Cabergoline treatment for surgery-naïve non-functioning pituitary macroadenomas.

PURPOSE: The treatment strategy of non-functioning pituitary adenomas (NFPAs) includes surgery, radiotherapy, medical therapy, or observation without intervention. Cabergoline, a dopaminergic agonist, was suggested for the treatment of NFPA remnants after trans-sphenoidal surgery. This study investigates the efficacy of cabergoline in surgery-naive patients with NFPA. METHODS: Retrospective cohort study including surgery-naive patients with NFPA ≥ 10 mm, treated with cabergoline at a dose of ≥ 1 mg/week for at least 24 months. Patients with chiasmal damage were excluded. Data collected included symptoms, in particular visual disturbances, hormonal levels, tumor characteristics and size evaluated by MRI. Tumor growth was defined as an increase in maximal diameter of ≥ 2 mm, and shrinkage as reduction of ≥ 2 mm. RESULTS: Our cohort included 25 patients treated with cabergoline as primary therapy. Mean age was 63.3 ± 17.3 years, 56% (14/25) were males. Mean tumor size at diagnosis was 18.6 ± 6.3 mm (median 17 mm, range 10-36), and the average follow-up period with cabergoline was 4.6 ± 3.4 years. Out of the 25 tumors, five tumors (20%) decreased in size (mean decrease of 5.0 ± 3.0 mm), 12 tumors (48%) remained stable, and eight (32%) increased in size (mean growth of 5.0 ± 3.3 mm) with cabergoline treatment. During the first two years of cabergoline treatment, the median tumor size exhibited a reduction of 0.5 mm. Patients with an increase in tumor size had larger adenomas at diagnosis and a longer follow-up. Two patients (8%) underwent surgery due to tumor enlargement. CONCLUSION: Primary treatment with cabergoline is a reasonable approach for selected patients with NFPAs without visual threat.

IGF-1 levels may increase paradoxically with dopamine agonist treatment for prolactinomas.

OBJECTIVE: Hyperprolactinemia is common in acromegaly and in these patients, insulin-like growth factor (IGF)-1 level may decrease with dopamine agonist. We report a series of patients with prolactinoma and a paradoxical increase of IGF-1 levels during cabergoline treatment. METHODS: Clinical characteristics and response to treatment of patients with prolactinomas, in whom normal or slightly elevated baseline IGF-1 levels increased with cabergoline. RESULTS: The cohort consisted of ten prolactinoma patients (nine males, mean age 48 ± 14 years). Mean adenoma size was 23.8 ± 16.2 mm, with cavernous sinus invasion in eight. In five patients baseline IGF-1 levels were normal and in four levels were 1.2-1.5-fold the upper limit of the normal (ULN). One patient had IGF-1 measured shortly after initiating cabergoline and it was 1.4 × ULN. During cabergoline treatment (dose range 0.5-2 mg/week) PRL normalization was achieved in all and tumor shrinkage occurred in seven patients. The mean IGF-1 increase on cabergoline was 1.7 ± 0.4 × ULN. Cabergoline dose reduction or interruption was attempted in five patients and resulted in decreased IGF-1 levels in all, including normalization in two patients. Three patients were eventually diagnosed with acromegaly, one was referred for pituitary surgery followed by complete remission, another patient was switched to somatostatin analogue, and the third was treated by combination of somatostatin analogues with pegvisomant, with reduction of IGF-1 in all these patients. CONCLUSION: IGF-1 levels may increase to clinically significant levels during cabergoline treatment for PRL-adenoma. We suggest IGF-1 monitoring in all patients treated with dopamine agonists and not only in those presenting symptoms of acromegaly.

Calcium levels on admission and before discharge are associated with mortality risk in hospitalized patients.

AIM: Investigate the association of calcium levels on admission and change in levels during hospitalization with hospitalization outcomes. METHODS: Historical prospective data of patients hospitalized to units of internal medicine between 2011 and 2013. Albumin-corrected-calcium levels were classified to marked hypocalcemia (<7.5 mg/dL), mild hypocalcemia (7.5-8.5 mg/dL), normal calcium (8.5-10.5 mg/dL), mild hypercalcemia (10.5-11.5 mg/dL), marked hypercalcemia (>11.5 mg/dL). Main outcomes were length-of-hospitalization, in-hospital and long-term mortality. RESULTS: Cohort included 30,813 patients (mean age 67 ± 18 years, 51% male). Follow-up (median ± standard deviation) was 1668 ± 325 days. Most patients had normal calcium on admission (93%), 3% had hypocalcemia, 3% had hypercalcemia. Common causes for marked hypercalcemia were malignancy (56%) and hyperparathyroidism (22%). Last calcium levels before discharge or death were normal in 94%, with similar rates of hypercalcemia or hypocalcemia (3% each). Compared to in-hospital mortality with normal calcium on admission (6%), mortality was higher with mild (8%) and marked hypocalcemia (11%), and highest with mild (18%) and marked hypercalcemia (22%). Mortality rate at the end of follow-up was 48% with normal calcium or mild hypocalcemia, 51% with marked hypocalcemia, 68 and 79% with mild and marked hypercalcemia, respectively. Patients with normal calcium on admission and before discharge had the best prognosis. Hypercalcemia on admission or before discharge was associated with a 70% mortality risk at the end of follow-up. Normalization of admission hypercalcemia had no effect on long-term mortality risk. CONCLUSIONS: Abnormal calcium on admission is associated with increased short-term and long-term mortality. The excess mortality risk is higher with hypercalcemia than hypocalcemia. Calcium normalization before discharge had no effect on mortality.

[CLINICAL CHARACTERISTICS OF MALE PATIENTS WITH OSTEOPOROSIS REFERRED TO THE ENDOCRINE CLINIC OF A TERTIARY HOSPITAL].

INTRODUCTION: Osteoporosis in men is underdiagnosed and undertreated. The prevalence of male osteoporosis increases with age and it becomes a significant public health burden. Currently, there are a few clinical studies on male osteoporosis with limited knowledge of effective therapeutic options. AIMS: Our study aimed to characterize men with osteoporosis in a referral metabolic clinic in Rabin Medical Center at the Beilinson Campus. METHODS: In this study we retrospectively analyzed the medical records of 270 consecutive male patients with osteoporosis diagnosed and treated in our clinic during 2013. RESULTS: A total of 270 of 1940 (14%) patients with osteoporosis in our clinic were males. The mean age of men with osteoporosis was 67.9 ± 13.6; 113 (40%) men suffered from osteoporotic fractures, 57 of them (51%) had vertebral fractures, 28 (25%) had more than one fracture. Osteoporotic fracture was the first presentation of osteoporosis in 82% of men with fractures (age of presentation 62.2 ± 14.5). Furthermore, 141 patients (52%) had vitamin D insufficiency (25OHD levels < 60 nmol/l, normal 75-250 nmol/l), and the mean level was 39.9±12.6 nmol/l. Secondary osteoporosis was identified in 166 (61%) men. The most common etiologies were chronic glucocorticoid treatment (45%), hypogonadism (36%), hypercalciuria (23.4%) and hyperparathyroidism (19%). Most men (223) received bisphosphonates as primary therapy and alendronate was the mostly commonly prescribed agent. CONCLUSIONS: Osteoporosis in men usually remains an underdiagnosed disorder until an osteoporotic fracture occurs. Secondary causes for osteoporosis are commonly encountered, of which glucocorticoid treatment and hypogonadism are the most prevalent etiologies. Increasing awareness of osteoporosis in men may prevent the deleterious consequences of this disabling, yet treatable disease.

Thiazide Treatment in Primary Hyperparathyroidism-A New Indication for an Old Medication?

Context: There is no therapy for control of hypercalciuria in nonoperable patients with primary hyperparathyroidism (PHPT). Thiazides are used for idiopathic hypercalciuria but are avoided in PHPT to prevent exacerbating hypercalcemia. Nevertheless, several reports suggested that thiazides may be safe in patients with PHPT. Objective: To test the safety and efficacy of thiazides in PHPT. Design: Retrospective analysis of medical records. Setting: Endocrine clinic at a tertiary hospital. Patients: Fourteen male and 58 female patients with PHPT treated with thiazides. Interventions: Data were compared for each patient before and after thiazide administration. Main Outcome Measures: Effect of thiazide on urine and serum calcium levels. Results: Data are given as mean ± standard deviation. Treatment with hydrochlorothiazide 12.5 to 50 mg/d led to a decrease in mean levels of urine calcium (427 ± 174 mg/d to 251 ± 114 mg/d; P < 0.001) and parathyroid hormone (115 ± 57 ng/L to 74 ± 36 ng/L; P < 0.001), with no change in serum calcium level (10.7 ± 0.4 mg/dL off treatment, 10.5 ± 1.2 mg/dL on treatment, P = 0.4). Findings were consistent over all doses, with no difference in the extent of reduction in urine calcium level or change in serum calcium level by thiazide dose. Conclusion: Thiazides may be effective even at a dose of 12.5 mg/d and safe at doses of up to 50 mg/d for controlling hypercalciuria in patients with PHPT and may have an advantage in decreasing serum parathyroid hormone level. However, careful monitoring for hypercalcemia is required.

Pituitary imaging findings in male patients with hypogonadotrophic hypogonadism.

CONTEXT: Data on pituitary imaging in adult male patients presenting with hypogonadotrophic hypogonadism (HH) and no known pituitary disease are scarce. OBJECTIVE: To assess the usefulness of pituitary imaging in the evaluation of men presenting with HH after excluding known pituitary disorders and hyperprolactinemia. DESIGN: A historical prospective cohort of males with HH. PATIENTS: Men who presented for endocrine evaluation from 2011 to 2014 with testosterone levels <10.4 nmol/L (300 ng/mL), normal LH and FSH levels and no known pituitary disease. RESULTS: Seventy-five men were included in the analysis. Their mean age and BMI were 53.4 ± 14.8 years and 30.7 ± 5.2 kg/m2, respectively. Mean total testosterone, LH, and FSH were 6.2 ± 1.7 nmol/L, 3.4 ± 2 and 4.7 ± 3.1 mIU/L, respectively. Prolactin level within the normal range was obtained in all men (mean 161 ± 61, range 41-347 mIU/L). Sixty-two men had pituitary MRI and 13 performed CT. In 61 (81.3%) men pituitary imaging was normal. Microadenoma was found in 8 (10.7%), empty sella and thickened pituitary stalk in one patient (1.3%) each. In other four patients (5.3%) a small or mildly asymmetric pituitary gland was noted. No correlation was found between testosterone level and the presence of pituitary anomalies. CONCLUSIONS: This study suggests that the use of routine hypothalamic-pituitary imaging in the evaluation of IHH, in the absence of clinical characteristics of other hormonal loss or sellar compression symptoms, will not increase the diagnostic yield of sellar structural abnormalities over that reported in the general population.

Influence of number of deliveries and total breast-feeding time on bone mineral density in premenopausal and young postmenopausal women.

OBJECTIVES: Pregnancy and lactation have been associated with decline in bone mineral density (BMD). It is not clear if there is a full recovery of BMD to baseline. This study sought to determine if pregnancy or breast-feeding or both have a cumulative effect on BMD in premenopausal and early postmenopausal women. STUDY DESIGN: We performed single-center cohort analysis. Five hundred women aged 35-55 years underwent routine BMD screening from February to July 2011 at a tertiary medical center. Patients were questioned about number of total full-term deliveries and duration of breast-feeding and completed a background questionnaire on menarche and menopause, smoking, dairy product consumption, and weekly physical exercise. Weight and height were measured. Dual-energy X-ray absorptiometry was used to measure spinal, dual femoral neck, and total hip BMD. MAIN OUTCOME MEASURES: Associations between background characteristics and BMD values were analyzed. RESULTS: Sixty percent of the women were premenopausal. Mean number of deliveries was 2.5 and mean duration of breast-feeding was 9.12 months. On univariate analysis, BMD values were negatively correlated with patient age (p=0.006) and number of births (p=0.013), and positively correlated with body mass index (p<0.001). On multiple (adjusted) logistic regression analysis, prolonged breast-feeding duration, but not number of deliveries, was significantly correlated to a low BMD (p=0.008). An effect was noted only in postmenopausal women. The spine was the most common site of BMD decrease. CONCLUSIONS: Prolonged breast-feeding may have a deleterious long-term effect on BMD and may contribute to increased risk of osteoporosis later in life.

Clinical characteristics and outcome of familial nonmedullary thyroid cancer: a retrospective controlled study.

BACKGROUND: Familial nonmedullary thyroid cancer (FNMTC) is a disease defined by clustering of thyroid cancers of follicular cell origin, and it is estimated to account for 5% of all thyroid cancers. Several studies found FNMTC to be more aggressive than sporadic disease, whereas others found them to have a similar course and outcome. The purpose of this study was to determine whether FNMTC is more aggressive than sporadic thyroid cancer. METHODS: A retrospective controlled study of FNMTC versus sporadic nonmedullary thyroid cancers was conducted using a registry of patients with thyroid cancer. Data on disease severity at presentation, treatment modalities, and outcome were collected. RESULTS: Sixty-seven patients with FNMTC and 375 controls with sporadic disease were included. Follow-up period was 8.6 ± 10 years for patients with FNMTC and 8.4 ± 9.1 years for sporadic cases. Patients with FNMTC had comparable disease severity at diagnosis as sporadic patients, underwent similar surgical and radioiodine treatments, and had similar long-term disease-free survival. Long-term outcome in families with three or more affected relatives was similar to families with only two affected relatives. CONCLUSIONS: Our results suggest that FNMTC is not more aggressive than sporadic thyroid cancer within our studied population. After a similar therapeutic strategy, FNMTC and sporadic cases had comparable prognosis, including in families with three or more affected members.

Impact of pregnancy on outcome and prognosis of survivors of papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) commonly affects women of child-bearing age. During normal pregnancy, several factors may have a stimulatory effect on normal and nodular thyroid growth. The aim of the study was to determine whether pregnancy in thyroid-cancer survivors poses a risk of progression or recurrence of the disease. METHODS: The files of 63 consecutive women who were followed at the Endocrine Institute for PTC in 1992-2009 and had given birth at least once after receiving treatment were reviewed for clinical, biochemical, and imaging data. Thyroglobulin levels and neck ultrasound findings were compared before and after pregnancy. Demographic and disease-related characteristics and levels of thyroid-stimulating hormone (TSH) during pregnancy were correlated with disease persistence before conception and disease progression during pregnancy using Pearson's analysis. RESULTS: Mean time to the first delivery after completion of thyroid-cancer treatment was 5.08 ± 4.39 years; mean duration of follow up after the first delivery was 4.84 ± 3.80 years. Twenty-three women had more than one pregnancy, for a total of 90 births. Six women had evidence of thyroid cancer progression during the first pregnancy; one of them also showed disease progression during a second pregnancy. Another two patients had evidence of disease progression only during their second pregnancy. Mean TSH level during pregnancy was 2.65 ± 4.14 mIU/L. There was no correlation of disease progression during pregnancy with pathological staging, interval from diagnosis to pregnancy, TSH level during pregnancy, or thyroglobulin level before conception. There was a positive correlation of cancer progression with persistence of thyroid cancer before pregnancy and before total I-131 dose was administered. CONCLUSIONS: Pregnancy does not cause thyroid cancer recurrence in PTC survivors who have no structural or biochemical evidence of disease persistence at the time of conception. However, in the presence of such evidence, disease progression may occur during pregnancy, yet not necessarily as a consequence of pregnancy. The finding that a nonsuppressed TSH level during pregnancy does not stimulate disease progression suggests that it may be an acceptable therapeutic goal in this setting.

Illness perception in patients with differentiated epithelial cell thyroid cancer.

BACKGROUND: Patients with differentiated thyroid cancer (DTC) usually have a good prognosis but may experience a decline in quality of life (QOL). The way patients perceive their illness may have a major impact on their QOL. Our hypothesis was that patients with DTC frequently perceive their illness as much more severe than its objective clinical characteristics indicate. The aim of the study was to investigate how patients with DTC perceive their illness and to correlate these findings to various demographic parameters as well as objective indices of disease severity. METHODS: The self-administered Illness Perception Questionnaire-Revised (IPQ-R) was completed by consecutive patients with DTC during routine follow-up at the endocrine clinic. The questionnaire consists of three parts that measure different aspects of illness perception. The patients' medical records were reviewed for data on demographic parameters (sex, age) and indices of disease severity (duration of DTC, disease stage at diagnosis, number of operations, number of radioactive iodine treatments, and evidence of disease persistence/recurrence). The patients were also asked for additional data on family status, level of education, and employment status. Pearson and Spearman correlations and analysis of variance were used for statistical analysis. RESULTS: The study group included 110 patients (91 women) of mean age 53.5 years. Level of education was the only demographic factor found to affect the patients' perception of their illness. There was no correlation of patient illness perception and cancer stage. Among the disease-severity parameters, time since last treatment, evidence of disease persistence, and number of iodine treatments were significantly associated with a negative disease perception. Number of iodine treatments was the most broadly affecting factor. There was a high correlation of scores among the various illness perception subscales. CONCLUSIONS: Patients with DTC perceive their illness on a subjective, emotional basis unrelated to its actual severity. To improve patients' illness representations and, consequently, their QOL, a trained psychologist should be included in the multidisciplinary team that manages patients with DTC. Attention should be particularly directed to less-educated patients and patients who require repeated iodine treatments.

Well-differentiated thyroid carcinoma: comparison of microscopic and macroscopic disease.

BACKGROUND: The rapid increase in the incidence of well-differentiated thyroid cancer in recent years is the result of smaller thyroid tumors (1 cm or less) being diagnosed more frequently. Few studies are available regarding the appropriate approach to this previously known postmortem incidental finding, and their results remain controversial. METHODS: In 2005, our center started a registry of all patients with nonmedullary thyroid carcinoma who were followed at our institute. In the present study, data on the background, clinical, and outcome characteristics were collected from the registry for 225 patients with microscopic disease and 543 patients with macroscopic disease. RESULTS: Patients with microscopic disease were slightly older (51 vs. 47.5 years, p = 0.003), had a higher female to male ratio (189:37 vs. 419:123; p = 0.06), and were affected more by papillary carcinoma (98.2% vs. 85.5%; p < 0.001). Multifocal disease was documented in 50.2% of the patients with microscopic disease and 46.8% of the patients with macroscopic disease (NS), and bilateral disease, in 42.6% and 36.8%, respectively (NS). Corresponding rates for the two groups for other tumor-related factors were as follows: lymph node involvement at initial treatment, 25.7% and 30% (NS); distant metastases, 2.4% and 5.1% (p = 0.16); persistent/recurrent disease, 11% and 32% (p < 0.001); and new distant metastases, 2.65% and 6.5% (p = 0.07). At a median follow-up of 5 years, 96% of the microscopic carcinoma group were disease free compared to 77% of the macroscopic group (p < 0.001). CONCLUSION: The differences between patients with microscopic and macroscopic well-differentiated thyroid carcinoma may not justify a different therapeutic approach.

Clinical and biochemical stabilization of Nelson's syndrome with long-term low-dose cabergoline treatment.

We report the results of long-term (6-year) treatment of Nelson's syndrome with the long-acting dopamine agonist, cabergoline, in a 55-year-old woman. The disease presented 26 years after bilateral adrenalectomy and radiation treatment for Cushing's disease, followed by glucocorticoid and mineralocorticoid replacement therapy. Signs of Nelson's syndrome included skin and mucosal hyperpigmentation accompanied by elevated plasma levels of adrenocorticotropic hormone (ACTH) (984 pmol/l; normal, 2.0-11.5 pmol/l). Magnetic resonance imaging of the pituitary demonstrated sellar enlargement with a 15 mm macroadenoma. The patient was initially treated with bromocriptine (10 mg/d) which had no effect on either ACTH level or tumor mass. Because of visual loss, transsphenoidal surgery was performed, with partial excision of the adenoma and chiasmal decompression, followed by radiosurgery. However, ACTH levels improved only temporarily, and then increased to previous levels. Therefore, cabergoline treatment (1.5 mg/week) was initiated. ACTH levels decreased dramatically from 1050 to 132 pmol/l, accompanied by clinical improvement. Repeated imaging studies demonstrated a stable residual pituitary tumor. This case demonstrates that long-term cabergoline treatment may be efficient in patients with Nelson's syndrome.