Androgen action on renal calcium and phosphate handling: Effects of bisphosphonate treatment and low calcium diet

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.status: publishe

Enobosarm (GTx-024) modulates adult skeletal muscle mass independently of the androgen receptor in the satellite cell lineage

Androgens increase skeletal muscle mass, but their clinical use is hampered by lack of tissue selectivity and subsequent side-effects. Selective androgen receptor modulators (SARMs) elicit muscle-anabolic effects while only sparingly affecting reproductive tissues. The SARM GTx-024 (enobosarm) is being investigated for cancer cachexia, sarcopenia, and muscle wasting diseases. Here, we investigate the role of muscle androgen receptor (AR) in the anabolic effect of GTx-024. In mice lacking AR in the satellite cell lineage (satARKO), the weight of the androgen-sensitive levator ani muscle was lower, but decreased further upon orchidectomy. GTx-024 was as effective as dihydrotestosterone (DHT) in restoring levator ani weights to sham levels. Expression of the muscle-specific androgen-responsive genes S-adenosylmethionine decarboxylase and myostatin was decreased by orchidectomy and restored by GTx-024 and DHT in control mice, while expression was low and unaffected by androgen status in satARKO. In contrast, insulin-like growth factor IEa expression was not different between satARKO and control muscle, decreased upon castration, and was restored by DHT and GTx-024 in both genotypes. These data indicate that GTx-024 does not selectively modulate AR in the satellite cell lineage and that cells outside this lineage remain androgen-responsive in satARKO muscle. Indeed, residual AR positive cells were present in satARKO muscle, coexpressing the fibroblast-lineage marker vimentin. AR positive, muscle-resident fibroblasts could therefore be involved in the indirect effects of androgens on muscle. In conclusion, both DHT and GTx-024 target AR pathways in the satellite cell lineage, but cells outside this lineage also contribute to the anabolic effects of androgens.status: publishe

Estradiol and Age-Related Bone Loss in Men

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Multicomponent Reactions upon the Known Drug Trimethoprim as a Source of Novel Antimicrobial Agents

Novel antibiotic compounds have been prepared through a selective multicomponent reaction upon the known drug Trimethoprim. The Groebke-Blackburn-Bienaymé reaction involving this α-aminoazine, with a range of aldehydes and isocyanides afforded the desired adducts in one-step. The analogs display meaningful structural features of the initial drug together with relevant modifications at several points, keeping antibiotic potency and showing satisfactory antimicrobial profile (good activity levels and reduced growth rates), especially against methicillin-resistant Staphylococcus aureus. The new products may open new possibilities to fight bacterial infections

Testosterone replacement in congenital hypogonadotropic hypogonadism maintains bone density but has only limited osteoanabolic effects

BACKGROUND: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition characterized by complete sex steroid deficiency. Therefore, CHH is a unique human model to study the impact of long-term testosterone replacement therapy (TRT) on bone. OBJECTIVE: In this single-center retrospective observational study, we assessed the long-term impact of TRT on femoral and lumbar bone mineral density (BMD) in adult CHH men. METHODS: A total of 25 patients with CHH were included. Femoral and lumbar BMD was assessed by dual-energy X-ray absorptiometry (DEXA) and reported as T-scores. In six patients (treatment-naive group), BMD was measured before start of TRT. The other 19 (pre-treated group) had received TRT for a median duration of 7 years (range 1-41 years) before first BMD measurement. RESULTS: Age at which TRT was started ranged from 12 to 57 years old. Median time between first and last DEXA scan was 11 years (range 2-28). At the first DEXA scan, 83% and 61% of CHH patients had lumbar and femoral osteopenia/osteoporosis, respectively. In the treatment-naive group, the increase in lumbar T-score was 2.19 ± 0.13 (mean ± SEM, p < 0.01 between first and last DEXA scan) and 1.47 ± 0.29 at femoral level (p < 0.001). For the pre-treated group, the increase in lumbar and femoral T-score was 0.77 ± 0.17 (p < 0.001) and 0.19 ± 0.12 (p = 0.13), respectively. However, lumbar and femoral osteopenia/osteoporosis persisted in 61% and 48% of CHH patients even after several years of continuous TRT. Additionally, BMD clearly decreased in patients who interrupted TRT. CONCLUSION: Despite modest improvement after starting TRT, BMD remains in the osteopenic/osteoporotic range in most patients with CHH. However, prolonged TRT prevents further bone loss, both at lumbar and femoral level.status: publishe

Sex steroid deficiency alters renal calcium transporter expression independently of its effect on bone resorption

It is well established that sex steroid deficiency induces bone loss, resulting in osteoporosis. Consequently, global androgen receptor knock out (ARKO) mice have trabecular and cortical osteopenia. Bone cell-specific ARKOs however, have a much less pronounced bone phenotype, suggesting that androgens have an influence on processes in other systems or organs which in turn have an impact on bone metabolism. The kidney is a likely candidate, as it plays an important role in calcium homeostasis, through reabsorption/excretion and synthesis of vitamin D. Therefore, we hypothesize that androgens regulate renal calcium homeostasis, hereby indirectly affecting bone resorption. To test this hypothesis, adult male C57BL6/J mice were orchidectomized (ORX vs SHAM) and treated with the antiresorptive drug risedronate (RIS vs vehicle), in order to study the effects of sex steroid depletion on renal calcium homeostasis independent of bone resorption. Orchidectomy resulted in a decreased kidney weight (2 weeks post-ORX), hypercalciuria (1 week post-ORX) which was normalized 2 weeks post-ORX along with normal serum levels of calcium, 1.25(OH)2D3, PTH, and FGF23. Orchidectomy combined with prior bone antiresorptive treatment abolished the early hypercalciuric phase and even resulted in transiently decreased serum calcium levels 1 week post-ORX. Compared to control mice, a significant upregulation of renal calcium transporters (TRPV5, PMCA, NCX1, CaBP9K and CaBP28K) was observed in both the ORX and ORX+RIS group, while intestinal calcium transporters (TRPV5, TRPV6, PMCA, CaBP9K) remained unchanged, suggesting that sex steroid deficiency might impact renal calcium homeostasis independent of its effect on bone resorptionstatus: publishe