Alessia Cozzolino

The Treatment of Cushing's Disease

Cushings disease (CD), or pituitary-dependent Cushings syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushings syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.

Pathophysiology of Diabetes Mellitus in Cushing's Syndrome

Cushing’s syndrome is commonly complicated with an impairment of glucose metabolism, which is often clinically manifested as diabetes mellitus. The development of diabetes mellitus in Cushing’s syndrome is both a direct and indirect consequence of glucocorticoid excess. Indeed, glucocorticoid excess induces a stimulation of gluconeogenesis in the liver as well as an inhibition of insulin sensitivity both in the liver and in the skeletal muscles, which represent the most important sites responsible for glucose metabolism. In particular, glucocorticoid excess stimulates the expression of several key enzymes involved in the process of gluconeogenesis, with a consequent increase of glucose production, and induces an impairment of insulin sensitivity either directly by interfering with the insulin receptor signaling pathway or indirectly, through the stimulation of lipolysis and proteolysis and the consequent increase of fatty acids and amino acids, which contribute to the development of insulin resistance. Moreover, the peculiar distribution of adipose tissue throughout the body, with the predominance of visceral adipose tissue, significantly contributes to the worsening of insulin resistance and the development of a metabolic syndrome, which participates in the occurrence and maintenance of the impairment of glucose tolerance. Finally, glucocorticoid excess is able to impair insulin secretion as well as act at the level of the pancreatic beta cells, where it inhibits different steps of the insulin secretion process. This phenomenon is probably responsible for the passage from an impairment of glucose tolerance to an overt diabetes mellitus in susceptible patients with Cushing’s syndrome.

Cardiovascular Disease in Cushing’s Syndrome: Heart versus Vasculature

Cushing’s syndrome (CS) causes metabolic abnormalities that determine an increased cardiovascular risk not only during the active phase of the disease but also for a long time after cure. Cardiovascular complications, such as premature atherosclerosis, coronary artery disease, heart failure, and stroke, in patients with CS cause a mortality rate higher than that observed in a normal population. The increased cardiovascular risk is mainly due to metabolic complications, such as metabolic syndrome, but also to vascular and cardiac alterations such as atherosclerosis and cardiac structural and functional changes. In the clinical management of patients with CS the focus should be on identifying the global cardiovascular risk and the aim should be to control not only hypertension but also other correlated risk factors, such as obesity, glucose intolerance, insulin resistance, dyslipidemia, endothelial dysfunction and the prothrombotic state. Considering that remission from hypercortisolism is often difficult to achieve and that the cardiovascular risk can persist even during disease remission, care and control of all cardiovascular risk factors should be one of the primary goals during the follow-up of these patients.

The hypertension of Cushing's syndrome: controversies in the pathophysiology and focus on cardiovascular complications

Cushings syndrome is associated with increased mortality, mainly due to cardiovascular complications, which are sustained by the common development of systemic arterial hypertension and metabolic syndrome, which partially persist after the disease remission. Cardiovascular diseases and hypertension associated with endogenous hypercortisolism reveal underexplored peculiarities. The use of exogenous corticosteroids also impacts on hypertension and cardiovascular system, especially after prolonged treatment. The mechanisms involved in the development of hypertension differ, whether glucocorticoid excess is acute or chronic, and the source endogenous or exogenous, introducing inconsistencies among published studies. The pleiotropic effects of glucocorticoids and the overlap of the several regulatory mechanisms controlling blood pressure suggest that a rigorous comparison of in-vivo and in-vitro studies is necessary to draw reliable conclusions. This review, developed during the first ‘Altogether to Beat Cushings syndrome’ workshop held in Capri in 2012, evaluates the most important peculiarities of hypertension associated with CS, with a particular focus on its pathophysiology. A critical appraisal of most significant animal and human studies is compared with a systematic review of the few available clinical trials. A special attention is dedicated to the description of the clinical features and cardiovascular damage secondary to glucocorticoid excess. On the basis of the consensus reached during the workshop, a pathophysiology-oriented therapeutic algorithm has been developed and it could serve as a first attempt to rationalize the treatment of hypertension in Cushings syndrome.

Is diabetes in Cushing's syndrome only a consequence of hypercortisolism?

OBJECTIVE Diabetes mellitus (DM) is one of the most frequent complications of Cushings syndrome (CS). The aim of this study was to define the changes in insulin sensitivity and/or secretion in relation to glucose tolerance categories in newly diagnosed CS patients. DESIGN Cross-sectional study on 140 patients with CS. METHODS A total of 113 women (80 with pituitary disease and 33 with adrenal disease, aged 41.7±15.7 years) and 27 men (19 with pituitary disease and eight with adrenal disease, aged 38.1±20.01 years) at diagnosis were divided according to glucose tolerance into normal glucose tolerance (CS/NGT), impaired fasting glucose and/or impaired glucose tolerance (CS/prediabetes), and diabetes (CS/DM) groups. RESULTS Seventy-one patients had CS/NGT (49.3%), 26 (18.5%) had CS/prediabetes and 43 (30.8%) had CS/DM. Significant increasing trends in the prevalence of family history of diabetes (P<0.001), metabolic syndrome (P<0.001), age (P<0.001) and waist circumference (P=0.043) and decreasing trends in HOMA-β (P<0.001) and oral disposition index (DIo) (P<0.002) were observed among the groups. No significant trends in fasting insulin levels, area under the curve for insulin (AUCINS), Matsuda index of insulin sensitivity (ISI-Matsuda) and visceral adiposity index were detected. CONCLUSIONS Impairment of glucose tolerance is characterized by the inability of β-cells to adequately compensate for insulin resistance through increased insulin secretion. Age, genetic predisposition and lifestyle, in combination with the duration and degree of hypercortisolism, strongly contribute to the impairment of glucose tolerance in patients with a natural history of CS. A careful phenotypic evaluation of glucose tolerance defects in patients with CS proves useful for the identification of those at a high risk of metabolic complications.

Neuropsychiatric disorders in Cushing's syndrome

Endogenous Cushings syndrome (CS), a rare endocrine disorder characterized by cortisol hypersecretion, is associated with psychiatric and neurocognitive disorders. Major depression, mania, anxiety, and neurocognitive impairment are the most important clinical abnormalities. Moreover, patients most often complain of impairment in quality of life, interference with family life, social, and work performance. Surprisingly, after hypercortisolism resolution, despite the improvement of the overall prevalence of psychiatric and neurocognitive disorders, the brain volume loss at least partially persists and it should be noted that some patients may still display depression, anxiety, panic disorders, and neurocognitive impairment. This brief review aimed at describing the prevalence of psychiatric and neurocognitive disorders and their characterization both during the active and remission phases of CS. The last section of this review is dedicated to quality of life, impaired during active CS and only partially resolved after resolution of hypercortisolism.

The kidney in acromegaly: renal structure and function in patients with acromegaly during active disease and 1 year after disease remission

BACKGROUND The GH/insulin-like growth factor 1 axis is physiologically involved in the regulation of electrolytes and water homeostasis by kidneys, and influences glomerular filtration and tubular re-absorption processes. The aim of the study was to investigate renal structure and function in acromegalic patients during active disease and disease remission. PATIENTS Thirty acromegalic patients (15 males and 15 females), aged 32-70 years, were enrolled for the study. Ten de novo patients had active disease, whereas 20 patients showed disease remission 1 year after medical treatment with somatostatin analogs (SA) (ten patients) or surgery (ten patients). Thirty healthy subjects matched for age, gender, and body surface area were enrolled as controls. RESULTS In both active (A) and controlled (C) patients, creatinine clearance (P<0.001) and citrate (P<0.05) and oxalate levels (P<0.001) were higher, whereas filtered Na (P<0.001) and K (P<0.001) fractional excretions were lower than those in the controls. Urinary Ca (P<0.001) and Ph (P<0.05) levels were significantly increased compared with the controls, and in patients with disease control, urinary Ca (P<0.001) levels were significantly reduced compared with active patients. Microalbuminuria was significantly increased in active patients (P<0.05) compared with controlled patients and healthy control subjects. The longitudinal (P<0.05) and transverse (P<0.05) diameters of kidneys were significantly higher than those in the controls. In all patients, the prevalence of micronephrolithiasis was higher than that in the controls (P<0.001), and was significantly correlated to disease duration (r=0.871, P<0.001) and hydroxyproline values (r=0.639, P<0.001). CONCLUSIONS The results of the current study demonstrated that acromegaly affects both renal structure and function. The observed changes are not completely reversible after disease remission.

Pituitary tumors and pregnancy: the interplay between a pathologic condition and a physiologic status.

Pregnancy is becoming a relatively common event in patients with pituitary tumors (PT), due to the increasing availability of medical treatments, which control pituitary diseases associated with the development of PT. However, the presence of PT and its treatment may be a disturbing factor for pregnancy, and pregnancy significantly influences the course and the management of PT. This review summarizes the knowledge about the management of PT during pregnancy and the occurrence of pregnancy in patients with pre-existent PT, focusing on secreting PT characterized by hormonal excess and on clinically non-functioning PT often associated to hormone deficiency, which configure the hypopituitaric syndrome.

Complete disappearance of a GH-secreting pituitary macroadenoma in a patient with acromegaly: effect of treatment with lanreotide Autogel and consequence of treatment withdrawal

BACKGROUND Somatostatin analogs (SA) are the cornerstone in the medical treatment of acromegaly, used as either primary or adjunctive therapy. In particular, SA are effective in inducing the biochemical remission of the disease and tumor shrinkage, although only few cases of complete disappearance of the pituitary tumor in patients treated with SA as long-acting formulations have been reported. SA withdrawal has been demonstrated to keep safe levels of GH and IGF1 at least in a small subset of patients well responsive to SA, although it is generally followed by disease recurrence after several months. CASE REPORT A 61-year-old female patient bearing a very large GH-secreting pituitary macroadenoma was treated with 12-month lanreotide Autogel (ATG), at the initial dose of 120 mg/28 days. After 3 months, GH and IGF1 levels were fully normalized, to prolong the administration interval from 28 to 56 days. After 6 months of treatment, a significant tumor shrinkage (90% of baseline size) was observed, whereas GH and IGF1 excess was still well controlled. After 12-month therapy, a complete disappearance of the pituitary tumor was observed, and the hormonal evaluation confirmed the complete biochemical remission of acromegaly. Lanreotide ATG treatment was withdrawn. The clinical, biochemical, and radiological remission of acromegaly was maintained 24 months after lanreotide ATG treatment discontinuation, without evidence of disease recurrence. CONCLUSIONS This report represents an exemplary case of the potentiality of treatment with lanreotide ATG in inducing a complete remission of acromegalic disease, persistent after a long period of time from treatment withdrawal.

Quality of life in patients with Cushing's disease: a modern approach

Cushing’s disease (CD) is known to be associated with an increased mortality, especially for cardiovascular diseases. Even years after cure, patients with a history of CD maintain an increased cardiovascular risk. The most important and frequent systemic complication in CD is represented by the metabolic syndrome, namely the combination of visceral obesity, systemic arterial hypertension, glucose intolerance and dyslipidaemia, which together with thrombosis diathesis is responsible for the increased cardiovascular risk. Glucocorticoids excess exerts important effects also on the skeletal system, determining osteoporosis, and on gonadal function, inducing polycystic ovary syndrome and menstrual disturbances in women or sexual dysfunction in men, with consequent damage of fertility. Overall, these complications induce significantly impaired health-related quality of life (HRQoL), which persists even after resolution of cortisol excess. Patients mainly complain of fatigue or weakness, changes in physical appearance, emotional instability, cognitive problems, depression and also sleeping difficulties; the majority of patients report interference with family life and relations with their partner and half of them with school or work performance. Despite successful treatment of CD, long-term residual effect on the HRQoL has been observed, which includes poorer physical and social functioning, role limitations because of physical and emotional problems, more pain and less general well-being. The mechanisms through which CD determines HRQoL impairment are probably multifactorial involving physical and psychological features. Severe fatigability and changes in body composition and image, anxiety, irritability, mood swings, depression, decreased memory, less self-confidence and difficulties in sleeping are common and the main concerns for these patients. Glucocorticoids are known to affect behaviour, mood, neural activity, memory and other processes in the central nervous system and to reduce brain volume in a reversible way when hypercortisolism is controlled. However, other dimensions such as cognition or body composition do not normalize with normalization of cortisol secretion, strongly suggesting that these changes are not fully reversible, as indicated by the persistent impairment in HRQoL. Several questionnaires and different criteria have been used to evaluate QoL in patients with CD. Milian et al. propose two studies in this issue of Clinical Endocrinology. The aim of the first study was to construct a disease-specific questionnaire that could assess HRQoL in patients with CD: the Tuebingen CD quality of life inventory (Tuebingen CD-25). The aim of the second study was to assess normative data from healthy controls to provide a comparison with results obtained in patients with CD. Sixty-three patients with CD entered the study and were divided into six age groups similar in size. A preliminary inventory comprising 64 HRQoL items was handed out to these patients. Twenty-five items remained in the final version of the questionnaire. The validity of the questionnaire was determined by the correlation between the total score of the Tuebingen CD-25 and the overall score of the well-established World Health Organization Quality of Life (WHOQoL-BREF) questionnaire. Tuebingen CD-25 includes six different subdomains correlated with the quality of life: (i) depression, (ii) sexual activity, (iii) environment, (iv) eating behaviour, (v) bodily restrictions, and (vi) cognition. Response options were on a five-point Likert scale, and the raw score could be transformed, ranging from a minimum of 10 to a maximum score of 100, higher scores corresponding to lower HRQoL. Expectedly, the authors found a significant correlation between the 24-h urinary free cortisol (UFC) excretion and the scale ‘Cognition’ and ‘Eating Behaviour’, suggesting a correlation between clinical severity of symptoms in CD and UFC levels. This correlation is clinically relevant as it is well known that UFC shows high intra-individual variability. In the second part of the study, 1784 healthy controls were recruited via an Internet survey. They participated voluntarily, and only volunteers without relevant comorbidities in their current or past medical history were asked to fill out the questionnaire and were assigned to seven age groups. The objective was to better understand how hypercortisolism affect the QoL in patients with CD, establishing a reference range for the Tuebingen CD-25. Compared with healthy individuals, a slight impairment was found in 28·6% and a severe impairment was found in 41·3% in the total score of patients with CD. So, nearly three-quarters of patients suffered from lower HRQoL and all subdomains *See related papers on pages 851–867.