Educating physicians prepared to improve care and safety is no accident: it requires a systematic approach.

While most newly qualified physicians are well prepared in the science base of medicine and in the skills that enable them to look after individual patients, few have the skills necessary to improve care and patient safety continuously. We apply a systems analysis from the field of human error to identify ways in which medical school education can increase the number of graduates prepared to reflect on and improve professional practice. Doing so requires a systematic approach involving entrance requirements, the curriculum, the organizational culture of training environments, student assessment, and program evaluation.

Gone but not forgotten: the search for the lost surgical specimens: application of quality improvement techniques in reducing medical error.

A lost surgical specimen prompted an investigation of both the human processes and the systemic factors involved in surgical specimen handling regarding how health care organizations approach medical error prevention and patient safety promotion. Quality improvement techniques and the conceptual error model of James Reasons were employed to understand the interaction between the local process of specimen handling and the systemic influences to medical error management. Error management recognizes the inevitability of both individual and systemic error. Through the use of quality improvement techniques and models of error analysis, health care organizations can investigate the error potential of health care delivery and address the human and organizational interaction necessary to improve patient safety and manage medical error.

The adrenal incidentaloma: disease of modern technology and public health problem.

The optimal strategy for evaluation of a patient with an incidentally discovered adrenal mass is unclear and remains controversial. A prospective multi-center randomized (or even non-randomized) trial would go a long way toward resolving the controversies. However, we lack such a study. Review of the literature supports the view that such patients are at somewhat increased risk of morbidity and mortality and this implies a benefit of early diagnosis for at least for some of the disorders. Our ability to accurately determine clinically those at increased risk among the vast majority who are not at increased risk is poor. We therefore rely on biochemical and radiological diagnostic tests, which have their own limitations. Subjecting patients to unnecessary testing and treatment carries its own set of risks. The diagnostic process itself may contribute considerable anxiety, expense, and if invasive cause pain and other morbidity. The harm that occurs as false positive results are pursued has been termed the "cascade effect" [34]. We must avoid the pitfalls of overestimation of disease prevalence and of the benefits of therapy resulting from advances in diagnostic imaging. In the meantime, we must use our best clinical judgement based upon the best available evidence to ensure that we maximize the benefit to those patients with AI who have clinically significant adrenal disorders and minimize the harm to those who do not.

The diagnostic dilemma of incidentalomas. Working through uncertainty.

The clinical evaluation of incidentally found nodules in the adrenal, thyroid, and pituitary glands is a challenge for physicians, regardless of their level of expertise. Choosing the most direct and cost-effective diagnostic approach and deciding when to treat or not to treat are common dilemmas in clinical practice. This article outlines one diagnostic approach using medical decision-making techniques such as heuristic thinking, critical appraisal of the literature, treatment threshold probability assessment, Bayes' theorem, and discriminant properties of diagnostic tests. These skills are usually discussed in postgraduate training curricula. Nevertheless, they often seem foreign to many clinicians. Evidence suggests that training in these techniques can improve clinical decision making. Use of the skills outlined herein provides a framework to work through the diagnostic uncertainty common in the evaluation of incidentalomas. This approach does not provide perfect answers, as noted in examplar 3 in which two experts argued about the actual pretest probability and treatment thresholds for pituitary incidentalomas. Even if there were no such disagreement, each patient presents unique issues, and there will always be some uncertainty. Nevertheless, this approach provides a starting point from which critical decisions can be made for individual patients.

Pituitary incidentalomas.

The optimal strategy for hormonal screening of a patient with any incidentally discovered pituitary mass is unknown. The authors' review of the endocrinologic literature supports the view that such patients are at slightly increased risk for morbidity and mortality. This risk implies a benefit of early diagnosis for at least for some of the disorders, suggesting the importance of case finding. Nevertheless, the data in Table 1 illustrate that clinically diagnosed hormone-secreting pituitary tumors are far less common than incidentalomas. Clinically, one cannot accurately determine the approximately 0.5% of patients with incidentaloma who are at increased risk among the vast majority who are not. Given the limitations of diagnostic tests, effective hormonal screening requires a sufficiently high pretest probability to limit the number of false-positive results. This condition is met to varying degrees in the patient with a small incidentally discovered pituitary mass but no signs or symptoms of hormone excess. Even the more common lesions, such as prolactinoma, are relatively rare. [table: see text] Subjecting patients to unnecessary testing and treatment is associated with risk. In addition to its initial cost, testing may result in further expense and harm as false-positive results are pursued, producing the "cascade effect" described by Mold and Stein as a "chain of events (which) tends to proceed with increasing momentum, so that the further it progresses the more difficult it is to stop." The extensive evaluations performed for some patients with incidentally discovered masses may reflect the unwillingness of many physicians to accept uncertainty, even in the case of an extremely unlikely diagnosis. This unwillingness may be driven, in part, by fear of potential malpractice liability, the failure to appreciate the influence of prevalence data on the interpretation of diagnostic testing, or other factors. The major justification for further evaluation of these patients is not so much to avoid morbidity and mortality for the rare patient who truly is at increased risk but to reassure patients in whom further testing is negative and the physician. Physicians must take care not to create inappropriate anxiety in patients by overemphasizing the importance of an incidental finding unless it is associated with a realistic clinical risk. The authors' recommendations are based on currently available information to minimize the untoward effects of the cascade. As evidence accumulates, these recommendations may need to be revised. The benefit of the diagnosis of an adrenal or pituitary disorder must be considered in the context of the patient's overall condition. Additional studies are needed to analyze the clinical utility of hormonal screening for these common radiologic findings. Data from these studies can be used to identify critical gaps in knowledge and to adopt the epidemiologic methods of evaluation of evidence that have been applied to preventive measures. One must be careful to recognize lead-time bias, in which survival can appear to be lengthened when screening simply advances the time of diagnosis, lengthening the period of time between diagnosis and death without any true prolongation of life; and length bias, which refers to the tendency of screening to detect a disproportionate number of cases of slowly progressive disease and to miss aggressive cases that, by virtue of rapid progression, are present in the population only briefly. Physicians must avoid the pitfalls of overestimation of disease prevalence and of the benefits of therapy resulting from advances in diagnostic imaging. Clinical judgment based on the best available evidence should be complemented and not replaced by laboratory data.

Management of pituitary incidentalomas. A survey of British and American endocrinologists.

The results of a survey of endocrinologists concerning their approaches to the evaluation of a patient with an incidentally discovered pituitary mass are presented in this article. The practices of British and American endocrinologists are compared. The wide variation in diagnostic approaches to the practice of ordering tests in the United Kingdom and the United States highlights the need for research and debate regarding the most appropriate management of patients with such findings.

Incidental pituitary macroadenoma: a population-based study.

Epidemiologic analysis of incidental macroadenoma is limited to autopsy studies and case series. There are no published data about prevalence of incidental pituitary macroadenoma in living patients. The objective of this study was to determine the prevalence of incidental pituitary macroadenoma. It was designed as an observational study of cranial computed tomography reports. An urban department of veterans affairs medical center was used for the setting. The subject group consisted of 3,550 consecutive patients at the Cleveland Department of Veterans Affairs Medical Center from January 1993 to January 1996. Patients with known or suspected pituitary or parasellar disease were excluded. Cranial computed tomography reports were reviewed. Original films and medical charts of all patients with pituitary macroadenoma were reviewed. Seven patients with incidentally discovered pituitary macroadenoma that ranged from 1 cm to 2.5 cm were found; prevalence was 0.20% (95% confidence interval 0.05, 0.35%). Evidence of partial hypopituitarism was found in most patients. All patients had normal visual fields at initial examination despite the size of the tumor, but 1 of 4 had a field cut demonstrated by Goldmann perimetry. These data confirm that, although the prevalence of incidental pituitary macroadenoma is low, screening identified patients to detect deficiency of corticotropin, thyroid-stimulating hormone, and gonadotropins and to detect visual field defects is important.

Management of incidental pituitary microadenomas: a cost-effectiveness analysis.

The objective of this study was to compare the cost-effectiveness of four management strategies for a patient with an incidentally discovered asymptomatic pituitary microadenoma. A decision analytic Markov model was used to determine the incremental cost-effectiveness of four clinical management strategies: 1) expectant management, 2) PRL screening, 3) an endocrine screening panel (PRL, insulin-like growth factor I, and 1-mg dexamethasone suppression test), and 4) magnetic resonance imaging (MRI) follow-up. The model incorporated the natural history of incidental microadenomas, test characteristics, pharmacological and surgical treatment outcomes, patient's quality of life, discounting, and the costs of hormone testing, bromocriptine, MRIs, hospitalization for surgery, and physician services. PRL screening, endocrine screening panel, and MRI follow-up all provided slightly greater quality-adjusted survival than expectant management, but the costs increased disproportionately more than the benefits. The incremental cost per quality-adjusted life year for PRL screening is $1,428, and that for the endocrine screening panel is $69,495. These results are most sensitive to patient anxiety about the microadenoma; increased anxiety shifts the recommended strategy to the endocrine screening panel. We conclude that in patients with an incidental asymptomatic pituitary microadenoma, a single PRL test may be the most cost-effective management strategy.

Effectiveness versus efficacy: the limited value in clinical practice of high dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome.

High dose dexamethasone suppression testing has been widely employed in the differentiation between pituitary ACTH-dependent hypercortisolism [Cushing's disease (CD)] and the ectopic ACTH syndrome. We hypothesized that the high dose dexamethasone suppression test as it is performed in practice does not improve the ability to differentiate between these two types of ACTH-dependent Cushing's syndrome. Cases were drawn from 112 consecutive patients with ACTH-dependent Cushing's syndrome, who were then classified based upon results of inferior petrosal sinus sampling for ACTH levels. Analysis of test characteristics of high dose dexamethasone suppression testing was performed in the 73 patients for whom results are available. Statistical modeling was performed using the 68 cases with complete data on all assessed variables. Logistic regression models were used to predict the probability of pituitary-dependent Cushing's syndrome (CD) given the results of high dose dexamethasone suppression testing before and after adjustment for the contribution of a series of potential covariates. Of the 112 patients with ACTH-dependent Cushing's syndrome, 15.2% had the ectopic ACTH syndrome, and the remainder had pituitary-dependent Cushing's syndrome (CD). Patients with the ectopic ACTH syndrome were significantly older (mean, 51.9 vs. 40.2), were more likely to be male (58.8% vs. 27.4%), had shorter duration of clinical findings (mean, 11.6 vs. 39.9 months), were more likely to have hypokalemia (50% vs. 8.6%), had higher baseline 24-h urinary free cortisol [mean, 8317 vs. 1164 nmol/day (3015 vs. 422 microg)] and plasma ACTH levels [mean, 47 vs. 17 pmol/L (210 vs. 78 pg/mL)] and were less likely to suppress urinary free cortisol or plasma cortisol with high dose dexamethasone using the standard criterion of 50% or more suppression compared with patients with pituitary-dependent Cushing's syndrome. Based upon the standard criterion, the sensitivity and specificity of the high dose dexamethasone suppression test for the diagnosis of pituitary-dependent Cushing's syndrome were 81.0% and 66.7%, respectively. Although the mean percent suppression was significantly greater for patients with CD than for those with the ectopic ACTH syndrome (72.2% vs. 41.3%), the range of suppression was 0-99% for each diagnosis. The area under the receiver operating characteristic curve was 0.710 (95% confidence interval, 0.541-0.879). Logistic regression models were used to evaluate the probability of CD given the responsiveness to high dose dexamethasone suppression testing before and after adjustment for the potential contributions of other factors. A model including all of the variables (age, sex, duration, presence of hypokalemia, urinary free cortisol, and plasma ACTH) had a diagnostic accuracy of 92.7%. A model including all of these variables plus a binary variable indicating whether the patient met the criterion of suppression by 50% or more resulted in 95.6% accuracy, whereas substitution of this binary variable by percent suppression resulted in a model with 94.1% accuracy. There were no statistically significant differences among these models; their values for the c statistic, which is equivalent to the area under the curve in a receiver operating characteristic analysis, were all greater than 0.9. Logistic regression models indicate that the results of the dexamethasone suppression test add little to the differential diagnosis of ACTH-dependent Cushing's syndrome, especially after taking other clinical information into account. In our patient population, the sensitivity and specificity of the dexamethasone suppression test were less than those reported by others. However, because 20-33% of cases of ectopic ACTH syndrome are misdiagnosed with these logistic regression models, other techniques are necessary to achieve greater diagnostic accuracy.

Incidentalomas. A disease of modern technology.

The optimal strategy for hormonal screening of a patient with any incidentally discovered adrenal or pituitary mass is unknown. Our review of the endocrinologic literature supports the view that such patients are at slightly increased risk for morbidity and mortality. There is a benefit of early diagnosis for at least for some of the disorders, suggesting the importance of case finding. The data in Tables 1 and 4 illustrate that clinically diagnosed hormone-secreting adrenal and pituitary tumors are far less common than incidentalomas. From a clinical perspective, our ability to determine accurately those at increased risk among the vast majority who are not at increased risk is poor. Given the limitations of diagnostic tests, effective hormonal screening requires a sufficiently high pretest probability to limit the number of false-positive results. This condition is met to varying degrees in the patient with an adrenal mass or small incidentally discovered pituitary mass but no signs or symptoms of hormone excess. Even the more common lesions such as pheochromocytoma and prolactinoma are relatively rare. Subjecting patients to unnecessary testing and treatment carries its own set of risks. Initial costs aside, testing may result in further expense and harm as false-positive results are pursued, producing the cascade effect described by Mold and Stein as a "chain of events (which) tends to proceed with increasing momentum, so that the further it progresses the more difficult it is to stop." The extensive evaluations performed in some patients with incidentally discovered masses may reflect the unwillingness of many physicians to accept uncertainty, even in the case of extremely unlikely diagnoses. This unwillingness may be driven, in part, by fear of potential malpractice liability, the failure to appreciate the influence of prevalence data on the interpretation of diagnostic testing, or other factors. Indeed, the major justification for further evaluation of these patients is not so much to avoid morbidity and mortality for rate patients who truly are at increased risk but rather to reassure those in whom further testing is negative (and to reassure ourselves). Physicians must take care not to create inappropriate anxiety in patients by overemphasizing the importance of an incidental finding unless it is associated with a realistic clinical risk. Our recommendations utilize currently available information to minimize the untoward effects of the cascade. As evidence accumulates, recommendations may need to be revised. The benefit of diagnosis of one of these adrenal or pituitary disorders must be considered in the context of the patient's overall condition. Studies are needed to analyze the utility in clinical practice of hormonal screening for these common radiologic findings. We need to use these studies to identify the critical gaps in our knowledge and to adopt the epidemiologic methods of evaluation of evidence that have been applied to preventive measures. We must be careful to recognize lead-time bias in which survival can seem to be lengthened when screening simply advances the time of diagnosis, lengthening the period of time between diagnosis and death without any true prolongation of life. Length bias refers to the tendency of screening to detect a disproportionate number of cases of slowly progressive disease and to miss aggressive cases that, by virtue of rapid progression, are present in the population only briefly. Endocrinologists must avoid the pitfalls of overestimation of disease prevalence and of the benefits of therapy resulting from advances in diagnostic imaging. Clinical judgment based on the best available evidence should be complemented and not replaced by laboratory data.

Hyperprolactinaemia and verapamil: prevalence and potential association with hypogonadism in men.

OBJECTIVE: Verapamil has been associated with hyperprolactinaemia, but there have been no population-based studies. Our objective was to determine the prevalence and degree of hyperprolactinaemia associated with verapamil in the clinical setting. DESIGN: Observation with cross-sectional and longitudinal components in the setting of an urban teaching hospital and its satellite out-patient clinics. PATIENTS: Male out-patients excluding those taking other drugs known to raise PRL, renal failure and known primary hypothyroidism (1265 eligible subjects). Control subjects were drawn from eligible out-patients not taking verapamil. MEASUREMENTS: Serum PRL levels, frequency of persistent hyperprolactinaemia and total testosterone levels. RESULTS: Prolactin levels were obtained in 449 subjects on verapamil (35.5% response rate) and 166 controls. The proportions of individuals with hyperprolactinaemia (PRL > 460 mU/l) were 0.085 and 0.030 in the verapamil and control groups, respectively (P = 0.012, X2-test). The mean (+/- SD) serum PRL levels were 267 +/- 205 and 203 +/- 118 mU/l in the verapamil and control groups, respectively (P < 0.001, independent t-test). Of the 38 patients with previously determined elevated PRL levels, follow-up data were obtained in 25 (65.8%); one was found to have a pituitary adenoma and was excluded from the analysis. Fifteen of the 24 were still on verapamil (Group 1) and 14 (93.3%) continued to be hyperprolactinaemic. In 9 patients verapamil had been discontinued (Group 2) and all had normal PRL levels. Continued verapamil use was associated with persistent hyperprolactinaemia (odds ratio > 120, P < 0.00001). The mean +/- SD serum testosterone levels at follow-up were significantly lower in Group 1 (6.16 +/- 2.52 nmol/l) than in Group 2 (9.42 +/- 3.92 nmol/l, P = 0.029, independent t-test). CONCLUSIONS: The prevalence of hyperprolactinaemia associated with verapamil use in this study of male out-patients was 8.5% (95% CI 5.9-11.1%). The persistence of hyperprolactinaemia when verapamil was continued (Group 1) and the return to normal PRL levels when verapamil was discontinued (Group 2) confirm verapamil's causal role in the development of hyperprolactinaemia. While low testosterone levels were common in both groups, testosterone levels were lower in patients on verapamil. Our data suggest that screening for hyperprolactinaemia should be considered in male patients taking verapamil.

Verapamil-induced hyperprolactinemia complicated by a pituitary incidentaloma.

OBJECTIVE: To describe a patient with an incidental pituitary lesion who experienced verapamil-induced hyperprolactinemia. CASE SUMMARY: A patient experiencing impotence was found to have increased prolactin and low testosterone concentrations. Verapamil as a cause for his increased prolactin concentration was not considered initially. The patient underwent extensive testing to rule out a pituitary tumor. Magnetic resonance imaging showed a 6-mm lesion consistent with a pituitary microadenoma that had remained unchanged for 6 months. Verapamil therapy was discontinued and within 1 month the patient's prolactin concentration decreased from 46.8 to 14.4 micrograms/L, and has remained within normal limits. DISCUSSION: We reviewed reports of verapamil-induced hyperprolactinemia. This case was unique as this patient had an incidental pituitary lesion that was not responsible for increasing the prolactin concentration in our patient, but rather complicated the identification of a drug-induced disorder. CONCLUSION: The failure to identify the hyperprolactinemic effect of verapamil may have resulted in performing unnecessary radiologic procedures in this patient. This case highlights the importance of obtaining a medication history in patients with hyperprolactinemia.

Pituitary tumors. Current concepts in diagnosis and management.

Diagnostic advances have resulted in earlier and more frequent recognition of pituitary tumors. Pituitary tumors cause problems owing to the hormones they secrete or the effects of an expanding sellar mass--hypopituitarism, visual field abnormalities, and neurologic deficits. Prolactin-secreting tumors (prolactinomas), which cause amenorrhea, galactorrhea, and hypogonadism, constitute the most common type of primary pituitary tumors, followed by growth hormone-secreting tumors, which cause acromegaly, and corticotropin-secreting tumors, which cause Cushing's syndrome. Hypersecretion of thyroid-stimulating hormone, the gonadotrophins, or alpha-subunits is unusual. Nonfunctional tumors currently represent only 10% of all clinically diagnosed pituitary adenomas, and some of these are alpha-subunit-secreting adenomas. Insights into the pathogenesis and biologic behavior of these usually benign tumors have been gained from genetic studies. We review some of the recent advances and salient features of the diagnosis and management of pituitary tumors, including biochemical and radiologic diagnosis, transsphenoidal surgery, radiation therapy, and medical therapy. Each type of lesion requires a comprehensive but individualized treatment approach, and regardless of the mode of therapy, careful follow-up is essential.

High-dose dexamethasone suppression testing versus inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome: a decision analysis.

Differentiation of adrenocorticotropin (ACTH)-dependent Cushing's syndrome between Cushing's disease and the occult ectopic ACTH syndrome is difficult. Simultaneous bilateral inferior petrosal sinus sampling (IPSS) for ACTH levels in response to corticotropin-releasing hormone has high diagnostic accuracy, but its cost-effectiveness has not been analyzed. In this study, decision analysis was used to compare two diagnostic strategies: IPSS versus high-dose dexamethasone suppression (HDD) followed by IPSS in those with a negative HDD test. Sensitivity analyses were performed for all variables. The authors found that at 100% accuracy, IPSS has an incremental cost-effectiveness ratio of $1,000,000 per life saved. Incremental cost, incremental effectiveness, and incremental cost-effectiveness are sensitive to the pretest probability of Cushing's disease, test characteristics, and test costs. As the pretest probability of Cushing's disease decreases, cost per life saved also decreases to less than 85%, the HDD strategy saves more lives and costs less. When the HDD test has a 83% sensitivity rate and a 100% specificity rate, the two strategy remains less expensive. The IPSS strategy saves lives whenever HDD specificity is less than 100%.(ABSTRACT TRUNCATED AT 250 WORDS)

Ectopic ACTH syndrome and CRH-mediated Cushing's syndrome.

The ectopic ACTH syndrome accounts for a substantial number of patients with naturally occurring Cushing's syndrome. Despite the progress achieved in elucidating the pathophysiology of Cushing's syndrome, clinicians continue to experience diagnostic and therapeutic challenges. This is especially true in those patients presenting with disease mediated by ectopically produced ACTH and CRH. Patients with these disorders may be indistinguishable based on clinical grounds or simple biochemical and radiologic testing from those with Cushing's disease. However, this differentiation is critical because their therapies differ. While clinical researchers continue to develop more effective diagnostic techniques and therapies, further advances in the molecular and cell biology of ACTH and CRH-producing tumors will undoubtedly shed light on the pathogenesis of this perplexing, fascinating and still controversial entity.

Molecular cloning of mouse insulin-like growth factor binding protein 4 (IGFBP4) cDNA and expression of a fusion protein with IGF-binding activity.

The TC-1 bone marrow stromal cell line expresses a 2.3 kb IGFBP-4 mRNA transcript. Reverse transcription/polymerase chain reaction was used to amplify the complete open reading frame of the insulin-like growth factor binding protein-4 (IGFBP-4) from poly(A)+ of a murine bone marrow stromal cell line (TC-1). Sequence analysis reveals that the murine IGFBP-4 is highly homologous to the rat IGFBP-4 and less so to the human IGFBP-4. The inferred amino acid sequence has a molecular weight of 25.7 kD. An IGFBP-4/maltose binding protein fusion peptide expression in the pMal-p2 vector produced a fusion protein exhibiting both IGFBP immunoreactivity and IGF-I binding activity with specificity characteristic of IGFBPs.

Management of gallstones in diabetic patients.

The management of gallstones in diabetic patients has traditionally been considered problematic. Autopsy findings and uncontrolled studies have documented a higher prevalence of cholelithiasis in diabetics, and early reports showed dramatically increased perioperative morbidity and mortality for treatment of diabetics with acute cholecystitis. As a result, some authorities have recommended prophylactic cholecystectomy for diabetic patients with asymptomatic gallstones, which is in contrast to recommendations for nondiabetics. More recent investigators have shown comparable rates of operative morbidity and mortality for biliary surgery in diabetics when compared with the general population. Recent studies have questioned whether diabetes is an independent risk factor for gallstone formation. Decision analyses using these new data have shown that prophylactic cholecystectomy is not of clear benefit and should not be routinely recommended for diabetics with asymptomatic gallstones. We believe that available data, although limited, indicate that asymptomatic patients with diabetes do not benefit from screening for gallstones and that cholecystectomy should only be performed in cases of symptomatic cholelithiasis, as is the case in the general population.

Familial adrenocorticotropin-independent Cushing's syndrome with bilateral macronodular adrenal hyperplasia.

Familial Cushing's syndrome is rare, and when it occurs, it is usually associated with primary micronodular dysplasia. We report two cases, a mother and daughter, who each presented with clinical features of Cushing's syndrome at age 38 yr and were found to have ACTH-independent macronodular adrenal hyperplasia. In each case, bilateral adrenalectomy revealed the massively thickened adrenal cortex with nodules up to 1.3 cm in diameter and hyperplasia between nodules. Dynamic testing showed no suppression of free cortisol with high dose dexamethasone and no stimulation of 17-hydroxycorticosteroids with metyrapone. Two samples of serum obtained preoperatively from one patient that showed ACTH immunoreactivity of 4.6 and less than 2.2 pmol/L, respectively, each showed less than 2.2 pmol/L ACTH bioactivity. The lack of suppression with high dose dexamethasone, lack of stimulation with metyrapone, and low levels of ACTH immunoreactivity and bioactivity suggest that the bilateral hyperplasia was not dependent upon ACTH. These patients represent the first cases of ACTH-independent macronodular adrenal hyperplasia occurring in two generations of one family and illustrate the expanding clinical spectrum of Cushing's syndrome.