Cushing's syndrome is considered a rare disease and its diagnosis can be challenging. Establishment of evidence-based recommendations is difficult. In 2008, several national and international consensus recommendations for the diagnosis or management of Cushing's syndrome were reported. The Endocrine Society, with the participation of the European Society of Endocrinology, has developed a task force to update recommendations for the diagnosis of Cushing's syndrome. The main aspects of these recommendations are presented in this article and discussed in the context of current research efforts in Europe focusing on the improvement of diagnosis and management of rare diseases including adrenal disorders such as Cushing's syndrome.
Laurence Guignat and Jérôme Bertherat
Charlotte De Bucy, Laurence Guignat, Tanya Niati, Jérôme Bertherat, and Joel Coste
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.
Prospective cohort study.
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.
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.
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.
Roula Bou Khalil, Camille Baudry, Laurence Guignat, Carmen Carrasco, Jean Guibourdenche, Stéphane Gaillard, Xavier Bertagna, and Jérôme Bertherat
To describe the sequence of hormonal changes during recurrence of Cushing's disease (CD) after successful transsphenoidal surgery (TSS).
Retrospective study in a single center.
Patients and methods
We studied 101 of the 127 patients treated by TSS for CD between 1996 and 2009, who had hypocortisolism or eucortisolism for at least 3 months post-TSS. We arbitrarily defined ‘overt recurrence’, as presence of two classical parameters of excess cortisol (increased midnight – either serum or salivary – and 24 h urinary cortisol (UC)), leading to further specific therapeutic action, and ‘mild recurrence’, as presence of a single classical parameter, leading to simple surveillance.
Of the 101 patients, 21 (20.8%) presented with recurrence, ‘mild’ or ‘overt’, during long-term follow-up (median 50.4 months, range 7–99). Recurrence occurred less frequently (16.8 vs 50%, P=0.02), and later (mean 44.7 months, median 43, range 7–94 vs mean 21.5 months, median 17, range 3–61, P=0.05), in patients with early post-TSS hypocortisolism compared with those with eucortisolism. Increase in midnight cortisol occurred in a mean time of 38.2 months, while UC elevation was observed at 50.6 months. Vasopressin analogs and CRH tests were eventually positive in 85 and 93% of all patients respectively; a positive response to one of the two dynamic tests preceded the increase in midnight cortisol or UC in 71 and 64% of the patients respectively.
A positive response to vasopressin analogs and/or CRH tests occurs early in recurrence, followed by an increase in midnight cortisol, while UC elevation is at a later stage.
Camille Baudry, Joël Coste, Roula Bou Khalil, Stéphane Silvera, Laurence Guignat, Jean Guibourdenche, Halim Abbas, Paul Legmann, Xavier Bertagna, and Jérôme Bertherat
Alternatives to transsphenoidal pituitary surgery may be required in Cushing's disease (CD) as a first- or second-line treatment. Mitotane is a potent anti-cortisolic drug but has been rarely investigated in the treatment of CD.
Evaluation of the efficacy and tolerance of mitotane in CD patients.
Design and setting
Retrospective analysis of 76 patients treated with mitotane from 219 patients diagnosed with CD between 1993 and 2009 in a single center.
Main outcome measure
Remission was defined as normalization of 24-h urinary free cortisol (24-h-UFC).
Remission was achieved in 48 (72%) of the 67 long-term treated patients, after a median time of 6.7 (5.2–8.2) months. Mean plasma mitotane concentration at the time of remission was 10.5±8.9 mg/l, with a mean daily dose of 2.6±1.1 g. A negative linear relationship was observed between plasma mitotane concentration and 24-h-UFC (P<0.0001). Seventeen of 24 (71%) patients with durable remission subsequently experienced recurrence, after a median time of 13.2 (5.0–67.9) months. At the time of treatment discontinuation, ACTH concentration was statistically associated with a lower recurrence probability (hazard ratios 0.57 (0.32–1.00), P=0.05). Intolerance leading to treatment discontinuation occurred in 19 patients (29%). A pituitary adenoma became identifiable during mitotane treatment in 12 (25%) of the 48 patients with initial negative pituitary imaging allowing subsequent transsphenoidal surgery.
Mitotane is useful at different stages of CD. Mitotane dose adjustment based on plasma concentration monitoring and side effects could control hypercortisolism in the majority of CD patients.
Rossella Libé, Joël Coste, Laurence Guignat, Frédérique Tissier, Hervé Lefebvre, Gaëlle Barrande, Christiane Ajzenberg, Igor Tauveron, Eric Clauser, Bertrand Dousset, Xavier Bertagna, Jérôme Bertherat, and Lionel Groussin
ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare and heterogeneous condition characterized by abnormal steroid production. Cortisol secretion can be regulated by aberrant hormone receptors.
A large series of patients with AIMAH were evaluated to provide information on the prevalence and profile of aberrant regulations, in relation with the functional status.
Design and patients
Thirty-two consecutive patients with AIMAH were prospectively studied: 10 had a Cushing's syndrome (CS), and 22 had a subclinical CS (SCS).
A baseline endocrine evaluation was followed by an in vivo protocol in search of aberrant cortisol responses (seven provocative tests). An acute inhibition test with the somatostatin analog octreotide was also performed.
At least one aberrant cortisol response was identified in 28 of 32 (87%) patients. The overall prevalence of aberrant responses was independent of the functional status. Responses to the upright posture and to metoclopramide were frequently observed (67 and 56% respectively). A glucagon response was frequently observed in the SCS group (58%). A cortisol inhibition by octreotide was specifically found in the three CS patients who positively responded to the mixed meal, and was observed also in 12 of 13 (92%) patients with SCS.
Cortisol responses indicative of aberrant receptor expression were highly prevalent in AIMAH. Thorough phenotyping of AIMAH may help uncover the underlying pathophysiology.
Florence Roucher-Boulez, Aude Brac de la Perriere, Aude Jacquez, Delphine Chau, Laurence Guignat, Christophe Vial, Yves Morel, Marc Nicolino, Gerald Raverot, and Michel Pugeat
Triple-A or Allgrove syndrome is an autosomal recessive disorder due to mutations in the AAAS gene, which encodes a nucleoporin named ALADIN. It is characterized by a classical clinical triad: alacrima, achalasia and adrenal insufficiency, the canonic symptoms that are associated with progressive peripheral neuropathy. Only a few cohorts have been reported. The objective of the present study was to characterize the various spectra of adrenal function in Triple-A patients.
A retrospective clinical and biological monitoring of 14 patients (10 families) was done in a single multidisciplinary French center. All had AAAS gene sequenced and adrenal function evaluation.
Nine different AAAS mutations were found, including one new mutation: c.755G>C, p.(Trp252Ser). Regarding adrenal function, defects of the zona fasciculata and reticularis were demonstrated by increased basal ACTH levels and low DHEAS levels in all cases regardless of the degree of glucocorticoid deficiency. In contrast, mineralocorticoid function was always conserved: i.e., normal plasma renin level associated with normal aldosterone level. The main prognostic feature was exacerbation of neuropathy and cognitive disorders.
These data suggest that, in Triple-A patients, adrenal function can be deficient, insufficient or compensated. In our cohort after the first decade of life, there does not appear to be any degradation of adrenal function over time. However, patients with compensated adrenal function should be informed and educated to manage a glucocorticoid replacement therapy in case of stressful conditions, with no need for systematic long-term treatment.
Sylvie Salenave, Valérie Bernard, Christine Do Cao, Laurence Guignat, Anne Bachelot, Sophie Leboulleux, Céline Droumaguet, Hélène Bry-Gauillard, Peggy Pierre, Lise Crinière, Pietro Santulli, Philippe Touraine, Philippe Chanson, Martin Schlumberger, Dominique Maiter, Eric Baudin, and Jacques Young
Mitotane is an adrenolytic and anticortisolic drug used in adrenocortical carcinoma (ACC), Cushing's disease (CD), and ectopic ACTH syndrome. Its effects on the ovaries are unknown.
To evaluate the ovarian and gonadotrope effects of mitotane therapy in premenopausal women.
We studied 21 premenopausal women (ACC: n=13; CD: n=8; median age 33 years, range 18–45 years) receiving mitotane at a median initial dose of 3 g/day (range 1.5–6 g/day).
Gynecological history was collected and ovarian ultrasound was performed. Four women also underwent ovarian CT or magnetic resonance imaging. Serum gonadotropin, estradiol (E2), androgens, sex hormone-binding globulin (SHBG), and circulating mitotane levels were determined at diagnosis and during mitotane therapy.
In the women included, ovarian macrocysts (bilateral in 51%) were detected after a median 11 months (range: 3–36) of mitotane exposure. The median number of macrocysts per woman was two (range: 1–4) and the median diameter of the largest cysts was 50 mm (range: 26–90). Menstrual irregularities and/or pelvic pain were present in 15 out of 21 women at macrocyst diagnosis. In two women, the macrocysts were revealed by complications (ovarian torsion and hemorrhagic macrocyst rupture) that required surgery. Mitotane therapy was associated with a significant decrease in androstenedione and testosterone levels and a significant increase in LH levels. Serum FSH and E2 levels were also increased, and SHBG levels rose markedly.
Mitotane therapy causes significant morphological and ovarian/gonadotrope hormonal abnormalities in premenopausal women. Follicular thecal steroid synthesis appears to be specifically altered and the subsequent increase in gonadotropins might explain the development of macrocysts. The mechanisms underlying these adverse effects, whose exact prevalence in this population still needs to be determined, are discussed.
Claire Chambre, Emily McMurray, Camille Baudry, Marine Lataud, Laurence Guignat, Sébastien Gaujoux, Najiba Lahlou, Jean Guibourdenche, Frédérique Tissier, Mathilde Sibony, Bertrand Dousset, Xavier Bertagna, Jérôme Bertherat, Paul Legmann, and Lionel Groussin
Computed tomography (CT) unenhanced attenuation value of <10 Hounsfield units (HU) has an excellent specificity (98%) to diagnose lipid-rich adrenocortical adenomas (ACAs) with a weaker sensitivity (71%).
To determine from a routine clinical perspective if unenhanced attenuation value is influenced by cortisol secretion in ACAs.
This was a retrospective study of cases collected between 2009 and 2012.
This study was conducted in a tertiary-care university hospital.
Seventy-two patients operated on for an ACA (Weiss score ≤2) were analysed. Thirty-four patients had an ACA oversecreting cortisol (Cush-ACA). Thirty-eight patients had an ACA without cortisol oversecretion (Non Hyper-ACA).
Main outcome measure
CT unenhanced attenuation value was correlated with the functional status. The Weiss score items were analysed.
Among the 34 patients with a Cush-ACA a minority (n=7) had an unenhanced attenuation value under 10 HU. Among the high precontrast density (>10 HU) Cush-ACAs, washout analysis after contrast administration was consistent with the benign nature of the tumor in ∼60% of the cases. Less than 25% clear cells (lipid-rich cells), a Weiss score item, was present in 50% of the Cush-ACAs in favour of a lipid-poor content.
Unenhanced attenuation value has a poor sensitivity to diagnose an ACA in case of cortisol oversecretion due to poor lipid content. Nevertheless, the accuracy of washout analysis was preserved in the group of Cush-ACAs.