Global clinical response in Cushing's syndrome patients treated with mifepristone.

OBJECTIVE: Mifepristone, a glucocorticoid receptor antagonist, improves clinical status in patients with Cushing's syndrome (CS). We examined the pattern, reliability and correlates of global clinical response (GCR) assessments during a 6-month clinical trial of mifepristone in CS. DESIGN: Post hoc analysis of secondary end-point data from a 24-week multicentre, open-label trial of mifepristone (300-1200 mg daily) in CS. Intraclass correlation coefficient (ICC) was used to examine rater concordance, and drivers of clinical improvement were determined by multivariate regression analysis. PATIENTS: Forty-six adult patients with refractory CS along with diabetes mellitus type 2 or impaired glucose tolerance, and/or a diagnosis of hypertension. MEASUREMENTS: Global clinical assessment made by three independent reviewers using a three-point ordinal scale (+1 = improvement; 0 = no change; -1 = worsening) based on eight broad clinical categories including glucose control, lipids, blood pressure, body composition, clinical appearance, strength, psychiatric/cognitive symptoms and quality of life at Weeks 6, 10, 16, and 24. RESULTS: Positive GCR increased progressively over time with 88% of patients having improved at Week 24 (P < 0·001). The full concordance among reviewers occurred in 76·6% of evaluations resulting in an ICC of 0·652 (P < 0·001). Changes in body weight (P < 0·0001), diastolic blood pressure (P < 0·0001), two-hour postoral glucose challenge glucose concentration (P = 0·0003), and Cushingoid appearance (P = 0·022) were strong correlates of GCR. CONCLUSIONS: Mifepristone treatment for CS results in progressive clinical improvement. Overall agreement among clinical reviewers was substantial and determinants of positive GCR included change in weight, blood pressure, glucose levels and appearance.

An approach to the patient with hirsutism.

Hirsutism is a common endocrinological complaint. The causes of this complaint can vary from dissatisfaction with a normal pattern of hair growth on the one hand, to the first clinical manifestation of androgen overproduction by an adrenal adenocarcinoma on the other. The purpose of this short review is to reexamine the physiology of hair growth in normal women, identify the common abnormal patterns, and explore the differential diagnosis associated with each. An approach to working through the differential diagnosis will be described, and the commonly available treatment modalities for the various forms of hirsutism will be examined in terms of risk and benefit. The review is written from the point of view of the physician and the most efficient, cost effective, and safe clinical approach to the patient with the problem.

Normal hypothalamic-pituitary-adrenal axis by high-dose cosyntropin testing in patients with abnormal response to low-dose cosyntropin stimulation: a retrospective review.

OBJECTIVE: To analyze the interpretation of the 1-microg low-dose adrenocorticotropic hormone (ACTH) test (LDT) for assessment of the presence of adrenal insufficiency (AI) in comparison with the 250-microg or standard high-dose ACTH test (HDT), which uses the same cutoff cortisol value of 18 microg/dL (500 nmol/L) as the lower limit of normal. METHODS: We present a retrospective review of 26 patients referred to the Pituitary Clinic who underwent both the LDT and the HDT for evaluation of the function of the hypothalamic-pituitary-adrenal axis. RESULTS: Of the 26 study patients, 23 had discordant findings--abnormal LDT and normal HDT results with use of the empiric cortisol cutoff of 18 microg/dL at 30 minutes in response to the ACTH dose. Glucocorticoid replacement therapy was stopped or not started in these patients, and no clinical symptoms of AI developed during a follow-up period ranging from 19 to 24 months. CONCLUSION: Our retrospective review of patients' discordant LDT and HDT results questions the reliability of the LDT as a screening test for AI, as currently interpreted. Our data suggest that abnormal results should be evaluated in the context of the clinical picture and that additional testing may be indicated to prevent unwarranted treatment with glucocorticoids. Further studies are needed to establish a safe, sensitive, and specific test for the diagnosis of AI.

"Relative" adrenal insufficiency in critical illness.

OBJECTIVE: To present a recommended approach to the problem of "relative" adrenal insufficiency (RAI) in the intensive care unit (ICU). METHODS: We examine historical data that support the traditional concepts of adrenal insufficiency and the idea that the increase in cortisol secretion during stress is needed to survive the stress. The controversial use of treatment with glucocorticoids (GCs) in patients with sepsis and septic shock in the ICU (and thus survival benefit) is also briefly discussed. RESULTS: During the past decade, the concept of RAI as the failure of cortisol secretion to increase in response to stress to sustain the patient through that stress has gained strength. In some studies, it has been suggested that as many as 75% of patients in an ICU setting have RAI. Experimental support for the concept is not possible because there is no clinically useful laboratory measure of GC action. Therefore, diagnosis is generally based on interpretation of the cosyntropin stimulation test. CONCLUSION: The best clinical judgment should always guide interpretation of any test results, and sharp categorization of patients on the basis of a single cutoff criterion should be avoided. Overall, the concept of RAI has no clinical utility. In these cases, administration of GCs adds cost without benefit and with increased risk.

Enhanced cortisol production rates, free cortisol, and 11beta-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss.

Controversy exists as to whether endogenous cortisol production is associated with visceral obesity and insulin resistance in humans. We therefore quantified cortisol production and clearance rates, abdominal fat depots, insulin sensitivity, and adipocyte gene expression in a cohort of 24 men. To test whether the relationships found are a consequence rather than a cause of obesity, eight men from this larger group were studied before and after weight loss. Daily cortisol production rates (CPR), free cortisol levels (FC), and metabolic clearance rates (MCR) were measured by stable isotope methodology and 24-h sampling; intra-abdominal fat (IAF) and subcutaneous fat (SQF) by computed tomography; insulin sensitivity (S(I)) by frequently sampled intravenous glucose tolerance test; and adipocyte 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD-1) gene expression by quantitative RT-PCR from subcutaneous biopsies. Increased CPR and FC correlated with increased IAF, but not SQF, and with decreased S(I). Increased 11beta-HSD-1 gene expression correlated with both IAF and SQF and with decreased S(I). With weight loss, CPR, FC, and MCR did not change compared with baseline; however, with greater loss in body fat than lean mass during weight loss, both CPR and FC increased proportionally to final fat mass and IAF and 11beta-HSD-1 decreased compared with baseline. These data support a model in which increased hypothalamic-pituitary-adrenal activity in men promotes selective visceral fat accumulation and insulin resistance and may promote weight regain after diet-induced weight loss, whereas 11beta-HSD-1 gene expression in SQF is a consequence rather than cause of adiposity.

Reflections on future research in adolescent reproductive health.

A group of basic scientists, clinicians, clinical investigators, psychologists, patient advocacy groups, and representatives from professional societies and governmental agencies met at the National Institutes of Health in October, 2007 with the long-term goal of having the menstrual cycle accepted and understood as a marker of general health in adolescent girls. An equally important goal was to develop a research agenda for this area of investigation. This chapter comprises the highlights of discussions throughout that meeting, with an emphasis on ideas generated during a final session led by an internationally renowned physician-scientist, in which reports from four breakout groups were presented. The specific goal assigned to each group was to develop an agenda that would set the stage for how research should be conducted over the next 100 years, and to identify the pressing research questions that should be addressed related to the menstrual cycle and adolescent health. The four research areas represented in discussion groups included: emotional health; genetics; metabolism and reproduction; and the promotion of conduct of clinical research. Insights are also provided by five clinical investigators, including two outside experts, on topics of priority for a research agenda in the area of adolescent reproductive health, as well as how the research itself should be conducted.

Second-line treatment for Cushing's disease when initial pituitary surgery is unsuccessful.

PURPOSE OF REVIEW: Adenectomy via transsphenoidal surgery is considered the treatment of choice for Cushing's disease. It is successful in about 80% of patients in the hands of an experienced surgeon. When transsphenoidal surgery fails or is contraindicated, a second-line treatment must be chosen. The review focuses on second-line treatment options. RECENT FINDINGS: Repeat pituitary surgery results in the cure of Cushing's disease in about 50% of cases. Bilateral adrenalectomy results in resolution of hypercortisolemia in almost all patients, but leaves the patient glucocorticoid and mineralocorticoid deficient. Nelson's syndrome, depending on the definition, occurs in up to 35% of these patients. Irradiation of the residual pituitary tumor typically takes several years before the full effect is realized; it can cause panhypopituitarism. Finally, pharmacologic treatment of persistent hypercortisolemia can be effective, but is often associated with untoward side effects. These side effects are a powerful deterrent to its use. Several new pharmacologic agents are being studied and show some promise. SUMMARY: Each of the second-line treatments for Cushing's disease currently available can be effective at treating hypercortisolism, but each has significant limitations. New pharmacologic agents may soon offer some very exciting treatment options.

Improved quality of life after bilateral laparoscopic adrenalectomy for Cushing's disease: a 10-year experience.

OBJECTIVE: To determine long-term quality of life after bilateral adrenalectomy for persistent Cushing's disease after transsphenoidal pituitary tumor resection. SUMMARY BACKGROUND DATA: Bilateral adrenalectomy for symptomatic relief of persistent hypercortisolism appears to be an effective treatment option. However, few studies have examined long-term outcomes in this patient population. METHODS: Retrospective review of 39 patients treated by bilateral laparoscopic adrenalectomy for Cushing's disease from 1994 to 2004. Patients completed a follow-up phone survey, including our Cushing-specific questionnaire and the SF-12v2 health survey. Patients then refrained from taking their steroid replacement for 24 hours, and serum cortisol and ACTH levels were measured. RESULTS: Three patients died at 12, 19, and 50 months following surgery from causes unrelated to adrenalectomy. The remaining 36 patients all responded to the study questionnaire (100% response rate). Patients were between 3 months and 10 years post-adrenalectomy. We had zero operative mortalities and a 10.3% morbidity rate. Our incidence of Nelson's syndrome requiring clinical intervention was 8.3%; 89% of patients reported an improvement in their Cushing-related symptoms, and 91.7% would undergo the same treatment again. Twenty of 36 (55%) and 29 of 36 (81%) patients fell within the top two thirds of the national average for physical and mental composite scores, respectively, on the SF-12v2 survey. An undetectable serum cortisol level was found in 79.4% of patients. CONCLUSIONS: Laparoscopic bilateral adrenalectomy for symptomatic Cushing's disease is a safe and effective treatment option. The majority of patients experience considerable improvement in their Cushing's disease symptoms, and their quality of life equals that of patients initially cured by transsphenoidal pituitary tumor resection.

Cortisol production rate in posttraumatic stress disorder.

CONTEXT: Several authors have reported the unsuspected finding of low cortisol levels (urinary, salivary, and serum) in patients with posttraumatic stress disorder (PTSD). OBJECTIVE: Our objective was to assess concentrations of cortisol and its predominant metabolites, cortisol production rate (CPR), and glucocorticoid receptor (GR) binding characteristics in PTSD compared with normal subjects. DESIGN: Matched PTSD patients and control subjects had CPR determined by a stable isotope dilution technique after infusion of deuterated cortisol. Serum cortisol, urinary cortisol, and its metabolites were measured by gas chromatography/mass spectrometry. GR binding capacity (R(o)) and ligand binding affinity (K(d)) were measured in mononuclear leukocytes. SETTING: All subjects were tested during a 40-h admission in an inpatient clinical research center. PATIENTS AND PARTICIPANTS: Ten patients with PTSD were matched by age and gender with 10 controls. OUTCOME MEASURES: Statistical comparison was conducted for various measures of cortisol in PTSD patients and normal subjects. RESULTS: No statistical difference was found in mean level or circadian pattern of cortisol secretion using serum or salivary immunoassay detection methods. Although in the normal range, urinary cortisol by immunoassay showed statistically lower values over a 24-h period in PTSD patients compared with controls. This finding was not confirmed by gas chromatography/mass spectrometry determination of cortisol or its metabolites. CPR was not statistically different between these groups. GR also showed no alteration in R(o) or K(d) between the groups. CONCLUSION: The data indicate that PTSD in the chronic and unprovoked state is not characterized by an acute biological stress response.

Association of 24-hour cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women.

The present study was designed to examine the hypothesis that hypothalamic-pituitary-adrenal axis activity as measured by 24-h cortisol production rate (CPR) and plasma levels of free cortisol is linked to increased body fat in adults, and that increased cortisol levels with aging results from increased CPR. Fifty-four healthy men and women volunteers with a wide range of body mass indexes and ages underwent measurement of CPR by isotope dilution measured by gas chromatography-mass spectroscopy, cortisol-binding globulin, and free cortisol in pooled 24-h plasma, body composition, and leptin. Cortisol clearance rates were determined from the 10-h disappearance curves of hydrocortisone after steady-state infusion in a separate group of lean and obese subjects with adrenal insufficiency. Although CPR significantly increased with increasing body mass index and percentage body fat, free cortisol levels remained independent of body composition and leptin levels due to increased cortisol clearance rates. CPR and free cortisol levels were, however, significantly higher in men than women. In addition, 24-h plasma free cortisol levels were increased with age in association with increased CPR, independent of body size. This increase in hypothalamic-pituitary-adrenal axis activity may play a role in the alterations in body composition and central fat distribution in men vs. women and with aging.

History of intramural clinical research at the National Institute of Child Health and Human Development (NICHD).

This article reviews the beginnings of the NICHD intramural clinical research program; it focuses on three men, Roy Hertz, Mort Lipsett, and Griff Ross, who were instrumental in providing the intramural research program with the vision and character seen today.

Epidemic of gynecomastia among haitian refugees: exposure to an environmental antiandrogen.

OBJECTIVE: To investigate an observed epidemic of gynecomastia among Haitian refugees in US detention centers in 1981 and 1982. METHODS: All identifiable environmental exposures were investigated for estrogenic and antiandrogenic activity. RESULTS: A high incidence of gynecomastia was observed among Haitian refugees in five detention centers in the United States. Of 284 men screened, 20 (from 18 to 53 years old) demonstrated new-onset gynecomastia (Tanner stages 2 to 5) in June 1982. The mean onset of gynecomastia was 130 +/- 12 days after arrival in the United States. Other symptoms included loss of libido (in all 20 patients) and decreased beard growth (in 10). Plasma concentrations of luteinizing hormone, follicle-stimulating hormone, prolactin, testosterone, and estradiol were not significantly different from those in 20 age-matched control subjects. Environmental substances, including tap water and the delousing agents Kwell shampoo and R&C Spray (applied to bedding and clothing), were tested for estrogenicity and androgenicity. None of these substances bound to cytosol estrogen receptors. The delousing agents were assayed for androgen binding by using genital skin fibroblasts. R&C Spray competed equally with testosterone for androgen-binding sites. Phenothrin, the "multi-cide" component of R&C Spray, reproduced this competitive binding result. When tested for antiandrogenic effects on prostate growth by using immature male rats treated with testosterone-filled Silastic capsules, phenothrin antagonized androgen action, as demonstrated by decreased prostate weights. CONCLUSION: The antiandrogenic activity of phenothrin may explain this unusual epidemic of gynecomastia.

Intracerebroventricular corticotropin-releasing factor increases limbic glucose metabolism and has social context-dependent behavioral effects in nonhuman primates.

Corticotropin-releasing factor (CRF) is a neuropeptide involved in integrating the behavioral, autonomic, and hormonal responses to stress within the central nervous system. Patients suffering from depression have abnormal activity in stress responsive brain regions and elevated cerebrospinal fluid CRF. The DSM-IV criteria for major depressive disorder include behavioral changes such as depressed mood, anhedonia, and psychomotor agitation/retardation. We studied the effects of 434 microgram of CRF given intracerebroventricularly over 40 min in group and individually housed monkeys to examine the role of elevated levels of central CRF on behavior. CRF elicited a wide range of behaviors, which fell into three broad categories: anxiety-like, depressive-like, and externally oriented. Externally oriented behaviors decreased, and anxiety-like behaviors increased regardless of how the animals were housed. Interestingly, increased depressive-like behaviors were only observed when the animals were socially housed. In a separate experiment, we examined the effects of the same dose of CRF on the regional cerebral glucose metabolism of lightly anesthetized monkeys by using positron emission tomography and [(18)F]fluorodeoxyglucose. CRF infusion increased glucose metabolism in the pituitary/infundibulum, the amygdala, and hippocampus. These results indicate that increased central CRF tone affects primate behavior in a context-dependent manner, and that it activates limbic and stress-responsive regions. The fact that intracerebroventricular CRF increases depressive-like behavior in socially housed animals and increases activity in limbic brain regions may help explain the behavioral and metabolic alterations in humans with affective disorders, and this model could therefore have significant value in the development of novel antidepressant treatments.