Nicoletta Sonino

Treatment of Adrenocorticotropin-Dependent Cushing’s Syndrome: A Consensus Statement

OBJECTIVE Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushings syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushings syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushings disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushings disease, and 5) management of ectopic ACTH syndrome, Nelsons syndrome, and special patient populations. EVIDENCE Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS ACTH-dependent Cushings syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushings syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushings disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushings syndrome, early diagnosis and prompt therapy are warranted.

Psychiatric disorders associated with Cushing's syndrome. Epidemiology, pathophysiology and treatment.

Cushing’s syndrome is caused by a chronic excess of glucocorticoids. A number of psychiatric and psychological disturbances may be associated with the condition, regardless of its aetiology. Major depression is the most common co-morbid disorder. Other psychopathological aspects of Cushing’s syndrome in adults include mania, anxiety disorders and cognitive dysfunction.The presence of depression connotes a severe clinical presentation and, in patients with hypothalamic-pituitary forms of Cushing’s syndrome, is prognostically useful. Inhibitors of corticosteroid production (e.g. ketoconazole, metyrapone, aminoglutethimide), rather than antidepressant drugs, are generally successful in relieving depressive symptoms, as well as other disabling symptoms. These drugs can be used to control symptoms prior to surgical treatment of Cushing’s syndrome.Long-standing hypercortisolism may cause some degree of irreversible pathological damage and induce highly individualised affective responses based on each patient’s psychological assets and liabilities. As a result, upon normalisation of cortisol levels, treatment may still be required, and should encompass both psychotherapeutic strategies (particularly cognitive-behavioural therapies that have been found to be effective in affective disorders) and psychotropic drug treatment [antidepressants such as tricyclic agents and selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors]. In patients with severe anxiety, benzodiazepines (e.g. clonazepam in small doses) may also be helpful.

Left ventricular structural and functional characteristics in Cushing's syndrome.

OBJECTIVES This study was designed to evaluate left ventricular (LV) anatomy and function in patients with Cushings syndrome. BACKGROUND A high prevalence of LV hypertrophy and concentric remodeling has been reported in Cushings syndrome, although no data have been reported on LV systolic and diastolic function. METHODS Forty-two consecutive patients with Cushings syndrome and 42 control subjects, matched for age, gender, and blood pressure, were studied. Left ventricular mass index (LVMI) and relative wall thickness (RWT) were measured by echocardiography, endocardial and midwall fractional shortening (FS) were assessed, and diastolic filling was measured by Doppler transmitral flow. RESULTS The RWT was significantly greater in Cushing patients than in controls. Left ventricular hypertrophy and concentric remodeling were observed in 10 and 26 patients with Cushings syndrome, respectively. In Cushing patients, midwall FS was significantly reduced compared with controls (16.2 +/- 3% vs. 21 +/- 4.5%, p = 0.01). The ratio of transmitral E and A flow velocities was reduced and E deceleration time was prolonged in Cushing patients compared with controls (p = 0.03 and p < 0.001, respectively). CONCLUSIONS In patients with Cushings syndrome, cardiac structural changes are associated with reduced midwall systolic performance and with diastolic dysfunction that may contribute to the high risk of cardiovascular events observed in these patients.

Psychosomatic Medicine: Emerging Trends and Perspectives

Developments have occurred in all aspects of psychosomatic medicine. Among factors affecting individual vulnerability to all types of disease, the following have been highlighted by recent research: recent and early life events, chronic stress and allostatic load, personality, psychological well-being, health attitudes and behavior. As to the interaction between psychological and biological factors in the course and outcome of disease, the presence of psychiatric (DSM-IV) as well as subclinical (Diagnostic Criteria for Psychosomatic Research) symptoms, illness behavior and the impact on quality of life all need to be assessed. The prevention, treatment and rehabilitation of physical illness include the consideration for psychosomatic prevention, the treatment of psychiatric morbidity and abnormal illness behavior and the use of psychotropic drugs in the medically ill. In the past 60 years, psychosomatic medicine has addressed some fundamental questions, contributing to the growth of other related disciplines, such as psychoneuroendocrinology, psychoimmunology, consultation-liaison psychiatry, behavioral medicine, health psychology and quality of life research. Psychosomatic medicine may also provide a comprehensive frame of reference for several current issues of clinical medicine (the phenomenon of somatization, the increasing occurrence of mysterious symptoms, the demand for well-being and quality of life), including its new dialogue with mind-body and alternative medicine.

Residual symptoms in depression: An emerging therapeutic concept

Cushings syndrome is due to chronic glucocorticoid excess that may have various etiologies. The most common endogenous form is pituitary-dependent bilateral adrenal hyperplasia, which is termed Cushings disease. Major depression occurs in more than half of the cases. The presence of depressive symptoms connotes severity of clinical presentation and, in patients with hypothalamic-pituitary forms, entails prognostic value. Medical treatment may be used while awaiting more definitive solutions for the illness by surgery. The inhibitors of steroid production (e.g., ketoconazole, metyrapone and aminoglutethimide), rather than antidepressant drugs, are generally successful in lifting depression as well as other disabling symptoms. Since central serotonergic regulation could have a role in the course of Cushings disease, serotonin antagonists (e.g., cyproheptadine, ritanserin and ketanserin) have been employed. Findings related to the pharmacological response of depression in Cushings disease were found to have implications for the pathophysiology of depression and the potential involvement of the hypothalamic-pituitary-adrenal axis (HPA axis) in resistance and tolerance to antidepressant drugs. The use of serotonergic drugs in Cushings disease may yield important insights in the understanding of serotonergic regulation both in Cushings disease and in the HPA axis in nonendocrine major depression.

The Biopsychosocial Model Thirty Years Later

As 30 years ago, the dominant model of disease today is biomedical, with molecular biology being the basic scientific discipline. Indeed, there has been a progressive decline of clinical observation as the primary source of scientific challenges [5] . Yet, the evidence supporting the biopsychosocial model has considerably increased over the years. A large body of research has documented the role of stressful life events and repeated or chronic environmental challenge in modulating individual vulnerability to illness [6] . The tendency to experience and communicate psychological distress in the form of physical symptoms and to seek medical help for them is a widespread clinical phenomenon that may involve up to 30 or 40% of medical patients and increases medical utilization and costs [7, 8] . Medically unexplained symptoms appear to be the rule in primary care [7, 8] and the traditional boundaries among medical specialties, based mostly on organ systems (e.g. cardiology, gastroenterology) appear to be more and more inadequate in dealing with symptoms and problems which cut across organ system subdivisions and require a holistic approach. Moreover, affective disturbances (such as depression, anxiety, hostility) and illness behavior, the ways in which individuals experience, perceive, evaluate and respond to their own health status, may affect the course, therapeutic response and outcome of a given illness episode [7] . Psychological well-being [9] was found to play a protective role in the dynamic balance between health and disease outlined by Engel [1] . The need to include considThirty years ago George L. Engel [1] highlighted the inadequacies and limitations of the traditional biomedical model and advocated the endorsement of a biopsychosocial approach. The article had a considerable impact on the scientific community and attracted nearly 1,900 citations over the years. The biopsychosocial model allows illness to be viewed as a result of interacting mechanisms at the cellular, tissue, organismic, interpersonal and environmental levels. Accordingly, the study of every disease must include the individual, his/her body and his/her surrounding environment as essential components of the total system [1, 2] . Psychosocial factors may operate to facilitate, sustain or modify the course of illness, even though their relative weight may vary from illness to illness, from one individual to another and even between 2 different episodes of the same illness in the same individual. The key characteristic of clinical science is its explicit attention to humanness, where ‘observation (outer viewing), introspection (inner viewing), and dialogue (interviewing) are the basic methodologic triad for clinical study and for rendering patient data scientific’ [3, p. 59]. Engel identified the biopsychosocial model as a more complete conceptual framework to guide clinicians in their everyday work with patients. He thought that the transition from the narrow biomedical model to the biopsychosocial model was the major challenge to medicine in the seventies [1] . Has the challenge been met? Not at all, as examined in a recent monograph on the biopsychosocial approach [4] .

Clinical correlates of major depression in Cushing's disease.

Major depression is a common, life-threatening complication of Cushing’s syndrome, with no significant differences between pituitary-dependent and -independent forms. Little is known about the clinical correlates of depression; in particular, whether patients with Cushing’s disease and major depression show some clinical features that are distinctive compared to those who are not depressed. The occurrence of major depression according to DSM-IV criteria was ascertained in 162 patients with pituitary-dependent Cushing disease. Major depression occurred in 88 of the patients (54%). It was significantly associated with older age, female sex, higher pretreatment urinary cortisol levels, relatively more severe clinical condition, and absence of pituitary adenoma. Patients with Cushing’s disease and depression appeared to suffer from a more severe form of illness, both in terms of cortisol production and clinical presentation, compared to those who were not depressed. Because of these connections, the presence of depression is an important clinical feature that should not be neglected. The findings in this study may have implications for a better understanding of the pathophysiological role of depression associated with medical illness.

MEDICAL THERAPY FOR CUSHING'S DISEASE

Various drugs have been employed in the management of pituitary-dependent Cushings disease. The neuromodulatory compounds used thus far have demonstrated true clinical efficacy only occasionally when employed as sole treatment. Steroid synthesis inhibitors are effective in the majority of cases in a dose-dependent manner. By their ability to correct hypercortisolism and its severe complications quickly, they are suitable for critical cases and in preparation for surgery. The clinical experience with the only glucocorticoid receptor antagonist that can be administered to humans is still too limited to assess its therapeutic validity. No medical strategy can be standardized for this complex condition. Different therapeutic tools should be selected according to the form of disease to be treated (hypothalamic/pituitary) and the peculiar clinical situation of each patient. Combined treatments may achieve better therapeutic efficacy.

Persistent Psychological Distress in Patients Treated for Endocrine Disease

Background: The purpose of the study was to assess the frequency and characteristics of psychological distress, even after adequate treatment, in the heterogeneous population of an endocrine outpatient clinic. Methods: 146 endocrine patients (31 males/115 females; age 39.4 ± 12.5 years), who were cured or in remission, were studied in a university endocrine outpatient clinic. Semistructured clinical interviews to assess psychiatric (Structured Clinical Interview for DSM-IV) and psychological (Diagnostic Criteria for Psychosomatic Research, DCPR) diagnoses were employed and were supplemented by self-rated instruments (the Psychosocial Index and the Medical Outcome Study short form General Health Survey) which could provide the patients’ perception of their own quality of life. Results: There were 118 patients (81%) who presented with at least 1 psychiatric (DSM-IV) or psychological (DCPR) diagnosis. The most frequent diagnostic findings were generalized anxiety disorder (29%), major depression (26%), irritable mood (46%), demoralization (34%) and persistent somatization (21%). By self-rated instruments, patients with at least 1 DSM-IV or DCPR diagnosis reported significantly more stressful life circumstances, psychological distress and an impaired quality of life compared to those who had none. Conclusions: A high prevalence of psychological distress may be encountered in the long-term follow-up of endocrine patients. A biopsychosocial consideration of the person and his/her quality of life appears to be mandatory for improving therapeutic effectiveness in endocrine disorders.

Adrenocortical Carcinoma: Experience in 45 Patients

Forty-five patients with adrenocortical carcinoma (13 nonfunctioning and 32 functioning carcinomas) were retrospectively studied. Five-year survival rate was 29% overall; for patients at stage I-II (n = 15) it was 70%, and for patients at stage III-IV (n = 30) it was 12%. In patients given mitotane + chemotherapy survival rate was similar to that observed in patients given chemotherapy alone, and significantly longer than in patients given mitotane alone (p < 0.05). There were no differences in disease-free interval and survival between adjuvant mitotane and no treatment. Optimization of therapeutic protocols in addition to early recognition may improve prognostic aspects of this type of malignancy for which treatment outcome is still unsatisfactory.