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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 Baid, MD, Staff Clinician
  • Susmeeta T. Sharma, MD, Clinical Fellow
  • 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. The reproductive disorder is common, poorly understood, and lacks optimal medical treatments.

Adrenal gland disorders

Observational studies show that glucocorticoid therapy and the endogenous hypercortisolism of Cushing's syndrome (CS) are associated with increased rates of cardiovascular morbidity and mortality. However, the causes of these findings remain largely unknown. Fifteen patients with ACTH–dependent CS and 15 matched control subjects underwent a multidetector CT (MDCT) coronary angiogram scan, and Agatston score (a measure of calcified plaque) and non-calcified coronary plaque volume were quantified. Compared with controls, the CS patients had significantly greater noncalcified plaque volume and Agatston score as well as higher systolic and diastolic blood pressures. We conclude that increased atherosclerosis may contribute to the increased rates of cardiovascular morbidity and mortality in patients with glucocorticoid excess.

In a cross-sectional study, we evaluated the relationship between blood cortisol levels and obesity and the metabolic syndrome (MS). We measured cortisol dynamics (24 h urine cortisol excretion [UFC], bedtime salivary cortisol, 1 mg dexamethasone suppression test) and metabolic parameters (BMI, blood pressure [BP]; fasting serum triglycerides, HDL, insulin, and glucose) in 369 overweight and obese subjects and measured UFC, salivary cortisol, and weight in 60 healthy volunteers. UFC and dexamethasone responses were not associated with BMI or weight. However, salivary cortisol showed a trend to increase as BMI increased (P < 0.0001), and correlated with waist circumference (WC) in men (rs = 0.28, P = 0.02) and systolic BP in women (rs = 0.24, P = 0.0008). Post-dexamethasone cortisol levels were weakly to moderately correlated with fasting insulin (rs = −0.31, P = 0.01) and HOMA-IR (homeostasis model of assessment - insulin resistance) (rs = −0.31, P = 0.01) in men and systolic (rs = 0.18, P = 0.02) and diastolic BP (rs = 0.20, P = 0.009) in women. As expected, WC correlated with fasting insulin, HOMA-IR, and systolic BP. Taken together, these data do not support a strong relationship between systemic cortisol or stress and obesity or MS.

We evaluated quality of life in a subset of the overweight and obese (OB) subjects above and compared it with that of CS patients, using the SF-36 survey and a locally created symptom questionnaire. We recruited 327 OB patients (48.1±11.7 years; 237 women) with weight gain and at least two features of CS, and 66 untreated patients with CS (41.6±13.2 years; 52 women). After adjusting for symptom count, OB patients had a significantly higher Health-Related Quality of Life (HRQL) measures and better mean physical component summary (PCS) scores than CS patients (44.9±0.6 vs. 35.4±1.5, P<0.0001). However, the mean mental component summary (MCS) score was lower (worse HRQL) in the OB group (41.6±0.6 vs. 50.7±1.6, P<0.0001). Symptom count showed significant correlations with PCS and MCS scores. BMI correlated with PCS (r = −0.29) in OB but not in CS patients. BMI was not associated with MCS in either group. Thus, HRQL differs significantly between OB and CS patients. Surprisingly, after adjusting for symptom count, OB patients showed worse mental health scores than the CS population. Significant differences in HRQL and symptom count may suggest which OB patients should be screened for CS.

We evaluated the lateralization accuracy of inferior petrosal sinus sampling (IPSS) in 501 consecutive patients with Cushing's disease (CD). IPSS confirmed a pituitary source of ACTH secretion in 491 patients (98%). All 10 patients with false-negative results had peak IPSS ACTH concentrations (before or after CRH) of less than 400 pg/ml. Interpetrosal (side-to-side) ratios were greater than or equal to 1.4 in 491 patients (98%). The ratio correctly predicted lateralization in 273 of 396 patients (69% positive predictive value) with a lateral adenoma. Left-sided IPSS lateralization (P = 0.008) and consistent lateralization before and after CRH administration (P = 0.02) were associated with enhanced accuracy. When positive, preoperative magnetic resonance imaging (MRI) correlated with adenoma location in 171 of 201 patients (86% positive predictive value). We conclude that potential false-negative results, the most common type of diagnostic error with IPSS for the differential diagnosis of CS, can be identified by peak IPSS ACTH values of less than 400 pg/ml. When MRI is normal, IPSS can be used to guide surgical exploration in patients with negative preoperative imaging. However, because of the limited accuracy of lateralization, thorough exploration of the pituitary gland is required when an adenoma is not readily discovered based on predicted location.

We also examined factors that influenced the outcome of surgical treatment of pediatric CD in a prospective observational study of 200 patients. We analyzed clinical, imaging, endocrinological, and operative outcomes. Mean age at NIH operation was 13.7 ± 3.7 years. Twenty-seven patients (13%) had undergone prior surgery at another institution. Magnetic resonance imaging identified adenomas in 97 patients (50%). When positive, MRI accurately defined a discrete adenoma in 96 of the 97 patients (99%), which was more accurate than the use of ACTH ratios during IPSS to determine adenoma lateralization (accurate in 72% of patients without prior surgery). A total of 195 of the 200 patients (98%) achieved remission after surgery (189 [97%] were hypocortisolemic; 6 [3%] were eucortisolemic postoperatively). Factors associated with initial remission (P < 0.05) included identification of an adenoma at surgery, immunohistochemical ACTH–producing adenoma, and noninvasive ACTH adenoma. Younger age, smaller adenoma, and absence of cavernous sinus wall or other dural invasion were associated with long-term remission (P < 0.05). A minimum morning serum cortisol of less than 1 μg/dl after surgery had a positive predictive value for lasting remission of 96%. With rare disorders, such as pediatric CD, enhanced outcomes are obtained by evaluation and treatment at centers with substantial experience. Resection of pituitary adenomas in pediatric CD in that setting can be safe, effective, and durable. Early postoperative endocrine testing predicts lasting remission. Because lasting remission is associated with younger age at surgery, smaller adenomas, and lack of dural invasion, early diagnosis should improve surgical outcome.

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 declined 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.

Additional Funding

  • Some of these projects received external funding from two cooperative research and development agreements (CRADAs) executed with HRA-Pharma, Paris France, under ongoing CRADAs.

Publications

  1. Neary NM, Booker OJ, Abel BS, Matta JR, Muldoon N, Sinaii N, Pettigrew RI, Nieman LK, Gharib AM. Hypercortisolism is associated with increased coronary arterial atherosclerosis: analysis of noninvasive coronary angiography using multidetector computerized tomography. J Clin Endocrinol Metab 2013;98:2045-2052.
  2. Wind JJ, Lonser RR, Nieman LK, DeVroom HL, Chang R, Oldfield EH. The lateralization accuracy of inferior petrosal sinus sampling in 501 patients with Cushing's disease. J Clin Endocrinol Metab 2013;98:2285-2293.
  3. Abraham SB, Rubino D, Sinaii N, Ramsey S, Nieman LK. Cortisol, obesity, and the metabolic syndrome: a cross-sectional study of obese subjects and review of the literature. Obesity (Silver Spring) 2013;21:E105-117.
  4. Abraham SB, Abel BS, Rubino D, Nansel T, Ramsey S, Nieman LK. A direct comparison of quality of life in obese and Cushing's syndrome patients. Eur J Endocrinol 2013;168:787-93.

Collaborators

  • 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
  • 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
  • Domenica Rubino, MD, Washington Center for Weight Management and Research, Arlington, VA
  • 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

Contact

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

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