Although weight gain and obesity are nearly universal features of Cushings syndrome, we hypothesized that screening results would have poor specificity in an obese population. The study is based in a weight loss clinic and enrolls individuals with at least two additional signs or symptoms of Cushings syndrome. Preliminary analysis suggests a high rate (nearly 20%) of falsely positive screening tests in patients who are found to be normal on subsequent confirmatory testing. If confirmed after further study, these results suggest that current recommendations for screening may need revision. [unreadable] [unreadable] As part of this study, we compared the performance of two techniques, RIA and LC-MS/MS, for measurement of salivary cortisol. We studied 261 obese subjects (186 female) with at least two additional features of Cushing's syndrome and 60 healthy volunteers (30 female) who provided split bedtime salivary samples for cortisol measurement. Using laboratory-provided normative ranges, RIA gave a lower specificity than LC-MS/MS in obese subjects (86 vs. 94%, P = 0.008) but not healthy volunteers (86 vs. 82%, P = 0.71). Among subjects with at least one abnormal result, both values were abnormal in 44% of obese and 75% of healthy volunteers. Cushing's syndrome was not diagnosed in any subject. Thus, salivary cortisol levels should not be used as the sole test to diagnose Cushing's syndrome if laboratory-provided reference ranges are used for diagnostic interpretation.[unreadable] [unreadable] Cushing's syndrome occurs rarely during pregnancy. We have investigated and treated four patients with pituitary-dependent Cushing's syndrome during pregnancy over a 15-year period at the NIH. Except for preservation of menses prior to conception, our patients presented with typical clinical features, increased urinary free cortisol, and loss of diurnal variation of cortisol. The diagnosis was facilitated, without complications, by the use of corticotropin-releasing hormone testing and inferior petrosal sinus sampling (IPSS) in three women. Transsphenoidal pituitary surgery (TSS) achieved remission in three women, but there were two fetal/neonatal deaths. [unreadable] [unreadable] This experience and review of 136 previous reports suggest that 1.) UFC in Cushing's syndrome patients overlaps the normal pregnant range, 2.) Adrenocorticotropic hormone (ACTH) levels are not suppressed in adrenal causes of Cushing's syndrome, which may be identified by the 8 mg dexamethasone test, 3.) IPSS and TSS, the optimal diagnostic test and treatment for non-pregnant patients, can safely facilitate the management of pregnant patients and 4.) Surgery may achieve remission during pregnancy, but the prognosis for the fetus remains guarded. It is likely that earlier recognition and treatment would improve outcome. There is a need for development of criteria for interpretation of diagnostic tests and for increased consideration of Cushing's syndrome in pregnancy.