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Investigation of Adrenal Gland Disorders and Disorders of Female Reproduction

Lynnette Nieman, MD, Head, Section on Reproductive Endocrinology
Smita Baid, MD, Staff Clinician
Qingxiang Wei, BS, Technician
Marina Zemskova, MD, Clinical Fellow

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 all consecutive 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 guidelines for the diagnosis and treatment of Cushing’s syndrome. The literature provides little guidance regarding the diagnosis and treatment of Cushing’s syndrome. In collaboration with international experts, we developed guidelines for diagnosis that call for four first-line tests (urine cortisol, salivary cortisol, and dexamethasone 1- and 2-mg tests), along with suggestions about their use and caveats. Similarly, we developed guidelines that advocated transsphenoidal surgery and adjunctive therapy for treatment.

Disorders of female reproduction

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 the follicular and luteal phases, respectively. In a small study of 18 women, we showed that CDB-2914, at a 10- or 20-mg daily dose, can reduce fibroid size. Ongoing studies are evaluating longer-term use. We are also using gene arrays to evaluate the pathophysiology of leiomyomata (fibroids).

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.

Additional Funding

Some of these projects received external funding from HRA-Pharma, Paris France, under a cooperative research and development agreement.

Publications

Levens ED, Potlog-Nahari C, Armstrong AY, Wesley R, Premkumar A, Blithe DL, Blocker WB, Nieman LK. A randomized, double-blind, placebo-controlled trial of CDB-2914 for uterine fibroid treatment. Obstet Gynecol 2008 111:1129-1136.
Biller BMK, Grossman AB, Stewart PM, Melmed S, Bertagna X, Bertherat J, Buchfelder M, Colao A, Hermus AR, Hofland LJ, Klibanski A, Lacroix A, Lindsay JR, Newell-Price J, Nieman LK, Petersenn S, Sonino N, Stalla GK, Swearingen B, Vance ML, Wass JAH, Boscaro M. Treatment of ACTH-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2008 93:2454-2462.
Zemskova MS, Nylen ES, Patronas NJ, Oldfield EH, Becker KL, Nieman LK. Diagnostic accuracy of chromogranin A and calcitonin precursors measurements for the discrimination of ectopic ACTH secretion from Cushing’s disease. J Clin Endocrinol Metab 2009 94:2962-2965.
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 I, 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) 2009 [E-pub ahead of print].

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 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
Catherine Chow, MD, Diagnostic Radiology, Clinical Center, NIH, Bethesda, MD
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, 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 in 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

Contact

For more information, email niemanl@mail.nih.gov.

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