Luiz Augusto Casulari

Nelson’s Syndrome: Complete Remission with Cabergoline but Not with Bromocriptine or Cyproheptadine Treatment

A woman affected by Cushing’s disease underwent bilateral adrenalectomy followed by radiotherapy of the hypothalamic-pituitary area when she was 18 years old. Thereafter, she used hydrocortisone acetate replacement therapy (35.5 mg divided into two daily doses). At the age of 26 years, the patient exhibited the clinical signs of the Nelson’s syndrome, i.e. skin and gingival hyperpigmentation accompanied by amenorrhea, and elevated ACTH plasma levels (2,850 pg/ml, normal range 15–80 pg/ml). The magnetic resonance imaging (MRI) analysis of the sellar region evidenced a pituitary macroadenoma, measuring 14 × 13 mm. The patient was initially treated with cyproheptadine hydrochloride (12 mg/day) for 18 months. There was a partial improvement of the symptoms, with a reduction of the ACTH plasma levels to 112 pg/ml, but without any modification of the tumor mass. Due to sleepiness and weight gain, the cyproheptadine treatment was interrupted and substituted by a cabergoline (0.5 mg twice a week) therapy. Soon after cabergoline was applied an improvement of the clinical symptoms and signs was observed such as a regression of the tumor mass and the normalization of the ACTH plasma titers (38 pg/ml). Later, cabergoline was substituted by bromocriptine (7.5 mg/day) and the plasma levels of ACTH increased again (247 pg/ml), and headache and cutaneous hyperpigmentation were recorded. When cabergoline was reintroduced there was a clinical improvement and normalization of ACTH plasma levels (64 pg/ml). The MRI analysis of the sella region demonstrated a complete remission of the pituitary adenoma. The results obtained show for the first time that a long-term treatment with cabergoline also brings about a complete remission of Nelson’s syndrome in the presence of a pituitary macroadenoma.

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.

Expression of p53, Ki-67 and c-erb B2 in growth hormone-and/or prolactin-secreting pituitary adenomas

The subcellular events implicated on the formation and behavior of pituitary adenomas are not fully understood. In this study we investigated the presence of p53, Ki-67 and c-erb B2 in 38 pituitary adenomas with immunohistochemical positivity for GH and prolactin (n=26; 68.4%), for prolactin (n=9; 23.7%) and for GH (n=3. 7.8%). The analyses revealed the following results: 24 (63.2%) tumors expressed variable positivity for c-erb B2, 11 (28.9%) expressed p53 positivity and 11 (28.9%) tumors were variably positive for Ki-67. Our results demonstrated a high percentage of GH/prolactin-, prolactin- and GH-secreting tumors with immunohistochemical positivity for c-erb B2. Once this membrane receptor is related to growth factors EGF and TGFalpha and both have a definite effect on tumor growth, our data suggest a possible role for c-erb B2 on the evolution of these tumors.

Evaluation of pituitary and thyroid hormones in patients with subarachnoid hemorrhage due to ruptured intracranial aneurysm

UNLABELLED It is well known that the central nervous system (CNS) influences the pituitary hormone secretions and that diseases of CNS are frequently associated with an altered endocrine function. The aim of this study has been the evaluation of the serum concentrations of the pituitary and thyroid hormones in a series of patients with subarachnoid hemorrhage due to a ruptured cerebral aneurysm. Thirty-five patients (23 females and 12 males), aged 51.9 +/- 13.3 years on the mean were admitted. They were evaluated to assess the clinical severity of the subarachnoid hemorrhage by Hunt & Hess scale: nine patients were in the grade I, 14 in the grade II, and 12 in the grade III. Blood samples were obtained between 8:00 and 9:00 a.m. and serum hormones were measured by commercial kits (IRMA or MEIA methods). Cortisol serum levels (normal range (NR) = 5 to 18 micro g/dL) were increased in all the patients (mean +/- standard deviation = 31.4 +/- 12.4 micro g/dL). Mean prolactin levels (NR < 20 ng/mL) were 18.6 +/- 17.1 ng/mL and five patients (14.2%) had levels higher than normal. FSH and LH levels were normal according to age and sex: men: FSH = 4 +/- 2.9 mUI/mL (NR = 1 to 10.5 mUI/mL); LH = 6.1 +/- 6.3 mUI/mL (NR = 2 to 12 mUI/mL); premenopausa women: FSH = 2.5 +/- 1.5 mUI/mL (NR = 2.4 to 9.3 mUI/mL); LH 3.9 +/- 5.1 mUI/mL (NR =2 to 15 mUI/mL); post- menopausal women: FSH = 48.3 +/- 18.5 mUI/mL (NR =31 to 134 mUI/mL); LH = 29 +/- 13.8 mUI/mL (NR =16 to 64 mUI/mL). Mean TSH levels were 3.9 +/- 5.2 micro UI/mL (NR =0.5 to 4.7 micro UI/mL) and five patients (14.2%) had levels higher than normal. Mean triiodothyronine levels (T3) were 66.4 +/- 18.7 ng/dL (NR = 45 to 137 ng/dL) and five patients (14.2%) had levels lower than normal (33.8 +/- 9 ng/dL). Mean thyroxine levels (T4) (NR= 4.5 to 12.5 micro g/dL) were 7.4 +/- 1.7 micro g/dL and two patients (5.6%) had levels lower than normal. Thyroglobulin and microsomal antibodies were not detectable. CONCLUSIONS In the first 24 hours following ictus, the hormonal changes may be due to the stress produced by the intracranial bleeding; thyroid hormone alterations suggest that patients with subarachnoid hemorrhage might have an euthyroid sick syndrome.

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.

Incidence of Obesity Does Not Appear to Be Increased after Treatment of Acute Lymphoblastic Leukemia in Brazilian Children: Role of Leptin, Insulin, and IGF-1

Background/Aims: It has been reported that children treated for acute lymphoblastic leukemia (ALL) in developed countries show an increased risk of overweight and obesity in adolescence and adulthood. However, the majority of patients who came to our observation in Brazil have low or normal body weight and only one of them was obese. Therefore, we have decided to assess some biochemical parameters possibly related to the intermediate metabolism and body composition in these patients. Methods: Two groups of subjects were studied: 27 survivors of childhood ALL (14.0 ± 4.2 years old; post-treatment interval 8.6 ± 3.9 years) (ALL group) and 17 healthy subjects (12.8 ± 4 years old) (control group) selected on the basis of their kinship with the patients. Results: 14/27 patients of the ALL group and 4/17 of the control group had leptin levels higher than the normal range for age and sex (p < 0.05). The leptin level was significantly higher in the ALL group (15.5 ± 1.8 ng/ml) than in the control group (10.7 ± 2 ng/ml) (p < 0.05). When adjusted by sex, BMI z-score, and age, the level of leptin in patients of the ALL group was 8.5 higher than in subjects of the control group (p = 0.006). Leptin/insulin correlation in the ALL group was 0.08 and in the control group it was +0.585 (p < 0.05). Conclusion: The data indicate the presence of alterations in the homeostatic regulatory mechanisms controlling body weight in Brazilian patients treated for ALL in childhood, still, it did not lead to obesity in the absence of favorable environmental conditions.

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.

Fibrous mastopathy: clinical, imaging, and histopathologic findings of 31 cases.

Aim:  The aim of this study was to analyze the cases of patients with a histological diagnosis of fibrous mastopathy, diabetic mastopathy, or lymphocytic mastopathy in association with other autoimmune diseases, and to conduct histological and imaging studies as well as follow up of the lesions.

Relationship between insulin and hypogonadism in men with metabolic syndrome.

OBJECTIVE To evaluate the incidence of hypogonadism in men with metabolic syndrome and its correlation with serum insulin levels. METHODS Observational, transversal study with 80 men with metabolic syndrome. The individuals were divided into two groups: Group 1: 56 patients (70%) with total testosterone > 300 ng/dL (normal gonadal function); Group 2: 24 patients (30%) with total testosterone < 300 ng/dL (hypogonadic). RESULTS The subjects from Group 2 compared to Group 1 presented higher body mass index (BMI), waist and hip circumferences, insulin, homeostasis model assessment insulin resistance index (Homa-IR) and beta cell (Homa-beta), and triglycerides, but lower SHBG and free testosterone values. Inverse correlations between insulin levels and total testosterone and SHBG, as well as between Homa-IR and total testosterone were observed. CONCLUSION In this series of men with metabolic syndrome, hypogonadism was associated with insulin resistance and may be a marker of metabolic abnormalities.