Testosterone and the Male Skeleton: A Dual Mode of Action

Testosterone is an important hormone for both bone gain and maintenance in men. Hypogonadal men have accelerated bone turnover and increased fracture risk. In these men, administration of testosterone inhibits bone resorption and maintains bone mass. Testosterone, however, is converted into estradiol via aromatization in many tissues including male bone. The importance of estrogen receptor alpha activation as well of aromatization of androgens into estrogens was highlighted by a number of cases of men suffering from an inactivating mutation in the estrogen receptor alpha or in the aromatase enzyme. All these men typically had low bone mass, high bone turnover and open epiphyses. In line with these findings, cohort studies have confirmed that estradiol contributes to the maintenance of bone mass after reaching peak bone mass, with an association between estradiol and fractures in elderly men. Recent studies in knock-out mice have increased our understanding of the role of androgens and estrogens in different bone compartments. Estrogen receptor activation, but not androgen receptor activation, is involved in the regulation of male longitudinal appendicular skeletal growth in mice. Both the androgen and the estrogen receptor can independently mediate the cancellous bone-sparing effects of sex steroids in male mice. Selective KO studies of the androgen receptor in osteoblasts in male mice suggest that the osteoblast in the target cell for androgen receptor mediated maintenance of trabecular bone volume and coordination of bone matrix synthesis and mineralization. Taken together, both human and animal studies suggest that testosterone has a dual mode of action on different bone surfaces with involvement of both the androgen and estrogen receptor

Contribution of recent transgenic models and transcriptional profiling studies to our understanding of the mechanisms by which androgens control spermatogenesis

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Calcium and Vitamin D Supplementation in Men

Calcium and vitamin D supplements reverse secondary hyperparathyroidism and are widely prescribed to prevent osteoporotic fractures, with proven antifracture efficacy when targeted to individuals with documented insufficiencies. Men who should particularly be considered for calcium and vitamin D supplements include elderly or institutionalized individuals, patients with documented osteoporosis on antiresorptive or anabolic medication, and individuals receiving glucocorticoids. Benefits are most apparent when a daily dose of 1000–1200 mg calcium is complemented with 800 IU vitamin D. Compliance is the key to optimizing clinical efficacy. While (conventionally dosed) vitamin D has not been associated with safety concerns, recent meta-analytic data have provided evidence to suggest that calcium supplements (without coadministered vitamin D) may potentially be associated with cardiovascular risks

Sex hormone-binding globulin regulation of androgen bioactivity in vivo : validation of the free hormone hypothesis

Sex hormone-binding globulin (SHBG) is the high-affinity binding protein for androgens and estrogens. According to the free hormone hypothesis, SHBG modulates the bioactivity of sex steroids by limiting their diffusion into target tissues. Still, the in vivo physiological role of circulating SHBG remains unclear, especially since mice and rats lack circulating SHBG post-natally. To test the free hormone hypothesis in vivo, we examined total and free sex steroid concentrations and bioactivity on target organs in mice expressing a human SHBG transgene. SHBG increased total androgen and estrogen concentrations via hypothalamic-pituitary feedback regulation and prolonged ligand half-life. Despite markedly raised total sex steroid concentrations, free testosterone was unaffected while sex steroid bioactivity on male and female reproductive organs was attenuated. This occurred via a liganddependent, genotype-independent mechanism according to in vitro seminal vesicle organ cultures. These results provide compelling support for the determination of free or bioavailable sex steroid concentrations in medicine, and clarify important comparative differences between translational mouse models and human endocrinology

The effect of lip closure on palatal growth in patients with unilateral clefts

Objectives The objective of this study was to compare maxillary dimensions and growth in newborns with Complete Unilateral Cleft Lip and Palate (UCLP) to healthy newborns before and after cheiloplasty. Additionally, a palatal growth curve is constructed to give more information about the natural growth before surgical intervention. Methods Twenty-eight newborns with complete UCLP were enrolled in this study. Multiple plaster-casts of each child during their first year were collected and grouped in before and after cheiloplasty. A previous developed semi-automatic segmentation tool was used to assess the maxillary dimensions and were compared to a healthy control group. Z-scores were calculated to indicate differences between the two populations and if cheiloplasty had influence on maxillary growth. Furthermore, the prediction model created in a previous study was used to indicate differences between predictions and the outcome in UCLP measurements. The analysis was tested for inter- and intra-observer variability. Results Results show differences in alveolar and palatal shape in UCLP patients in comparison with healthy controls. Prior to cheiloplasty an increased width and alveolar length was observed while the palatal depth was decreased. After cheiloplasty the widths moved towards normal but were still significantly larger

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

Androgen receptor uses relaxed response element stringency for selective chromatin binding and transcriptional regulation in vivo

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Nationwide epidemiological approach to identify associations between keratoconus and immune-mediated diseases

Background: The aetiology of keratoconus (KC) remains poorly understood. KC has typically been described as a non-inflammatory disorder of the cornea. Nonetheless, there is increasing presumptive evidence for the role of the immune system in the pathogenesis of KC. Aim: To evaluate the association between KC and immune-mediated diseases on a population level. We hypothesise that KC is immune-mediated rather than a predominantly degenerative disease. Methods: Data were obtained from the largest health insurance provider in the Netherlands. Dutch residents are obligatorily insured. The data contained all medical claims and sociodemographic characteristics from all KC patients plus all those data from a 1:6 age-matched and sex-matched control group. The primary outcome was the association between KC and immune-mediated diseases, as assessed by conditional logistic regression. Results: Based on our analysis of 2051 KC cases and 12 306 matched controls, we identified novel associations between KC and Hashimoto's thyroiditis (OR=2.89; 95% CI: 1.41 to 5.94) and inflammatory skin conditions (OR=2.20; 95% CI: 1.37 to 3.53). We confirmed known associations between KC and atopic conditions, including allergic rash (OR=3.00; 95% CI: 1.03 to 8.79), asthma and bronchial hyperresponsiveness (OR=2.51; 95% CI: 1.63 to 3.84), and allergic rhinitis (OR=2.20; 95% CI: 1.39 to 3.49). Conclusion: Keratoconus appears positively associated with multiple immune-mediated diseases, which provides a population-based argument that systemic inflammatory responses may influence its onset. The identification of these particular diseases might shed light on potential comparable pathways through which this proinflammatory state is achieved, paving the way for pharmacological treatment strategies

Early effects of androgen deprivation on bone and mineral homeostasis in adult men: a prospective cohort study

Objective: Long-term androgen deprivation therapy (ADT) negatively influences bone. The short term effects on bone and mineral homeostasis are less known. Therefore, we aimed to investigate the early effects of ADT on calcium/phosphate homeostasis and bone turnover. Design: Prospective cohort study Methods: Eugonadal adult male sex offenders, who were referred for ADT to the endocrine outpatient clinic, received cyproterone acetate. Changes in blood markers of calcium/phosphate homeostasis and bone turnover between baseline and first follow-up visit were studied. Results: Of 26 screened patients, 17 were included. The median age was 44 (range 20-75) years. The median time interval between baseline and first follow-up was 13 (6-27) weeks. Compared to baseline, an 81% decrease was observed for median total testosterone (to 3.4 nmol/L (0.4-12.2); P<0.0001) and free testosterone (to 0.06 nmol/L (0.01-0.18); P<0.0001). Median total estradiol decreased 71% (to 17.6 pmol/L (4.7-35.6); P<0.0001). Increased serum calcium (P<0.0001) and phosphate (P=0.0016) was observed, paralleled by decreased PTH (P=0.0156) and 1,25 dihydroxyvitamin D3 (P=0.0134). The stable calcium isotope ratio (δ44/42Ca) decreased (P=0.0458), indicating net calcium loss from bone. Bone-specific alkaline phosphatase and osteocalcin decreased (P<0.0001 and P=0.0056, respectively), periostin tended to decrease (P=0.0500) whereas sclerostin increased (P<0.0001), indicating suppressed bone formation. Serum bone resorption markers (TRAcP5b, CTX) were unaltered. Conclusions: In adult men, calcium release from the skeleton occurs early following sex steroid deprivation, reflecting early bone resorption. The increase of sclerostin and reduction of bone formation markers, without changes in resorption markers, suggests a dominant negative effect on bone formation in the acute phase

Crosstalk between androgen receptor and WNT/β-catenin signaling causes sex-specific adrenocortical hyperplasia in mice

Female bias is highly prevalent in conditions such as adrenal cortex hyperplasia and neoplasia, but the reasons behind this phenomenon are poorly understood. In this study, we show that overexpression of the secreted WNT agonist R-spondin 1 (RSPO1) leads to ectopic activation of WNT/β-catenin signaling and causes sex-specific adrenocortical hyperplasia in mice. Although female adrenals show ectopic proliferation, male adrenals display excessive immune system activation and cortical thinning. Using a combination of genetic manipulations and hormonal treatment, we show that gonadal androgens suppress ectopic proliferation in the adrenal cortex and determine the selective regulation of the WNT-related genes Axin2 and Wnt4. Notably, genetic removal of androgen receptor (AR) from adrenocortical cells restores the mitogenic effect of WNT/β-catenin signaling. This is the first demonstration that AR activity in the adrenal cortex determines susceptibility to canonical WNT signaling-induced hyperplasia.</p