Sex-Specific Limitations in Physical Health in Primary Adrenal Insufficiency.

Background: Patients with primary adrenal insufficiency (PAI) suffer reduced quality of life (QoL), but comparisons with large-scale normative data are scarce. The clinical characteristics associated with reduced QoL are largely unknown. Methods: Cross-sectional data on clinical characteristics and QoL scores from 494 patients were included. QoL was measured using RAND-36 (generic) and AddiQoL (-30 and -8, disease-specific). RAND-36 is reported as subdomain scores as well as physical (PCS) and metal (MCS) summary scores and compared with normative data. Results: Perception of physical role was consistently decreased across age groups in patients with PAI compared with normative data [75 (0-100) vs. 100 (50-100), p<0.001]. Men with PAI reported significantly lower scores for social functioning [88 (75-100) vs. 100 (75-100), p<0.001], as well as for vitality and physical role. In women, the greatest impairment was seen in physical role [50 (0-100) vs. 100 (50-100), p<0.001], followed by social functioning, vitality, physical function, general health, mental health, and emotional role. Overall, better QoL was associated with male sex (AddiQoL-30: 89 ± 13 vs. 82 ± 13, p<0.002), younger age (e.g. 20-29 vs. 80-89 years: PCS 59 [50-62] vs. 46 [37-53], p<0.001), autoimmune etiology [PCS: 53 (45-59) vs.. 45 (38-54), p<0.001], and absence of autoimmune comorbidity [PCS: 54 (45-59) vs. 50 (43-58), p<0.001]. There were no significant differences in QoL scores between different doses or dosing regimens of glucocorticoid or mineralocorticoid replacement. Conclusion: QoL is reduced in patients with PAI, especially perception of physical role in women and social functioning in men. Among patients with PAI, female sex, higher age, non-autoimmune etiology, and autoimmune comorbidity was associated with lower QoL-scores.

Sleep, Cognition and Cortisol in Addison's Disease: A Mechanistic Relationship.

Sleep is a critical biological process, essential for cognitive well-being. Neuroscientific literature suggests there are mechanistic relations between sleep disruption and memory deficits, and that varying concentrations of cortisol may play an important role in mediating those relations. Patients with Addison's disease (AD) experience consistent and predictable periods of sub- and supra-physiological cortisol concentrations due to lifelong glucocorticoid replacement therapy, and they frequently report disrupted sleep and impaired memory. These disruptions and impairments may be related to the failure of replacement regimens to restore a normal circadian rhythm of cortisol secretion. Available data provides support for existing theoretical frameworks which postulate that in AD and other neuroendocrine, neurological, or psychiatric disorders, disrupted sleep is an important biological mechanism that underlies, at least partially, the memory impairments that patients frequently report experiencing. Given the literature linking sleep disruption and cognitive impairment in AD, future initiatives should aim to improve patients' cognitive performance (and, indeed, their overall quality of life) by prioritizing and optimizing sleep. This review summarizes the literature on sleep and cognition in AD, and the role that cortisol concentrations play in the relationship between the two.

Longitudinal AddiQoL scores may identify higher risk for adrenal crises in Addison's disease.

PURPOSE: Several studies have shown a reduced quality of life (QoL) in patients with Addison's disease (AD), but investigations of QoL over a long-term course are lacking. Adrenal crises (AC) are life-threatening complications in AD. The purpose of this prospective study was to test whether the repeated use of QoL-questionnaires can detect prodromal periods of an AC. METHODS: 110 patients with AD were asked to complete the disease specific-QoL questionnaire AddiQoL and a short questionnaire about adverse events once monthly over a period of ten months. AC was defined if at least two of the following symptoms were reported: (a) hypotension, (b) nausea or vomiting, (c) severe fatigue, (d) documented hyponatremia, hyperkalemia, or hypoglycemia, and subsequent parenteral glucocorticoid administration was carried out. RESULTS: Prevalence of AC was 10.9/100 patient years. AddiQoL scores in patients with AC showed a trend (p = 0,08) to a wider fluctuation over time. Subjective precrises not meeting the criteria for AC were reported by 31 patients who had significantly lower AddiQoL scores (p = 0,018). CONCLUSIONS: These are the first data showing the course of QoL during a period of ten months in patients with AD. Incidence of AC exceeds previous data. Our data show, that subjective precrises in AD associate with lower QoL. AC, as well as precrises affect intraindividual AddiQol-scores over time with a trend to a stronger fluctuation. Longitudinal AddiQol scores and self-reporting of precrises via patient diaries are additional clinical tools to identify higher risk for critical events.

Exploration of knowledge and understanding in patients with primary adrenal insufficiency: a mixed methods study.

BACKGROUND: Primary adrenal insufficiency (PAI) is a rare and severe condition requiring lifelong steroid replacement. During acute illness or stressful events, it is important to appropriately adjust glucocorticoid dose; failure to do so may lead to an adrenal crisis. The aim of the study was to explore patients PAI knowledge and understanding of the condition, steroid replacement adjustment during acute illness or stress and provided education. METHODS: Ten adult patients with PAI were purposefully recruited from two hospitals in a tertiary NHS Trust in England, UK. Data was collected using a mixed method approach utilising semi-structured audio-recorded interviews and hospital case note review. Interviews were transcribed verbatim and analysed using Burnard's content analysis framework. Information from the hospital case note review was captured using a matrix table based on pre-defined criteria. RESULTS: Four key themes emerged: 'Addison's disease and hydrocortisone replacement'; 'stress and corticosteroids'; 'patient compliance/adherence' and 'transition'. Patients reported feelings of 'going through a transition from uncertainty to adaption' following diagnosis. All participants had a good level of knowledge and understanding of required medication however application in times of need was poor. Medication adherence and prevention of a crisis relied not only on patient knowledge and application but also the support of family and health professionals. Health care professional knowledge required improvement to aid diagnosis and management of PAI. CONCLUSION: Patients with PAI did not apply existing knowledge to adjust steroid dose during acute illness or stress. Although a sample of limited size, our study identified there is a need to further explore why patients with Addison's disease do not apply existing knowledge during times of increased need. Future research should consider appropriate behaviour change interventions to promote medication adherence to reduce risk of an adrenal crisis.

Adjuvant psychological therapy in long-term endocrine conditions.

Consideration of psychological distress in long-term endocrine conditions is of vital importance given the prevalence of anxiety and depression in such disorders. Poor mental health can lead to compromised self-care, higher utilization of health services, lower rates of adherence, reduced quality of life and ultimately poorer outcomes. Adjuvant psychological therapy offers an effective resource to reduce distress in endocrine conditions. While the vast majority of work in this area has focused on psychological screening and intervention in diabetes, identification and recognition of psychological distress are equally important in other endocrinological conditions, with supportive evidence in polycystic ovary syndrome and Addison's disease. Referral pathways and recommendations set out by UK guidelines and the Department of Health mandate requires greater attention across a wider range of long-term endocrine conditions to facilitate improved quality of life and health outcome.

A Complex Interplay: Cognitive Behavioural Therapy for Severe Health Anxiety in Addison's Disease to Reduce Emergency Department Admissions.

BACKGROUND: Addison's disease (AD) is a rare chronic illness caused by adrenocortical insufficiency. Due to the pivotal role of the regulating hormone cortisol in AD, there is a common symptom overlap between the presentation of anxiety and adrenal crisis. Previous literature has identified the prevalence of anxiety in endocrinological disorders, however there is a paucity of research examining the complex interplay between AD and anxiety. AIMS: This paper describes a single case study of a patient with severe health anxiety and co-morbid AD. The aims of the study were to establish if standard cognitive behavioural therapy for health anxiety in AD can lead to a reduction in psychological distress, and whether this approach is an effective intervention for the reduction of Emergency Department admissions. METHOD: A single case design was used, with pre- and post-measures of health anxiety, general anxiety and depression. Data on Emergency Department admissions prior to and following treatment were used to assess change in this domain. RESULTS: Reliable and clinically significant reductions were seen across all measures, from severe to sub-clinical levels. There was a complete amelioration of Emergency Department admissions in the 12 months following completion of treatment. CONCLUSIONS: This preliminary study provides a sound rationale for further research into AD complicated by anxiety. Findings support the clinical utility of the cognitive behavioural therapy model for complex presentations of AD, offering a potential treatment option where anxiety is elevated and interfering with self-management and leading to high levels of health service use.

Health-related quality of life of patients with hypothalamic-pituitary-adrenal axis dysregulations: a cohort study.

OBJECTIVE: Health-related quality of life (HrQoL) is increasingly considered to be an important outcome of care for hypothalamic-pituitary-adrenal (HPA) axis dysregulation. The objective of this study was to assess the influence of type of HPA axis dysregulation and cortisol status on HrQOL and its evolution with time and treatment. DESIGN: Prospective cohort study. METHODS: Between September 2007 and April 2014, HrQoL questionnaires were administered during routine management to all patients with HPA axis dysregulation hospitalized in a single department, and this was repeated after 6- 12-, 24- and 36-month during standard follow-up. The Medical Outcomes Study 36-item short-form health survey (SF-36) and the General Health Questionnaire 12 (GHQ-12) were used simultaneously, with a common time schedule to measure the impact of HPA axis dysregulation on HrQoL. Multivariate mixed linear regression models were constructed to adjust for potential confounders. RESULTS: 343 patients (206 with Cushing's syndrome of pituitary origin, 91 with Cushing's syndrome of adrenal origin and 46 with Addison's disease) responded to the questionnaires. Overall, HrQoL scores were well below population values. Cushing syndrome of pituitary origin was associated with worse HrQoL, especially in physical dimensions. More than half of the patients, of all diagnoses and cortisol status, had psychological distress requiring attention according to the GHQ-12. Hypercortisolism had the greatest negative influence on HrQoL. CONCLUSIONS: HRQoL appears significantly altered by all forms of HPA axis dysregulation, and most substantially and broadly by Cushing's syndrome, notably during periods of hypercortisolism. These effects on HRQoL deserve further consideration both in clinical practice and research.

Impaired quality and efficiency of sleep impairs cognitive functioning in Addison's disease.

BACKGROUND: Standard replacement therapy for Addison's disease (AD) does not restore a normal circadian rhythm. Periods of sub- and supra- physiological cortisol levels experienced by patients with AD likely induce disrupted sleep. Given that healthy sleep plays an important role in memory consolidation, the novelty of the current study was to characterise, using objective measures, the relationship between sleep and memory in patients with AD, and to examine the hypothesis that poor sleep is a biological mechanism underlying memory impairment in those patients. METHODS: We used a within-subjects design. Ten patients with AD and 10 matched healthy controls completed standardised neuropsychological tests assessing declarative memory (Rey Auditory Verbal Learning Test) and procedural memory (Finger Tapping Task) before and after a period of actigraphy-measured sleep, and before and after a period of waking. RESULTS: Relative to healthy controls, patients with AD experienced disrupted sleep characterised by poorer sleep efficiency and more time spent awake. Patients also showed impaired verbal learning and memory relative to healthy controls (p=0.007). Furthermore, whereas healthy controls' declarative memory performance benefited from a period of sleep compared to waking (p=0.032), patients with AD derived no such benefit from sleep (p=0.448). Regarding the procedural memory task, analyses detected no significant between-group differences (all p's<0.065), and neither group showed significant sleep-enhanced performance. CONCLUSIONS: We demonstrated, using actigraphy and standardized measures of memory performance, an association between sleep disturbances and cognitive deficits in patients with AD. These results suggest that, in patients with AD, the source of memory deficits is, at least to some extent, disrupted sleep patterns that interfere with optimal consolidation of previously-learned declarative information. Hence, treating the sleep disturbances that are frequently experienced by patients with AD may improve their cognitive functioning.

Mild cognitive deficits in patients with primary adrenal insufficiency.

BACKGROUND: The brain is a major target organ for cortisol considering its high density of glucocorticoid receptors. Several states of hypothalamus-pituitary-adrenal dysregulation point towards impairments in cognitive functioning. However, there is a very limited body of research on the effects of hypocortisolism on cognitive functioning. AIM: To evaluate cognitive functioning in patients with hypocortisolism (i.e., primary adrenal insufficiency (PAI)) and to examine the possible effect of postponing early-morning hydrocortisone intake on cognitive functioning. METHODS: Thirty-one patients with PAI on regular morning hydrocortisone intake and 31 healthy matched controls underwent nine neuropsychological tests, evaluating memory and executive functioning. In addition, the effect of normal timing and postponement of morning hydrocortisone intake on neuropsychological tests were assessed in an additional 29 patients with PAI. RESULTS: Compared to controls, patients with PAI performed worse on auditory and visual memory tasks (all P ≤ 0.024) and executive functioning tasks (all P ≤ 0.012). In contrast, patients performed better on a concentration and an attention task (both P<0.05). Postponement of hydrocortisone intake in the morning did not affect the outcomes of neuropsychological tests. CONCLUSION: Patients on long-term hydrocortisone replacement for PAI show mild cognitive deficits compared to controls. There was no effect of postponement of regular hydrocortisone intake on cognition.

Poor quality of life, depressed mood, and memory impairment may be mediated by sleep disruption in patients with Addison's disease.

Standard replacement therapy for Addison's disease (AD) does not restore a normal circadian rhythm. In fact, hydrocortisone replacement in AD patients likely induces disrupted sleep. Given that healthy sleep plays an important role in improving quality of life, optimizing cognition, and ensuring affect regulation, the aim of this study was to investigate whether poor quality of life, mood alterations, and memory complaints reported by AD patients are associated with their disrupted sleep patterns. Sixty patients with AD and 60 matched healthy controls completed a battery of self-report questionnaires assessing perceived physical and mental health (Short-Form 36), mood (Beck Depression Inventory-II), sleep quality (Pittsburgh Sleep Quality Index), and cognition (Cognitive Failures Questionnaire). A latent variable model revealed that although AD had a significant direct effect on quality of life, the indirect effect of sleep was significantly greater. Furthermore, although AD had no direct effect on cognitive functioning, the indirect effect of sleep was significant. The overall model showed a good fit (comparative fit index = 0.91, root mean square of approximation = 0.09, and standardized root mean square residual = 0.05). Our findings suggest that disrupted sleep, and not the disease per se, may induce poor quality of life, memory impairment, and affect dysregulation in patients with AD. We think that improving sleep architecture may improve cognitive, affective, and physical functioning.

Autoimmune polyglandular syndrome type 2: a rare condition in childhood.

Autoimmune polyglandular syndrome type 2 is defined as the occurrence of Addison's disease concomitantly with autoimmune thyroid disease and/or type 1 diabetes mellitus. An 11-year-old boy with Hashimoto's disease, Addison's disease, celiac disease and Langerhans islet cell autoimmunity is described in this case report. Treatment of an endocrine disease may also trigger the onset of another endocrine disease. This case report underlines the importance of early recognition and treatment of critical endocrine diseases as well as the necessity to investigate pediatric patients with autoimmune diseases for coexisting conditions. Furthermore, the role of psychological stress as an inducer of autoimmunity was also discussed.

Cognitive function in patients with primary adrenal insufficiency (Addison's disease).

BACKGROUND: Patients with primary adrenal insufficiency (AI) need to replace glucocorticoids and mineralocorticoids that act on glucocorticoid (GR) and mineralocorticoid receptors (MR). Both receptors are highly expressed in the hippocampus and are closely associated with cognitive function, which might be impaired by insufficient or increased GR and MR stimulation. However, little is known about cognitive function in patients with AI. METHODS: It was examined whether patients with AI exhibit worse cognitive function compared to sex-, age-, and education-matched controls. Cognitive function (executive function, concentration, verbal memory, visual memory, working memory, and autobiographical memory) was assessed in 30 patients with AI (mean age 52.4 yrs. ±14.4, n=21 women, mean duration of illness 18.2 yrs. ±11.1) and 30 matched controls. We also measured depressive symptoms, body mass index (BMI), and blood pressure. RESULTS: Patients with AI showed more depressive symptoms, had a greater BMI and lower systolic blood pressure compared to controls. Adjusted analyses controlling for these variables revealed that patients with AI performed significantly worse in verbal learning (F=7.8, p=.007). Executive function, concentration, working memory, verbal memory, visuospatial memory, and autobiographical memory did not differ between groups. CONCLUSIONS: No clinically relevant cognitive impairment was found in patients with AI compared to matched controls. Even long-term glucocorticoid and mineralocorticoid substitution over almost two decades appears to have only subtle effects on cognition in patients with AI.

Health-related quality of life in primary and secondary adrenal insufficiency.

Adrenal insufficiency (AI) is characterized by a deficient production of glucocorticoids with or without associated mineral corticoid and/or adrenal androgen deficiencies. Despite the low prevalence of AI, its impact on the affected patient is very high, and can be life-threatening disease if not adequately treated. Several glucocorticoid treatment regimens are available, but none is capable of perfectly imitating the cortisol circadian rhythm. Cortisol rhythmicity and treatment of other possible concomitant conditions often associated (e.g., autoimmune disorders and panhypopituitarism) are essential to improve outcome of AI. Morbidity often present in treated AI include an unhealthy metabolic profile, bad quality of sleep, infertility, sexual dysfunction and worse health-related quality of life. This review focuses on psychological morbidity and impaired quality of life in patients with primary or secondary AI of any origin, including a special section devoted to congenital adrenal hyperplasia.

Patients with adrenal insufficiency hate their medication: concerns and stronger beliefs about the necessity of hydrocortisone intake are associated with more negative illness perceptions.

CONTEXT: Patients with adrenal insufficiency (AI) require daily and life-long hydrocortisone substitution with risks of under- and overreplacement, the necessity to adjust the dose in stressful situations, and a lack of clinical and biochemical parameters to assess optimal dosing. The spectrum of medication beliefs in patients with AI is currently unknown. OBJECTIVE: The objective of the study was to examine the possible association between illness perceptions and medication beliefs about hydrocortisone (HC) in patients with AI. DESIGN AND SUBJECTS: This was a cross-sectional evaluation of illness perceptions and medication beliefs in 107 patients with primary AI (n = 49), secondary AI after the treatment of Cushing's syndrome (n = 29), or treatment of nonfunctioning pituitary adenoma (n = 29). The Illness Perception Questionnaire-Revised and the Beliefs about Medicines Questionnaire were used for the assessment. RESULTS: Stronger beliefs about the necessity of HC and stronger concerns about the adverse effects of HC were associated with attribution of more symptoms to AI, to the perception of AI being more cyclical, to the perception of more negative consequences of AI, and to the presence of stronger emotional representations (all P < .05). Furthermore, stronger beliefs about the necessity of HC intake were associated with feelings of less personal control over AI (P < .05). Stronger concerns about the adverse effects of HC were associated with lower perceived treatment control and lower illness coherence (both P < .05). In addition, patients with Cushing's syndrome reported stronger beliefs regarding the necessity of taking HC, compared with patients with Addison's disease (P = .039) or nonfunctioning pituitary adenoma (P < .001). CONCLUSION: Specific beliefs about the necessity of hydrocortisone replacement and concerns about its adverse effects were strongly associated with more negative illness perceptions. These specific beliefs differed, depending on the etiology of AI. These results need to be taken into account in the treatment of patients with AI and may serve to enable the development of psychosocial education/self-management programs aiming at improving quality of life.

Determinants of altered sleep-wake rhythmicity in patients treated for nonfunctioning pituitary macroadenomas.

CONTEXT AND OBJECTIVE: In a cohort of 17 patients treated for nonfunctioning pituitary macroadenoma (NFMA), we observed alterations in polysomnographic sleep characteristics and actigraphic sleep-wake rhythmicity, and subjective fatigue, daytime somnolence, and low sleep quality. We aimed to confirm the actigraphic data in a larger scale cohort of NFMA patients, powered to address risk factors for altered rhythmicity, including the effects of hydrocortisone replacement. METHODS: Sleep-wake rhythmicity in treated NFMA patients was measured using actigraphy for 7 days, and subjective sleep quality and quality of life (QoL) with validated questionnaires. To assess the influence of hydrocortisone dependency, we additionally studied patients with Addison's disease (AD). The results were compared with matched healthy controls. RESULTS: We included 69 NFMA patients in long-term remission after trans-sphenoidal surgery on stable replacement therapy for hypopituitarism, 21 AD patients, and 58 controls. NFMA patients reported severely impaired QoL, sleep quality, and increased daytime sleepiness. The day-night dichotomy of activity was fragmented, with decreased daytime activity and a tendency for increased nighttime activity. Preoperative visual field defects (VFD) were associated with this fragmentation, and vasopressin deficiency with decreased sleep efficiency, independent of age, hypopituitarism, or radiotherapy. AD patients showed similar decreases in daytime functioning, but normal subjective and objective sleep, and no daytime sleepiness. CONCLUSION: NFMA patients suffer from altered sleep-wake rhythmicity. Hydrocortisone dependency may explain part of the decreased daytime functioning, but the independent influence of VFD and differences between AD and NFMA patients point towards a role for dysfunction of the adjacent suprachiasmatic nucleus (SCN).

Psychological morbidity and impaired quality of life in patients with stable treatment for primary adrenal insufficiency: cross-sectional study and review of the literature.

CONTEXT: A high prevalence of psychological morbidity and maladaptive personality as well as impaired quality of life (QoL) is observed in patients with and without hydrocortisone dependency following (cured) Cushing's syndrome. However, it is currently unclear whether a similar pattern is present in patients with chronic glucocorticoid replacement for primary adrenal insufficiency (PAI). OBJECTIVE: To evaluate psychological functioning, personality traits, and QoL in patients with PAI. DESIGN AND SUBJECTS: A cross-sectional study including 54 patients with stable treatment for PAI and 54 healthy matched controls. Both patients and controls completed questionnaires on psychological functioning (Apathy Scale, Irritability Scale, Mood and Anxiety Symptoms Questionnaire short form, and Hospital Anxiety and Depression Scale), personality traits (Dimensional Assessment of Personality Pathology short form), and QoL (Multidimensional Fatigue Inventory, Short Form 36, EuroQoL-5D, Nottingham Health Profile, and Physical Symptom Checklist). RESULTS: Patients with PAI suffered from more psychological morbidity (i.e. irritability and somatic arousal) and QoL impairments compared with controls (all P<0.01). There were no differences regarding maladaptive personality traits between patients and controls. However, there was a strong and consistent positive association between the daily hydrocortisone dose and prevalence of maladaptive personality traits (i.e. identity problems, cognitive distortion, compulsivity, restricted expression, callousness, oppositionality, rejection, conduct problems, social avoidance, narcissism, and insecure attachment, all P<0.05). There was also a strong relation between the mean daily hydrocortisone dose and both psychological morbidity (i.e. depression, P<0.05) and QoL impairments (i.e. general health perception, several measures of physical functioning, and vitality, all P<0.05). CONCLUSION: Patients on stable glucocorticoid replacement therapy for PAI report psychological morbidity and impaired QoL. Psychological morbidity, impaired QoL, and maladaptive personality traits were all associated with higher dosages of hydrocortisone.

Episodic memory impairment in Addison's disease: results from a telephonic cognitive assessment.

Patients with Addison's disease frequently self-report memory and attention difficulties, even when on standard replacement therapy. However, few published studies examine, using objective measures and assessing across multiple domains, the cognitive functioning of Addison's disease patients relative to healthy controls. The primary aim of this study was to investigate whether the previously reported subjective cognitive deficits in Addison's disease are confirmed by objective measures. Conducting comprehensive neuropsychological assessments of patients with relatively rare clinical disorders, such as Addison's disease, is challenging because access to those patients is often limited, and because their medical condition might prevent extended testing sessions. Brief telephonic cognitive assessments are a useful tool in such circumstances. Hence, we administered the Brief Test of Adult Cognition by Telephone to 27 Addison's disease patients and 27 matched healthy controls. The instrument provides objective assessment of episodic memory, working memory, executive functioning, reasoning, and speed of processing. Statistical analyses confirmed that, as expected, patients performed significantly more poorly than controls on the episodic memory subtest. There were, however, no significant between-group differences on the attention, executive functioning, reasoning, and speed of processing subtests. Furthermore, patients with a longer duration of illness performed more poorly across all domains of cognition. We conclude that, for Addison's disease patients, previously reported subjective cognitive deficits are matched by objective impairment, but only in the domain of episodic memory. Future research might investigate (a) whether these memory deficits are material-specific (i.e., whether non-verbal memory is also affected), and (b) the neurobiological mechanisms underlying these deficits.

History of stress-related health changes: a cue to pursue a diagnosis of latent primary adrenal insufficiency.

OBJECTIVE: Routine delays in the diagnosis of primary adrenal insufficiency (PAI) are well known and conceivably attributable to the absence of cues, other than anti-adrenal autoantibodies, to pursue subclinical PAI. Subclinical PAI is latent unless the afflicted patient encounters stress such as an acute illness, surgery, psychosocial burden, etc. It remains to be demonstrated whether a history of stress-related health changes is a useful cue to pursue a diagnosis of latent PAI. METHODS: The patients were selected for a history of recurrent symptoms, i.e., gastrointestinal symptoms, fatigue, or lassitude, aggravated by stress and alleviated by the removal of stress, and signs, i.e., weight loss, hypotension, and hyperpigmentation. As the early morning cortisol levels were low or low-normal and the adrenocorticotropic hormone (ACTH) levels were within the reference ranges, provocation tests, i.e., insulin-induced hypoglycemia tests and low-dose (1 µg) corticotropin tests (LDTs), were used to estimate the hypothalamus-pituitary-adrenal (HPA) axis status. Patients with the HPA axis dysfunction on two provocation tests were supplemented with physiologic doses of glucocorticoids (GCs). The effects of GC supplementation on stress-related health changes were observed. RESULTS: The ACTH levels after insulin-induced hypoglycemia were higher and the cortisol levels were lower in the patients than in the control subjects. The cortisol levels in the patients were increased less significantly by LDT than those observed in the control subjects. Stress-related health changes ceased to recur and signs, i.e., a low body weight, hypotension, and hyperpigmentation, were ameliorated following GC supplementation. CONCLUSION: A history of stress-related health changes is useful as a cue to pursue latent PAI in patients with low or low-normal early morning cortisol levels.

Differential diagnosis and the suspension of judgment.

In this paper I argue that ethics and evidence are intricately intertwined within the clinical practice of differential diagnosis. Too often, when a disease is difficult to diagnose, a physician will dismiss it as being "not real" or "all in the patient's head." This is both an ethical and an evidential problem. In the paper my aim is two-fold. First, via the examination of two case studies (late-stage Lyme disease and Addison's disease), I try to elucidate why this kind of dismissal takes place. Then, I propose a potential solution to the problem. I argue that instead of dismissing a patient's illness as "not real," physicians ought to exercise a compassionate suspension of judgment when a diagnosis cannot be immediately made. I argue that suspending judgment has methodological, epistemic, and ethical virtues and therefore should always be preferred to patient dismissal in the clinical setting.