Service, Clinical Center, NIH, Bethesda, MD
  • Maria Merino, MD, Laboratory of Pathology, NCI, Bethesda, MD
  • Tonja Nansel, MD, Prevention Research Branch, NICHD, Bethesda, MD
  • Edward H. Oldfield, MD, Surgical Neurology Branch, NINDS, Bethesda, MD
  • Karel Pacak, MD, PhD, Program on Reproductive and Adult Endocrinology, NICHD, Bethesda, MD
  • Nicholas Patronas, MD, Diagnostic Radiology, Clinical Center, NIH, Bethesda, MD
  • Ahalya Premkumar, MD, Diagnostic Radiology, Clinical Center, NIH, Bethesda, MD
  • James C. Reynolds, MD, Nuclear Medicine Department, Clinical Center, NIH, Bethesda, MD
  • Domenica Rubino, MD, George Washington University Weight Management Program (GWUWMP), Washington, DC
  • Ninet Sinaii, MPH, PhD, Office of the Deputy Director for Clinical Care, Clinical Center, NIH, Bethesda, MD
  • Bob Welsey, PhD, Biostatistics and Clinical Epidemiology Service, Clinical Center, NIH, Bethesda, MD


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