Monica De Leo

The Medical Treatment of Cushing’s Disease: Effectiveness of Chronic Treatment with the Dopamine Agonist Cabergoline in Patients Unsuccessfully Treated by Surgery

BACKGROUND The role of dopamine agonists in the treatment of Cushings disease (CD) has been previously debated. AIM The aim of this study was to evaluate the effectiveness of short-term (3 months) and long-term (12-24 months) treatment with cabergoline in patients with CD. PATIENTS AND METHODS 20 patients with CD unsuccessfully treated by surgery entered the study. Cabergoline was administered at an initial dose of 1 mg/wk, with a monthly increase of 1 mg, until urinary cortisol levels normalized or the maximal dose of 7 mg/wk was achieved. The responsiveness to treatment was evaluated according to changes in urinary cortisol excretion. A decrease greater than 25% was considered as a partial response, whereas complete normalization was considered as a full response at short-term evaluation; persistence of normal cortisol excretion was the only criterion to evaluate the response at long-term evaluation. RESULTS After short-term treatment, 15 (75%) patients were responsive to cabergoline treatment. Among these, normalization of cortisol excretion was maintained in 10, whereas treatment escape was observed in five patients after 6-18 months. Among the 10 long-term responsive patients, eight were followed for 24 months, whereas the remaining two were followed for 12-18 months, due to cabergoline withdrawal for intolerance. A sustained control of cortisol secretion for 24 month cabergoline treatment at the maximal dose ranging from 1-7 mg/wk (median: 3.5) without significant side effects, was obtained in eight of 20 (40%) patients. CONCLUSIONS The results of this study demonstrated that cabergoline treatment is effective in controlling cortisol secretion for at least 1-2 yr in more than one third of a limited population of patients with CD. If this evidence is confirmed by additional studies, this agent may be considered as a useful treatment option in patients with CD who are unsuccessfully treated by neurosurgery.

Cushing's Syndrome

Cushings syndrome is a rare endocrine disease characterized by cortisol hypersecretion, induced mainly by a pituitary tumor (Cushings disease) or, rarely, by an adrenal or an ectopic neuroendocine tumor. Cushings syndrome is associated with severe morbidities and an increased mortality. The major systemic complications and the main cause of death are represented by cardiovascular disease. The prognosis of the disease is mainly affected by the difficulties in the diagnosis and treatment of the disease, which remain a considerable challenge.

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.

Cushing's syndrome: aftermath of the cure

Cushings syndrome (CS) is a chronic and systemic disease caused by endogenous or exogenous hypercortisolism, associated with an increase of mortality rate due to the clinical consequences of glucocorticoid excess, especially cardiovascular diseases. After cure, usually obtained by the surgical removal of the tumor responsible for the disease, the normalization of cortisol secretion is not constantly followed by the recovery of the clinical complications developed during the active disease, and it is often followed by the development of novel clinical manifestations induced by the fall of cortisol levels. These evidences were mostly documented in patients with pituitary-dependent CS, after surgical resection of the pituitary tumor. Indeed, despite an improvement of the mortality rate, metabolic syndrome and the consequent cardiovascular risk have been found to partially persist after disease remission, strictly correlated to the insulin resistance. Skeletal diseases, mainly osteoporosis, improve after normalization of cortisol levels but require a long period of time or the use of specific treatment, mainly bisphosphonates, to reach the normalization of bone mass. A relevant improvement or resolution of mental disturbances has been described in patients cured from CS, although in several cases, cognitive decline persisted and psychological or psychiatric improvement was erratic, delayed, or incomplete. On the other hand, development or exacerbation of autoimmune disorders, mainly thyroid autoimmune diseases, was documented in predisposed patients with CS after disease remission. The totality of these complications persisting or occurring after successful treatment contribute to the impairment of quality of life registered in patients with CS after disease cure.

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.

Drug Insight: cabergoline and bromocriptine in the treatment of hyperprolactinemia in men and women

Prolactinoma is the most frequent pituitary tumor histotype. Men generally have macroadenomas whereas women generally have microadenomas. The major objectives of treating prolactinomas are to suppress excessive hormone secretion and its clinical consequences, to remove the tumor mass while preserving the residual pituitary function, and possibly to prevent disease recurrence or progression. Primary therapy of prolactinomas is based on use of dopamine-receptor agonists. Bromocriptine induces normalization of prolactin levels in 80–90% of patients with microprolactinomas and approximately 70% of those with macroprolactinomas. Tumor-mass shrinkage and improvement of visual-field defects are found in the majority of treated macroprolactinomas, but bromocriptine often causes side effects. Cabergoline is very effective and well tolerated in more than 90% of patients with either microprolactinomas or macroprolactinomas. Cabergoline treatment also induces tumor shrinkage in the majority of patients with macroprolactinomas. Tumor shrinkage is more evident if patients have not previously been treated with other dopamine agonists. Fewer results are available for men than for women, but there is no evidence that men are less responsive to dopamine agonists than are women.

Effects of sex steroids on bone in women with subclinical or overt endogenous hypercortisolism

OBJECTIVE Glucocorticoid-induced osteoporosis is the most frequent cause of secondary osteoporosis. Nevertheless, limited data are available on bone status in patients with endogenous cortisol excess. This study is aimed at investigating the role of sex steroids and severity of hypercortisolism on bone mineral density (BMD) and prevalence of vertebral fractures in female patients. DESIGN Cross-sectional, case-control study. PATIENTS Seventy-one consecutive women were enrolled: 36 with overt hypercortisolism (26 with ACTH-secreting pituitary adenoma and 10 with cortisol-secreting adrenal tumor) and 35 with subclinical hypercortisolism due to adrenal incidentalomas. They were compared with 71 matched controls. METHODS At diagnosis, we measured serum cortisol, FSH, LH, estradiol, testosterone, androstenedione and DHEAS, and urinary cortisol excretion. BMD was determined by dual energy X-ray absorptiometry at the lumbar spine and femoral neck. Vertebral fractures were investigated by a semiquantitative scoring method. RESULTS Between women with overt and subclinical hypercortisolism BMD values and prevalence of any vertebral (69 vs 57%, P = 0.56), clinical (28 vs 11.4%, P = 0.22), and multiple vertebral fractures (36 vs 31%, P = 0.92) did not differ. Among patients with subclinical hypercortisolism, amenorrhoic women had a lower BMD (P = 0.035) and more frequent vertebral fractures (80 vs 40%; P = 0.043) when compared with the eumenorrhoic ones. Among women with overt hypercortisolism, there was no difference in lumbar BMD (P = 0.37) and prevalence of fractures (81 vs 60%; P = 0.26) between those amenorrhoic and eumenorrhoic. By logistic regression analysis, lumbar spine BMD values and cortisol-to-DHEAS ratio were the best predictors of vertebral fractures (P < 0.01). CONCLUSIONS Vertebral fractures are very common in women with endogenous cortisol excess, regardless of its severity. The deleterious effects of hypercortisolism on the spine may be partly counterbalanced by DHEAS increase at any degree of cortisol excess, and by preserved menstrual cycles in women with subclinical but not in those with overt hypercortisolism.

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.