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RHYPERCORTISOLISM AND REPRODUCTIVE DISORDERS; ENDOMETRIAL PHYSIOLOGY
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Lynnette
Nieman, MD, Head, Section on
Reproductive Medicine Nannan
Zhu, MD, Research Fellow Ioannis
Ilias, MD, Visiting Fellow Clariss
Potlog-Nahari, MD, Visiting Fellow Pamela
Stratton, MD, Staff Clinician Hannah
Chapin, BS, Predoctoral Fellow Mary-Kathleen
Nilson, BS, Predoctoral Fellow Ninet
Sinaii, MPH, Predoctoral Fellow Rhonda
Hearns-Stokes, MD, Guest Researcher |
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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 (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 ACTH-producing tumors.
We also evaluate the pathophysiology 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
assessment in Cushing’s syndrome Nieman; in
collaboration with Nansel We
are exploring quality-of-life issues in patients before and after successful
treatment of Cushing’s syndrome. We use the entire SF-36 questionnaire developed
by John Ware and colleagues; the questionnaire has been validated for use in
healthy individuals and various disease states. Patients also complete a
symptom checklist and a questionnaire about recurrence, satisfaction with
treatment, current treatment, and demographics. Initial analysis suggests
that patients with active Cushing’s syndrome experience significant
impairment in physical activities and cognitive function and that they limit
their social activities. Patients also demonstrate significant but less
profound abnormalities in their sense of well-being and general health
perception compared with the general population. Preliminary evaluation of
patients after treatment suggests improvement in these areas, but some do not
regain scores similar to the general population for as long as five years
after treatment, suggesting significant long-term impairment of quality of
life. Localization
of ectopic ACTH-secreting tumors Nieman; in
collaboration with Pacak Imaging
studies are the gold standard for tumor localization in patients with
Cushing’s syndrome caused by ectopic adrenocorticotropin hormone (ACTH)
secretion (EAS). Computed tomography (CT) and magnetic resonance imaging
(MRI) are used most commonly to localize the source of EAS. However, in 30 to
50 percent of patients with EAS, the source of ACTH secretion cannot be found
despite repeated studies over time. 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 physiological and
pathophysiological processes, and, among these techniques, positron emission
tomography (PET) studies are finding increasing use in oncology. We evaluated
whether [18F]-fluorodeoxyglucose (FDG) PET, or [111In-DTPA-D-Phe]-pentetreotide
(OCT) at higher-than-standard doses of radionuclide (18 mCi; H-OCT), can
detect ACTH-secreting tumors. Seventeen patients with presumed EAS based on
inferior petrosal sinus sampling results underwent routine anatomical imaging
studies (CT and MRI) as well as OCT scintigraphy with 6 mCi (L-OCT). Research
studies included FDG-PET in all patients and H-OCT if L-OCT was negative.
Nine of 17 CT, six of 16 MRI, six of 17 FDG-PET, eight of 17 L-OCT, and one
of nine H-OCT studies were true positives. ACTH-secreting tumors were
localized in 13 patients and were occult in four. We found tumors in the neck,
thorax, and abdomen. The sensitivity of CT or H- and L-OCT scintigraphy was
higher (both 53 percent) than that of MRI or FDG-PET. FDG-PET did not detect
tumors that were occult on CT/MRI. L-OCT was a useful complementary modality
to CT and MRI. Thus, conventional modalities of CT and MRI should be used to
image the neck, thorax, and abdomen in presumed EAS patients. Octreotide is a
useful adjunctive modality, but FDG-PET does not provide additional
information. Given that H-OCT identified a tumor in one patient with
otherwise negative imaging, we recommend its use when other imaging
modalities fail to localize the ACTH-secreting tumor in patients with EAS. Pacak K, Ilias I, Carrasquillo JA, Chen C, Whatley M, Wesley RA,
Nieman LK. The role of [18F]-fluorodeoxyglucose positron emission
tomography and [111In]-diethylenetriaminepetaacetate-D-phe-pentetreotide
scintigraphy in the diagnostic localization of ectopic
adrenocorticotropin-secreting tumors causing Cushing’s syndrome. J
Clin Endocrinol Metab 2004;89:2214-2221. Uwaifo GI, Koch CA, Hirshberg B, Chen CC, Hartzband P, Nieman
LK, Pacak K. Is there a therapeutic role for octreotide in patients with
ectopic Cushing’s syndrome? J Endocrinol Invest 2003;26:710-717. Jugular
venous sampling Ilias, Nieman; in collaboration
with Oldfield, Pacak We
have evaluated the effectiveness of internal jugular vein (IJV) sampling as a
substitute for the more invasive and technically demanding inferior petrosal
sinus sampling (IPSS) to discriminate patients with Cushing’s disease
from those with ectopic ACTH syndrome. To interpret the results, we used
cut-off points that correctly identified all patients with ectopic ACTH
secretion. In 65 patients with surgically proven Cushing’s disease and
13 with known or occult ectopic ACTH secretion, IJV sampling had a
sensitivity of 83 percent (CI: 71 to 91 percent), and IPSS had a sensitivity
of 92 percent (CI: 82 to 97 percent). While IPSS sampling yielded better
diagnostic accuracy, confidence intervals overlapped (95 percent, CI 90 to100
percent versus 86 percent, CI 78 to 94 percent). Further validation of IJV
would allow local medical centers without expertise in IPSS to localize
directly the source of ACTH hypersecretion in ACTH-dependent
hypercortisolism, whereas at present the IPSS test is available in only a few
highly specialized centers. Thus, centers with limited sampling experience
might choose to use the simpler and safer jugular vein procedure and refer
patients for petrosal sinus sampling when results are negative. Ilias I, Chang R, Pacak K, Oldfield EH, Wesley R, Doppman J,
Nieman LK. Jugular venous sampling: an alternative to petrosal sinus sampling
for the evaluation of ACTH-dependent Cushing’s syndrome. J Clin
Endocrinol Metab 2004;89:3795-3800. Estrogen
receptors in normal endometrium and endometriosis Hearns-Stokes, Nieman;
in collaboration with Mayers, Segars, Zahn We
characterized the spatial and temporal localization of estrogen receptor (ER)
alpha and beta in both the endometrium and endometriosis explants from women
with pelvic pain from endometriosis. Samples were obtained during
laparoscopic laser excision surgery. Immunohistochemical staining for ER
alpha showed nuclear localization that was greatest in the epithelium during
the proliferative phase but then decreased during the late secretory phase.
ER beta showed a similar nuclear and epithelial cell preference, but the
intensity of ER beta immunostaining increased during the secretory phase. ER
beta increased in endometriotic explants. Raloxifene
as an adjunct treatment for endometriosis Stratton, Sinaii,
Potlog-Nahari, Zhu, Lopez,a Nilson, Nieman; in collaboration with
Azumi, Chow, Daly, Karp, Koziol, Merino, Reynolds, Wesley, Winkel We are
conducting a randomized, double-blind placebo-controlled study of surgery
with or without raloxifene (Evista®) for the treatment of pain from
endometriosis. To date, we have examined the utility of MRI in diagnosing
endometriosis and correlated histopathology with laparoscopic findings,
showing that MRI has a low detection rate of biopsy-proven endometriosis
lesions and is relatively insensitive in determining whether a woman has
endometriosis. In comparing surgical and histopathologic findings, only about
70 percent of endometriosis lesions seen at surgery are proven by biopsy. We
postulated that vascular endothelial growth factors (VEGFs) may mediate
neovascularization and allow implantation of endometrial implants in the
peritoneal cavity. Such correlation would suggest a new noninvasive and
inexpensive way both to diagnose endometriosis and evaluate its treatment,
perhaps allowing for earlier diagnosis of the disease without need for
surgical confirmation. Accordingly, we studied 62
women undergoing laparoscopy for possible endometriosis-related pelvic pain.
Of these, 40 had histology-proven endometriosis and 22 had no histological
proof of the disease. Urine VEGF levels corrected for creatinine excretion
were similar in women with (83.6 ± 11.3 pg/mg Cr) and without (88.5 ± 10.4
pg/mg Cr) endometriosis. The frequency distribution of urine VEGF
measurements for women with and without endometriosis was similar. No
significant difference was noted in urinary VEGF levels when comparing
endometriosis stages or endometriomas versus controls. Urine VEGF did not
vary significantly over the menstrual cycle or between groups by cycle phase.
No cut point discriminated individuals with and without the condition. Thus,
it appears that VEGF is not a good marker for endometriosis. The
cell surface metalloendopeptidase CD10 is present in normal endometrial
stroma. We hypothesized that CD10 immunohistochemistry (IHC) would increase
the sensitivity of the histologic diagnosis of endometriosis by improving the
recognition of the ectopic stromal cells. To examine such a possibility, we
compared the diagnostic efficacy of hematoxylin and eosin (H and E) staining
with and without adjunctive CD10 IHC in biopsies of surgically diagnosed
endometriosis. CD10 was consistently present in endometrial stroma. Of the 70
specimens initially judged negative by H and E staining, CD10 staining led to
the diagnosis of endometriosis in 11. With the addition of CD10 ICH, we
detected more positive endometriosis lesions than with H and E staining alone
(45 versus 35 percent, P < 0.0001). In three women with minimal
endometriosis at surgery but initially negative histopathology, CD10 IHC
changed the histologic diagnosis to endometriosis. Thus, the use of CD10 IHC
as an adjunct improves diagnostic sensitivity for endometriosis, especially
for those patients with minimal disease. Catherino WH, Leppert PC, Stenmark MH, Payson M, Potlog-Nahari
C, Nieman LK, Segars JH. Reduced dermatopontin expression is a molecular link
between uterine leiomyomata and keloids. Genes Chromosomes Cancer 2004;40:204-217. Catherino WH, Prupas C, Tsibris JCM, Leppert PC, Payson M,
Nieman LK, Segars JH. Strategy for elucidating differentially expressed genes
in leiomyoma identified by microarray technology. Fertil Steril 2003;80:282-290. Potlog-Nahari C, Feldman AL, Stratton P, Zhu N, Nilson MK,
Sinaii N, Koziol DE, Wesley R, Winkel CA, Segars J, Merino MJ, Nieman LK.
CD10 immunohistochemical staining enhances the histological detection of
endometriosis. Fertil Steril 2004;82:86-92. Potlog-Nahari C, Stratton P, Winkel CA, Widra E, Sinaii N,
Connors S, Merino MJ, Nieman LK. Urine vascular endothelial growth factor-A
(VEGF-A) is not a useful marker for endometriosis. Fertil Steril 2004;81:1507-1512. CDB-2914
as a potential therapeutic agent for fibroids Potlog-Nahari, Nilson,
Chapin, Nieman; in collaboration with Armstrong, Catherino, Leppert,
Premkumar, Segars 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. Ongoing studies are designed to
evaluate whether the agent may shrink fibroid size. We are also using gene arrays
to evaluate the pathophysiology of leiomyomata. Blithe DL, Nieman LK, Blye RP, Stratton P, Passaro M.
Development of the selective progesterone receptor modulator CDB-2914 for
clinical indications. Steroids 2003;68:1013-1017. aVanessa Lopez, former HHMI
Scholar COLLABORATORS Alicia Armstrong, MD, Pediatric and
Reproductive Endocrinology Branch, NICHD, Jorge Carrasquillo, MD, Nuclear Medicine Department,
Warren Grant Magnuson Clinical Center, Bethesda, MD William Catherino, MD, Pediatric and
Reproductive Endocrinology Branch, NICHD, Richard Chang, MD, Diagnostic Radiology,
Warren Grant Magnuson Clinical Center, Clara Chen, MD, Nuclear Medicine
Department, Warren Grant Magnuson Clinical Center, Catherine Chow, MD, Diagnostic Radiology,
Warren Grant Magnuson Clinical Center, Robert Daly, MD, Behavioral Endocrinology
Branch, NIMH, Barbara Karp, MD, Office of the Clinical
Director, NINDS, Deloris Koziol, PhD, MPH, Biostatistics and
Clinical Epidemiology Service, Warren Grant Magnuson Clinical Center, Phyllis Leppert, MD, PhD, Reproductive
Sciences Branch, NICHD, Chantal Mayers, BS, Pediatric and
Reproductive Endocrinology Branch, NICHD, Maria Merino, MD, Laboratory of Pathology,
NCI, Tonya R. Nansel, PhD, Division of
Epidemiology, Statistics and Prevention Research, NICHD, Edward H. Oldfield, MD, Surgical Neurology
Branch, NINDS, Nicholas Patronas, MD, Diagnostic
Radiology, Warren Grant Magnuson Clinical Center, James C. Reynolds,
MD, Nuclear Medicine, Warren Grant Magnuson Clinical Center, James Segars, MD, Pediatric and Reproductive
Endocrinology Branch, NICHD, Bob Wesley, PhD, Biostatistics and Clinical
Epidemiology Service, Warren Grant Magnuson Clinical Center, Craig Winkel, MD, Christopher Zahn, MD, Uniformed For
further information, contact niemanl@mail.nih.gov |
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