Sex steroids are important for the growth and maintenance of both the female and the male skeleton. However, the relative contribution of androgens versus estrogens in the regulation of the male skeleton is unclear. Experiments using mice with inactivated sex steroid receptors demonstrated that both activation of the estrogen receptor (ER)α and activation of the androgen receptor result in a stimulatory effect on both the cortical and trabecular bone mass in males. ERβ is of no importance for the skeleton in male mice while it modulates the ERα-action on bone in female mice. Previous in vitro studies suggest that the membrane G protein-coupled receptor GPR30 also might be a functional ER. Our in vivo analyses of GPR30-inactivated mice revealed no function of GPR30 for estrogen-mediated effects on bone mass but it is required for normal regulation of the growth plate and estrogen-mediated insulin-secretion. Recent clinical evidence suggests that a threshold exists for estrogen effects on bone in men: rates of bone loss and fracture risk seem to be the highest in men with estradiol levels below this threshold. Taken together, even though these findings do not exclude an important role for testosterone in male skeletal homeostasis, it is now well-established that estrogens are important regulators of bone health in men.
Claes Ohlsson and Liesbeth Vandenput
John-Olov Jansson, Sofia Movérare-Skrtic, Anna Berndtsson, Ingrid Wernstedt, Hans Carlsten and Claes Ohlsson
Objective: Ovariectomized (OVX) mice are known to gain body fat while exposure to estrogens decreases fat mass. We have previously shown that estrogen replacement therapy enhances the expression of receptors for the cytokine, leukemia inhibitory factor (LIF). LIF and other cytokines acting via the gp130 signal transducing receptor have been reported to decrease obesity. In the present study, we investigated whether LIF treatment can reduce obesity in OVX mice.
Design: Eight-week-old female C57Bl/6 mice were OVX or sham-operated. The mice were treated with LIF, 30 μg/kg or PBS via daily i.p. injections for 15 days (n = 9–10).
Methods: Dual X-ray absorptiometry and computerized tomography.
Results: We found that LIF treatment of OVX mice caused a significant reduction in the weight of white fat depots (P = 0.017) and serum leptin levels (P = 0.011). LIF also caused a significant decrease in brown fat mass (P = 0.036). Treatment with LIF decreased thymus weight but did not affect crown-rump length, femur length, trabecular bone mineral density or the weight of several non-fat organs including the uterus.
Conclusion: The cytokine, LIF, decreases body fat mass in OVX mice, suggesting that estrogen signaling is not required for this effect.
Liesbeth Vandenput, Dan Mellström, Magnus K Karlsson, Eric Orwoll, Fernand Labrie, Östen Ljunggren and Claes Ohlsson
Association studies in men have shown that androgens are inversely related to fat measures, while the relation between sex steroids and lean mass remains unclear. We, therefore, investigated the associations between serum sex steroid levels and body composition in elderly men with a main focus on lean mass measures.
Design and methods
A cross-sectional survey of a population-based cohort of 3014 elderly men, aged 69–80 years (Osteoporotic Fractures in Men study, Sweden). Serum levels of testosterone and estradiol (E2) were measured by mass spectrometry, sex hormone-binding globulin (SHBG) levels were measured by IRMA, and measures of body composition were obtained by dual-energy X-ray absorptiometry.
Total as well as free serum testosterone associated independently inversely (P<0.001), while total as well as free serum E2 associated independently directly (P<0.001) with total body fat mass and trunk fat mass. Serum SHBG associated independently inversely with central fat distribution. Serum E2 and free E2 but not serum testosterone or free testosterone levels associated positively with lean mass (P<0.01). Elderly men within the lowest quartile of free E2 had 0.5 kg less lean mass in the legs than subjects within the highest quartile, while the subjects in the different quartiles of free testosterone did not differ in lean mass.
Serum E2, but not serum testosterone, is directly associated with lean mass in this large study of elderly Swedish men. In addition, serum SHBG is associated with central fat distribution and we confirmed that serum testosterone is inversely associated with fat mass.
Tung Wai Auyeung, Jenny Shun Wah Lee, Timothy Kwok, Jason Leung, Claes Ohlsson, Liesbeth Vandenput, Ping Chung Leung and Jean Woo
To examine the relationship between different measures of testosterone and estradiol (E2), muscle mass, muscle strength, and physical performance; and to test whether the association of sex hormone level with muscle strength and physical performance was independent of muscle mass.
Design and methods
A cross-sectional survey on 1489 community-dwelling men older than 64 years of age. Serum levels of testosterone and E2 were measured by mass spectrometry, and sex hormone-binding globulin (SHBG) levels were measured by immunoradioassay. Muscle mass was examined by dual-energy X-ray absorptiometry and physical performance was assessed by hand-grip strength, gait speed, step length and chair-stand test.
Appendicular skeletal mass (ASM) was positively associated with total testosterone (TT; P<0.001), free testosterone (FT; P<0.001), and total E2 (P<0.001) but not with free E2 (P=0.102). After adjustment for age, serum SHBG and relative ASM, both TT and FT were significantly associated with grip strength, narrow-walk speed and the composite neuromuscular score. Higher total E2, but not free E2 was associated with lower grip strength (P<0.05) after adjustment for age, FT, SHBG and relative ASM.
Testosterone level was related to both muscle mass, strength and physical performance. Total E2 level, though related to muscle mass positively, affected muscle strength adversely in older men.
Richard Marsell, Elin Grundberg, Tijana Krajisnik, Hans Mallmin, Magnus Karlsson, Dan Mellström, Eric Orwoll, Claes Ohlsson, Kenneth B Jonsson, Östen Ljunggren and Tobias E Larsson
Fibroblast growth factor-23 (FGF23) is a circulating factor involved in phosphate (Pi) and vitamin D metabolism. Serum FGF23 is increased at later stages of chronic kidney disease due to chronic hyperphosphatemia and decreased renal clearance. Recent studies also indicate that FGF23 may directly regulate the expression of parathyroid hormone (PTH) in vitro. Therefore, the objective of the current study was to determine the relationship between FGF23, PTH, and other biochemistries in vivo in subjects with no history of renal disease.
Serum biochemistries were measured in a subsample of the population-based Swedish part of the MrOS study. In total, 1000 Caucasian men aged 70–80 years were randomly selected from the population.
Intact FGF23, Pi, calcium, albumin, estimated glomerular filtration rate (eGFR, calculated from cystatin C), PTH, and 25(OH)D3 were measured. Association studies were performed using linear univariate and multivariate regression analyses.
The median FGF23 level was 36.6 pg/ml, ranging from 0.63 to 957 pg/ml. There was a significant correlation between log FGF23 and eGFR (r=−0.21; P<0.00001) and log PTH (r=0.13; P<0.001). These variables remained as independent predictors of FGF23 in multivariate analysis. In addition, log PTH (β=0.082; P<0.05) and eGFR (β=−0.090; P<0.05) were associated with log FGF23 in subjects with eGFR>60 ml/min. Only eGFR (β=−0.35; P<0.0001) remained as a predictor of log FGF23 in subjects with eGFR<60 ml/min.
Serum FGF23 and PTH are associated in vivo, supporting recent findings that FGF23 directly regulates PTH expression in vitro. Additionally, eGFR is associated with FGF23 in subjects with normal or mildly impaired renal function, indicating that GFR may modulate FGF23 levels independent of serum Pi.