Lynnette Nieman, MD, Head, Section on Reproductive Medicine
Ioannis Ilias, MD, Visiting Fellow
Smita Baid, MD, Clinical Associate
Iffat Chowdhury, MD, Clinical Associate
John Lindsay, MD, Clinical Associate
Pamela Stratton, MD, Staff Clinician
James St. Clair, BS, Predoctoral Fellow
Ninet Sinaii, MPH, Predoctoral Fellow
Qingxiang Wei, BS, Technician
Rhonda Hearns-Stokes, MD, Guest Researcher
Wendy Blocker, RNP, Nurse Practitioner

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 the localization of ectopic adrenocorticotropic hormone-producing tumors. We also evaluate the pathophysiology of and potential new treatments for endometriosis and fibroids in women. These reproductive disorders are common, poorly understood, and lack optimal medical treatments.

Quality of life in Cushing's syndrome

Nieman, Lindsay, Baid; in collaboration with Nansel

We used the entire SF-36 questionnaire to explore the quality of life in Cushing's syndrome patients. We found that patients with active Cushing's syndrome have great impairment in physical activities and cognitive function that limit social activities. Patients also demonstrate significant but less profound abnormalities in their sense of well-being and general health perception as compared with the general population. Quality of life improves in the first five years after treatment, but some areas remain subnormal for up to 15 years after treatment, suggesting significant long-term impairment of quality of life in Cushing's patients.

Localization of ectopic ACTH-secreting tumors

Nieman, Chowdhury; in collaboration with Carrasquillo, Chen, Pacak

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 percent of patients with EAS. Up to half of these 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 enable in vivo imaging of pathophysiological processes; among these techniques, positron emission tomography (PET) studies are increasingly used in oncology. We previously evaluated the utility of [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) or [111In-DTPA-D-Phe]-pentetreotide (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, given that FDG-PET does not provide additional information, conventional modalities of CT and MRI should be used in Cushing's patients,. H-OCT, however, 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 Cushing's patients. This compound is a precursor for serotonin production in neuroendocrine tumors and thus a good candidate for PET examination in that most occult ACTH-secreting tumors are neuroendocrine.

Performance of screening tests for Cushing's syndrome in obese patients

Nieman, Baid; in collaboration with Frank, Rubino, Wesley

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. With weight gain and obesity nearly universal features of Cushing's syndrome, we hypothesized that Cushing's patients should undergo screening but that screening tests may have poor specificity. We are conducting a study that is based in a weight loss clinic and enrolls 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 tests in patients found to be normal on subsequent confirmatory testing. If confirmed after further study, the results will suggest possible revision of current recommendations for screening.

Pregnancy in Cushing's syndrome

Nieman, Lindsay; in collaboration with Oldfield

Cushing's syndrome occurs rarely during pregnancy. We have investigated and treated four patients with pituitary-dependent Cushing's syndrome during pregnancy. Except for preservation of menses before conception, our patients presented with typical clinical features, increased urinary free cortisol, and loss of diurnal variation of cortisol. The diagnosis was facilitated in three women, without complications, by the use of corticotropin-releasing hormone testing and inferior petrosal sinus sampling (IPSS). Transsphenoidal pituitary surgery (TSS) achieved remission in three women, but two fetal/neonatal deaths occurred.

This experience and review of 136 previous reports suggest that (1) urinary free cortisol in Cushing's syndrome patients overlaps the normal pregnant range; (2) ACTH levels are not suppressed in adrenal causes of Cushing's syndrome, which may be identified by the 8 mg dexamethasone test; (3) IPSS and TSS, the optimal diagnostic test and treatment for non-pregnant patients, can safely facilitate the management of pregnant patients; and (4) surgery may achieve remission during pregnancy, although the prognosis for the fetus remains guarded. It is likely that earlier recognition and treatment would improve pregnancy outcomes. There is a need to develop criteria for the interpretation of diagnostic tests and for increased consideration of Cushing's syndrome in pregnancy.

Estrogen receptors in endometrium of women with endometriosis

Nieman, Hearns-Stokes; in collaboration with Gustafsson, Mayers, Segars, Zahn

We characterized the spatial and temporal localization of estrogen receptor (ER) alpha and breast cancer nuclear receptor auxiliary factor (Brx) in the eutopic endometrium of 35 healthy women and 29 women with endometriosis. Samples were obtained during laparoscopic laser excision surgery. Expression of ERα and ERβ was highest in the proliferative phase and was similar in both groups. Brx expression differed between healthy volunteers and those with endometriosis. During the proliferative phase, immunostaining intensity of Brx was greater in both the glandular and stromal compartments of biopsies from patients with endometriosis than in healthy volunteers; nuclear stromal Brx staining was more common in patients with endometriosis. The spatiotemporal expression of Brx was altered in the eutopic endometrium of women with endometriosis. These findings suggest a fundamental alteration in the endometrium of women with endometriosis. The role of Brx in ectopic implantation of endometrium deserves further study.

Raloxifene as an adjunctive treatment for endometriosis

Nieman, Stratton, Sinaii, Potlog-Nahari ¹; in collaboration with Azumi, Chow, Karp, Koziol, Merino, Reynolds, Wesley, Winkel

We have conducted a randomized, double-blind placebo controlled study of surgery with or without raloxifene (Evista®) for the treatment of pain from endometriosis. In conjunction with the study, we are exploring the hypothesis that endometriosis may impair bone mineral density.

CDB-2914 as a potential therapeutic agent for fibroids

Nieman, St. Clair, Wei, Blocker; in collaboration with Armstrong, Premkumar, Segars

We 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. Ongoing studies evaluate whether the agent may shrink fibroid size. We are also using gene arrays to evaluate the pathophysiology of leiomyomata.

Hearns-Stokes R, Mayers C, Zahn C, Cruess D, Gustafsson J-Å, Segars J, Nieman L. Expression of the proto-oncoprotein breast cancer nuclear receptor auxiliary factor (Brx) is altered in eutopic endometrium of women with endometriosis. Fertil Steril 2006;85:63-70.

¹ Clariss Potlog-Nahari, MD, former Visiting Fellow

COLLABORATORS

Alicia Armstrong, MD, Reproductive Biology and Medicine Branch, NICHD, Bethesda, MD
Norio Azumi, MD, Georgetown University Medical Center, Washington, DC
Diana Blithe, PhD, Contraception and Reproductive Health Branch, NICHD, Bethesda, MD
Jorge Carrasquillo, MD, Nuclear Medicine Department, Warren G. Magnuson Clinical Center, NIH, Bethesda, MD
Richard Chang, MD, Diagnostic Radiology, Warren G. Magnuson Clinical Center, NIH, Bethesda, MD
Clara Chen, MD, Nuclear Medicine Department, Warren G. Magnuson Clinical Center, NIH, Bethesda, MD
Catherine Chow, MD, Diagnostic Radiology, Warren G. Magnuson Clinical Center, NIH, Bethesda, MD
Arthur Frank, MD, George Washington University Weight Management Program (GWUWMP), Washington, DC
Jan-Åke Gustafsson, MD, PhD, Karolinska Institute, Huddinge, Sweden
Barbara Karp, MD, Office of the Clinical Director, NINDS, Bethesda, MD
Deloris Koziol, PhD, Biostatistics and Clinical Epidemiology Service, Warren G. Magnuson Clinical Center, NIH, Bethesda, MD
Chantal Mayers, BS, Reproductive Biology and Medicine Branch, NICHD, Bethesda, MD
Maria Merino, MD, Laboratory of Pathology, NCI, NIH, Bethesda, MD
Tonja Nansel, PhD, Prevention Research Branch, NICHD, Bethesda, MD
Edward H. Oldfield, MD, Surgical Neurology Branch, NINDS, Bethesda, MD
Karel Pacak, MD, Reproductive Biology and Medicine Branch, NICHD, Bethesda, MD
Nicholas Patronas, MD, Diagnostic Radiology, Warren G. Magnuson Clinical Center, NIH, Bethesda, MD
Ahalya Premkumar, MD, Diagnostic Radiology, Warren G. Magnuson Clinical Center, NIH, Bethesda, MD
James C. Reynolds, MD, Nuclear Medicine Department, Warren G. Magnuson Clinical Center, NIH, Bethesda, MD
Domenica Rubino, MD, George Washington University Weight Management Program, Washington, DC
James Segars, MD, Reproductive Biology and Medicine Branch, NICHD, Bethesda, MD
Bob Wesley, PhD, Biostatistics and Clinical Epidemiology Service, Warren G. Magnuson Clinical Center, NIH, Bethesda, MD
Craig Winkel, MD, Georgetown University Medical Center, Washington, DC
Christopher Zahn, MD, Uniformed Services University of the Health Sciences, Bethesda, MD

For further information, contact niemanl@mail.nih.gov.