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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
  • Susmeeta T. Sharma, MD, Clinical Fellow

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

Identification of a pituitary corticotropinoma is essential for cure of Cushing's disease. Inferior petrosal sinus sampling (IPSS) is considered the gold standard test to distinguish between Cushing's disease (CD) and ectopic ACTH syndrome (EAS). Anomalous venous drainage, abnormal venous anatomy, and lack of expertise can lead to false-negative IPSS results and thereby misclassification of patients with ACTH–dependent Cushing's syndrome. We found that prolactin measurement during IPSS can improve diagnostic accuracy and reduce false-negative results. A baseline ratio of inferior petrosal sinus prolactin to peripheral (IPS/P) prolactin (ipsilateral to the dominant post-CRH ACTH IPS/P ratio) of 1.8 or more suggests successful catheterization during IPSS. Prolactin-normalized ACTH IPS/P ratios can then be used to differentiate between a pituitary and an ectopic source of ACTH. Values less or equal to 0.7 are suggestive of EAS and those of 1.3 or over are indicative of CD, but the implication of values between 0.7 and 1.3 remains unclear and needs further investigation. Larger prospective studies are also needed for further evaluation of the role of contralateral prolactin IPS/P ratios, post–CRH prolactin values, and prolactin-adjusted ACTH inter-sinus ratios for tumor localization in CD.

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 a 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 by 7% in the PLC group, but by 17% and 24% in the CDB10 and CDB20 groups, respectively. TFV declined further after treatment 2 (by 11%). Amenorrhea occurred in 20 out of 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.

The agent has been approved in Europe for pre-operative treatment of anemic women with fibroids.

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. Sharma ST, Nieman LK. Is prolactin measurement of value during inferior petrosal sinus sampling in patients with adrenocorticotropic hormone-dependent Cushing's Syndrome? J Endocrinol Invest 2013;36:1112-1116.
  2. Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing's syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr Physiol 2014;4:739-769.
  3. Nieman LK. Update in the medical therapy of Cushing's disease. Curr Opin Endocrinol Diabetes Obes 2013;20:330-334.

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
  • 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
  • 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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