Abstract
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.
Although Klinefelter syndrome (KS) is the most frequent sex-hormone disorder, there is ongoing uncertainty about the often associated sex-hormone deficiency, its impact on common comorbidities, and ...therefore about prevention and treatment. In this study, we focus on bone loss, reported to occur in over 40% of KS patients, and the impact of testosterone replacement therapy (TRT) on this comorbidity.
This single-center retrospective cohort study in a tertiary hospital compared the effect of treatment with TRT to no TRT on evolution of bone mineral density (BMD) in KS patients.
After a medical chart review, a total of 52 KS subjects were included in this study. BMD was measured by dual-energy X-ray absorptiometry (DXA) and expressed as T-scores.
The subjects were divided into three groups, according to TRT. In the subgroup that only started TRT after baseline measurements (mean age 31 years), we observed significant gain in BMD T-score at the lumbar spine (0.58 ± 0.60, p = 0.003; mean gain of 0.62% areal BMD per year) and total femur T-score (0.24 ± 0.39, p = 0.041; mean gain of 0.25% areal BMD per year) after a mean follow-up period of 7.5 years. Compared to untreated subjects, a significant difference in evolution was demonstrated at the lumbar level (+0.58 ± 0.60 vs. -0.14 ± 0.42, p = 0.007). In untreated subjects with normal testosterone levels, a loss of BMD (-0.27 ± 0.37, p = 0.029; mean loss of 0.49% areal BMD per year) at the femoral neck was measured. This decline was equal to the predicted loss seen in the general male population.
TRT results in BMD gain in patients with KS with testosterone deficiency, mainly at the lumbar spine. However, this effect is limited (0.62% per year). Patients who were not treated with TRT because of sufficient endogenous testosterone levels, showed only the predicted age-related bone loss during follow-up. The need for TRT in maintaining bone health in KS should be evaluated on an individual basis according to the degree of sex steroid deficiency.
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 compared to 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 which was not different from their control littermates. In conclusion, we show that the presence of AR or ERα in extrahypothalamic neurons is dispensable for the osteogenic response to mechanical loading in male mice.
Renal calcium and phosphate handling is an important contributor to mineral homeostasis and bone health and the androgen receptor (AR) is highly expressed in the kidney. We investigated the short ...term effects of androgen deprivation on renal calcium and phosphate reabsorption, independent of their effects on bone. Two weeks following orchidectomy (ORX) of adult mice, bone loss occurred along with hypercalciuria, which was similarly prevented by testosterone and dihydrotestosterone supplementation. Treatment with bisphosphonates prior to ORX also inhibited hypercalciuria, indicating that the calcium flux originated from the bone. Renal calcium and phosphate transporter expression was increased post-ORX, independent of bisphosphonates. Furthermore, androgen deprivation appeared to stimulate local synthesis of 1,25(OH)2D3. When bisphosphonate-treated mice were fed a low calcium diet, bone resorption was no longer blocked and secondary hyperparathyroidism developed, which was more pronounced in ORX mice than sham-operated mice. In conclusion, this study shows that androgen deprivation increased renal calcium and phosphate transporter expression, independent of bone, and underlines the importance of adequate intestinal calcium supply in circumstances of androgen deprivation and bisphosphonate treatment.
•Two weeks after orchidectomy, acute trabecular bone loss is induced in adult male mice.•Androgens modulate renal calcium and phosphate handling.•Androgens modulate renal vitamin D metabolism.•Hypogonadism and low calcium diet decrease the efficiency of bisphosphonates.
Context:
Increased thyroid cancer incidence is at least partially attributed to increased detection and shows considerable regional variation.
Objective:
We investigated whether regional variation in ...cancer incidence was associated with variations in thyroid disease management.
Design:
We conducted a retrospective population-based cohort study that involved linking data from the Belgian Health Insurance database and the Belgian Cancer Registry to compare thyroid-related procedures between regions with high and low cancer incidence.
Main Outcome Measures:
Primary outcome measures were rates of TSH testing, imaging, fine-needle aspiration cytology (FNAC), and thyroid surgery. Secondary study outcomes were proportions of subjects with thyrotoxicosis and nodular disease treated with surgery, of subjects treated with surgery preceded by FNAC or with synchronous lymph node dissection, and of thyroid cancer diagnosis after surgery.
Results:
The rate of TSH testing was similar, but the rate of imaging was lower in the low incidence region. The rate of FNAC was similar, whereas the rate of surgery was lower in the low incidence region (34 95% CI 33; 35 vs 80 95% CI 79; 81 per 100 000 person years in the high incidence region; P < .05). In the low incidence region compared to the high incidence region, surgery represented a less chosen therapy for euthyroid nodular disease patients (47% 95% CI 46; 48 vs 69% 95% CI 68; 70; P < .05), proportionally more surgery was preceded by FNAC, more cancer was diagnosed after total thyroidectomy, and thyroid cancer patients had more preoperative FNAC and synchronous lymph node dissection.
Conclusion:
Regional variation in thyroid cancer incidence, most marked for low-risk disease, is associated with different usage of thyroid imaging and surgery, supporting variable detection as a key determinant in geographic variation.
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.
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.
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-ERaKO), 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-ERaKO 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 ERa 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. Key Words: sex steroids, testosterone, estradiol, hypogonadism, fat mass, physical activity
Abstract
Thyroid hormones play an essential role in central nervous system development, normal physiological brain function and repairing mechanisms. On one hand, thyroid hormone alterations ...influence cortical excitability and on the other hand anti-epileptic drugs (AEDs) are associated with alterations in thyroid hormone metabolism. Although this interaction has long been described, and epilepsy is a common and chronic neurological disease, studies describing the interplay are often small and retrospective.
We performed a systematic review of the current literature on epilepsy, AED therapy and thyroid hormone metabolism. Forty-seven studies were included.
Most studies were retrospective cross-sectional studies (n=25) and investigated thyroid function alterations in patients on older AEDs such as phenobarbital, phenytoin, carbamazepine and valproic acid. Overall, almost one third of patients with epilepsy had subclinical hypothyroidism, especially patients on valproate and carbamazepine. Studies with patients receiving polytherapy are scarce, but reported a higher risk for hypothyroidism in patients with older age, female sex, longer duration of epilepsy, intractable epilepsy and polytherapy. Studies on newer AEDs are also scarce and further studies essential to improve the care for epilepsy patients.
AEDs are associated with alterations in thyroid hormone metabolism. Thyroid function monitoring is indicated in patients on AEDs, especially those with refractory chronic epilepsy and those on polytherapy. We provide a practical guideline for thyroid function monitoring for the clinician taking care of patients on AEDs.
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