Changes in bone and mineral homeostasis after short-term androgen deprivation therapy with or without androgen receptor signalling inhibitor - substudy of a single-centre, double blind, randomised, placebo-controlled phase 2 trial.

BACKGROUND: Prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) have an increased fracture risk. Exploring biomarkers for early bone loss detection is of great interest. METHODS: Pre-planned substudy of the ARNEO-trial (NCT03080116): a double blind, randomised, placebo-controlled phase 2 trial performed in high-risk PCa patients without bone metastases between March 2019 and April 2021. Patients were 1:1 randomised to treatment with gonadotropin-releasing hormone antagonist (degarelix) + androgen receptor signalling inhibitor (ARSI; apalutamide) versus degarelix + matching placebo for 12 weeks prior to prostatectomy. Before and following ADT, serum and 24-h urinary samples were collected. Primary endpoints were changes in calcium-phosphate homeostasis and bone biomarkers. FINDINGS: Of the 89 randomised patients, 43 in the degarelix + apalutamide and 44 patients in the degarelix + placebo group were included in this substudy. Serum corrected calcium levels increased similarly in both treatment arms (mean difference +0.04 mmol/L, 95% confidence interval, 0.02; 0.06), and parathyroid hormone and 1,25-dihydroxyvitamin D3 levels decreased. Bone resorption markers increased, and stable calcium isotope ratios reflecting net bone mineral balance decreased in serum and urine similarly in both groups. INTERPRETATION: This exploratory substudy suggests that 12 weeks of ADT in non-metastatic PCa patients results in early bone loss. Additional treatment with ARSI does not seem to more negatively influence bone loss in the early phase. Future studies should address if these early biomarkers are able to predict fracture risk, and can be implemented in clinical practice for follow-up of bone health in PCa patients under ADT. FUNDING: Research Foundation Flanders; KU Leuven; University-Hospitals-Leuven.

Germline founder variant c.1998delinsTTCT in the RET oncogene: a cohort study in 15 Belgian families.

OBJECTIVE: The c.1998delinsTTCT variant in the RET gene (codon 666) is linked to medullary thyroid carcinoma in Belgium. We aimed to study the clinical phenotype and the age-dependent penetrance in predictive variant carriers. DESIGN: Retrospective study of index patients and predictive variant carriers, identified through familial cascade testing between 2001 and 2020. RESULTS: The total cohort comprised 119 patients: 15 index patients, 102 heterozygous, and 2 homozygous predictive variant carriers. Among heterozygous carriers, high suspicion of clinical disease was present in 25 patients at initial evaluation and in 3 patients during follow-up. No high suspicion of clinical disease was observed during surveillance in 56 patients, and 18 patients did not proceed to screening for clinical disease. Compared to index patients, surgically treated heterozygous predictive variant carriers had a lower presurgical basal calcitonin, a lower disease stage, less need for adjuvant therapy, and higher chances of remission. In heterozygous carriers, median age at developing high suspicion of disease is 52 years (range 7-75), with a predicted penetrance of 62% (9% SE) at the age of 70 years. Two patients were identified with pheochromocytoma and 1 patient with primary hyperparathyroidism. The 2 homozygous predictive variant carriers presented with higher disease severity at first clinical evaluation. CONCLUSION: The c.1998delinsTTCT variant in the RET gene is pathogenic and associated with a moderate risk for medullary thyroid carcinoma and rarely with other multiple endocrine neoplasia type 2A (MEN2A) manifestations. Active surveillance is a possible option in heterozygous gene carriers with a negative first clinical evaluation.

Higher Thyroid fT3-to-fT4 Ratio Is Associated with Gestational Diabetes Mellitus and Adverse Pregnancy Outcomes.

Aim: To determine the association between thyroid function and the risk of developing gestational diabetes mellitus (GDM) and adverse pregnancy outcomes. Methods: This case−control study was a sub-analysis of the BEDIP-N study, in which 199 GDM women were matched for age and body mass index with 398 controls. Thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), and thyroid peroxidase (TPO) antibodies were measured at 6−14 weeks and 26−28 weeks during pregnancy. TSH and fT4 were also measured in early postpartum in GDM women. Results: The fT3-to-fT4 ratio at 26−28 weeks was positively associated with GDM risk with an adjusted odds ratio (aOR for smoking, education, parity, ethnicity, gestational weight gain, and (family) history of diabetes or GDM) of 2.12 (95% CI 1.07; 4.23), comparing the highest with the lowest tertile. Higher fT3 levels and a higher fT3-to-fT4 ratio were associated with a less favorable metabolic profile with higher BMI and more insulin resistance during pregnancy and postpartum. Women in the upper fT3 tertile and the upper fT3-to-fT4 ratio had a higher rate of preeclampsia [4.6% (10) vs. 1.0% (2), p = 0.040, and 4.4% (9) vs. 0.5% (1), p = 0.020], gestational hypertension [8.3% (18) vs. 3.1% (6), p = 0.034 and 8.9% (18) vs. 2.0% (4), p = 0.003], and caesarean sections [29.4% (63) vs. 16.1% (31), p = 0.002 and 32.2% (65) vs. 12.7% (25), p < 0.001]. Conclusion: A higher fT3-to-fT4 ratio late into pregnancy was associated with GDM, adverse pregnancy outcomes, and an adverse metabolic profile in early postpartum.

Endocrine-related adverse conditions in patients receiving immune checkpoint inhibition: an ESE clinical practice guideline.

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but are associated with significant autoimmune endocrinopathies that pose both diagnostic and treatment challenges. The aim of this guideline is to provide clinicians with the best possible evidence-based recommendations for treatment and follow-up of patients with ICI-induced endocrine side-effects based on the Grading of Recommendations Assessment, Development, and Evaluation system. As these drugs have been used for a relatively short time, large systematic investigations are scarce. A systematic approach to diagnosis, treatment, and follow-up is needed, including baseline tests of endocrine function before each treatment cycle. We conclude that there is no clear evidence for the benefit of high-dose glucocorticoids to treat endocrine toxicities with the possible exceptions of severe thyroid eye disease and hypophysitis affecting the visual apparatus. With the exception of thyroiditis, most endocrine dysfunctions appear to be permanent regardless of ICI discontinuation. Thus, the development of endocrinopathies does not dictate a need to stop ICI treatment.

Inactivation of AR or ERα in Extrahypothalamic Neurons Does not Affect Osteogenic Response to Loading in Male Mice.

Failure of bone mass maintenance in spite of functional loading is an important contributor to osteoporosis and related fractures. While the link between sex steroids and the osteogenic response to loading is well established, the underlying mechanisms are unknown, hampering clinical relevance. Androgens inhibit mechanoresponsiveness in male mice, but the cell type mediating this effect remains unidentified. To evaluate the role of neuronal sex steroid receptor signaling in the male bone's adaptive capacity, we subjected adult male mice with an extrahypothalamic neuron-specific knockout of the androgen receptor (N-ARKO) or the estrogen receptor alpha (N-ERαKO) to in vivo mechanical stimulation of the tibia. Loading increased cortical thickness in the control animals mainly through periosteal expansion, as total cross-sectional tissue area and cortical bone area but not medullary area were higher in the loaded than the unloaded tibia. Trabecular bone volume fraction also increased upon loading in the control group, mostly due to trabecular thickening. N-ARKO and N-ERαKO males displayed a loading response at both the cortical and trabecular bone compartments that was not different from their control littermates. In conclusion, we show that the presence of androgen receptor or estrogen receptor alpha in extrahypothalamic neurons is dispensable for the osteogenic response to mechanical loading in male mice.

Combining data to perform population-based observational studies: know your sources. The case of thyroid cancer in Belgium.

BACKGROUND: Large scale observational studies are crucial to study thyroid cancer incidence and management, known to vary in time and place. Combining cancer registry data with other data sources enables execution of population-based studies, provided data sources are accurate. The objective was to compare thyroid tumour and treatment information between the available data sources in Belgium. METHODS: We performed a retrospective national population-based cohort study. All patients with thyroid cancer diagnosis in Belgium between 2009 and 2011 (N = 2659 patients) were retrieved from the Belgian Cancer Registry database, containing standard patient and tumour characteristics. Additionally, information was obtained from the following sources: a) detailed pathology reports b) the health insurance company database for reimbursed performed therapeutic acts (both available for N = 2400 patients) c) registration forms for performed and/or planned treatments at the time of the multidisciplinary team meeting (available for N = 1819 patients). More precisely, information was retrieved regarding characteristics of the tumour (histologic subtype, tumour size, lymph node status (source a)) and the treatment (thyroid surgery (a,b,c), lymph node dissection (a,b), postoperative administration of radioactive iodine (b,c)). RESULTS: High concordance in histological cancer subtype (> 90%), tumour size (96.2%) and lymph node involvement (89.2%) categories was found between the cancer registry database and the pathology reports. Tumour subcategories (such as microcarcinoma, tumor ≤1 cm diameter) were more specified in the pathology reports. The therapeutic act of thyroid surgery as mentioned in the pathology reports and health insurance company database was concordant in 92.7%, while reports from multidisciplinary team meetings showed 88.5% of concordance with pathology reports and 86.1% with health insurance data. With regard to postoperative radioiodine administration, reports from multidisciplinary teams and health insurance data were concordant in 76.8%. CONCLUSION: Combining registered and/or administrative data results in sufficiently accurate information to perform large scale observational studies on thyroid cancer in Belgium. However, thorough and continuous quality control and insight in strengths and limitations of each cancer data source is crucial.

The impact of androgen deprivation therapy on bone mineral density in men treated for paraphilic disorder: A retrospective cohort study.

BACKGROUND: Guidelines suggest treating men with paraphilic disorder with androgen-deprivation therapy (ADT). However, little evidence is available about the long-term impact on bone loss and how to manage this adverse event. OBJECTIVES: The aim of this study is to assess the impact of ADT on bone mineral density (BMD) in men treated for paraphilic disorder with the androgen receptor blocker cyproterone acetate (CPA) and/or GnRH agonist triptoreline (GnRHa) and to evaluate the effect of treatment with bisphosphonates. METHODS: Baseline and follow-up dual-energy X-ray absorptiometry scan (DXA-scan) data (lumbar and femoral T-scores) were retrospectively extracted from electronic medical files of paraphilic men who received CPA and/or GnRHa. RESULTS: A total of 53 patients with a mean age of 39.1 years (range 17.5-74.6) were included. Lumbar (-0.39 ± 0.17, Mean ± SEM, p = 0.046), femoral neck (-0.34 ± 0.09, p = 0.002) and total femur (-0.33 ± 0.12, p = 0.014) T-scores decreased significantly in the CPA-only group (n = 13) during a mean follow-up of 6.0 ± 5.3 years. In the GnRHa group (n = 29), T-scores at all sites decreased significantly over 6.6 ± 4.4 years (lumbar: -0.55 ± 0.12, p < 0.001, femoral neck: -0.53 ± 0.09, total femur: -0.44 ± 0.09, p < 0.001). In the group, who received bisphosphonates (n = 11), no significant T-score change was observed (lumbar: -0.25 ± 0.14, p = 0.106, femoral neck -0.15 ± 0.17, p = 0.402, total femur -0.25 ± 0.14, p = 0.106) during 5.0 ± 2.8 years of follow-up. DISCUSSION AND CONCLUSION: Following a mean duration of 6 years of ADT, we observed a significant decline in BMD of approximately half a standard deviation in T-score at lumbar and femoral site. Although the number of patients who received bisphosphonates was limited, this treatment seems to have a positive stabilizing effect on bone density.

Neoplasia in Turner syndrome: a retrospective cohort study in a tertiary referral centre in Belgium.

OBJECTIVES: Patients with Turner syndrome (TS), the most common sex chromosome abnormality in women, can suffer from a variety of well-researched reproductive, cardiovascular, metabolic, and autoimmune comorbidities. Few studies investigate the neoplasia risk. We assessed the general neoplasia risk in TS women, and more specifically, the gonadoblastoma/dysgerminoma risk in the subgroup with Y chromosome mosaicism, and evaluated potential risk factors for neoplasia development, such as karyotype, metabolic and autoimmune comorbidity, and treatment with growth hormone and/or estrogen replacement. DESIGN: 10-year retrospective cohort study in a tertiary referral centre in Belgium. RESULTS: 105 TS women were included (median age 29; range 2-69). Six malignant tumours were detected in 5 (4.8%) patients (SIR = 0.6, 95% CI 0.2-1.0). In addition, 2 benign meningiomas were observed, resulting in 3 (2.9%) tumours of the central nervous system (CNS; SIR = 19.9, 95% CI 4.0-35.8). No breast cancer was noted. Benign neoplasms occurred in 22 women (21.0%), with skin lesions being the most frequent. All patients with Y chromosome mosaicism (n = 9; 8.6%) underwent prophylactic gonadectomy, but gonadoblastoma/dysgerminoma was not detected. A weak association was found between any tumour type and autoimmune comorbidity (r = 0.24; p = 0.02). CONCLUSION: The overall malignancy risk was not increased, but a different pattern of occurrence is apparent, with an increased risk of CNS and skin tumours and a decreased breast cancer risk. Gonadoblastoma/dysgerminoma was not reported. There is a need for centralised multidisciplinary care and prospective research to unravel and predict the neoplasia risk.

Radiation Treatment for Inoperable Local Relapse of Parathyroid Carcinoma With Symptomatic Hypercalcemia: A Case Report.

BACKGROUND: Parathyroid carcinoma (PC) is an extremely rare malignancy, characterized by slow progression, frequent recurrences and difficult-to-control hypercalcemia which is typically the main contributor to the morbidity and mortality of these patients. Patients often undergo repeated surgical resections, whether or not in combination with adjuvant radiation treatment. The role of radiation therapy within the symptomatic treatment of PC currently remains unclear. CASE DESCRIPTION: We describe a 30-year-old male patient with an inoperable local relapse of PC and secondary symptomatic hypercalcemia, maximally pharmacologically treated. After a local radiation treatment to a total dose of 70 Gray in 35 fractions serum calcium and parathyroid hormone (PTH) levels decreased, accompanied by improvement of the severe gastro-intestinal disturbances. CONCLUSION: For patients with inoperable symptomatic PC despite maximal medical treatment who are in a good overall condition, radiation treatment can be considered in well-defined cases to decrease symptoms and improve quality of life.

18F-FDG PET/CT Sheds Light on a Case of Hyponatremia.

A 76-y-old man with hypoosmolar hyponatremia of unknown origin was referred to the nuclear medicine department for 18F-FDG PET/CT to exclude a malignant cause. Increased 18F-FDG uptake in both adrenal glands was observed and investigated.

Influence of medication and PTH levels on detection of parathyroid adenomas with dual isotope parathyroid scintigraphy.

Localization of parathyroid adenomas is a crucial step to facilitate minimally invasive parathyroidectomy. In this study, we investigated sensitivity and positivity rate of SPECT-based dual isotope parathyroid scintigraphy in detecting parathyroid adenomas, and the effect of medication and parathyroid hormone (PTH)-level on detection of adenomas. Two hundred and thirty-seven patients with primary hyperparathyroidism undergoing dual isotope parathyroid scintigraphy with SPECT-CT in our centre between January 1st 2013 and December 31st 2017 were included in this retrospective study. Sensitivity and positivity rate for accurate location of parathyroid adenomas, based on histopathological findings after surgery and follow-up PTH and calcium, were calculated. The impact of pre-operative medication (thyroxin, calcium-antagonists, antacids, vitamin D, bisphosphonates and calcium) and PTH-levels between positive and negative scans was evaluated by using univariate and multivariate analysis, and a ROC analysis respectively. Overall patient-based sensitivity of scintigraphy for finding parathyroid adenomas was 72% for scintigraphy, with a positivity rate of 60%. No significant effect of investigated medication on positivity rate was found. PTH-level was significantly higher in patients with positive scintigraphy (median 96.3 ng/L vs 75.2 ng/L, P < 0.01). Optimum cut-off for detection of adenomas for PTH was 79.4 ng/L with a sensitivity of 67% and a specificity of 63%. In this retrospective cohort, sensitivity and positivity rate of dual-isotope SPECT-CT for parathyroid adenomas were in line with previous studies. No statistically significant influence of medication on positivity of scintigraphy was found, suggesting these medication types should not be stopped prior to scintigraphy. PTH level was no useful parameter to predict positivity of scintigraphic imaging.

Testosterone Reduces Body Fat in Male Mice by Stimulation of Physical Activity Via Extrahypothalamic ERα Signaling.

Testosterone (T) reduces male fat mass, but the underlying mechanisms remain elusive, limiting its clinical relevance in hypogonadism-associated obesity. Here, we subjected chemically castrated high-fat diet-induced adult obese male mice to supplementation with T or the nonaromatizable androgen dihydrotestosterone (DHT) for 20 weeks. Both hormones increased lean mass, thereby indirectly increasing oxygen consumption and energy expenditure. In addition, T but not DHT decreased fat mass and increased ambulatory activity, indicating a role for aromatization into estrogens. Investigation of the pattern of aromatase expression in various murine tissues revealed the absence of Cyp19a1 expression in adipose tissue while high levels were observed in brain and gonads. In obese hypogonadal male mice with extrahypothalamic neuronal estrogen receptor alpha deletion (N-ERαKO), T still increased lean mass but was unable to decrease fat mass. The stimulatory effect of T on ambulatory activity was also abolished in N-ERαKO males. In conclusion, our work demonstrates that the fat-burning action of T is dependent on aromatization into estrogens and is at least partially mediated by the stimulation of physical activity via extrahypothalamic ERα signaling. In contrast, the increase in lean mass upon T supplementation is mediated through the androgen receptor and indirectly leads to an increase in energy expenditure, which might also contribute to the fat-burning effects of T.

Novel model to study the physiological effects of temporary or prolonged sex steroid deficiency in male mice.

Sex steroids are critical for skeletal development and maturation during puberty as well as for skeletal maintenance during adult life. However, the exact time during puberty when sex steroids have the highest impact as well as the ability of bone to recover from transient sex steroid deficiency is unclear. Surgical castration is a common technique to study sex steroid effects in rodents, but it is irreversible, invasive, and associated with metabolic and behavioral alterations. Here, we used a low dose (LD) or a high dose (HD) of gonadotropin-releasing hormone antagonist to either temporarily or persistently suppress sex steroid action in male mice, respectively. The LD group, a model for delayed puberty, did not show changes in linear growth or body composition, but displayed reduced trabecular bone volume during puberty, which fully caught up at adult age. In contrast, the HD group, representing complete pubertal suppression, showed a phenotype reminiscent of that observed in surgically castrated rodents. Indeed, HD animals exhibited severely impaired cortical and trabecular bone acquisition, decreased body weight and lean mass, and increased fat mass. In conclusion, we developed a rodent model of chemical castration that can be used as an alternative to surgical castration. Moreover, the transient nature of the intervention enables to study the effects of delayed puberty and reversibility of sex steroid deficiency.NEW & NOTEWORTHY We developed a rodent model of chemical castration, which can be used as an alternative to surgical castration. Moreover, the transient nature of the intervention enables to study the effects of delayed puberty and reversibility of sex steroid deficiency.

A Case of a Heterozygous Inactivating CASR Variant with Adult-Onset Symptomatic Hypercalcemia Requiring Extensive Surgery.

We describe the case of an adult female patient with symptomatic familial hypocalciuric hypercalcemia requiring a step-wise therapeutic approach and the eventual need for a total parathyroidectomy and thyroidectomy to cure symptoms. Genetic analysis demonstrated a heterozygous R227L inactivating CASR gene variant, previously only described in neonatal severe hyperparathyroidism. Post-operative histology showed diffuse hyperplasia of all four parathyroid glands along with the presence of intrathyroidal parathyroid tissue. With regard to clinical management this case suggests that familial hypocalciuric hypercalcemia should be classified as an atypical form of primary hyperparathyroidism rather than a distinct entity.

Estrogen receptor alpha signaling in extrahypothalamic neurons during late puberty decreases bone size and strength in female but not in male mice.

Sexually dimorphic bone structure emerges largely during puberty. Sex steroids are critical for peak bone mass acquisition in both genders. In particular, the biphasic effects of estrogens mediate the skeletal sexual dimorphism. However, so far the stimulatory vs inhibitory actions of estrogens on bone mass are not fully explained by direct effects on bone cells. Recently, it has become evident that there is possible neuroendocrine action of estrogen receptor alpha (ERα) on the skeleton. Based on these considerations, we hypothesized that neuronal ERα-signaling may contribute to the skeletal growth during puberty. Here, we generated mice with tamoxifen-inducible Thy1-Cre mediated ERα inactivation during late puberty specifically in extrahypothalamic neurons (N-ERαKO). Inactivation of neuronal ERα did not alter the body weight in males, whereas N-ERαKO females exhibited a higher body weight and increased body and bone length compared to their control littermates at 16 weeks of age. Ex vivo microCT analysis showed increased radial bone expansion of the midshaft femur in female N-ERαKO along with higher serum levels of insulin-like growth factor (IGF)-1 as well as IGF-binding protein (IGFBP)-3. Furthermore, the 3-point bending test revealed increased bone strength in female N-ERαKO. In contrast, inactivation of neuronal ERα had no major effect on bone growth in males. In conclusion, we demonstrate that central ERα-signaling limits longitudinal bone growth and radial bone expansion specifically in females potentially by interacting with the GH/IGF-1 axis.

The Impact of Regional Variation in Clinical Practice on Thyroid Cancer Diagnosis: A National Population-Based Study.

OBJECTIVE: Regional variation in thyroid cancer incidence in Belgium, most pronounced for low risk cancer, was previously shown to be related to variation in clinical practice, with higher thyroid surgery rates and lower proportions of preoperative fine-needle aspiration (FNA) in regions with high thyroid cancer incidence (period 2004-2006). The objective of this study was to investigate regional thyroid cancer incidence variation in relation with variation in thyroid surgery threshold in a more recent Belgian thyroid cancer cohort. METHODS: A population-based cohort of thyroid cancer patients that underwent a (near) total thyroidectomy in the period 2009-2011 (n = 2,329 patients) was identified and studied by linking data from the Belgian cancer registry and the Belgian health insurance companies, and case-by-case study of the pathology protocols. The execution of preoperative FNA and the thyroid resection specimen weight were compared between high and low thyroid cancer incidence regions. Thyroid weight in the pT1a-restricted group was studied as a proxy for surgical threshold for benign nodular goiter. Furthermore, time trend analyses were performed for the execution of FNA for the period 2004-2012. RESULTS: Although a lower proportion of FNA in the high thyroid cancer incidence region persisted in the period 2009-2011 (41.2% [31.9-50.9] vs. 72.9% [64.9-79.7] in the low-incidence region (LIR), p < 0.001), a positive time trend was observed for the period 2004-2012. The median thyroid surgical specimen weight was lower in the high incidence region compared to the LIR (27.0 g [IQR 18.0-45.3] vs. 36.0 g [IQR 22.0-73.0], p < 0.0001), and this finding was corroborated in the pT1a-restricted group. CONCLUSION: Interregional differences in use of FNA and surgical thyroid specimen weight are consistent with an inverse relation between thyroid cancer incidence and thyroid surgery threshold, carrying risk for overdiagnosis.

2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy.

Thyroid dysfunction (TD) frequently occurs as an autoimmune complication of immune reconstitution therapy (IRT), especially in individuals with multiple sclerosis treated with alemtuzumab, a pan-lymphocyte depleting drug with subsequent recovery of immune cell numbers. Less frequently, TD is triggered by highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV), or patients undergoing bone-marrow/hematopoietic-stem-cell transplantation (BMT/HSCT). In both alemtuzumab-induced TD and HIV/HAART patients, the commonest disorder is Graves' disease (GD), followed by hypothyroidism and thyroiditis; Graves' orbitopathy is observed in some GD patients. On the contrary, GD is rare post-BMT/HSCT, where hypothyroidism predominates probably as a consequence of the associated radiation damage. In alemtuzumab-induced TD, the autoantibodies against the thyrotropin receptor (TRAb) play a major role, and 2 main aspects distinguish this condition from the spontaneous form: (1) up to 20% of GD cases exhibit a fluctuating course, with alternating phases of hyper- and hypothyroidism, due to the coexistence of TRAb with stimulating and blocking function; (2) TRAb are also positive in about 70% of hypothyroid patients, with blocking TRAb responsible for nearly half of the cases. The present guidelines will provide up-to-date recommendations and suggestions dedicated to all phases of IRT-induced TD: (1) screening before IRT (recommendations 1-3); (2) monitoring during/after IRT (recommendations 4-7); (3) management of TD post-IRT (recommendations 8-17). The clinical management of IRT-induced TD, and in particular GD, can be challenging. In these guidelines, we propose a summary algorithm which has particular utility for nonspecialist physicians and which is tailored toward management of alemtuzumab-induced TD. However, we recommend prompt referral to specialist endocrinology services following diagnosis of any IRT-induced TD diagnosis, and in particular for pregnant women and those considering pregnancy.

Androgen Receptor in Neurons Slows Age-Related Cortical Thinning in Male Mice.

Androgens via the androgen receptor (AR) are required for optimal male bone health. The target cell(s) for the effects of androgens on cortical bone remain(s) incompletely understood. In females, estrogen receptor alpha in neurons is a negative regulator of cortical and trabecular bone. Whether neuronal AR regulates bone mass in males remains unexplored. Here, we inactivated AR in neurons using a tamoxifen-inducible CreERT2 under the control of the neuronal promoter Thy1. Tamoxifen induced a 70% to 80% reduction of AR mRNA levels in Thy1-CreERT2-positive brain regions cerebral cortex and brainstem as well as in the peripheral nervous tissue of male neuronal AR knockout (N-ARKO) mice. Hypothalamic AR mRNA levels were only marginally reduced and the hypothalamic-pituitary-gonadal axis remained unaffected, as determined by normal levels of serum testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). In contrast to orchidectomy, deletion of neuronal AR did not alter body weight, body composition, hindlimb muscle mass, grip strength, or wheel running. MicroCT analysis of the femur revealed no changes in bone accrual during growth in N-ARKO mice. However, 36- and 46-week-old N-ARKO mice displayed an accelerated age-related cortical involution, namely a more pronounced loss of cortical thickness and strength, which occurred in the setting of androgen sufficiency. Neuronal AR inactivation decreased the cancellous bone volume fraction in L5 vertebra but not in the appendicular skeleton of aging mice. MicroCT findings were corroborated in the tibia and after normalization of hormonal levels. Serum markers of bone turnover and histomorphometry parameters were comparable between genotypes, except for a 30% increase in osteoclast surface in the trabecular compartment of 36-week-old N-ARKO mice. Cortical bone loss in N-ARKO mice was associated with an upregulation of Ucp1 expression in brown adipose tissue, a widely used readout for sympathetic tone. We conclude that androgens preserve cortical integrity in aging male mice via AR in neurons. © 2018 American Society for Bone and Mineral Research.

Prospective evaluation of hypogonadism in male metastatic renal cell carcinoma patients treated with targeted therapies.

OBJECTIVES: To study the prevalence of hypogonadism in male patients with metastatic renal cell carcinoma (mRCC) starting with targeted therapies and the impact of the vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) sunitinib and pazopanib on the luteinizing hormone (LH)/testosterone (TT)-axis. METHODS: Male mRCC patients starting with targeted therapies were prospectively included in this study. TT- and LH-levels were sampled at start as well as during systemic therapy. Endpoints of the study were gonadal status (TT- and LH-levels) at start of targeted therapy and TT- and LH-evolution during targeted therapy. RESULTS: Sixty-three patients were included in this study. At start of targeted therapy, 30% of patients were eugonadal and 48% had secondary hypogonadism. Decreased TT- and increased LH-levels were associated with inflammatory state and poor prognosis. During sunitinib therapy, TT-levels decreased with 32% (p = 0.004) and LH-levels with 14% (p = 0.03). TT-levels were 13% lower (p = 0.007) and LH-levels 15% lower (p = 0.004) on day 28 compared to day 1. In four patients, a dramatic TT decrease was observed shortly after starting sunitinib. In patients treated with pazopanib, no impact on TT- or LH-levels was observed. CONCLUSION: Hypogonadism is a frequent finding in male mRCC-patients at start of targeted therapies. In contrast to pazopanib, during sunitinib therapy, TT- and LH-levels tend to decrease, leading to an increased incidence of secondary hypogonadism.

ABCG2 Polymorphism rs2231142 and hypothyroidism in metastatic renal cell carcinoma patients treated with sunitinib.

BACKGROUND AND AIM: Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) cause significant adverse events including thyroid dysfunction, mainly hypothyroidism, in a considerable proportion of patients. In a series of metastatic renal cell carcinoma (mRCC) patients treated with sunitinib, we aimed to study the correlation between hypothyroidism and single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics and pharmacodynamics. PATIENTS AND METHODS: We included 79 mRCC patients who started sunitinib between November 2005 and March 2016. Serum thyroid function markers were collected at start and during sunitinib therapy. Germ-line DNA genotyping for 16 SNPs in 8 candidate genes was performed. Endpoints were time to increase in thyroid stimulating hormone (TSH) and time to decrease in T4 or free T4 (FT4) on day 1 and day 28 of each sunitinib cycle. RESULTS: Patients with the ABCG2 rs2231142 CC-genotype had a significantly longer time-to-TSH-increase on day 1 (11 vs. 5 cycles; p = 0.0011), and time-to-T4/FT4-decrease on day 1 (not reached vs. 10 cycles; p = 0.013) and day 28 (28 vs. 7 cycles; p = 0.03) compared to CA-carriers. Patients with the CYP3A5 rs776746 GG-genotype had a significantly longer time-to-TSH-increase at day 1 compared to GA-patients: 11 vs. 5 cycles (p = 0.0071). Significant associations were also found between PDGFRA rs35597368 and rs1800812 and time-to-TSH-increase at day 28. CONCLUSION: Polymorphism rs2231142 in the efflux pump ABCG2 is associated with hypothyroidism in mRCC patients treated with sunitinib.