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Carole Guerin, David Taieb, Giorgio Treglia, Thierry Brue, André Lacroix, Frederic Sebag, and Frederic Castinetti

Therapeutic options available for the treatment of Cushing's syndrome (CS) have expanded over the last 5 years. For instance, the efficient management of severe hypercortisolism using a combination of fast-acting steroidogenesis inhibitors has been reported. Recent publications on the long-term efficacy of drugs or radiation techniques have also demonstrated low toxicity. These data should encourage endocrinologists to reconsider the place of bilateral adrenalectomy in patients with ACTH-dependent aetiologies of CS; similarly, the indication of bilateral adrenalectomy is reassessed in primary bilateral macronodular adrenal hyperplasia. The objective of this review is to compare the efficacy and side effects of the various therapeutic options of hypercortisolism with those of bilateral adrenalectomy, in order to better define its indications in the 21st century.

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Dimitra A Vassiliadi and Stylianos Tsagarakis

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a highly heterogeneous entity. The incidental identification of an increasing number of cases has shifted its clinical expression from the rarely encountered severe forms, regarding both cortisol excess and adrenal enlargement, to mild forms of asymptomatic or oligosymptomatic cases with less impressive imaging phenotypes. Activation of cAMP/PKA pathway, either due to alterations of the different downstream signaling pathways or through aberrantly expressed G-protein-coupled receptors, relates to both cortisol secretion and adrenal growth. Germline ARMC5 mutations are a frequent genetic defect. The diagnostic approach consists of both imaging and hormonal characterization. Imaging characterization should be done separately for each lesion. Endocrine evaluation in cases with clinically overt Cushing’s syndrome (CS) is similar to that applied for all forms of CS. In incidentally detected PBMAH, hormonal evaluation includes testing for primary aldosteronism, pheochromocytoma and evaluation for autonomous cortisol secretion, using the 1 mg overnight dexamethasone suppression test. Midnight cortisol or 24-h urinary free cortisol may aid in establishing the degree of cortisol excess. In patients with hypercortisolism, ACTH levels should be measured in order to establish ACTH independency. At variance with other forms of CS, PBMAH may be characterized by a distinct pattern of inefficient steroidogenesis. The appropriate management of PBMAH remains controversial. Bilateral adrenalectomy results in lifetime steroid dependency and is better reserved only for patients with severe CS. Unilateral adrenalectomy might be considered in selected patients. In cases where the regulation of cortisol secretion is mediated by aberrant receptors there is some potential for medical therapy.

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Takako Araki, Ning-Ai Liu, Yukiko Tone, Daniel Cuevas-Ramos, Roy Heltsley, Masahide Tone, and Shlomo Melmed

Cushing’s syndrome is caused by excessive adrenocorticotropic hormone (ACTH) secretion derived from pituitary corticotroph tumors (Cushing disease) or from non-pituitary tumors (ectopic Cushing’s syndrome). Hypercortisolemic features of ectopic Cushing’s syndrome are severe, and no definitive treatment for paraneoplastic ACTH excess is available. We aimed to identify subcellular therapeutic targets by elucidating transcriptional regulation of the human ACTH precursor POMC (proopiomelanocortin) and ACTH production in non-pituitary tumor cells and in cell lines derived from patients with ectopic Cushing’s syndrome. We show that ectopic hPOMC transcription proceeds independently of pituitary-specific Tpit/Pitx1 and demonstrate a novel E2F1-mediated transcriptional mechanism regulating hPOMC. We identify an E2F1 cluster binding to the proximal hPOMC promoter region (−42 to +68), with DNA-binding activity determined by the phosphorylation at Ser-337. hPOMC mRNA expression in cancer cells was upregulated (up to 40-fold) by the co-expression of E2F1 and its heterodimer partner DP1. Direct and indirect inhibitors of E2F1 activity suppressed hPOMC gene expression and ACTH by modifying E2F1 DNA-binding activity in ectopic Cushing’s cell lines and primary tumor cells, and also suppressed paraneoplastic ACTH and cortisol levels in xenografted mice. E2F1-mediated hPOMC transcription is a potential target for suppressing ACTH production in ectopic Cushing’s syndrome.

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E Louiset, K Isvi, J M Gasc, C Duparc, B Cauliez, A Laquerrière, J M Kuhn, and H Lefebvre

Abnormal expression of membrane receptors has been previously described in benign adrenocortical neoplasms causing Cushing's syndrome. In particular, we have observed that, in some adreno corticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia tissues, cortisol secretion is controlled by ectopic serotonin7 (5-HT7) receptors. The objective of the present study was to investigate in vitro the effect of serotonin (5-hydroxy tryptamine; 5-HT) on cortisol and renin production by a left adrenocortical carcinoma removed from a 48-year-old female patient with severe Cushing's syndrome and elevated plasma renin levels. Tumor explants were obtained at surgery and processed for immunohistochemistry, in situ hybridization and cell culture studies. 5-HT-like immunoreactivity was observed in mast cells and steroidogenic cells disseminated in the tissue. 5-HT stimulated cortisol release by cultured cells. The stimulatory effect of 5-HT on cortisol secretion was suppressed by the 5-HT7 receptor antagonist SB269970. In addition, immunohistochemistry showed the occurrence of 5-HT7 receptor-like immunoreactivity in carcinoma cells. mRNAs encoding renin as well as renin-like immunoreactivity were detected in endothelial and tumor cells. Cell incubation studies revealed that the adrenocortical tissue also released renin. Renin production was inhibited by 5-HT but was not influenced by ACTH and angiotensin II (Ang II). In conclusion, the present report provides the first demonstration of ectopic serotonin receptors, i.e. 5-HT7 receptors, in an adrenocortical carcinoma. Our results also indicate that 5-HT can influence the secretory activity of malignant adrenocortical tumors in an autocrine/paracrine manner. The effects of 5-HT on adrenocortical tumor cells included a paradoxical inhibitory action on renin production and a stimulatory action on cortisol secretion involving 5-HT7 receptors.

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Christina Wei and Elizabeth C Crowne

Endocrine abnormalities are common among childhood cancer survivors. Abnormalities of the hypothalamic–pituitary–adrenal axis (HPAA) are relatively less common, but the consequences are severe if missed. Patients with tumours located and/or had surgery performed near the hypothalamic–pituitary region and those treated with an accumulative cranial radiotherapy dose of over 30 Gy are most at risk of adrenocorticotrophic hormone (ACTH) deficiency. Primary adrenal insufficiency may occur in patients with tumours located in or involving one or both adrenals. The effects of adjunct therapies also need to be considered, particularly, new immunotherapies. High-dose and/or prolonged courses of glucocorticoid treatment can result in secondary adrenal insufficiency, which may take months to resolve and hence reassessment is important to ensure patients are not left on long-term replacement steroids inappropriately. The prevalence and cumulative incidences of HPAA dysfunction are difficult to quantify because of its non-specific presentation and lack of consensus regarding its investigations. The insulin tolerance test remains the gold standard for the diagnosis of central cortisol deficiency, but due to its risks, alternative methods with reduced diagnostic sensitivities are often used and must be interpreted with caution. ACTH deficiency may develop many years after the completion of oncological treatment alongside other pituitary hormone deficiencies. It is essential that health professionals involved in the long-term follow-up of childhood cancer survivors are aware of individuals at risk of developing HPAA dysfunction and implement appropriate monitoring and treatment.

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Y de Keyzer, D Vieau, A Picon, and X Bertagna

Cushing's syndrome refers to the manifestations induced by chronic exposure to glucocorticoid excess and may result from various causes that are all associated with tumors. The most frequent one, that which was first recognized by Harvey Cushing (Cushing 1932) – and therefore called Cushing's disease – is due to adrenocorticotropin (ACTH) hypersecretion by a pituitary corticotrope adenoma; the ectopic ACTH syndrome is another, much rarer (∼5-10%) one, caused by a variety of so-called ACTH-secreting non-pituitary tumors; finally, approximately 30% of Cushing's syndromes are ACTH-non-dependent, caused by primary adrenocortical tumors, most often unilateral and either benign or malignant. The first case of ectopic ACTH syndrome was probably reported by Brown (1928) who described the case of a bearded woman with diabetes. At that time the author had no idea that ACTH existed. The discovery of ACTH, the development of an ACTH bioassay, and the pioneering work of Liddle's group eventually led
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R van der Pas, W W de Herder, L J Hofland, and R A Feelders

Cushing's syndrome (CS) is a severe endocrine disorder characterized by chronic cortisol excess due to an ACTH-secreting pituitary adenoma, ectopic ACTH production, or a cortisol-producing adrenal neoplasia. Regardless of the underlying cause, untreated CS is associated with considerable morbidity and mortality. Surgery is the primary therapy for all causes of CS, but surgical failure and ineligibility of the patient to undergo surgery necessitate alternative treatment modalities. The role of medical therapy in CS has been limited because of lack of efficacy or intolerability. In recent years, however, new targets for medical therapy have been identified, both at the level of the pituitary gland (e.g. somatostatin, dopamine, and epidermal growth factor receptors) and the adrenal gland (ectopically expressed receptors in ACTH-independent macronodular adrenal hyperplasia). In this review, results of preclinical and clinical studies with drugs that exert their action through these molecular targets, as well as already established medical treatment options, will be discussed.

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Rossella Libè, Amato Fratticci, and Jérôme Bertherat

Adrenocortical cancer (ACC) is a rare tumor with a poor prognosis. By contrast, benign adrenocortical tumors are frequent, underlying the importance of a correct diagnosis of malignancy of such tumors. ACC can be diagnosed by the investigation of endocrine signs of steroid excess, symptoms due to tumor growth or an adrenal incidentaloma. Hormonal investigations demonstrate in most ACC steroid oversecretion, the dominant characteristics being a co-secretion of cortisol and androgens. Imaging by CT-scan or MRI shows a large heterogeneous tumor with a low fat content. Careful pathological investigation with the assessment of the Weiss score is important for the diagnosis of malignancy. Molecular markers can also be helpful and in the future might be important for prognosis. Tumors localized to the adrenal gland (McFarlane stages 1 and 2) have a better outcome than invasive and metastatic tumors (stages 3 and 4). Tumor removal by a specialized team is crucial for treatment and should always aim at complete removal. In patients with metastatic or progressive disease, medical treatment is started with mitotane that requires a close monitoring of its blood level. Surgery is indicated when possible for local recurrence but also in some cases of metastasis. Local treatment (radiofrequency, chemoembolization, and radiation therapy) can have some indications for metastatic disease. In patients with disease progression cytotoxic chemotherapy can be used. Despite the best care, the overall prognosis of ACC is poor with a 5-year survival rate below 30% in most series. Therefore, progress in the understanding of the pathophysiology of ACC is important. Despite the rarity of ACC, significant advances have been made in the understanding of its pathogenesis the last decade. These progresses came mainly from the study of the genetics of ACC, both at the germline level in rare familial diseases, and at the somatic level by the study of molecular alterations in sporadic tumors. These advances underline the importance of genetic alterations in ACC development and point-out to various chromosomal regions (2, 11p15, 11q, 17p13) and genes (IGF-II, p53, β-catenin, ACTH receptor). This review will summarize these advances as well as the current clinical management of ACC.

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Aristides Lytras and George Tolis

In the context of multiple neuroendocrine tumor syndromes, reproductive abnormalities may occur via a number of different mechanisms, such as hyperprolactinemia, increased GH/IGF-1 levels, hypogonadotropic hypogonadism, hypercortisolism, hyperandrogenism, hyperthyroidism, gonadotropin hypersecretion, as well as, tumorigenesis or functional disturbances in gonads or other reproductive organs. Precocious puberty and/or male feminization is a feature of McCune–Albright syndrome (MAS), neurofibromatosis type 1 (NF1), Carney complex (CNC), and Peutz–Jeghers syndrome (PJS), while sperm maturation and ovulation defects have been described in MAS and CNC. Although tumorigenesis of reproductive organs due to a multiple neuroendocrine tumor syndrome is very rare, certain lesions are characteristic and very unusual in the general population. Awareness leading to their recognition is important especially when other endocrine abnormalities coexist, as occasionally they may even be the first manifestation of a syndrome. Lesions such as certain types of ovarian cysts (MAS, CNC), pseudogynecomastia due to neurofibromas of the nipple–areola area (NF1), breast disease (CNC and Cowden disease (CD)), cysts and ‘hypernephroid’ tumors of the epididymis or bilateral papillary cystadenomas (mesosalpinx cysts) and endometrioid cystadenomas of the broad ligament (von Hippel–Lindau disease), testicular Sertoli calcifying tumors (CNC, PJS) monolateral or bilateral macroochidism and microlithiasis (MAS) may offer diagnostic clues. In addition, multiple neuroendocrine tumor syndromes may be complicated by reproductive malignancies including ovarian cancer in CNC, breast and endometrial cancer in CD, breast malignancies in NF1, and malignant sex-cord stromal tumors in PJS.

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M J Reed, R W Cheng, P A Beranek, and V H T James

There is evidence that the free, biologically active fraction of sex steroids in the plasma, is increased in subjects with endocrine-dependent tumours. However, little is known about factors which influence the distribution of these hormones in plasma. In order to investigate this, cortisol (14 μM) was infused, or ACTH (Synacthen, 250 μg, i.v.) was injected into male subjects and this resulted in a significant decrease (up to 38% from basal values) in the fraction of testosterone not bound to sex-hormone binding globulin (non-SHBG bound testosterone). The decrease in the non-SHBG bound testosterone fraction was accompanied by an increase (up to 20% from basal values) in the non-SHBG bound oestradiol fraction after ACTH injection. No significant changes in the unbound concentrations of testosterone or oestradiol were detected. The addition of cortisol (250 nM) to a plasma pool obtained from male subjects resulted in a similar decrease in the non-SHBG bound testosterone