The aims of this study were to: 1) determine the prevalence of hyperprolactinaemia in patients with newly diagnosed subclinical and overt hypothyroidism, and 2) investigate the change in PRL levels with treatment. In this observational study, patients with a new diagnosis of hypothyroidism in our endocrinology clinic were approached for participation, as were healthy controls. Patients with medical reasons for having elevated PRL levels, lactating and pregnant women were excluded from the study. No patient had kidney or liver disease. After examination to determine if clinical causes of PRL elevation were present, serum levels of thyrotropin (TSH), free thyroxine, free triiodothyronine and PRL were measured and correlation of PRL levels with the severity of hypothyroidism (overt or subclinical) was performed. Fifty-three patients (45 women, 8 men, mean age 45.3±12.2 years) had overt hypothyroidism. One hundred forty-seven patients (131 women, 16 men, mean age 42.9±12.6 years) had subclinical hypothyroidism. One hundred healthy persons (85 women, 15 men, mean age 43.9±11.4 years) participated as controls. The same blood tests were repeated in patients after normalization of TSH levels with L-thyroxine treatment. PRL elevation was found in 36% of patients with overt hypothyroidism, and in 22% of patients with subclinical hypothyroidism. PRL levels decreased to normal in all patients after thyroid functions normalized with L-thyroxine treatment. In the hypothyroid patients (overt and subclinical) a positive correlation was found between TSH and PRL levels (r=0.208, p=0.003). PRL regulation is altered in overt and subclinical hypothyroidism, and PRL levels normalize with appropriate L-thyroxine treatment.

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The prevalence of menstrual disturbances, including secondary amenorrhea, hypomenorrhea, oligomenorrhea, hypermenorrhea, polymenorrhea and irregular menstrual cycle were prospectively examined in 586 patients with hyperthyroidism due to Graves’ disease, 111 with hypothyroidism, 558 with euthyroid chronic thyroiditis, 202 with painless thyroiditis and 595 with thyroid tumor. In the overall patient group, the prevalence did not different from that in 105 healthy controls. However, patients with severe hyperthyroidism showed a higher prevalence of secondary amenorrhea (2.5%) and hypomenorrhea (3.7%) than those (0.2% and 0.9%, respectively) with mild or moderate hyperthyroidism. Moreover, patients with severe hypothyroidism had a higher prevalence (34.8%) of menstrual disturbances than mild-moderate cases (10.2%). Menstrual disturbances in thyroid dysfunction were less frequent than previously thought.

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Diabetes insipidus is a rare disorder in pregnant women, predating pregnancy or appearing for the first time during gestation. In pregnancy it usually affects women with HELLP syndrome or acute fatty liver of pregnancy and results from the reduced hepatic degradation of placental vasopressinase leading to its increased activity. Although infiltrative diseases have been found to cause diabetes insipidus in non-pregnant population, very few studies showed that these disorders may manifest for the first time during gestation. We describe here the case of transient diabetes insipidus in two subsequent pregnancies of a female with hemochromatosis. The first symptoms of this disease appeared for the first time at the beginning of the third trimester of her second pregnancy, and diagnosis was established on the basis of typical clinical presentation, confirmed by a water deprivation test. Diabetes insipidus resulted from the increased activity of vasopressinase, caused by hemochromatosis-induced liver dysfunction, the presence of which was confirmed between the pregnancies by liver biopsy and identification of the HFE gene mutation. Subsequent desferrioxamine treatment resulted in a less severe clinical course of diabetes insipidus in the last patient’s pregnancy. In both pregnancies, the patient was successfully treated with oral desmopressin, which is resistant to degradation by placental vasopressinase. Although unrecognized pituitary disorders may pose a serious health problem to the mother and fetus, hemochromatosis-induced diabetes insipidus, as the case of our patient demonstrates, if effectively diagnosed and treated, cannot be regarded as a contraindication for pregnancy.

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Oxidative stress and consequent oxidized lipoprotein production is thought to play a central role in both the initiation and progression of atherosclerosis. Oxidized low-density lipoprotein (oxLDL)/β2-glycoprotein I (β2GPI) complexes are etiologically important in the development of atherosclerosis. The aim of the present study was to investigate whether long-term treatment with conventional hormone replacement therapy (HRT) in postmenopausal women could affect total serum antioxidant capacity (TAC) and serum levels of oxLDL/β2GPI complexes. A total of 60 normolipidemic postmenopausal women treated with oral estrogen together with progestin therapy for 3 months were selected. TAC and serum levels of oxLDL/β2GPI complexes were measured at the beginning and end of the HRT. HRT led to a significant increase in TAC (15%, P=0.02) and a minor but statistically nonsignificant decrease of oxLDL/β2GPI complexes (3%, P=0.30) when compared with the baseline control levels. There was also no significant association between TAC and oxLDL/β2GPI complexes changes related to HRT. This study indicates that, HRT in postmenopausal women leads to an increase in TAC without an equivalent change in serum levels of oxLDL/β2GPI complexes. It is concluded that beneficial effects of HRT could be explained, at least in part, by improving antioxidant status, but may not be directly associated with a change in oxidized lipoprotein production.

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Therapeutic effects of presurgical long-acting octreotide treatment on tumor shrinkage, and short- and long-term postoperative GH and IGF-1 levels of acromegaly patients with invasive pituitary macroadenomas were investigated prospectively in Huashan Hospital, Shanghai, China. Thirty-nine untreated acromegaly patients, all with invasive pituitary macroadenomas, were randomly divided into two groups: experimental group (n=19), and control group (n=20). Patients in the experimental group received a three-month course of long-acting octreotide treatment before transsphenoidal surgery; the control group underwent surgery directly. Tumor shrinkage after drug treatment and short- and long-term postoperative GH and IGF-1 levels were analyzed in the two groups. Long-acting octreotide treatment reduced tumor size from 7893 ± 6450 to 4794 ± 4682 mm³. Mean shrinkage rate was 37.4 ± 30.9%. GH and IGF-1 levels of the experimental group were lower than the control group at 3 months, 6 months after surgery, and after long-term follow-up. Remission rate (both GH and IGF-1 normal) of the experimental group was higher at 3 and 6 months follow-up, but exhibited no advantage in long-term follow-up. In the experimental group, the total resection rate was higher in patients whose Hardy-Knosp grading decreased to ≤ 2 than those whose Hardy-Knosp grading is still ≥ 3 after drug pretreatment. In conclusion, presurgical long-acting octreotide treatment effectively reduces tumor size and invasion, which helps enhance early remission rates of invasive macroadenomas by transsphenoidal surgery, but does not appear to improve the long-term cure rate.

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Tumor localization is difficult in patients with medullary thyroid carcinoma (MTC) that have persistent hypercalcitoninemia after thyroidectomy. In this study, the ¹¹C-methionine positron emission tomography/computed tomography (PET/CT) was compared with the ¹⁸F-FDG PET/CT for diagnostic sensitivity in detecting residual or metastatic disease. ¹¹C-methionine PET/CT and ¹⁸F-FDG PET/CT were performed on 16 consecutive patients with MTC that had persistent hypercalcitoninemia after surgery in this prospective, single-center study. Patient- and lesion-based analyses were performed using a composite reference standard which was the sum of the lesions confirmed by all combined modalities, including neck ultrasonography (US) with or without fine needle aspiration cytology, CT, bone scan, magnetic resonance imaging (MRI), and surgery. By patient-based analysis, the sensitivities of ¹¹C-methionine PET/CT and ¹⁸F-FDG PET/CT were both 63%. By lesion-based analysis, the sensitivity of ¹¹C-methionine PET/CT was similar to ¹⁸F-FDG PET/CT (73% vs. 80%). Excluding hepatic lesions, which could not be detected because of physiological uptake of methionine by the liver, the sensitivity of ¹¹C-methionine PET/CT was better than ¹⁸F-FDG PET/CT especially for detecting cervical lymph node lesions; however, it was not superior to US. All patients with serum calcitonin levels ≥370 pg/mL showed uptake by ¹¹C-methionine PET/CT and ¹⁸F-FDG PET/CT. This preliminary data showed that despite its similar sensitivity to ¹⁸F-FDG PET/CT for detecting residual or metastatic MTC, ¹¹C-methionine PET/CT provided minimal additional information compared to combined ¹⁸F-FDG PET/CT and neck US.

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Testotoxicosis, also known as familial male-limited precocious puberty, is an autosomal dominant form of gonadotropin-independent precocious puberty caused by heterozygous constitutively activating mutations of the LHCGR gene encoding the luteinizing hormone/choriogonadotropin receptor (LH/CGR). The patient is an 8-year-old boy who started to develop pubic hair and penile enlargement at 6 years of age. The patient had elevated serum testosterone levels, but initially exhibited a prepubertal response of gonadotropins to GnRH, which was followed by central activation of the hypothalamo-pituitary-gonadal axis. The father reported having experienced precocious puberty, and is 158 cm tall. There is no history of short stature and precocious puberty in the family except for the father. The LHCGR gene was analyzed by direct DNA sequencing of amplified PCR products from the patient and his parents. The wild-type and mutant LH/CGRs were transiently expressed in COS-1 cells and cAMP levels in the cells were determined with or without hCG stimulation. Genetic analysis revealed a novel C617Y mutation of the LHCGR gene in the patient and his mother, while his father had no mutations. Functional expression study demonstrated around 15% increase in the basal intracellular cAMP level in cells expressing the mutant LH/CGR compared with that in cells expressing the wild-type receptor. We have reported the first missense C617Y mutation located in the 7th transmembrane segment of LH/CGR causing testotoxicosis. The modest phenotype of our patient may be explained, at least in part, by the modest increase in the intracellular cAMP level caused by the C617Y mutation.

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Ectopic ACTH syndrome (EAS) is a diagnostic challenge because it is often indistinguishable from Cushing’s disease. We describe our series of EAS patients referred to us during 1992-2009. Among 16 cases (9 females / 7 males), with mean age of 58.4 ± 19.0yr, the ectopic source was identified in ten (proven EAS), whereas unidentified in six (occult/unknown EAS). Their salient clinical manifestations included Cushingoid feature (88%), skin pigmentation (88%), profound hypokalemia (88%), hypertension (75%), diabetes/impaired glucose tolerance (75%), hyperlipidemia (69%), and severe infection (44%). Dynamic endocrine tests revealed markedly elevated plasma ACTH levels (211 ± 116pg/mL) and cortisol levels (60.9 ± 30.1μg/dL) which showed resistance to overnight high-dose (8mg) dexamethasone suppression test in 15 (94%) and unresponsiveness to CRH stimulation in 12 (75%). No ACTH gradient during inferior petrosal sampling was noted in 13 of 15 (87%). Imaging tests by CT/MRI identified the tumors in 8 of 16 (50%), in 4 of 11 (36%) and 4 of 6 (66.7%) octreotide-responders by somatostatin receptor scintigraphy, but in only one of 9 (11.1%) by FDG-PET scan. Six cases deceased, including small cell carcinoma (2) and adenocarcinoma (1) of lung, neuroendocrine carcinoma of pancreas (1) and stomach (1), and olfactory neuroblastoma (1), whereas 4 cases survived after removal of the tumors, including bronchial carcinoid tumor (3) and thymic hyperplasia (1). Six occult/unknown EAS patients survived for 67.5 months after medical treatment with metyrapone to control hypercortisolism. Thus, various endocrine tests combined with imaging studies are required to correctly localize the tumors. Control of hypercortisolemia by metyrapone, even if tumor is unrecognized, is critical for better prognosis, and the long-term follow-up by repeated endocrine and imaging tests is mandatory.

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GH secretion is mainly regulated at the hypothalamus by a dual interplay between growth hormone releasing hormone (GHRH) and somatostatin, which are modulated by various factors. We examined the regulatory mechanism of GH secretion in an apparently healthy young man without decreased IGF-1 concentration and nocturnal GH secretion, but who showed low responses to insulin tolerance (ITT) and to GHRP-2 tests. The patient also had no GH response to acute aerobic exercise. However, he had normal secretion of pituitary hormone based on hypothalamic releasing hormone tests combined with CRH, GRH as GHRH, LH-RH and TRH. In addition, he had a GH response without paradoxical secretion to TRH stimulation as well as an ACTH response to subcutaneous glucagon stimulation, and AVP secretion responded to 5% hypertonic saline infusion, though it was not adequately stimulated by ITT. MRI showed no structural abnormalities in the hypothalamus-pituitary gland. These findings indicate that this subject may have an undiscovered neurocircuit for regulating GH secretion, as well as other neurohormones, to maintain homeostasis, even though there were low responses of the hormones to ITT and GHRP-2 stimuli, probably via altered secretion of hypothalamic hormones.

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Some benign thyroid nodules are stationary in size over time while others grow progressively, indicating that there is a broad individual variability within benign nodules. To date, it is very difficult to predict if a benign thyroid nodule will grow in size and which will be its trend over time. While BRAF^V600E is a highly specific marker of thyroid cancer, RET rearrangements have been disclosed also in non malignant thyroid lesions and their biological significance is debated. We compared the clinical history of three histologically benign thyroid nodules harboring RET rearrangements with that of 6 benign nodules bearing wild type RET. The nodules negative for RET rearrangements were followed for 10 years by ultrasonographic evaluation, showing a slow, constant enlargement. Three patients with benign nodules diagnosed at FNAC, were followed for 11, 9 and 7 years by annual ultrasonographic evaluation. After several years of latency, the nodules had an unexpected and gradual increase in their dimensions, reaching a large final size. A second FNAC confirmed the previous cytologic diagnosis of benign lesion. Because of the increasing size of the nodules, the patients were advised to surgery. Before undergoing thyroidectomy, we performed molecular diagnostic tests that revealed the absence of BRAF^V600E and the presence of RET/PTC-1 in one nodule and RET/PTC-3 in the two others. Despite the presence of this oncogene, the samples were histologically classified as benign hyperplastic nodules. These findings lead us to speculate that histologically benign hyperplastic thyroid nodules containing RET rearrangements might represent a subgroup of nodules with a rapid size increase.

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Figure 2 contains some typographical errors.

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