Over the past decade, investigators at the NICHD made major contributions to the differential diagnosis of hypercortisolism. They 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.

The Section on Reproductive Medicine, directed by Lynnette Nieman, investigates the biochemical and physiologic mechanisms of the reproductive cycle and pregnancy in women and the pathophysiology of endometrial disorders and infertility. Progesterone is required for the development of a functional secretory endometrium. Abnormal endometrial development, whether because of inadequate progesterone secretion or an inadequate endometrial response, may underlie infertility or multiple abortions.

New Treatment and Quality-of-Life Assessment in Cushing's Syndrome
Nieman in collaboration with Nansel, Krakoff
We are now 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 have great impairment in physical activities and cognitive function and that they also limit social activities. They 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 patients do not regain scores similar to the general population for as long as two years after treatment, suggesting significant long-term impairment of quality of life in some individuals. Another evaluation was directed to the need for parenteral medical therapy of hypercortisolism to inhibit steroidogenesis and reduce the risk of complications. We successfully used the propylene glycol preparation of etomidate to control hypercortisolism for 5.5 months in a man with severe hypercortisolism who was unable to take oral medications.

Internal Jugular Vein Sampling
Nieman in collaboration with Oldfield and Chang
In current clinical studies, we are evaluating the effectiveness of internal jugular vein (IJV) sampling as a substitute for the more invasive and technically demanding inferior petrosal sinus (IPS) sampling to discriminate patients with Cushing's disease from those with ectopic ACTH syndrome. Preliminary data in 20 patients with surgically proven Cushing's disease showed a sensitivity of 90 percent for IJV sampling and 95 percent for IPS sampling. Further validation of this diagnostic procedure would allow local medical centers without expertise in IPSS to localize directly the source of ACTH hypersecretion in ACTH-dependent hypercortisolism, whereas at present only a few highly specialized centers offer the IPSS test.

Endometrial Physiology
Christian, Stratton, Weil, Lopez, Hearns-Stokes, Segars, Neiman
Recent studies characterized the biologic action of a selective progesterone receptor modulator, showing it to inhibit endometrial development when given to women in the luteal phase. When given within two days of the LH surge, ultrasound and endometrial biopsy performed four to six days later showed a dose-dependent decrease in endometrial thickness, a delay in endometrial maturation as judged by Noyes criteria, and an increase in glandular progesterone receptors among the treatment groups. A second study during the past year was designed to characterize the spatial and temporal localization of estrogen receptor (ER) alpha and beta and the oncogene Brx in the endometrium of normally cycling women throughout the menstrual cycle. Immunohistochemical staining for ER alpha showed nuclear localization that was greatest in the epithelium during the proliferative phase and that decreased during the late secretory phase. ER beta showed a similar nuclear and epithelial cell preference, but the intensity of ER beta immunostaining was increased during the secretory phase. Brx was uniformly localized within the cytoplasm of glandular and luminal epithelial during the proliferative phase and became localized to both the nucleus and cytoplasm during the secretory phase. These different patterns of staining during the menstrual cycle with nuclear down-regulation of ER alpha and up-regulation of ER beta in the glandular epithelium during the secretory phase suggest differential regulation and possibly different roles of the two receptors in the endometrium. We also are conducting a randomized, double- blind placebo controlled study of surgery with or without raloxifene, EvistaTM, for the treatment of pain from endometriosis. In addition, we are studying the comorbidities of endometriosis, including psychiatric, autoimmune, and other disease states.