Lucio Vilar

Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients

BACKGROUND Dopamine agonist resistance in prolactinoma is an infrequent phenomenon. Doses of cabergoline (CAB) of up to 2.0 mg/week are usually effective in controlling prolactin (PRL) secretion and reducing tumor size in prolactinomas. The clinical presentation, management, and outcome of patients that are not well controlled by such commonly used doses of CAB-resistant patients are poorly understood. DESIGN AND METHODS A multicenter retrospective study was designed to collect a large series of resistant prolactinoma patients, defined by uncontrolled hyperprolactinemia on CAB ≥2.0 mg weekly. RESULTS Ninety-two patients (50 F, 42 M) were analyzed. At diagnosis, most had macroprolactinomas (82.6%); males were significantly older than females (P=0.0003) and presented with a more aggressive disease. A genetic basis was identified in 12 patients. Thirty-six patients (39.1%) received only medical therapy, most underwent surgery (60.9%, including multiple interventions in 10.9%), and 14.1% received postoperative radiotherapy. Eight patients developed late CAB resistance (8.7%). The median maximal weekly dose of CAB (CAB(max/w)) was 3.5 mg (2.0-10.5). Despite a higher CAB(max/w) in patients treated with multimodal therapy (P=0.003 vs exclusive pharmacological treatment), a debulking effect of surgery was shown in 14 patients, with a higher rate of PRL control (P=0.006) and a significant reduction in CAB(max/w) (P=0.001) postoperatively. At last follow-up (median 88 months), PRL normalization and tumor disappearance were achieved in 28 and 19.9% of the patients respectively, with no significant sex-related difference observed in CAB(max/w) or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%). CONCLUSION CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome.

Cushing's syndrome in pregnancy: an overview

Cushings syndrome (CS) during pregnancy is a rare condition with fewer than 150 cases reported in the literature. Adrenal adenomas were found to be the commonest cause, followed by Cushings disease. The gestation dramatically affects the maternal hypothalamic-pituitary-adrenal axis, resulting in increased hepatic production of corticosteroid-binding globulin (CBG), increased levels of serum, salivary and urinary free cortisol, lack of suppression of cortisol levels after dexamethasone administration and placental production of CRH and ACTH. Moreover, a blunted response of ACTH and cortisol to exogenous CRH may also occur. Therefore, the diagnosis of CS during pregnancy is much more difficult. Misdiagnosis of CS is also common, as the syndrome may be easily confused with preeclampsia or gestational diabetes. Because CS during pregnancy is usually associated with severe maternal and fetal complications, its early diagnosis and treatment are critical. Surgery is the treatment of choice for CS in pregnancy, except perhaps in the late third trimester, with medical therapy being a second choice. There does not seem to be a rationale for supportive treatment alone.

Pitfalls in the diagnosis of Cushing's syndrome

Among endocrine disorders, Cushings syndrome (CS) is certainly one of the most challenging to endocrinologists due to the difficulties that often appear during investigation. The diagnosis of CS involves two steps: confirmation of hypercortisolism and determination of its etiology. Biochemical confirmation of the hypercortisolaemic state must be established before any attempt at differential diagnosis. Failure to do so will result in misdiagnosis, inappropriate treatment, and poor management. It should also be kept in mind that hypercortisolism may occur in some patients with depression, alcoholism, anorexia nervosa, generalized resistance to glucocorticoids, and in late pregnancy. Moreover, exogenous or iatrogenic hypercortisolism should always be excluded. The three most useful tests to confirm hypercortisolism are the measurement of 24-h urinary free cortisol levels, low-dose dexamethasone-suppression tests, and determination of midnight serum cortisol or late-night salivary cortisol. However, none of these tests is perfect, each one has different sensitivities and specificities, and several are usually needed to provide a better diagnostic accuracy. The greatest challenge in the investigation of CS involves the differentiation between Cushings disease and ectopic ACTH syndrome. This task requires the measurement of plasma ACTH levels, non-invasive dynamic tests (high-dose dexamethasone suppression test and stimulation tests with CRH or desmopressin), and imaging studies. None of these tests had 100% specificity and their use in combination is usually necessary. Bilateral inferior petrosal sinus sampling is mainly indicated when non-invasive tests do not allow a diagnostic definition. In the present paper, the most important pitfalls in the investigation of CS are reviewed.

INCREASE OF CLASSIC AND NONCLASSIC CARDIOVASCULAR RISK FACTORS IN PATIENTS WITH ACROMEGALY

OBJECTIVE To evaluate the prevalence of classic and nonclassic cardiovascular risk factors in patients with acromegaly. METHODS Sixty-two patients with acromegaly (50 with active disease and 12 with controlled acromegaly) and 36 healthy persons (the control group) underwent measurement of lipids, fasting plasma glucose, homeostasis model assessment of insulin resistance (HOMA-IR) index, Lp(a), high-sensitivity C-reactive protein (hsCRP), homocysteine, and variables primarily related to thrombogenesis (fibrinogen, antithrombin III, protein C, and protein S). RESULTS In comparison with control subjects, patients with active acromegaly had significantly higher mean values of fasting plasma glucose, total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein (VLDL) cholesterol, triglycerides, Lp(a), HOMA-IR, and fibrinogen as well as lower mean levels of high-density lipoprotein cholesterol and protein S. In both groups, homocysteine, antithrombin III, protein C, and hsCRP levels were similar. Moreover, patients with active acromegaly, in comparison with those who had controlled acromegaly, presented with significantly higher values of fasting plasma glucose, HOMA-IR, triglycerides, VLDL cholesterol, Lp(a), and fibrinogen, whereas hsCRP and protein S were significantly lower. Finally, low levels of high-density lipoprotein cholesterol and protein S as well as elevated values of VLDL cholesterol, triglycerides, HOMA-IR, and fasting plasma glucose were more prevalent in patients with active acromegaly than in the other groups. CONCLUSION Our findings demonstrate that, in comparison with control subjects and patients with controlled acromegaly, patients with active acromegaly had a higher frequency of classic and nonclassic cardiovascular risk factors. These findings are potentially very important because acromegaly is associated with a 2- to 3-fold increase in mortality rate, predominantly related to cardiovascular disease.

Challenges in the diagnosis and management of acromegaly: a focus on comorbidities

IntroductionAcromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life.MethodsWe conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment.Findings and conclusionsSuccessful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.

Frequency and risk factors associated with non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus

OBJECTIVE To evaluate the frequency of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (DM2) and to describe its risk factors. SUBJECTS AND METHODS Blood samples of 78 patients were collected for assessment of glycemic and lipid profile, liver enzymes, TNF-alpha and HOMA-IR. The diagnosis of NAFLD was established by ultrasound. RESULTS NAFLD was observed in 42% of patients who had greater BMI (p < 0.001), and frequency of hypertension (p < 0.001). Metabolic syndrome was more frequent in those with NAFLD (p = 0.019). The levels of aspartate, alanine aminotransferase, gamma-glutamyl transpeptidase, uric acid, TNF-alpha, insulin and HOMA-IR were significantly higher in patients with NAFLD than those without NAFLD. CONCLUSION Almost half of patients with DM2 were found to have NAFLD, and they have more elevated BMI, as well as higher levels of aminotransferases, gamma-GT, uric acid, TNF-alpha, insulin and HOMA-IR than subjects without NAFLD.

Challenges and pitfalls in the diagnosis of hyperprolactinemia

The definition of the etiology of hyperprolactinemia often represents a great challenge and an accurate diagnosis is paramount before treatment. Although prolactin levels > 200-250 ng/mL are highly suggestive of prolactinomas, they can occasionally be found in other conditions. Moreover, as much as 25% of patients with microprolactinomas may present prolactin levels < 100 ng/mL, which are found in most patients with pseudoprolactinomas, drug-induced hyperprolactinemia, or systemic diseases. On the other hand, some conditions may lead to falsely low PRL levels, particularly the so-called hook effect, that is an assay artifact caused by an extremely high level of PRL, and can be confirmed by repeating assay after a 1:100 serum sample dilution. The hook effect must be considered in all patients with large pituitary adenomas and PRL levels within the normal range or only modestly elevated (e.g., < 200 ng/mL). An overlooked hook effect may lead to incorrect diagnosis and unnecessary surgical intervention in patients with prolactinomas. Another important challenge is macroprolactinemia, a common finding that needs to be identified, as it usually requires no treatment. Although most macroprolactinemic patients are asymptomatic, many of them may present galactorrhea or menstrual disorders, as well as neuroradiological abnormalities, due to the concomitance of other diseases. Finally, physicians should be aware that pituitary incidentalomas are found in at least 10% of adult population.

ADRENAL INCIDENTALOMAS: DIAGNOSTIC EVALUATION AND LONG-TERM FOLLOW-UP

OBJECTIVE To evaluate the cause and the clinical and laboratory features of adrenal incidentalomas (AI) in 52 patients and to assess the evolution of nonsurgically treated lesions during long-term follow-up. METHODS We retrospectively analyzed the medical records of 52 patients with AI undergoing routine follow-up in 2 Brazilian endocrine centers. RESULTS In our study group, nonfunctioning adenomas were the most frequent cause of AI (42%), followed by cortisol-secreting adenomas (15%), metastatic disease (10%), pheochromocytomas (8%), myelolipomas (6%), cysts (6%), carcinomas (4%), lymphomas (4%), tuberculosis (4%), and aldosteronoma (2%). Only 13 lesions (25%) were functioning (8 cortisol-secreting adenomas, 4 pheochromocytomas, and 1 aldosteronoma). Carcinomas were the largest adrenal masses (mean diameter, 11.7 +/- 1.3 cm). With the exception of 1 pheochromocytoma, 1 cyst, and 1 myelolipoma, all AI larger than 6 cm were carcinomas. During follow-up of 21 patients with nonsurgically treated AI for 6 to 36 months (mean, 24.8 +/- 8.9), no patient had tumor reduction or disappearance. After 12 months of follow-up, however, a 45-year-old woman had adrenal mass enlargement from 3.2 cm to 4.4 cm; the excised lesion proved to be an adenoma. Moreover, evidence of cortisol hypersecretion developed after 24 months of follow-up in a 30-year-old man with a 3.5-cm adenoma in the left adrenal gland. CONCLUSION Our findings demonstrate that most AI are nonfunctioning benign lesions and emphasize the need for long-term follow-up of patients with conservatively managed lesions, in light of the potential for evolution to hormonal hypersecretion or tumor growth.

Substantial Shrinkage of Adenomas Cosecreting Growth Hormone and Prolactin with use of Cabergoline Therapy

OBJECTIVE To present 2 cases of patients with acromegaly and severe hyperprolactinemia whose primary therapy with cabergoline resulted in hormonal normalization and a considerable reduction in the size of their somatotroph macroadenomas. METHODS We summarize the clinical presentation and the pertinent laboratory findings in 2 patients with acromegaly, as well as their clinical response to the therapy with cabergoline. A review of the literature regarding the use of cabergoline in acromegaly is also presented. RESULTS A 48-year-old man (case 1) and a 26-year-old woman (case 2) were found to have acromegaly associated with very high levels of serum prolactin (2,700 and 5,250 ng/mL, respectively). These patients received first line therapy with cabergoline that resulted not only in clinical improvement and normalization of growth hormone, prolactin, and insulin-like growth factor-I levels but also in a substantial reduction in the size of their somatotroph macroadenomas. By 6 months after the patients began to take cabergoline, tumor shrinkage of 94% (in case 1) and of 70% (in case 2) was demonstrated by magnetic resonance imaging. CONCLUSION Our findings demonstrate that cabergoline should be considered for medical treatment of adenomas cosecreting growth hormone and prolactin, even in the presence of large tumors with appreciable suprasellar extension, because substantial tumor shrinkage is possible with this therapy.

Prevalência da macroprolactinemia entre 115 pacientes com hiperprolactinemia

Macroprolactinemia is characterized by the predominance in the serum of macroprolactin, a prolactin (PRL) with high molecular mass and low biological activity that does not need treatment. The prevalence of macroprolactinemia was evaluated in 115 consecutive patients with hyperprolactinemia. Among them, 19 (16.5%) had solely macroprolactinemia, 4 (3.5%) polycystic ovary syndrome, 7 (6.1%) acromegaly, 8 (6.9%) idiopathic hyperprolactinemia, 10 (8.6%) primary hypothyroidism, 14 (12.2%) clinically non-functioning pituitary adenomas, 20 (17.4%) drug-induced hyperprolactinemia and 33 (28.7%) prolactinomas. The diagnosis of macroprolactinemia was established by the demonstration of a PRL recovery < 30% after treatment of sera with polyethylene glycol. Among the 19 patients with isolated macroprolactinemia, 16 (84.2%) were female and 12 (63.2%) were asymptomatic, while 4 (21%) presented with oligomenorrhea and 3 (15.8%) with galactorrhea. In contrast, only 11.5% of individuals with other causes of hyperprolactinemia were asymptomatic (p< 0.001). Prolactin levels in cases of macroprolactin ranged from 45.1 to 404 ng/mL (mean 113.3 +/- 94.5) but in 15 (78.9%) were < 100 ng/mL. Our findings demonstrate that macroprolactinemia is a common condition and, therefore, we suggest that it should be routinely screened in patients with hyperprolactinemia.