Paradoxical effect of dopamine-agonists on IGF-1 in patients with prolactinoma: the role of weight.

PURPOSE: An increase of IGF-1 has been reported during therapy with dopamine agonists (DA) for prolactinomas; in such cases a correct diagnosis is pivotal to avoid an unnecessary reduction or withdrawal of DA, which are needed to maintain normal prolactin levels. This study was aimed to measure IGF-1 levels, at baseline and during follow-up, in a cohort of patients with prolactinoma, treated with cabergoline, stratified by body mass index. METHODS: We retrospectively enrolled 35 patients (15 F/20 M; age m ± SD, years: 43.4 ± 13.7) with prolactinoma (21 microadenomas and 14 macroadenomas) who were followed-up at the Endocrinology Unit, in Siena, and with available pituitary hormone assessment at baseline and during follow-up (m ± SD, years: 2.74 ± 0.55). RESULTS: IGF-1 increased in the whole cohort, but remaining within normal range, except two patients, in whom acromegaly was ruled out with oral glucose tolerance test. After dividing patients by weight, this trend was confirmed only in subjects with overweight and obesity (OV/OB) (p = 0.04). Interestingly, the reduction of prolactin levels was significantly greater in the OV/OB compared to normal-weight patients (median decrease of 97.5% versus 88.2%, p = 0.04). CONCLUSIONS: Since DA and normalization of prolactin are known to improve insulin sensitivity, we speculated they have favored the increase of IGF-1 in OV/OB. Our results should be confirmed and the hypothesis proven by further studies.

Baseline serum TSH levels predict the absence of thyroid dysfunction in cancer patients treated with immunotherapy.

PURPOSE: Immunotherapy against immune checkpoints has significantly improved survival both in metastatic and adjuvant setting in several types of cancers. Thyroid dysfunction is the most common endocrine adverse event reported. Patients who are at risk of developing thyroid dysfunction remain to be defined. We aimed to identify predictive factors for the development of thyroid dysfunction during immunotherapy. METHODS: This is a retrospective study including a total of 68 patients who were treated with immune checkpoint inhibitors (ICIs) for metastatic or unresectable advanced cancers. The majority of patients were treated with anti-PD1 drugs in monotherapy or in combination with anti-CTLA4 inhibitors. Thyroid function and anti-thyroid antibodies, before starting immunotherapy and during treatment, were evaluated. Thyroid ultrasound was also performed in a subgroup of patients at the time of enrolment in the study. RESULTS: Eleven out of 68 patients (16.1%) developed immune-related overt thyroid dysfunction. By ROC curve analysis, we found that a serum TSH cut-off of 1.72 mUI/l, at baseline, had a good diagnostic accuracy in identifying patients without overt thyroid dysfunction (NPV = 100%, p = 0.0029). At multivariate analysis, both TSH and positive anti-thyroid antibodies (ATAbs) levels, before ICIs treatment, were independently associated with the development of overt thyroid dysfunction during immunotherapy (p = 0.0001 and p = 0.009, respectively). CONCLUSIONS: Pre-treatment serum TSH and ATAbs levels may help to identify patients at high risk for primary thyroid dysfunction. Our study suggests guidance for an appropriate timely screening and for a tailored management of thyroid dysfunctions in patients treated with ICIs.

Should familial disease be considered as a negative prognostic factor in micropapillary thyroid carcinoma?

PURPOSE: An increased aggressiveness of familial papillary thyroid carcinoma (FPTC) compared with sporadic form has been reported. On the contrary, the biological behavior of familial microPTC (FmPTC) is still debated. To assess if familial diseases should be considered as a negative prognostic factor in mPTC, the clinical presentation and outcome of FmPTC and sporadic mPTC (SmPTC) were compared. METHODS: We retrospectively analyzed 291 mPTC (SmPTC n = 248, FmPTC n = 43) patients followed for a median follow-up of 8.3 years. FmPTC was defined as the presence of PTC in two or more first-degree relatives, after excluding hereditary syndromes associated with PTC. RESULTS: FmPTC patients had more frequently bilateral tumor (32.6% versus 16.5%, p = 0.01) and lymph node metastases at diagnosis (30.2% versus 14.9%, p = 0.02). At the first follow-up, FmPTC patients had a higher rate of structural disease and a lower rate of remission compared to SmPTC (p = 0.01). Also in a multivariate model, using a "CHAID tree-building algorithm", familial disease correlated with a worse clinical presentation and outcome of mPTC patients. Familial disease was associated with a higher rate of intermediate risk patients in non incidental mPTC and with a higher rate of structural incomplete response in mPTC without lymph node metastases (p = 0.01). CONCLUSIONS: Like in macroPTC, the familial form of the diseases has been shown to be a negative prognostic factor also in mPTC, therefore, it should be highly regarded in the management of mPTC patients.

Small papillary thyroid carcinoma with minimal extrathyroidal extension should be managed as ATA low-risk tumor.

PURPOSE: According to American Thyroid Association (ATA) guideline, papillary thyroid cancer (PTC) with minimal extrathyroidal extension (mETE) is classified at "intermediate risk" of persistent/recurrent disease. However, the impact of mETE per se on patients' outcome is not fully understood. The aim of our study was to evaluate the prognostic significance of mETE in patients with PTC not submitted to therapeutic or prophylactic lymph node dissection, according to tumor size and other prognostic factors. PATIENTS AND METHODS: We retrospectively evaluated a total of 514 PTC patients: 127 (24.7%) had mETE (pT3Nx) and 387 (75.3%) had negative margins (pT1-2Nx). At a median follow-up of 9.1 years, patients were divided in two groups: patients with "good outcome" (no evidence of disease) and patients with "poor outcome" (persistent structural disease or recurrent disease or tumor-related death). RESULTS: The rate of patients with "poor outcome" was significantly higher in patients with mETE compared with patients with negative margins (11.8 versus 5.1%; OR 2.4576, 95% CI 1.2178-4.9594, p = 0.01). However, mETE was significantly associated with poor outcome only in patients with tumors larger than 1.5 cm. CONCLUSIONS: mETE is an unfavorable prognostic factor in tumors larger than 1.5 cm, suggesting that, in the absence of other unfavorable characteristics, smaller tumors with mETE should be classified and managed as "low risk" tumors.

Prevalence of mutations in LEP, LEPR, and MC4R genes in individuals with severe obesity.

Obesity is a major public health concern; despite evidence of high heritability, the genetic causes of obesity remain unclear. In this study, we assessed the presence of mutations in three genes involved in the hypothalamic leptin-melanocortin regulation pathway (leptin, LEP; leptin receptor, LEPR; and melanocortin-4 receptor, MC4R), which is important for energy homeostasis in the body, in a group of patients with severe obesity. For this study, we selected 77 patients who had undergone bariatric surgery and had a pre-operative body mass index (BMI) >35 kg/m2, early onset and a family history of being overweight. Candidate genes were screened by direct sequence analysis to search for rare genetic variations. The common LEP -2548 G/A polymorphism was also evaluated for its influence on the BMI (in obesity patients) and for obesity risk, using a case-control study involving 117 healthy individuals. Two different non-synonymous alterations in MC4R were found in two patients: the p.(Thr112Met), previously described in the literature as a probable gene involved in the obesity phenotype, and the novel p.(Tyr302Asp) variant, predicted to be pathogenic by in silico evaluations and family segregation studies. The LEP -2548 G/A polymorphism was not associated with the BMI or obesity risk. In conclusion, we have reported a novel mutation in MC4R in a family of Italian patients with severe obesity. Screening for MC4R could be important for directing the carriers of mutations towards therapy including partial agonists of the MC4R that could normalize their appetite and inhibit compulsive eating. Next-generation sequencing could be used to clarify the genetic basis of obesity in the future.

Inflammatory bowel disease: an increased risk factor for recurrent laryngeal nerve palsy in thyroid surgery.

Transient or permanent recurrent laryngeal nerve palsy is a well known complication in thyroid surgery with reported incidences of 5-8% and 1-3%, respectively (1). Diplegia has an incidence of 0.4% (2). Inflammatory bowel disease (IBD) is an important cause of peripheral neurosensitivity, particularly autonomic neuropathy, which can lead to transient or permanent laryngeal nerve palsy when neural structures are involved during surgery. Several mechanisms have been implicated in the physiopathology of these neurological disorders, but the actual mechanism is still unknown. Herein we report on two patients with IBD presenting with transient bilateral recurrent laryngeal nerve palsy after total thyroidectomy without any evident mechanical or traumatic manoeuvres on apparently preserved nerves.

Serum ghrelin levels in growth hormone-sufficient and growth hormone-deficient patients during growth hormone-releasing hormone plus arginine test.

BACKGROUND AND AIMS: Ghrelin is an orexigenic hormone produced in the stomach and in other organs, exerting a wide range of metabolic functions, including stimulation of GH secretion. Ghrelin secretion is decreased by iv or oral glucose load as well as during euglycemic-hyperinsulinemic clamp and hypoglycemia. We evaluated the circulating ghrelin levels in GH-deficient (GHD) and in GH-sufficient (GHS) patients during GHRH plus arginine test. MATERIALS AND METHODS: The study group comprised 35 patients, including 20 with pituitary tumors, 12 with empty sella, 2 with short stature, and 1 with post-traumatic isolated GH deficiency. According to the results of GHRH plus arginine test, 14 patients were defined as GHD and 21 as GHS. Patients with central hypothyroidism, hypocorticism, and hypogonadism had been on replacement therapy for at least 3 months at the moment of the study. Blood samples were collected every 20 min up to 60 min after GHRH and arginine administration. RESULTS: By definition, GH response to GHRH plus arginine was higher in GHS than GHD group (p<0.0001). Basal serum ghrelin levels were not different in the two groups and did not correlate with body mass index, GH, IGFI and insulin concentrations. After GHRH plus arginine, serum ghrelin decreased significantly in both groups, with percent decreases ranging 13.3-66.6% in GHD patients (p=0.001) and 7.2-42.2% in GHS patients (p=0.004), with no significant difference in the two groups (p=0.12). CONCLUSION: Our results show that ghrelin secretion is not modulated by acute GH increase observed in GHS subjects during GHRH plus arginine infusion. The similar decrease of serum ghrelin after GHRH plus arginine stimulation in both GHS and GHD subjects demonstrated that there is no negative feedback of GH on ghrelin secretion.

Effectiveness of radioiodine (131-I) as definitive therapy in patients with autoimmune and non-autoimmune hyperthyroidism.

We evaluated the outcome of radioiodine (RAI) therapy in 100 consecutive patients treated in the period 2000-2001 for hyperthyroidism due to Graves' disease (GD), toxic adenoma (TA) and toxic multinodular goiter (TMG). Thyroid function was measured before and after therapy every 3-6 months up to 3 yr. Three years after therapy, 75% of TA patients were euthyroid, 18.7% were hypothyroid and 6.3% hyperthyroid. Of the TMG patients, 62.2% were euthyroid, 18.9% were hypothyroid and 18.9% hyperthyroid. In GD patients euthyroidism was achieved in 12.9% of the patients, hypothyroidism in 74.2% and hyperthyroidism persisted in 12.9%. Definitive hypothyroidism was significantly higher in GD (p<0.0001) than in TA and TMG patients. Overall, positive effect of RAI (definitive hypothyroidism or euthyroidism) was very high: 93.7% in TA, 81.1% in TMG and 87.1% in GD patients. Thyroid volume reduction was observed in all patients, but was higher in GD patients (mean reduction of 76%) and in TA patients (mean nodule reduction of 69%). In TMG, mean reduction was of 32%. The median activity of RAI received by the 86 cured patients was 555 MBq (15 mCi) compared to 407 Mbq (11 mCi) received by the 14 patients who remained hyperthyroid. No influence was found between outcome and clinical parameters at the moment of 131-I therapy. In conclusion, our results indicate that RAI therapy is highly effective and safe for the control of hyperthyroidism.

Cyclic Cushing's disease with paradoxical response to dexamethasone.

Cyclic Cushing's disease is an unusual disorder characterised by ACTH-dependent periodical increase of serum cortisol levels, clinically accompanied by peripheral edema, abnormalities of cardiac rhythm and hypokalemia. The condition may be unrecognised for years, since the typical features of Cushing's disease are usually absent due to the intermittent and brief duration of cortisol hypersecretion. We describe the case of a 42-yr-old man with Cyclic Cushing's disease due to an ACTH-producing pituitary macroadenoma, who presented two episodes of hypercortisolism in a 3-yr-period, clinically characterised by peripheral edema, hypokalemia and arrhythmia. The diagnosis was suspected because of a paradoxical increase of plasma ACTH and cortisol after dexamethasone administration during an asymptomatic period and was confirmed by pituitary imaging and by final histology after transphenoidal resection of the pituitary adenoma. After surgery, the patient resumed a normal pituitary-adrenal function with restoration of the normal ACTH and cortisol suppression after dexamethasone. Cyclic Cushing's disease should be considered in the differential diagnosis of several conditions characterised by recurrent episodes of idiopathic edema, hypokalemia or unexplained cardiac arrhythmia. In such patients, the pituitary-adrenal axis should be tested possibly during the acute phase of their disease or using the dexamethasone suppression test during asymptomatic intervals.

Effects of pravastatin treatment on vitamin D metabolites.

Hyperlipidemias, and notably hypercholesterolemia, represent important risk factors for atherosclerotic vascular disease. The enzymatic inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a selective and specific key enzyme involved in endogenous cholesterol synthesis, cause a significant mean reduction in low-density lipoprotein (LDL) cholesterol, both in familial and nonfamilial hypercholesterolemic forms. It has been hypothesized that these compounds might interfere with vitamin D endogenous synthesis secondarily to their effects on cholesterol. To verify this hypothesis, we studied 14 hypercholesterolemic patients treated as follows: 4 weeks of low-lipid, fiber-rich diet followed by 8 weeks of pravastatin treatment at the oral evening dose of 20 mg/d and by a 1-month washout period. No significant changes in serum calcium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were noticed; on the contrary, significant (P < 0.01) reductions in total cholesterol and LDL cholesterol and a significant (P < 0.05) increase in high-density lipoprotein cholesterol were observed. After the final 1-month washout period, all values returned to baseline levels. In conclusion, our study confirms the clinical efficacy of pravastatin on lipid fractions and demonstrates the absence of any interference on the circulating levels of the main vitamin D metabolites.