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Investigation of Adrenal Gland Disorders and Disorders of Female Reproduction
- Lynnette Nieman, MD, Head, Section on Reproductive Endocrinology
- Smita Abraham, MD, Staff Clinician
- Mahtab Niyyati, MD, Clinical Fellow
- Susmeeta T. Sharma, MD, Clinical Fellow
- Qingxiang Wei, BS, Technician
- Mai Lloyd, RN, Nurse Coordinator
Over the past decade, we have made important 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 for 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 endometrial function and 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
Utility of prolactin for interpretation of inferior petrosal sinus sampling (IPSS): Improper catheterization of the petrosal sinuses can give false negative results in patients with Cushing's disease (CD). Measurement of prolactin has been suggested as a way to "normalize" the ACTH results. We evaluated prolactin levels in basal and CRH-stimulated IPSS samples in 29 patients with ACTH–dependent Cushing's syndrome (CS) (2007–2010). Twenty-five of 29 patients had a diagnosis proven by pathology (17 CD and eight ectopic ACTH syndrome [EAS]). IPSS results were partitioned into true positive for CD (n = 16), true negative (n = 7), false negative (n = 1), and false positive (n = 1). The prolactin ratio of the inferior petrosal sinus to peripheral blood (IPS/P) suggested successful IPSS in eight of 11 with abnormal venograms. Baseline prolactin IPS/P ratio was helpful in two patients with abnormal venograms and false-negative (catheterization unsuccessful) or true-negative (catheterization successful) IPSS results; the normalized ratio correctly diagnosed their disease. Normalized ACTH IPS/P ratio was at least 1.3 in all with CD, but prolactin IPS/P ratios were misleadingly low in two. One patient with cyclic EAS had a false-positive IPSS when eucortisolemic (baseline prolactin IPS/P = 1.7; normalized ratio = 5.6). All other EAS patients had normalized ratios no higher than 0.7. Thus, prolactin measurement and evaluation of the venogram can improve diagnostic accuracy when IPSS results suggest EAS but are not necessary with positive IPSS results. Confirmation of hypercortisolemia remains a prerequisite for IPSS. A normalized ratio of 0.7-1.3 was not diagnostic.
Characterization of patients with thymic ACTH-producing neuroendocrine tumor: There are few data regarding ACTH–producing neuroendocrine tumor (NET) of the thymus, which is a rare cause of CS. We reported the NIH findings on 12 cases (eight males and four females) diagnosed between 1986 and 2010 with CS and thymic NET who underwent surgical resection, and we performed a meta-analysis of other published cases of CS associated with thymic NET. Eleven of 12 patients presented with classic features of CS at a median age of 21 yr (range, 7–51); four were children. The 24-h urine free cortisol (UFC) was 16-fold higher than normal, and biochemical testing was consistent with ectopic ACTH production in all 11 patients. Another patient presenting with pulmonary embolus had a thymic mass and was later diagnosed with CS. All patients underwent thymectomy, and nine of 10 tumors exhibited positive ACTH immunochemistry. Median tumor diameter was 5 cm (range, 1–11.5). Six patients recurred 20–28 months after surgery with metastases to mediastinal lymph nodes (n = 5), bone (n = 5), liver (n = 1), parotid gland (n = 1), and breast (n = 1). Four of five patients treated with radiation therapy also received chemotherapy. All recurrent patients received ketoconazole; four later underwent bilateral adrenalectomy. The six recurrent patients died within 22–90 months (median, 57) after thymectomy. At last review, six patients were alive 14–90 months (median, 49) after thymectomy. These data are similar to those from the meta-analysis. From this analysis, we concluded that thymic ACTH-producing NET is an aggressive disease that should be considered in CS with ectopic ACTH secretion, particularly in younger patients.
Sporadic remission of ectopic ACTH secretion after long-term steroidogenesis inhibitor treatment: Spontaneous remission is rare in EAS. We described four patients with presumed EAS in whom long-term treatment with steroidogenesis inhibitors was followed by prolonged remission of hypercortisolemia. Biochemical testing was consistent with EAS, but imaging failed to identify a tumor. Patients were treated with ketoconazole alone or with mitotane and/or metyrapone to control hypercortisolemia. Dexamethasone was added when a block-and-replace strategy was used. Treatment with steroidogenesis inhibitors for 3–10 years in these patients was followed by a prolonged period of remission (15–60 months). During remission, the first patient had an elevated ACTH, low cortisol and 24-h UFC, and adrenal atrophy on computerized tomography scan during remission, suggesting a direct toxic effect on the adrenal glands. Cases 2 and 3 had normal to low ACTH levels and low-normal UFC, consistent with an effect at the level of the ectopic tumor. They did not have a history of cyclicity, and case 3 has been in remission for about 5 years, making cyclic Cushing's syndrome less likely. Case 4, with a history of cyclic hypercortisolism, had normal to slightly elevated ACTH levels and low-normal UFC during remission. The most likely etiology of remission is cyclic production of ACTH by the ectopic tumor. We conclude that spontaneous and sustained remission of hypercortisolemia is possible in EAS after long-term treatment with steroidogenesis inhibitors; a drug holiday may be warranted during chronic therapy to evaluate this. The pathophysiology remains unclear but may involve several different mechanisms.
Cushing's syndrome in MEN-1: In patients with multiple endocrine neoplasia type 1 (MEN1), CS from endogenous hypercortisolism can result from pituitary, adrenal, or other endocrine tumors. For 19 NIH patients (eight males, 11 females) with CS and MEN1 seen over 40 years an etiology was determined for 14 of the 19 patients: 11 (79%) had CD and three (21%) had ACTH–independent CS owing to adrenal tumors, frequencies that are indistinguishable from sporadic CS. Three of 11 MEN1 patients with CD (27%) had additional non-ACTH–secreting pituitary microadenomas identified at surgery, an incidence 10-fold higher than in sporadic CD. Ninety-one per cent of MEN1 patients with CD were cured after surgery. Two of three MEN1 patients with ACTH–independent CS (67%) had adrenocortical carcinoma. One patient with adrenal cancer and another with adrenal adenoma were cured by unilateral adrenalectomy. No case of ectopic ACTH secretion was identified in our patient cohort. The etiology of CS could not be defined in five patients; in three of these, hypercortisolism appeared to resolve spontaneously. We concluded that the tumor multiplicity of MEN1 can be reflected in the anterior pituitary, MEN1–associated ACTH–independent CS may be associated with aggressive adrenocortical disease, and an etiology for CS in MEN1 may be elusive in a substantial minority of patients.
Disorders of female reproduction
We evaluated the efficacy and tolerability of CDB-2914 (Ulipristal, CDB) for the treatment of symptomatic fibroids. Premenopausal women with symptomatic uterine fibroids participated in this randomized, placebo-controlled double-blind clinical trial. Each received once-daily oral CDB (10 or 20 mg) or placebo (PLC) for 12 weeks (treatment 1). A second 3-month treatment with CDB (treatment 2) was offered. A computer-generated blocked randomization was used. Magnetic resonance imaging (MRI)–determined total fibroid volume (TFV) change was the primary outcome; amenorrhea and quality of life (QOL) were secondary end points. After treatment 1, TFV increased 7% in the PLC group, but decreased 17% and 24% in the CDB10 and CDB20 groups. The TFV decreased further after treatment 2 (−11%). Amenorrhea occurred in 20/26 women taking CDB and in none on PLC. Ovulation resumed after CDB. Hemoglobin improved only with CDB (11.9 ± 1.5 to 12.9 ± 1.0 g/dL) as did the Fibroid QOL Questionnaire symptom severity, energy/mood, and concern subscores, and overall QOL scores. CDB was well tolerated, with no serious adverse events. Adverse events were unchanged during treatments. Thus, administration of CDB-2914 for 3–6 months controls bleeding, reduces fibroid size, and improves QOL.
- Some of these projects received external funding from two cooperative research and development agreements (CRADAs) executed with HRA-Pharma, Paris France, under ongoing CRADAs.
- Nieman LK, Blocker W, Nansel T, Mahoney S, Reynolds J, Blithe D, Wesley R, Armstrong A. Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study. Fertil Steril 2011;95:767-772.
- Neary NM, Lopez-Chavez A, Abel BS, Boyce AM, Schaub N, Kwong K, Stratakis CA, Moran CA, Giaccone G, Nieman LK. Neuroendocrine ACTH-producing tumor of the thymus—experience with 12 patients over 25 years. J Clin Endocrinol Metab 2012;97:2223-2230.
- Sharma ST, Nieman LK. Prolonged remission after long-term treatment with steroidogenesis inhibitors in Cushing's syndrome caused by ectopic ACTH secretion. Eur J Endocrinol 2012;166:531-536.
- Sharma ST, Raff H, Nieman LK. Prolactin as a marker of successful catheterization during IPSS in patients with ACTH-dependent Cushing's syndrome. J Clin Endocrinol Metab 2011;96:3687-3694.
- Simonds WF, Varghese S, Marx SJ, Nieman LK. Cushing's syndrome in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf) 2012;76:379-386.
- Alicia Armstrong, MD, Program in Reproductive and Adult Endocrinology, NICHD, Bethesda, MD
- Diana Blithe, PhD, Contraception and Reproductive Health Branch, NICHD, Bethesda, MD
- Richard Chang, MD, Diagnostic Radiology, NIH Clinical Center, Bethesda, MD
- Clara Chen, MD, Nuclear Medicine Department, NIH Clinical Center, Bethesda, MD
- Ahmed Gharib, MD, Office of the Scientific Director, NHLBI, Bethesda, MD
- King Kwong, MD, Surgery Branch, NCI, Bethesda, MD
- Russell Lonser, MD, Surgical Neurology Branch, NINDS, Bethesda, MD
- Stephen Marx, MD, Metabolic Diseases Branch, NIDDK, Bethesda, MD
- Maria Merino, MD, Laboratory of Pathology, NCI, Bethesda, MD
- Tonja Nansel, MD, Prevention Research Branch, NICHD, Bethesda, MD
- Edward H. Oldfield, MD, University of Virginia, Charlottesville, VA
- Nicholas Patronas, MD, Diagnostic Radiology, NIH Clinical Center, Bethesda, MD
- James C. Reynolds, MD, Nuclear Medicine Department, NIH Clinical Center, Bethesda, MD
- William Simonds, MD, Metabolic Diseases Branch, NIDDK, Bethesda, MD
- Ninet Sinaii, MPH, PhD, Biostatistics and Clinical Epidemiology Service, NIH Clinical Center, Bethesda, MD
- Bob Welsey, PhD, Biostatistics and Clinical Epidemiology Service, NIH Clinical Center, Bethesda, MD
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