ACTA ENDOCRINOLOGICA (BUC)

INTRODUCTION: The aim of our study was to evaluate the cure rate of macroprolactinomas treated for a long term (> 4 years) or a short term (<4 years) with dopamine agonists (DA) alone or combined with radiotherapy (RT). Sometimes pituitary\r\nsurgery was performed.\r\nMATERIAL AND METHODS: We performed a retrospective study in 111 patients with macroprolactinomas, hospitalized in the Institute of Endocrinology, Bucharest, between 1978-2005. There were two groups, according to the length of DA therapy: group\r\nA =41 patients, treated more than 4 years and group B =70 patients, treated less than 4 years. Overall, 25 patients underwent additional radiotherapy, 13 in group A and 12 in group B. 28 patients were submitted to pituitary surgery, 9 in group A and 19 in group B.\r\nRESULTS: The cure rate (i.e. normalization of prolactin=PRL level and absence or minimal residual tumor mass, stable minimum 2 years after DA withdrawal) was 5/41 (12.1%) in group A and none in group B. 48 out of 111 patients achieved significant improvement (serum prolactin level less than 20 ng/ml and tumor shrinkage more than 50%) during DA therapy, but not after DA withdrawal: 17/41patients (41.5%) in group A and in 31/70 patients (44.3%) in group B, p=NS. Radiotherapy produced an additional improvement: in serum PRL levels only in group A, in 4/13 patients- 2/8 patients responsive to DA therapy and 2/5 patients resistant to DA therapy. In group B, the 3 patients resistant to DA submitted to radiotherapy were evaluated before the interval necessary for maximal effect of radiotherapy, but in 4/9 patients responsive to DA, we noticed further reduction in tumor volume, 2/4 progressing from mild to significant tumor shrinkage and ? progressing from no shrinkage to mild shrinkage. After radiotherapy, the medium prolactin level was 5.1 ng/ml in 10 patients from both groups on low bromocriptine (BRC) dose (7.5 mg/day), significantly less than in patients without radiotherapy, i.e. than in 19 patients from group A (serum PRL 49.5 ng/ml, p=0.02) and in 29 patients from group B (serum PRL 30.3 ng/ml, p=0.01). So, the daily BRC dose could safely decrease from 30 mg/day to 7.5 mg/day in those patients previously submitted to radiotherapy. Among 23 patients resistant to initial DA treatment, only 8 patients were submitted to radiotherapy, 2 became responsive to DA thereafter and 2 others obtained a significant decrease of prolactin levels.\r\nCONCLUSIONS: The overall cure rate is quite low in prolactinomas and it was noticed only after long-term treatment with dopamine agonists; it was improved up to 12.1% by the additional high voltage radiotherapy, useful even in DA resistant cases. The addition of radiotherapy is indicated for the cure of most prolactinomas.

Background. In most type 1 and mixed forms of amiodarone-induced thyrotoxicosis (AIT), after restoration of euthyroidism and whether amiodarone can be withdrawn, an ablative therapy (thyroidectomy or radioiodine) is required. Radioiodine ablation of the thyroid was reported to prevent recurrence of AIT after amiodarone reintroduction.\r\nAims. To assess the efficacy and safety of radioiodine treatment in type 1 and mixed forms of AIT.\r\nPatients and methods. 9 patients (6M/3F) with type 1 and mixed form of AIT, mean age 62.2 ? 13.3 years (range: 50-85 years), pretreated with methimazole, received radioiodine treatment. The underlying thyroid disease was Graves disease (n= 5), toxic multinodular goiter (n= 3) and toxic adenoma (n=1). TSH, total T3, total T4, free T4, TPOAb were measured by radioimmunoassay; radioiodine uptake, thyroid ultrasonography, color flow Doppler ultrasonography were performed.\r\nResults. Multiple radioiodine doses were required in 4 out of 9 patients. Pretreatment 24 hours radioiodine uptake exceeded 10% in 12 out of 16 doses. Mean cumulative dose was 23.17 ? 17.48 mCi 131I (range 6-50 mCi). The period between amiodarone withdrawal and 131I administration was 11.72 ? 12.45 months (range: 2-41 months). Mean cumulative 131I dose was higher in AIT due to toxic multinodular goiter and toxic adenoma (30.25 ? 20.09, range: 11-50 mCi) versus Graves disease (17.5 ? 14.76, range: 6.5-40 mCi). In one patient with toxic adenoma, thyroidectomy was contraindicated due to a comorbidity-central core disease - a non-progressive congenital myopathy, associated with an increased risk for malignant hyperthermia. Hypothyroidism occurred in all patients but one (euthyroid), within 14 ? 3 months (range: 5-27) after the first radioiodine dose. Sinus rhythm was restored in 3 out of 5 patients. One case of radiation thyroiditis occurred after a single 6.5 mCi 131I dose.\r\nConclusion. Radioiodine ablation therapy is an effective and safe alternative in patients with type 1 and mixed forms of amiodarone-induced thyrotoxicosis. Since amiodarone should need sometimes to be restarted, post radioiodine hypothyroidism should be viewed as a goal rather than a complication.

Hyperosmolar hyperglycemic non-ketotic state is a life-threatening emergency manifested by a marked elevation of blood glucose, hyperosmolarity, and little or no ketosis. It most frequently develops in middle-aged or elderly patients, often in the setting of previously mild type 2 diabetes and in the presence of one of the established risk factors (e.g. infection, cerebrovascular accident, myocardial infarction). We present the case of a 48 years old woman with no past history of diabetes who developed hyperosmolar hyperglycemic nonketotic state after transsphenoidal surgery for a large macroprolactinoma. Despite having symptoms (secondary amenorrhoea and galactorrhoea) for many years the patient only had inconsistent medical follow-up and eventually she developed optic chiasm syndrome. She was referred for pituitary surgery performed by transsphenoidal route. After surgery there was marked improvement of the visual signs but few days after intervention the patient presented with polydipsia, polyuria and paresthesiae. Based on laboratory tests that showed a markedly elevated blood glucose level (1088 mg/dl), hyperosmolarity, no acidosis therefore, a diagnosis of hyperglycemic hyperosmolar state was made. With rehydration and insulinotherapy she recovered and the evolution was favourable over weeks with discontinuation of insulin administration. The patient still had high prolactin level after surgery (3060.3 ng/dl) so we also initiated dopamine agonist bromocriptine treatment. In addition to the well known effects of dopamine agonist upon prolactinoma it also has beneficial effects on glycemic control in diabetics (it reduces insulin resistance, both fasting and postprandial plasma glucose levels and HbA1c levels). We discuss the possible explanations of the syndrome and the effects of bromocriptine treatment.

OBJECTIVE: To report an unusual cause of respiratory failure in a 33-year old Caucasian woman, diagnosed at 26 years with pulmonary lymphangioleiomyomatosis (LAM) and treated with gonadoliberin analogs (aGnRH) four years.\r\nMETHODS: The respiratory failure was diagnosed on functional tests (spirometry, oxymetry, diffusing capacity of carbon monoxide). High resolution chest computed tomographic (HRCT) scan and open lung biopsy with specific immunohistochemistry certified the diagnosis.\r\nRESULTS: The diagnosis of pulmonary LAM was established after one year on chest HRCT and lung biopsy which revealed the proliferation of smooth muscle of pulmonary vessels, positive for actin, desmin, vimentin, estrogen- and progesterone- receptors. Spirometry revealed mixed obstructive and restrictive dysfunction. A correlation between worsening of dyspnea and estradiol peaks occurred during three gestation periods. Despite a short treatment with medroxyprogesterone 10 mg/day and tamoxifen (20 mg/day), the patient?s symptoms and pulmonary function tests worsened. aGnRH treatment improved both symptoms and pulmonary function tests during the first year and was associated with a slow decline in pulmonary function tests and stabilization of the cystic lesions during the following 3 years. The patient did not develop LAM-complications such as: pneumothorax, chylothorax, or hemoptysis.\r\nCONCLUSION: Treatment with aGnRH is effective in slowing the evolution of pulmonary LAM.

Aims: To assess if amiodarone maintains its antiarrhythmic efficacy in the presence of amiodarone-induced hyperthyroidism (AIT) and to identify the tri-iodothyronine (T3) threshold for atrial fibrillation in patients with AIT versus common hyperthyroidism.\r\nPatients and methods. Study group A consists in 49 patients (25 M/24 F) with AIT (220.83 ? 71.33 mg/day along 2.36 ? 2.25 years) and severe cardiopathies (9 valvulopathies, 40 ischaemic, dilatative and hypertensive cardiomyopathies), aged 57.87?12.63 years. Control group B consists in 51 hypothyroid (B1) or euthyroid patients (B2) treated with amiodarone (222.55 ? 68.78 mg/day along 2.67 ? 1.84 years) and also in 100 patients (23M/77F) with overt hyperthyroidism (B3), without major heart diseases, aged 52.74?12.85 years; TSH, total T3, total T4, free T4 were measured by radioimmunoassay. All were clinically, ECG and echocardiography evaluated.\r\nResults. Prevalence of arrhythmias recurrence was 59.2% (29/49 patients) in group A, significantly higher than in each control subgroups B: B1- 28% (7/25), B2- 15.45% (4/26) and B3- 20% (20/100), P< 0.001. Patients from study group A with AIT and T3 levels >250 ng/dL developed significantly more frequent atrial fibrillation (p= 0.04). However, in control group B3 with common hyperthyroidism, no T3 threshold for arrhythmias could be identified. Overall, there were no significant differences in total T3 levels with respect to the presence of atrial fibrillation in both study group A and subgroup B3 with common hyperthyroidism (p=ns).\r\nConclusion. Amiodarone antiarrhythmic efficacy is surpassed in AIT by the increased arrhythmic susceptibility of damaged myocardial tissue to minimally increased thyroid hormones levels. A tri-iodothyronine level > 250 ng/dL superimposed on preexistent proarrhythmic substrate in amiodarone-induced hyperthyroidism should be avoided.

Anthracyclines are used in breast cancer both in early and advanced stages and their recommendation together with taxanes, either concurrently or sequentially, is debatable and individualized by phenotype. Circulating biomarkers have already been introduced in clinical practice for metastatic disease monitoring. We questioned whether it might be a role for these markers in neoadjuvant and adjuvant settings too and a general review was conducted. CK18 and CTC were found predictive for anthracycline related response in preoperative setting. Soluble E-cadherin is promising, a retrospective analysis showing a direct correlation with clinical response. CEA, CA 15-3 and HER2 ECD are not of interest for their predictive role.

The subCarpathian areas of Arges county are now characterized by a moderate endemia of iodine deficiency disorders (IDD) due to salt iodization. However, we found some cases of endemic cretinism (EC), that is the major expression of anomalies in the physical and intellectual development caused by a severe iodine deficiency. There are presented 5 patients, 4 men and 1 woman, with neurological endemic cretinism (NEC) (n=2) and mixed forms of the disease (n=3), coming from 2 old endemic areas (medium urinary iodine excretion in the studied patients 20.8 g/day), diagnosed and treated in outpatients clinics or in hospitals. Four patients are members of the same family. The age of the patients is between 36 and 84 years old, the average age being 69. The intellectual capacity was assessed by using the Wechsler and Raven tests, the average intelligence quotient (IQ) value was of 20.8 points ? 1.47. The thyroid volumes (TV) were estimated by palpatory method and by ultrasonography and were between 8.7-200 ml. TSH values in studied patients ranged between 3.8-26 IU/ml and free T4 ranged between 0.272-1.22 ng/dl. Aggregation of more cases of endemic cretinism in the same family suggests the occurrence of some genetic factors. In conclusion, the old age (over 70 years old) of 4 cretins shows they are remnants of the old IDD endemia. However, there is also an isolated case of middle age (36 years old) suggesting an inadequate iodine intake, despite a law regarding salt iodization which has been operating since 1962. More attention to the universal salt iodization and to consumption of iodized salt in the rural areas is necessary.

An 18 years old, tall man presented for circumoral numbness, paresthesias, and hypocalcaemia, without carpopedal spasm or seizures. Previous medical history revealed bilateral cataract and osseous cysts on limbs at the age of 12. Hypocalcaemia resistant to calcium treatment and mild increased TSH levels were present. At diagnosis, we noticed a normal phenotype with tall stature, moderate hypocalcaemia (5.8 mg/dL), hyperphosphatemia (5.08 mg/dL) and significantly higher than normal intact parathormone (PTH) levels (518 pg/mL), in the presence of normal serum levels of 25-hydroxy vitamin D (53.56 ng/mL). The mother and the family members have been found in good health. All these data strongly suggested sporadic pseudohypoparathyroidism type Ib (PHP-Ib), but with some features of PHP - type Ia, like the osseous cysts. We were not able to perform molecular genetic tests. The nearly complete recovery of clinical and biochemical signs (normalization of PTH, calcaemia, phosphatemia, and a normal DXA osteodensitometry) after 2 years of chronic treatment with activated 1,25- dihydroxycholecalciferol (2.00-0.75 &#956;g/day) indirectly, but strongly confirmed the diagnosis of pseudohypoparathyroidism. The patient may have resistance to TSH evidenced by high TSH\r\n(range 4.8-7.5 mIU/L), with normal thyroid hormone levels, absence of goiter and normal TPO antibodies. The TRH test (400 &#956;g i.v.) showed a response of TSH, and also of serum thyroxine and triiodothyronine in a range that did not clarify the diagnosis. This association of the resistance to TSH with type Ib PHP was relatively recently reported by two groups (17,20) and before them it was reported only in PHP-Ia. Our patient also showed mild thrombocytopenia, with normal bleeding time, indicating also a possible Gs&#945; deficiency in platelets. In conclusion, our patient with sporadic pseudohypoparathyroidism without clinical phenotype of Albright hereditary osteodystrophy is highly suggestive for the type Ib PHP. A possible resistance to TSH and thrombocytopenia associated are features related to the genetic mechanisms found also in type Ia PHP. It is tempting to suggest that this case is one of the new variants of pseudohypoparathyroidism-Ib, recently reported.

Aims. To assess the impact of prognostic factors on the outcome of ovarian carcinoma (OC) and to determine the difference between pre and postmenopausal patients. Design. Retrospective cohort, single centre study Subjects and Methods. One-hundred-sixty patients with stage IC-IV OC diagnosed between 2004-2016 were included. Treatment consisted in primary surgery followed by adjuvant chemotherapy (n=127, 79.4%), neoadjuvant chemotherapy followed by surgery (n=27, 16.9%) and chemotherapy alone (3.7%). Results. At diagnosis 62 patients (38.8%) were premenopausal. Most patients presented with advanced OC (stage III/IV, 63.1%). After a median follow-up of 60 months, median progression free survival (PFS) for all stages was 36 months and median overall survival (OS) was 96 months. Postmenopausal patients had a poorer oncologic outcome compared with pre-menopausal women (PFS 24 vs. 72 months, p=0.0001, HR=2.32). Other clinical prognostic factors identified were performance status 1 vs. 0 (p=0.0001), ascites (p=0.027). Pathology prognostic factors were tumour grade (G1 vs. G2 and G3, p=0.0001) and endometrioid subtype compared to serous (p=0.008). Patients with residual disease after surgery had an increased risk of recurrence and death (HR=6.1, p=0.0001 and HR=4.2, p=0.0001). Conclusion. Premenopausal patients had a better oncologic long-term outcome and stage, ascites, grading, residual disease, were independent prognostic factors.