Insulin resistance during androgen deprivation therapy in men with prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear. METHODS: The ADT & Metabolism Study was a single-center, 24-week, prospective observational study that enrolled ADT-naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non-ADT group, n = 23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks. RESULTS: At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], -2.10 to 4.43; p = .47) or skeletal muscle (-3.2; 95% CI, -7.07 to 0.66; p = .10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non-ADT group. Men undergoing ADT gained 3.7 kg of fat mass. CONCLUSIONS: In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short-term ADT.

Gaining metabolic insight in older men undergoing androgen deprivation therapy for prostate cancer (the ADT & Metabolism Study): Protocol of a longitudinal, observational, cohort study.

Androgen deprivation therapy (ADT), a cornerstone of treatment for patients with locally advanced and metastatic prostate cancer, is associated with many adverse effects, including osteoporosis, sexual dysfunction, fatigue, and vasomotor symptoms. It is also associated with loss of muscle mass and increased adiposity. This change in body composition is likely the inciting event in the development of insulin resistance, an independent risk factor for diabetes mellitus and cardiovascular disease. Although the occurrence of insulin resistance during ADT has been reported, it remains unclear whether this insulin resistance is primarily hepatic or muscular. Similarly, the mechanisms that lead to insulin resistance also remain unknown. The ADT & Metabolism Study was designed to address these knowledge gaps, as the elucidation of the predominant site of insulin resistance will allow prevention strategies and the use of targeted, tissue-specific insulin-sensitizing agents in patients undergoing ADT. This prospective, mechanistic, single-center, 24-week, observational cohort study will enroll treatment-naïve adult men with prostate cancer about to undergo surgical or medical ADT for at least 24 weeks (ADT group; n = 50) and a control group of men who had undergone radical prostatectomy and are in remission (non-ADT group, n = 25). The primary outcome is to determine the site of insulin resistance (skeletal muscle or liver) using frequent sampling oral glucose tolerance test at baseline and 12 and 24 weeks after commencement of ADT (ADT group) or after enrollment in the study (non-ADT group). Secondary outcomes will assess changes in hepatic and intramyocellular fat (using magnetic resonance spectroscopy), inflammatory markers, adipokines, free fatty acids, and changes in body composition (assessed using dual-energy x-ray absorptiometry) and their correlation with the development of insulin resistance. Exploratory outcomes will include changes in muscle performance, physical function, physical activity, vitality, and sexual drive.

Lack of an effect of high dose isoflavones in men with prostate cancer undergoing androgen deprivation therapy.

PURPOSE: The profound hypogonadism due to androgen deprivation therapy for prostate cancer results in complications such as sexual dysfunction, poor quality of life, vasomotor symptoms and altered cognition. Since estrogen is associated with cardiovascular risks, phytoestrogens are being increasingly evaluated as a potential treatment for these adverse effects. We evaluated the effects of high dose isoflavones, equivalent to that consumed by Asian populations, on the aforementioned consequences of androgen deprivation therapy. MATERIALS AND METHODS: A total of 33 men undergoing androgen deprivation therapy for prostate cancer were enrolled in this randomized, double-blind, placebo controlled, 12-week pilot trial. Participants were randomly assigned to receive 20 gm soy protein containing 160 mg total isoflavones (17) vs taste matched placebo, that is 20 gm whole milk protein (16). The study was performed at a tertiary care center in the United States. RESULTS: At baseline the groups were well matched in demographic parameters, sleep quality, cognition and overall quality of life. However, men in the isoflavone group had a higher baseline prevalence of hot flashes and poor intercourse satisfaction compared to those on placebo. At 12 weeks there were no significant differences between the 2 groups in any outcome measure. CONCLUSIONS: This pilot study of high dose isoflavones in androgen deprived men showed no significant improvement in cognition, vasomotor symptoms or any other aspect of quality of life measures compared to placebo. Future studies should use variable doses of isoflavones for a longer period before ruling out beneficial isoflavone effects in this population.

Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis.

CONTEXT: Prostate cancer (PCa) is the most common cancer in men. Androgen-deprivation therapy (ADT) is generally employed in the treatment of locally advanced and metastatic PCa. Although its use as an adjuvant therapy has resulted in improved survival in some patients, ADT has negative consequences. Complications like osteoporosis, sexual dysfunction, gynecomastia, and adverse body composition are well known. Recently, metabolic complications like insulin resistance, diabetes, dyslipidemia, and metabolic syndrome have emerged, which may be responsible for the increased cardiovascular mortality in this population. EVIDENCE ACQUISITION: A MEDLINE search was conducted for articles published over the last 20 yr based on the key words androgen deprivation therapy AND insulin resistance, hyperglycemia, diabetes, dyslipidemia, metabolic syndrome, and cardiovascular disease. Relevant studies in non-PCa populations evaluating the association between testosterone and metabolism were also reviewed and briefly mentioned where relevant. EVIDENCE SYNTHESIS: Prospective studies evaluating early (3-6 months) metabolic changes of ADT show development of hyperinsulinemia; however, glucose levels remain normal. Cross-sectional studies of men undergoing long-term (> or =12 months) ADT reveal higher prevalence of diabetes and metabolic syndrome compared with controls. Furthermore, men undergoing ADT also experience higher cardiovascular mortality. CONCLUSION: Long-term prospective studies of ADT are needed to determine the timing of onset of these metabolic complications and to investigate the mechanism behind them. In the meantime, we recommend baseline and serial screening for fasting glucose, lipids, and other cardiovascular risk factors in men receiving ADT. Glucose tolerance tests and cardiac evaluation may be required in selected cases.

Circulating inflammatory cytokine expression in men with prostate cancer undergoing androgen deprivation therapy.

Prostate cancer (PCa) is one of the most common cancers in men. Androgen deprivation therapy (ADT) is employed in the treatment of patients with metastatic or recurrent PCa, resulting in castrate levels of testosterone. Recent studies have shown that male hypogonadism is associated with increased levels of proinflammatory and diminished concentrations of anti-inflammatory cytokines, which normalize upon testosterone treatment. Furthermore, an inflammatory state is associated with osteoporosis, sarcopenia and metabolic abnormalities. We examined 3 groups of men: 1) 20 men with PCa undergoing ADT for at least 12 months prior to the onset of the study (ADT group); 2) 18 age-matched men with non-metastatic PCa who had undergone local surgery and/or radiotherapy and had not yet received ADT and were eugonadal (non-ADT group); and 3) 20 age-matched healthy eugonadal men (control group). None of the subjects were suffering from any acute or chronic inflammatory conditions. Mean age was similar in the 3 groups (P = .41). Men in the ADT and non-ADT groups had higher BMI compared to the control group (P = .0005 and P = .01, respectively). Men in the ADT group had significantly lower mean serum total (P < .0001) and free (P < .0001) testosterone and estradiol (P < .0001) levels compared to the other 2 groups. No significant differences in serum levels of pro-inflammatory or anti-inflammatory cytokines were observed between the 3 groups. These data suggest that men with PCa undergoing long-term ADT do not have elevated levels of pro-inflammatory cytokines compared to age and disease matched controls. Prospective studies are needed to evaluate for any acute changes in these inflammatory markers that might occur after the initiation of ADT.

Endocrine complications of androgen-deprivation therapy in men with prostate cancer.

Prostate cancer is one of the most common cancers in men. Androgen-deprivation therapy (ADT) is often employed in the treatment of recurrent and metastatic prostate cancer. Although its use as an adjuvant therapy has resulted in improved survival in a subset of patients, ADT also results in a multitude of endocrine complications. These complications affect quality of life and sense of well-being in these men. Some of the endocrine complications of ADT such as osteoporosis, sexual dysfunction, hot flashes, gynecomastia, and adverse body composition are well-known. Recently, insulin resistance, hyperglycemia, and metabolic syndrome have emerged as metabolic complications of castration and may be responsible for increased cardiovascular mortality in this population. In this article, we provide a detailed review of the endocrine complications of ADT, touching upon management strategies where applicable.

Clinical review 158: Beyond radioiodine: a review of potential new therapeutic approaches for thyroid cancer.

One of the greatest challenges in the management of patients with follicular cell-derived thyroid cancer is the treatment of tumors that progress despite surgery, radioiodine, and T(4) suppression of TSH. As knowledge of thyroid cancer biology improves, the potential exists to develop compounds targeted to treat thyroid cancers that do not respond to traditional therapy. Recently, the development of therapies targeted against specific molecular pathways involved in cancer progression has resulted in dramatic responses in patients with chronic myelogenous leukemia, gastrointestinal stromal tumors, and other cancers. A number of compounds are currently being evaluated in clinical trials that alter pathways involved thyroid cancer, and several of these agents have been tested in thyroid cancer in vitro and in vivo. In this review we will discuss the mechanisms of action and preclinical/clinical data for several of these compounds that have the potential to play an important role in the management of thyroid cancer in the future.

17-Allylamino-17-demethoxygeldanamycin activity against thyroid cancer cell lines correlates with heat shock protein 90 levels.

Heat shock protein 90 (Hsp90) is a molecular chaperone that stabilizes growth factor receptors and signaling molecules. Disruption of this action inhibits the MAPK and phosphatidylinositol-3 kinase cascades and can induce cancer cell death. The goal of this study was to determine whether thyroid cancer cells are sensitive to the cytotoxic effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor in clinical trials, and to determine predictors of this response. Papillary (NPA), follicular (WRO), and anaplastic (ARO) thyroid cancers were incubated with 17-AAG in vitro. Surprisingly, the ARO cells were most sensitive to the cytotoxic effects of this agent. Conversely, all cell lines displayed similar responses to specific blockers of phosphatidylinositol-3 kinase and MAPK kinase (LY294002 and U0126, respectively). Western blot demonstrated that the NPA cells that were most resistant to 17AAG-induced cytotoxicity had the lowest levels of Hsp90 and were the only cells with persistent levels of Akt protein. Interestingly, even the WRO and ARO cell lines that were sensitive to 17-AAG-induced cell death did not undergo apoptosis. These data suggest that sensitivity of thyroid cancer cells to 17-AAG-induced cytotoxicity relates to Hsp90 levels rather than histological subtype and that thyroid cancer cells have a reduced apoptotic response to 17-AAG.

Preoperative embolization of thyroid arteries in a patient with large multinodular goiter and papillary carcinoma.

We herein report the case of a 51-year-old woman, who presented with a large goiter (250-300 g on palpation) with extension to the mediastinum and compression of the trachea causing dyspnea and with associated lumbar pain. Although two fine-needle aspiration biopsies of the gland were negative, a biopsy of a lesion in the spine shown on computed tomography (CT) scan was positive for metastatic papillary thyroid carcinoma. Because of the extent of the goiter and the potential of significant blood loss, total thyroidectomy was considered to be high risk. In an attempt to reduce the goiter size and try to minimize surgical risks, preoperative embolization with polyvinyl alcohol in an emulsion with histoacryl particles was performed 7 days before surgery under conventional angiography. This procedure allowed a significant reduction in blood perfusion to the gland, which resulted in a decrease on the size of the goiter facilitating surgical removal of the gland.

A rare cause of pituitary stalk enlargement and panhypopituitarism.

Pituitary stalk involvement is seen in a variety of medical conditions such as infectious diseases, infiltrative diseases and tumors (intracranial and metastatic). Metastatic cancer has a greater propensity to involve the infundibulum and neurohypophysis. We report a case of a 68-year-old man who presented with thickening of the stalk, panhypopituitarism, diabetes insipidus and generalized lymphadenopathy. Lymphoma was diagnosed on axillary lymph node biopsy and lymphomatous involvement of the infundibulum was suspected. Although infundibular thickening resolved and diabetes insipidus improved after chemotherapy, panhypopituitarism persisted.

[Treatment of autonomous and cystic thyroid nodules with intranodular ethanol injection]. / Tratamento de nódulos autónomos e císticos da tireóide com injeção intranodular de etanol.

UNLABELLED: Intranodular ethanol injection has been used for the past 10 years as an efficient modality for treating patients with thyroid nodules. Several studies have reported the success of this therapy in autonomous and cystic nodules and, more recently, in cold benign nodules. PURPOSE: To evaluate the efficacy of this therapeutic modality on the treatment of autonomous and cystic thyroid nodules. METHODS: 42 patients (26 with cystic and 16 with autonomous nodules) were treated with ultrasound guided intranodular 99% ethanol injection and followed for 6 months. RESULTS: No major complications were observed during or after treatment, however, most of the patients reported slight to moderate pain and/or discomfort after the injection. Most of the nodules showed reduction after the treatment. Autonomous nodules had a mean reduction of 50.3% and cystic nodules of 69.3%. No significant differences in pretreatment serum total T3, total T4 or TSH were observed among the patients in the cystic group. Patients in the autonomous group with hyperfunctioning nodules showed a decrease in serum total T3, total T4 and an increase in serum TSH levels, hence, proving the effectiveness of this therapy. CONCLUSIONS: Intranodular ethanol injection is a safe and efficient treatment for autonomous and cystic nodules of the thyroid.

Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy.

PURPOSE: Prostate cancer (PCa) is one of the most common cancers in men. Men with recurrent or metastatic PCa are treated with androgen-deprivation therapy (ADT), resulting in profound hypogonadism. Because male hypogonadism is a risk factor for metabolic syndrome and men with PCa have high cardiovascular mortality, we evaluated the prevalence of metabolic syndrome in men undergoing long-term ADT. PATIENTS AND METHODS: This was a cross-sectional study. We evaluated 58 men, including 20 with PCa undergoing ADT for at least 12 months (ADT group), 18 age-matched men with nonmetastatic PCa who had received local treatment and were recently found to have an increasing prostate-specific antigen (non-ADT group), and 20 age-matched controls (control group). Men in the non-ADT and control groups were eugonadal. Metabolic syndrome was defined according to the Adult Treatment Panel III criteria. RESULTS: Mean age was similar among the groups. Men on ADT had significantly higher body mass index and lower total and free testosterone levels. The prevalence of metabolic syndrome was higher in the ADT group compared with the non-ADT (P < .01) and control (P = .03) groups. Among the components of metabolic syndrome, men on ADT had a higher prevalence of abdominal obesity and hyperglycemia. Androgen-deprived men also had elevated triglycerides compared with controls (P = .02). The prevalence of hypertension and low high-density lipoprotein levels were similar. CONCLUSION: These data suggest that metabolic syndrome was present in more than 50% of the men undergoing long-term ADT, predisposing them to higher cardiovascular risk. Abdominal obesity and hyperglycemia were responsible for this higher prevalence. We recommend prospective studies to further delineate this association.

Pseudo-central hypothyroidism.

Central hypothyroidism is an exceedingly rare form of hypothyroidism that results from a variety of conditions affecting the hypothalamus and the pituitary gland. The classic biochemical abnormality seen in these patients includes a low serum level of circulating thyroxine (T4) concomitant with an inappropriately low level of thyrotropin. Because patients with isolated triiodothyronine (T3) toxicosis also present with this biochemical pattern, it is important to measure T3 levels in such patients before making a diagnosis of central hypothyroidism.

Sonographically guided percutaneous ethanol treatment of a symptomatic complex nodule with a large cystic component in a patient with thyroid hemiagenesis.

Thyroid hemiagenesis is a rare anomaly that is usually discovered incidentally during the evaluation of unrelated thyroid disorders. We present the case of a patient with hemiagenesis of the left thyroid lobe and a large, recurrent, symptomatic complex nodule with a large cystic component that occupied most of the right lobe. She had previously undergone multiple unsuccessful aspirations of the cyst. The patient was successfully treated with an intranodular injection of ethanol under sonographic guidance. The success of this procedure resulted in the resolution of symptoms and avoidance of surgical resection of the right lobe, with resulting hypothyroidism. We recommend that ethanol injections be considered for treatment of symptomatic cystic or benign solid nodules in patients with thyroid hemiagenesis and in those who have undergone hemithyroidectomy and have symptomatic nodules.

Chronic expression of RET/PTC 3 enhances basal and insulin-stimulated PI3 kinase/AKT signaling and increases IRS-2 expression in FRTL-5 thyroid cells.

The RET/PTC3 oncogene is a genetically rearranged and constitutively activated tyrosine kinase receptor that is common in papillary thyroid cancer. Because RET/PTC3 is chronically overexpressed in these thyroid cancer cells, and RET/PTC3-expressing tumors are associated with overactivity of tyrosine kinase signaling pathways and a more aggressive clinical course, we questioned whether chronic RET/PTC3 expression enhances cellular responses to thyroid mitogens in vitro. We stably transfected FRTL-5 cells with the RET/PTC3 gene; transfected and control cell lines were cultured without insulin, TSH, or serum. Thymidine incorporation into DNA was enhanced in the RET/PTC3 cells, but transformation was not observed. RET/PTC3 cells demonstrated higher basal and insulin-stimulated levels of activated Akt, both of which were reduced by LY294002, a PI3 kinase inhibitor, but not PD98059, a MEK inhibitor. By contrast, mitogen activated protein kinase (MAP kinase) was only minimally activated in RET/PTC3 cells before and after stimulation. Consistent with preferential activation of PI3 kinase, increased levels of total and phosphorylated IRS2 protein, relative activation of PDK-1, and enhanced IRS2-p85 interactions were identified in RET/PTC3-expressing cells. RET/PTC3 cells were also sensitized to insulin-induced thymidine incorporation; this effect was blocked by PI3 kinase (LY294002) rather than MEK 1/2 (PD98059) inhibitors. In summary, we have demonstrated that RET/PTC3 expression enhances basal and insulin-stimulated DNA synthesis through PI3 kinase, cooperatively activates Akt with insulin via PI3 kinase, and preferentially activates the Akt rather than MAP kinase pathway in FRTL-5 cells.

Tratamento de nódulos autônomos e císticos da tireóide com injeção intranodular de etanol / Treatment of autonomous and cystic thyroid nodules with intranodular ethanol injection

O tratamento com injeçäo intranodular de etanol vem sendo utilizado há uma década como modalidade terapêutica eficaz no manejo de pacientes com nódulos da tireóide. Diversos estudos validaram o papel desta forma de tratamento em nódulos autônomos, císticos e, mais recentemente, nódulos frios benignos. OBJETIVO: Avaliar a efetividade da injeçäo intranodular de etanol no tratamento de nódulos císticos e autônomos da tireóide. MÉTODOS: 42 pacientes (26 pacientes com nódulos císticos e 16 com nódulos autônomos da tireóide) foram submetidos a tratamento com aplicaçäo intranodular de etanol a 99 por cento, guiada por ultra-sonografia e acompanhados por um período mínimo de seis meses. RESULTADOS: Näo observamos a ocorrência de complicaçöes maiores durante ou após o tratamento, porém, na maioria dos casos, houve queixa de dor de leve a moderada intensidade e/ou desconforto após a aplicaçäo do etanol. A maioria dos nódulos apresentou reduçäo volumétrica significativa. A média de reduçäo obtida para os nódulos autônomos foi de 50,3 por cento e para os nódulos císticos, 69,3 por cento. Näo houve diferença significativa entre os valores basais de T3 total, T4 total e TSH em comparaçäo aos valores obtidos seis meses após o tratamento para o grupo de pacientes com nódulos císticos. O grupo de pacientes com nódulos autônomos apresentou reduçäo nos valores séricos de T3 total e T4 total, assim como elevaçäo dos níveis de TSH, confirmando a efetividade do tratamento. CONCLUSÄO: A injeçäo intranodular de etanol é uma alternativa segura e eficaz no tratamento de nódulos autônomos e císticos da tireóide