|
 
 |
| INVITED REVIEW |
|
| Year : 2014 | Volume
: 16
| Issue : 2 | Page : 213-222 |
|
Androgens and estrogens in skeletal sexual dimorphism
Michaël Laurent1, Leen Antonio2, Mieke Sinnesael3, Vanessa Dubois4, Evelien Gielen5, Frank Classens4, Dirk Vanderschueren6
1 Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine; Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, KU Leuven; Geriatric Medicine, University Hospitals Leuven, Leuven, Belgium
2 Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine; Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven; Endocrinology and Andrology, University Hospitals Leuven, Leuven, Belgium
3 Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
4 Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
5 Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, KU Leuven; Geriatric Medicine, University Hospitals Leuven; Centre for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium
6 Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven; Endocrinology and Andrology; Centre for Metabolic Bone Diseases; Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium
| Date of Submission | 06-Jun-2013 |
| Date of Acceptance | 02-Jul-2013 |
| Date of Web Publication | 23-Dec-2013 |
Correspondence Address:
Michaël Laurent
Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine; Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, KU Leuven; Geriatric Medicine, University Hospitals Leuven, Leuven
Belgium
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/1008-682X.122356
Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T) to estradiol (E2) by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution) peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refi ned our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen defi ciency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the fi eld of sex steroid actions in male bone homeostasis. Keywords: androgen receptor; bone mineral density; estradiol; estrogen receptor; male; osteoblast; osteoclast; osteocyte; osteoporosis;
sex hormone-binding globulin; testosterone
How to cite this article:
Laurent M, Antonio L, Sinnesael M, Dubois V, Gielen E, Classens F, Vanderschueren D. Androgens and estrogens in skeletal sexual dimorphism. Asian J Androl 2014;16:213-22 |
How to cite this URL:
Laurent M, Antonio L, Sinnesael M, Dubois V, Gielen E, Classens F, Vanderschueren D. Androgens and estrogens in skeletal sexual dimorphism. Asian J Androl [serial online] 2014 [cited 2021 Aug 3];16:213-22. Available from: https://www.ajandrology.com/text.asp?2014/16/2/213/122356 - DOI: 10.4103/1008-682X.122356 |
| Introduction | |  |
Bone is an endocrine tissue sensitive to androgens and estrogens. [1] The epidemiology and clinical approach to male osteoporosis have recently been reviewed elsewhere. [2] Here, we will review the literature on the role of sex steroids in male bone health and more specifically in osteoporosis, the most common metabolic bone disease. We will focus on human data with support from recent evidence from knockout mouse models. The latter are covered in more detail elsewhere in this issue (See Rana et al. in this theme issue).
Men contribute considerably to the disease burden of osteoporosis
Although still perceived by the public, patients and most physicians as a typically female condition, men account for a substantial proportion of the burden of osteoporosis. At age 50, the remaining lifetime risk of osteoporotic fractures is 20% - 25% in Caucasian men versus 45% - 55% in women. [2] About one-third of the 9 million osteoporotic fractures worldwide occurs in men. [3] For hip fractures, a review of worldwide epidemiological data recently showed that while incidence varied more than 10-fold between countries, men almost invariably have twofold lower risk (except perhaps in regions where incidence is very low). [4] Male osteoporosis is responsible for about 25% of the economic burden of osteoporosis in the United States (US$17 billion total costs) and Canada (2.3 billion Canadian dollars). [5],[6],[7] Nevertheless, osteoporosis remains even more underdiagnosed and undertreated in men compared to women, regardless of whether it is evidenced by low bone mineral density (BMD), [8] a low-energy fracture [9],[10] or absolute 10-year fracture probability. [11],[12]
Basic sex steroid physiology in relation to bone health
Metabolism and regulation of circulating sex steroids
Sex steroid serum concentrations are determined by their synthesis in the gonads and adrenals as well as by catabolic enzyme activity. Testosterone (T), the principal circulating androgen, can be aromatized to estradiol (E2, the principal estrogen) or 5α-reduced to dihydrotestosterone (DHT), a non-aromatizable androgen. Thus, in bone T may stimulate the androgen receptor (AR), either directly or as DHT, as well as estrogen receptors (ER) following aromatization. [13] The synthesis of sex steroids is under hypothalamic-pituitary feedback control via gonadotropins (follicle stimulating hormone (FSH) and luteinizing hormone (LH)). Several high-profile reports have suggested that FSH contributes to hypogonadal bone loss in female rodents, [14],[15] but other groups have failed to confirm the presence of FSH receptors in bone cells or a physiological effect thereof. [16],[17],[18],[19] Gonadotropin inhibition also does not seem to influence bone turnover markers independent of sex steroid levels in men. [20]
Serum bioactivity of sex steroids is restricted in humans by their high affinity binding to sex hormone-binding globulin (SHBG). About 45% of T, the principal circulating androgen, is bound to SHBG in normal men; only the non-SHBG-bound fraction is considered bioactive. Most of this fraction is bound nonspecifically to albumin and other carrier proteins, while only about 2% of T and E2 and <1% of DHT circulates freely in normal men. [21] According to the free hormone hypothesis however, this constitutes the most physiologically important fraction. [22] Others have pointed to the limitations of this theory and have pleaded to "stop looking backwards" and focusing exclusively on free sex steroid levels. Indeed, even if only a small portion of the protein-bound sex steroids is physiologically active, it is likely to have more influence than the 1% - 2% that is free. [23]
Sex steroid nuclear receptor signaling
Sex steroids classically act via their nuclear receptors (NRs: AR, ERα and ERβ), which bind directly or indirectly via other proteins to cognate DNA response elements (androgen response elements and estrogen response elements), recruit coactivators and other regulatory proteins, and influence gene transcription. [24] Two types of androgen response elements exist (classical and selective), but mice with abrogated AR binding to selective androgen response elements only show a sex organ phenotype. [25] Nonclassical signaling pathways of these NRs have also been described but remain somewhat controversial (especially for AR). These have not yet been successfully translated (therapeutically) to studies in humans, and will therefore not be further discussed here.
Androgen and estrogen deficiency also have important indirect effects via other signaling pathways in bone (e.g. insulin-like growth factor I (IGF-1) [26] ), potentially via AR and ER in other tissues like muscle, fat, and the nervous system, or via, for example, decreased physical activity in AR knockout (ARKO) mice. [27],[28] Therefore, caution needs to be exerted regarding the roles of AR and ER specifically in bone cells when interpreting the results of gonadectomy or ARKO/ERKO models. These limitations have been overcome recently using Cre/LoxP mouse models (see below). The fact that these cell-specific models show less dramatic bone phenotypes than their global ARKO/ERKO counterparts confirms the importance of pleiotropic actions of sex steroids on bone.
| Structural Basis of Male Bone Strength | | |
The musculoskeletal system is sexually dimorphic, being on average (but obviously not in all cases) larger and more robust in men compared to women. Bone strength is determined by peak bone mass (PBM) acquisition in young adulthood and subsequent turnover in different compartments (cortical and trabecular bone), resulting in gender differences in bone length, bone mineral density (BMD), geometry, and microarchitecture. For other determinants like material properties, gender differences require further investigation. Osteoporotic fracture risk is not only determined by purely skeletal factors but also by risk of falls, which should also be evaluated and treated in osteoporotic men. [29],[30]
In the following paragraphs, we will discuss the structural basis of male bone strength. It is well-known that men have higher peak areal BMD (aBMD) in young adulthood and aBMD declines slower as they age. [31] However, this should be interpreted with caution because of the projectional nature of dual energy X-ray absorptiometry (DXA), which leads to potential confounding by bone size, geometry, and porosity rather than true volumetric density (vBMD). In this respect, quantitative computed tomography (qCT), especially high resolution peripheral qCT (HR-pqCT), has recently led to a major advance in our understanding of the gender dimorphism in the structural determinants of bone strengths.
Bone size
Men are on average taller due to the actions of sex steroids on the growth plate (see below). From a biomechanical point of view, longer bones (which are also wider and have greater bone mass) are more resistant to bending. However, several cohort studies have found a positive association between height and risk of low-energy fractures, although the results in men are scant and only bordered significance. [32],[33] This may be explained by greater loads when falling from a larger height, longer arms of moment, as well as by relatively thinner cortices and greater cortical porosity in larger bones; although definitive data in men are currently lacking. [34]
Peak bone mass
Bone mineral mass can be low in old age because insufficient PBM attainment during skeletal growth (modeling phase) or due to an imbalance in the normally coupled process of bone turnover (remodeling phase), either by excessive bone resorption or decreased bone formation. The risk of many chronic diseases which manifest in old age, including osteoporosis, is determined at least in part by childhood or even prenatal experiences. PBM is largely (60%-80%) genetically determined, but the remainder is determined by environmental factors, some of which (e.g. maternal age and vitamin D status during pregnancy) are potentially amenable to interventions. [35],[36] Theoretically, small increases in PBM translate into a large delay in osteoporosis onset, [37] although it remains to be established whether bone mass increments early in life can be sustained into old age. [38]
The age of PBM or peak bone density differs between studies and depends on the measured site. In a prospective study with 15 years of follow-up, BMC in boys plateaued first at the femoral neck, followed by the total hip, lumbar spine, and whole body, respectively at the age of 2, 3, 4, and 6 years after peak height velocity (PHV, average age 14 in men). [39] Hip aBMD decreases early after it peaks. [40] Longitudinal studies across a wider age range have however estimated that lumbar spine BMD may peak as late as age 33 and 40 in men and women, respectively. Bone area increments are followed 1 - 2 years later by mineralization, and there are little differences between men and women when the age of PHV is used as the reference. [41] The peripubertal years (age 12 - 16) contributed 33% - 46% to adult-level BMC, demonstrating the importance of this window of opportunity for interventions to optimize PBM. [39] There is considerable variation in the timing of male puberty, but neither early nor late normal puberty seem to compromise PBM. [42]
Bone geometry and microarchitecture
Men develop wider bones even after adjustment for height because of greater periosteal apposition in the appendicular skeleton, whereas girls predominantly decrease their endosteal perimeter. [1] As a result, cortical bone in men is placed further away from the neutral axis, providing greater resistance to bending, but no difference in size-independent biomechanical indices. [43],[44] Bone width predicts fractures in older men independently of aBMD, and men with low bone width combined with BMD T-scores <−1 have similar fracture incidence as men with T-scores <−2. [45]
Recently, most cross-sectional studies using HR-pqCT have documented cortical and trabecular bone across the lifespan in more detail [Figure 1]. | Figure 1: Structural determinants of bone strength in men based on high resolution peripheral computed tomography (HR-pqCT) at the ultradistal radius. Adapted, with permission, from Khosla et al.46 Tb.Th, trabecular thickness; BV/TV, trabecular bone volume/tissue volume; TbN, trabecular number; TbSp, trabecular separation; Cort vBMD, cortical volumetric bone mineral density; Ct.Th, cortical thickness.
Click here to view |
At PBM, men have higher trabecular bone volume fraction [ Figure 1]a due to thicker [Figure 1]c, more plate-like trabeculae. On the other hand, cortical porosity is greater (not shown) and cortical vBMD slightly lower [Figure 1]f, while trabecular vBMD (not shown) and cortical thickness [Figure 1]e are not yet greatly different. [43],[46],[47],[48] Increasing cross-sectional area and cortical thickness, ongoing cortical mineralization and decreasing porosity contribute to ongoing aBMD and estimated strength increases during the 3 rd decade of life in men, whereas in women cortical perimeter and strength do not increase during young adulthood. [40],[49]
Both cortical and trabecular vBMD losses are more pronounced with age in women, although rates of trabecular bone loss vary across sites. [43],[50] With ageing, endocortical resorption outpaces periosteal apposition leading to a thinner cortex in both sexes, but older women show dramatically greater medullary expansion and thus cortical thinning [Figure 1]e and [Figure 3]. [43],[51],[52],[53] This was nicely illustrated in one prospective pqCT study [Figure 2], which also demonstrated the limitations of capturing bone geometrical changes across the lifespan from cross-sectional data. [51] | Figure 2: Schematic model of bone geometry changes at the tibia during adult lifespan in men and women. When comparing young women and men, men have greater cortical thickness due to greater periosteal perimeter (shown in black), while women mainly decrease their endocortical perimeter (also shown in black). With ageing, cortical thinning results from endocortical bone resorption in both genders (difference compared to age 20 shown in blue), but this is much more pronounced in women, and ongoing periosteal apposition (difference compared to age 20 shown in red) in both genders is unable to compensate for the differences. On the other hand, bone is placed further away from the central axis in men at all ages, and this dramatically improves biomechanics. Adapted, with permission, based on data from Lauretani et al.51
Click here to view |
Cortical porosity is greater in young men, but increases faster in women, especially after menopause, resulting in similar porosity after age 50. [43],[44] Cortical vBMD decreases from midlife in women, but only after age 75 in men, whereas trabecular bone loss starts almost immediately after PBM in both sexes [Figure 1]a but more so in women, with acceleration during perimenopause. [50],[53] Bone loss in men is more due to decreased formation rather than increased resorption, therefore trabeculae become thinner [Figure 1]c but less perforated, disconnected and thus widely spaced [Figure 1]b and d compared to postmenopausal women. [46],[54] Poor trabecular microarchitecture predisposes men to multiple and severe vertebral and peripheral fractures. [55] At the femoral neck, men have higher aBMD despite lower vBMD, due to greater length and femoral neck area, showing the importance of geometry over mineralization in the decreased hip fracture risk in men. [56] This also explains why men and women have the same strength for the same femoral neck aBMD: because of the offsetting effects of higher bone area and lower vBMD in men. [57]
In conclusion, detailed imaging techniques have greatly improved our understanding of the structural basis for gender differences in bone strength. How and to what extent sex steroids regulate this sexual dimorphism in cortical and trabecular bone will be discussed below.
| Sex Steroid Signaling is Key to Musculoskeletal Sexual Dimorphism | | |
Are gender differences in bone phenotype due to sex steroid signaling or other pathways? Sex steroids and especially estrogens were once considered a central hub on which bone signaling pathways converged in both genders, [58] but this unitary estrogen-centric view has been modified. [59],[60] Both at PBM and during ageing, BMD, bone geometry, bone turnover, and skeletal muscle mass in men have now been associated with multiple hormones (e.g., IGF-1 and IGF binding proteins, [61],[62],[63],[64] endogenous PTH, [63],[65] vitamin D, [66],[67] and thyroid hormone within the normal range), [68],[69] immunological, and other pathways in bone (e.g., CRP, [70] RANK/RANKL/OPG), oxidative stress, [71],[72],[73] and classical ageing pathways, [60] etc. Mostly similar associations have however been reported in women, and a recent meta-analysis of genome-wide BMD association studies failed to identify any significant gene-by-sex interactions. [74] Fundamental gender differences in key bone signaling pathways therefore seem unlikely.
Conversely, the musculoskeletal system of transsexual men shows a dramatic shift from the female to male phenotype after ovariectomy and prolonged T treatment. [75] Similarly, XY women with complete androgen insensitivity syndrome due to inactivating AR mutations have reduced BMD and a bone geometry intermediate between male and female, and estrogen treatment does not induce periosteal bone apposition in these subjects. [76] BMD is however much lower in both XY and XX women with gonadal dysgenesis, implying that gonadal status or sex steroids are more important than chromosomal determinants. [77] Overall, we can conclude that androgens (or AR mediated androgen action) are necessary for musculoskeletal sexual dimorphism in development and ageing, although they probably have important indirect actions on bone via aromatization, oxidative stress, [78] proinflammatory cytokines, [79],[80] growth factors (e.g. transforming growth factor (TGF)-β, IGF-1), [1],[26],[81] etc.
| Sex Steroid Regulation of Male Bone Metabolism | | |
Sex steroids control longitudinal bone size at the growth plate
It is generally accepted that delayed estrogen-mediated closure of epiphyseal growth plate cartilage contributes to greater bone length in men. T on the other hand probably also stimulates height velocity mainly via aromatization and estrogen-mediated pituitary growth hormone release. Non-aromatizable androgens increase growth rate in boys without altering serum GH/IGF-1, possibly via the AR in chondrocytes and local IGF-1 signaling in the growth plate. [1],[82] Pubertal height velocity acceleration and subsequent growth plate closure seem to be absent in men with inactivating ERα mutations [83] or aromatase deficiency [84],[85],[86],[87] who show steady, continuous growth, suggesting that estrogens have a dominant role in these processes. A recent study using ERαKO mice with no residual truncated isoforms confirmed the continuing longitudinal growth seen in the ERαKO (see next paragraph). [88] The fact that 46, XY girls with complete androgen insensitivity syndrome have a growth spurt similar in timing and amplitude as 46, XX girls [89] is probably due to estrogen effects, but it does not exclude a role for AR itself. Male ARKO mice have been anecdotally noted to have increased femur length, [90] but in men the effects of increased estrogen due to aromatization probably override any possible direct effect of T on the growth plate. On the other hand, further research on androgen regulation of (growth plate) chondrocytes would be of interest.
Estrogen deficiency: the primary mediator of bone loss in older hypogonadal men
The primary role of estrogens in postmenopausal osteoporosis was proposed by Albright et al., in 1941. [91] Similarly, hypogonadal men with low T were noted to have increased risk of osteoporosis and fractures. [92],[93] The historic dichotomous view that estrogens were important for bone health in women and androgens in men was however challenged by a unique report of a man with an ERα mutation. [83] He presented with tall stature, incomplete epiphyseal closure in adulthood and markedly decreased bone density. In 1998, investigators from the Mayo Clinic proposed a unitary model for the pathogenesis of osteoporosis with a central responsibility for estrogens, not only in post-menopausal but also in male osteoporosis and even in the negative calcium balance and secondary hyperparathyroidism in age-related osteoporosis. [58] This was based on seminal observations, [94] subsequently confirmed in multiple prospective cohort studies, of a strong association between (calculated free or bioavailable) E2, bone turnover, and bone density in community-dwelling men; whereas, the same associations with T were variable, weak, absent, or disappeared after correcting for E2 or other variables. [95],[96],[97],[98],[99],[100],[101],[102],[103],[104],[105] On the other hand, threshold effects (i.e., greater decreases in serum E2 in women compared to relatively normal androgen levels in ageing men) probably limit the conclusions that can be drawn from such cohort studies. Indeed, in several studies, E2 (and SHBG, see below) have been associated with bone loss below a certain threshold, [96],[101],[106] while this has not been confirmed in younger cohorts of men. [105],[107] In the European Male Ageing Study (EMAS) of men aged 40 - 79 years, the prevalence of T between 11 and 8 nmol l−1 was 12.9%, while only 4.1% had T <8 nmol/l, showing that most hypogonadism is mild in cohort studies. [108] Nevertheless, several complimentary lines of evidence [Table 1] [84],[85],[86],[87],[109],[110],[111],[112],[113],[114],[115],[116],[117],[118],[119],[120] confirm that estrogens are crucial to restrain bone turnover in ageing men. Thus, the finding that T blocks orchidectomy-induced bone loss in ERαKO mice [121] has been contradicted by human experiments, [120] which is possibly due to limitations of the ERαKO mouse model (which shows high bone mass due to increased T, which also contrasts with the situation in an ERαKO man). [83]  | Table 1: Evidence supporting the primary role of estrogens in bone loss in older men
Click here to view |
Low testosterone and high sex hormone-binding globulin pose additional risks
The overall conclusion thus appears to be that estrogens are more important than androgens in maintaining bone health in ageing men. Yet low T and high SHBG may still harbor additional detriments. Free or bioavailable T has been associated with BMD (at predominantly cortical sites), bone area, muscle area and strength, reduced fat mass and hip, vertebral and non-vertebral fractures in different large studies in older men. [107],[122],[123],[124] Late-onset hypogonadism (LOH) as defined by the presence of three sexual symptoms according to criteria from the EMAS appears to correlate more strongly than low T alone with low ultrasound-estimated BMD. [125] Similarly, risk for hip fractures has been found highest in men with both low E2 and T. [126] We have previously shown in mice that optimal effects of T require a functional AR. [127] These data are in agreement with findings from a man with concomitant aromatase deficiency and low T, in whom T and E2 replacement showed additive effects. [128]
In the largest study, low E2 and high SHBG were independent predictors of BMD losses and fracture risk in men, but risks were highest when both bioavailable E2 and T were combined with high SHBG. [129],[130] SHBG has been associated independently of bioavailable T and E2 with improved cortical bone development in young men, but accelerated bone losses with ageing and consequently increased fracture risk. [106],[131],[132],[133],[134] The mechanisms by which SHBG may influence bone in this apparently paradoxical manner require further investigation. [135]
The role of catabolic enzymes
Not only synthetic but also catabolic enzymes control steady state sex steroid serum levels. In the Swedish MrOS study, specific androgen metabolites correlated with male BMD, while T itself did not. [102] Polymorphisms in the enzymes catechol-O-methyl-transferase (COMT, an estrogen degrading enzyme) and uridine diphosphate glucuronosyltransferase 2B7 (which inactivates mainly androgens but also some estrogens) have been associated with increased sex steroid levels and bone geometry in young men. [136],[137],[138],[139] In another large population-based study, the COMT polymorphism was independently associated with fracture risk but not BMD, and only in men. [140] The activity of these and other steroid metabolizing enzymes, and whether they exert their influence mainly systemically or locally in bone, merits further study.
The contribution of 5α-reductase type 1
Only a small percentage of DHT enters the circulation, and this fraction does not correlate with male BMD. [102] 5α-reductase (encoded by Srd5a) type 2 is primarily expressed in male reproductive tissues including the prostate; whereas, type 1 and 3 are expressed in many tissues including reproductive tissues and bone. [141] The 5α-reductase inhibitor finasteride inhibits type 2 and 3; whereas, dutasteride inhibits all three. It is therefore not unexpected that finasteride does not affect bone density, turnover, fracture risk, or muscle anabolic effects of androgens. [142],[143],[144],[145],[146],[147],[148] In contrast, male Srd5a1-/- mice have recently been characterized as having reduced bone mass and muscle strength despite normal androgen serum levels. [149] Human RCTs however have not shown effects of dutasteride on bone metabolism, [145],[150] nor does dutasteride influence the anabolic effects of T on muscle. [151] Whether or not 5α-reductase type 1 activity contributes to male bone mass, thus merits further investigation.
Meanwhile, aromatizable androgens may be used preferentially to simultaneously compensate androgen and estrogen deficiency in men with LOH. In a small randomized controlled trial (RCT), DHT gel treatment in older men with low T suppressed endogenous T without affecting E2 or BTMs, [152] while another RCT showed decreased E2 as well as spinal BMD. [153] Therefore, the main effect of androgens or selective AR modulators (SARMs) may depend on their suppression of estrogens. We have previously shown in rodents that androgens and estrogens apparently act via different pathways and that their combination might be beneficial compared to each strategy alone, [154],[155] although this requires confirmation in men with LOH.
| Relative Contributions of Androgen Receptor, Estrogen Receptorα, and Estrogen Receptorβ In Cortical Vs Trabecular Bone | | |
Although observational studies in humans are important to deermine the influence of sex steroids on male bone, the study of the respective contributions of AR and ER require knockout animal models as well as confirmation in rare human genetic disorders. These studies have revealed unexpected complexity regarding the roles of these NRs in different bone compartments. [26]
Both AR and ERα are required for optimal periosteal bone expansion, [90],[156] although estrogens limit periosteal expansion in early puberty, probably because of time-specific and independent effects on IGF-1. [26],[81] For trabecular bone development on the other hand, AR is solely responsible. [90],[156] Indeed, ARKO decreases cancellous bone, while systemic ERαKO increases it (probably due to increased androgen levels in this animal model) [121],[157] and combined AR/ERαKO does not decrease trabecular bone more than ARKO alone. [90] Compared to wild-type females, male pubertal ARKO mice have equal length, decreased trabecular bone, and identical cortical bone parameters; showing that androgens are required for optimal bone development, especially trabecular but also cortical, but not for longitudinal growth. [158] These results are confirmed in humans: estrogen therapy in young aromatase-deficient men indeed improves cortical thickness and area; however, without increasing trabecular vBMD. [86] Nevertheless, more recent animal studies using cell-specific ERαKO models do also suggest a role for ERα in trabecular bone formation (see below). ERβ plays a role in female bone health, [157],[159],[160] but male ERβKO mice have normal bones and ERαβKO show no difference to ERαKO alone. [154]
| Action Mechanisms of AR And ERα in Specific Bone Cells | | |
Androgens control osteoblasts and osteocytes, while estrogens also regulate osteoclasts
Cell culture experiments from ARKO mice have suggested that AR controls mainly osteoblasts and their indirect control of osteoclastogenesis. [161] However, as mentioned above, global ARKO/ERKO models or gonadectomy/antagonist studies preclude definitive conclusions about the cellular targets of AR and ER in male bone. Indirect evidence suggested that AR and ER signaling targets mainly osteoblasts and osteoclasts, respectively. These assumptions have only recently been verified using Cre/LoxP mouse models, although this requires careful verification that neither the Cre driver nor the floxed genotypes have effects themselves (see Rana et al. in this theme issue).
Androgen receptor in the osteoblast lineage
Osteocalcin-Cre driven ARKO revealed that androgens stimulate mineralizing osteoblasts, thus indirectly inhibiting cortical and trabecular bone resorption, especially during times of bone accrual. [162] Col2.3-Cre driven ARKO showed that mature osteoblasts contribute to trabecular bone maintenance. [163] However, periosteal apposition was not influenced by AR deficiency in these mature cells, probably because the periosteum contains more pre- and proliferating osteoblasts. Indeed, AR overexpression in immature osteoblasts increases periosteal and decreases endosteal bone formation; whereas, osteogenesis was inhibited at both envelopes following AR overexpression in mature osteoblasts. [164],[165] Recently, we have shown in Dmp1-Cre mice that loss of AR in osteocytes results in similar, moderate impairment of trabecular bone maintenance. [166] Importantly, AR expression increased with the maturation of osteoblasts towards osteocytes. [166] These different phenotypes suggest that AR has a direct role across the entire osteoblast lineage.
Androgen receptor and estrogen receptor alpha in osteoclasts
Clearly, AR signaling has important indirect restraining effects on osteoclasts, for example by controlling cytokine production in bone marrow stromal cells. [79] AR has been detected in vitro and with immunohistochemistry in rodent osteoclasts albeit at very low levels, and it may be absent in human osteoclasts. [1],[167],[168] Several though not all studies have suggested that androgens also directly suppress in vitro osteoclast formation from hematopoietic precursors. [1],[168],[169],[170],[171] Although they could not confirm the presence of AR in osteoclasts, the group of Kato found to their surprise that cathepsin K-Cre-driven ARKO also induces bone resorption (although this data has only been published in abstract), [172] in a similar way as they and others have reported for osteoclast-specific ERαKO in female (but not male) mice. [173],[174] Thus, a direct in vivo role for AR in osteoclasts merits independent confirmation.
Estrogen receptor alpha in osteoblasts
ERα has recently been established to have a role in osteoblasts and osteocytes too. It was already known that osteoblast-specific overexpression of aromatase increases bone mass in male mice. [175] Prx1 Cre and Osterix-Cre mice have now been used to selectively excise ERα from pluripotent mesenchymal progenitors in the limb bud of the appendicular skeleton, and respectively, osteoblast progenitors. These mice showed mainly cortical bone deficits resulting from decreased periosteal bone formation, although cortical bone deficits were overcome during adulthood in Prx1-Cre ERαKO males. [176] Deletion of ERα using the Col1a1 deleter did not affect cortical or trabecular bone. However, this should not be taken as evidence that ERα has no role downstream in osteoblast differentiation. Indeed, osteocalcin-Cre ERαKO decreased trabecular bone in males, and both trabecular and cortical bone in females. [177] Dmp1-Cre ERαKO males also showed decreased bone formation and less trabecular bone, but there was no effect on cortical bone, or any effect in females. The authors concluded that the trabecular bone-sparing effects of estrogens are mediated by osteocyte ERα in males, but probably by osteoclast ERα in females. [178] Interestingly, both ERαKO [179] and ARKO [180] have been known to influence the response to mechanical loading, but the response to mechanical loading was unaltered in the respective osteocyte-specific knockout mice. [166],[178]
In summary, these studies in male mice suggest that both AR and ERα are required for optimal cortical bone expansion via actions in immature osteoblasts, and trabecular bone maintenance via actions in more differentiated osteoblasts and osteocytes [Figure 3]. | Figure 3: Schematic illustration of the cellular targets of androgen receptor (AR) and estrogen receptor (ER) α on periosteal, endocortical, and trabecular surfaces in male mice. Based on a μCT image of the proximal murine tibia
Click here to view |
Indirect effects of androgen receptor and estrogen receptors on bone via muscle, fat, and the nervous system
The interaction of bone with muscle, adipose, and neural systems is increasingly studied. Tissue-specific ARKO models are discussed in more detail in the accompanying review by Rana et al. in this theme issue.
Bone-muscle interaction
Male ARKO mice have impaired muscle development, [181] and additional ERαKO further reduces muscle mass. [90] However, muscle-specific ARKO mice did not show altered bone metabolism and only slightly reduced peripheral skeletal muscle mass, possibly because only perineal muscles display high AR content and androgen regulation in mice. [182],[183] This contrasts with the well-known anabolic effects of androgens on human muscle. [184] Thus, although the effects of androgens on bone in mice are unlikely to be mediated via the AR in muscle, it remains unclear whether sarcopenia in older men with LOH contributes directly or is merely associated with bone loss and fractures. [2],[185],[186]
Bone-fat interaction
Clinical evidence suggests a positive association between bone and fat, but mainly in females, possibly because adipocyte aromatase activity influences circulating E2 or because of increased gravitational loading. [2],[185] Fat mass is principally regulated by estrogens since double knockouts have similar adiposity compared to ERαKO alone, [90] although androgens also have clear lipolytic activity, and male ARKO mice have increased adiposity. [28] A link between glucose, insulin, and bone metabolism has also been suggested in mice, and male bone metabolism is altered in diabetes and the metabolic syndrome. Thus, whether AR or ER signaling in adipocytes modulates sex steroid effects on bone would be of interest.
Central nervous system control of bone mass
Central nervous system regulation of bone mass has been demonstrated recently with often opposite effects to peripheral signaling. This also seems to be the case for estrogens, since neuron-specific ERαKO using nestin-Cre increases bone formation via leptin. [187] Conditional inactivation of AR in the nervous system of mice however disrupts the somatotropic axis as evidenced by growth retardation and twofold lower serum IGF-1, without relative differences in total bone mass or body composition. [188] This reiterates that the skeletal sexual dimorphism resulting from sex steroids is dependent on indirect effects via growth hormone, IGF-1 and IGF binding proteins in brain, bone, and liver. [26],[81],[189]
| Conclusions | | |
The musculoskeletal system is more robust in men, and sex steroid signaling remains essential for this sexual dimorphism. The advent of high resolution imaging has allowed better insights into the microarchitectural determinants of male bone strength. Specifically, androgens may promote trabecular bone development and thickness in young adulthood, as well as cortical consolidation in midlife and maintenance of cortical thickness and trabecular bone volume in older men by stimulating periosteal apposition and trabecular bone formation. Thus, although estrogen deficiency is the primary mediator of hypogonadal bone loss in men, high SHBG and low T probably pose additional detriments. The role of sex steroid catabolic enzymes and local lipid metabolism within bone (e.g. by 5α-reductase type 1) requires further investigation. Recent studies using knockout mouse models have refined our understanding of the contributions of AR and ERα in osteoclasts, osteoblasts, and osteocytes to cortical and trabecular bone development and maintenance. At the same time, they have reinforced the notion that sex steroids must have important pleiotropic effects on bone, for example, via interaction with the nervous system, IGF-1 and altered response to mechanical loading. A better understanding of the microarchitectural, cellular and molecular mechanisms of actions of androgens and estrogens continues to be necessary to develop therapeutic strategies which can exploit their benefits for bone health without unwanted side effects in other tissues.
| Acknowledgements | | |
M. Laurent and V. Dubois are research fellows of the Research Foundation Flanders. This work was supported by the Research Foundation Flanders via grants G.0858.11N and G.0684.12N and OT/11/081 from KU Leuven.
| Competing Interests | | |
Authors would declare that we have no financial or other competing interests.
| References | | |
| 1. | Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, et al. Androgens and bone. Endocr Rev 2004;25:389-425. 
|
| 2. | Laurent M, Gielen E, Claessens F, Boonen S, Vanderschueren D. Osteoporosis in older men: recent advances in pathophysiology and treatment. Best Pract Res Clin Endocrinol Metab 2013;27:527-39.
|
| 3. | Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17:1726-33.
|
| 4. | Kanis Ja, Oden A, Mccloskey EV, Johansson H, Wahl DA, et al. IOF Working Group on Epidemiology and Quality of Life. A systematic review of hip fracture incidence and probability of fracture worldwide. Osteoporos Int 2012;23:2239-56.
|
| 5. | Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res 2007;22:465-75.
|
| 6. | Tarride JE, Guo N, Hopkins R, Leslie WD, Morin S, et al. The burden of illness of osteoporosis in Canadian men. J Bone Miner Res 2012;27:1830-8.
|
| 7. | Tarride JE, Hopkins RB, Leslie WD, Morin S, Adachi JD, et al. The burden of illness of osteoporosis in Canada. Osteoporos Int 2012;23:2591-600.
|
| 8. | Frost M, Wraae K, Abrahamsen B, Hoiberg M, Hagen C, et al. Osteoporosis and vertebral fractures in men aged 60-74 years. Age Ageing 2012;41:171-7.
|
| 9. | Nurmi-Luthje I, Sund R, Juntunen M, Luthje P. Post-hip fracture use of prescribed calcium plus vitamin d or vitamin d supplements and antiosteoporotic drugs is associated with lower mortality: a nationwide study in Finland. J Bone Miner Res 2011;26:1845-53.
|
| 10. | Wastesson JW, Ringback Weitoft G, Parker MG, Johnell K. educational level and use of osteoporosis drugs in elderly men and women: a Swedish nationwide register-based study. Osteoporos Int 2013;24:433-42.
|
| 11. | Curtis JR, Mcclure LA, Delzell E, Howard VJ, Orwoll E, et al. Population-based fracture risk assessment and osteoporosis treatment disparities by race and gender. J Gen Intern Med 2009;24:956-62.
|
| 12. | Shibli-Rahhal A, Vaughan-Sarrazin MS, Richardson K, Cram P. Testing and treatment for osteoporosis following hip fracture in an integrated U.S. healthcare delivery system. Osteoporos Int 2011;22:2973-80.
|
| 13. | Callewaert F, Boonen S, Vanderschueren D. Sex steroids and the male skeleton: a tale of two hormones. Trends Endocrinol Metab 2010;21:89-95.
|
| 14. | Sun L, Peng Y, Sharrow AC, Iqbal J, Zhang Z, et al. FSH directly regulates bone mass. Cell 2006;125:247-60.
|
| 15. | Zhu LL, Blair H, Cao J, Yuen T, Latif R, et al. Blocking antibody to the beta-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis. Proc Natl Acad Sci U S A 2012;109:14574-9.
|
| 16. | Yarram SJ, Perry MJ, Christopher TJ, Westby K, Brown NL, et al. Luteinizing hormone receptor knockout (Lurko) mice and transgenic human chorionic gonadotropin (Hcg)-overexpressing mice (Hcg Alphabeta+) have bone phenotypes. Endocrinology 2003;144:3555-64.
|
| 17. | Seibel MJ, Dunstan CR, Zhou H, Allan CM, Handelsman DJ. Sex steroids, not FSH, influence bone mass. Cell 2006;127:1079.
[PUBMED] |
| 18. | Allan CM, Kalak R, Dunstan CR, Mctavish KJ, Zhou H, et al. Follicle-stimulating hormone increases bone mass in female mice. Proc Natl Acad Sci U S A 2010;107:22629-34.
|
| 19. | Rouach V, Katzburg S, Koch Y, Stern N, Somjen D. Bone loss in ovariectomized rats: dominant role for estrogen but apparently not for FSH. J Cell Biochem 2011;112:128-37.
|
| 20. | Uihlein A, Kumbhani R, Siwila-Sackman E, Finkelstein J, Lee H, et al. FSH suppression in eugonadal men does not change bone turnover markers. J Bone Miner Res 2012; 27.
|
| 21. | Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 1981;53:58-68.
[PUBMED] |
| 22. | Mendel CM. The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev 1989;10:232-74.
[PUBMED] |
| 23. | Caldwell JD, Jirikowski GF. Sex hormone binding globulin and aging. Horm Metab Res 2009;41:173-82.
|
| 24. | Helsen C, Kerkhofs S, Clinckemalie L, Spans L, Laurent M, et al. Structural basis for nuclear hormone receptor DNA binding. Mol Cell Endocrinol 2012;348:411-7.
|
| 25. | Schauwaers K, De Gendt K, Saunders PT, Atanassova N, Haelens A, et al. Loss of androgen receptor binding to selective androgen response elements causes a reproductive phenotype in a knockin mouse model. Proc Natl Acad Sci U S A 2007;104:4961-6.
|
| 26. | Callewaert F, Sinnesael M, Gielen E, Boonen S, Vanderschueren D. Skeletal sexual dimorphism: relative contribution of sex steroids, GH-IGF1, and mechanical loading. J Endocrinol 2010;207:127-34.
|
| 27. | Ophoff J, Callewaert F, Venken K, De Gendt K, Ohlsson C, et al. Physical activity in the androgen receptor knockout mouse: evidence for reversal of androgen deficiency on cancellous bone. Biochem Biophys Res Commun 2009;378:139-44.
|
| 28. | Rana K, Fam BC, Clarke MV, Pang TP, Zajac JD, et al. Increased adiposity in dna binding-dependent androgen receptor knockout male mice associated with decreased voluntary activity and not insulin resistance. Am J Physiol Endocrinol Metab 2011;301:E767-78.
|
| 29. | Boonen S, Dejaeger E, Vanderschueren D, Venken K, Bogaerts A, et al. Osteoporosis and osteoporotic fracture occurrence and prevention in the elderly: a geriatric perspective. Best Pract Res Clin Endocrinol Metab 2008;22:765-85.
|
| 30. | Masud T, Binkley N, Boonen S, Hannan MT. Official positions for frax (R) clinical regarding falls and frailty: can falls and frailty be used in frax (R)? from joint official positions development conference of the international society for clinical densitometry and international osteoporosis foundation on frax (R). J Clin Densitom 2011;14:194-204.
|
| 31. | Looker AC, Melton LJ 3 rd , Harris T, Borrud L, Shepherd J, et al. Age, gender, and race/ethnic differences in total body and subregional bone density. Osteoporos Int 2009;20:1141-9.
|
| 32. | Meyer HE, Tverdal A, Falch JA. Risk factors for hip fracture in middle-aged norwegian women and men. Am J Epidemiol 1993;137:1203-11.
|
| 33. | Joakimsen RM, Fonnebo V, Magnus JH, Tollan A, Sogaard AJ. The tromso study: body height, body mass index and fractures. Osteoporos Int 1998;8:436-42.
|
| 34. | Bjornerem A, Bui Q, Ghasem-Zadeh A, Hopper JL, Zebaze R, et al. Fracture risk and height: an association partly accounted for by cortical porosity of relatively thinner cortices. J Bone Miner Res 2013;28:2017-26.
|
| 35. | Rudang R, Mellstrom D, Clark E, Ohlsson C, Lorentzon M. Advancing maternal age is associated with lower bone mineral density in young adult male offspring. Osteoporos Int 2011;23:475-82.
|
| 36. | Cooper C, Westlake S, Harvey N, Javaid K, Dennison E, et al. Review: developmental origins of osteoporotic fracture. Osteoporos Int 2006;17:337-47.
|
| 37. | Hernandez CJ, Beaupre GS, Carter Dr. A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis. Osteoporos Int 2003;14:843-7.
|
| 38. | Gafni RI, Baron J. Childhood bone mass acquisition and peak bone mass may not be important determinants of bone mass in late adulthood. Pediatrics 2007; 119 Suppl 2: S131-6.
|
| 39. | Baxter-Jones AD, Faulkner RA, Forwood MR, Mirwald RL, Bailey DA. Bone mineral accrual from 8 to 30 years of age: an estimation of peak bone mass. J Bone Miner Res 2011;26:1729-39.
|
| 40. | Ohlsson C, Darelid A, Nilsson M, Melin J, Mellstrom D, et al. Cortical consolidation due to increased mineralization and endosteal contraction in young adult men: a five-year longitudinal study. J Clin Endocrinol Metab 2011;96:2262-9.
|
| 41. | Berger C, Goltzman D, Langsetmo L, Joseph L, Jackson S, et al. CaMos Research Group. Peak bone mass from longitudinal data: implications for the prevalence, pathophysiology, and diagnosis of osteoporosis. J Bone Miner Res 2010;25:1948-57.
[PUBMED] |
| 42. | Darelid A, Ohlsson C, Nilsson M, Kindblom JM, Mellstrom D, et al. Catch up in bone acquisition in young adult men with late normal puberty. J Bone Miner Res 2012;27:2198-207.
|
| 43. | Burghardt AJ, Kazakia GJ, Ramachandran S, Link TM, Majumdar S. Age- and gender-related differences in the geometric properties and biomechanical significance of intracortical porosity in the distal radius and tibia. J Bone Miner Res 2010;25:983-93.
|
| 44. | Macdonald HM, Nishiyama KK, Kang J, Hanley DA, Boyd SK. Age-related patterns of trabecular and cortical bone loss differ between sexes and skeletal sites: a population-based HR-pQCT study. J Bone Miner Res 2011;26:50-62.
|
| 45. | Szulc P, Munoz F, Duboeuf F, Marchand F, Delmas PD. Low width of tubular bones is associated with increased risk of fragility fracture in elderly men: the MINOS study. Bone 2006;38:595-602.
|
| 46. | Khosla S, Riggs BL, Atkinson EJ, Oberg AL, Mcdaniel LJ, et al. Effects of sex and age on bone microstructure at the ultradistal radius: a population-based noninvasive in vivo assessment. J Bone Miner Res 2006;21:124-31.
|
| 47. | Dalzell N, Kaptoge S, Morris N, Berthier A, Koller B, et al. Bone micro-architecture and determinants of strength in the radius and tibia: age-related changes in a population-based study of normal adults measured with high-resolution pQCT. Osteoporos Int 2009;20:1683-94.
|
| 48. | Kirmani S, Christen D, van Lenthe GH, Fischer PR, Bouxsein ML, et al. Bone structure at the distal radius during adolescent growth. J Bone Miner Res 2009;24:1033-42.
|
| 49. | Walsh JS, Paggiosi MA, Eastell R. Cortical consolidation of the radius and tibia in young men and women. J Clin Endocrinol Metab 2012;97:3342-8.
|
| 50. | Riggs BL, Melton LJ, Robb RA, Camp JJ, Atkinson EJ, et al. A population-based assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men. J Bone Miner Res 2008;23:205-14.
|
| 51. | Lauretani F, Bandinelli S, Griswold ME, Maggio M, Semba R, et al. Longitudinal changes in BMD and bone geometry in a population-based study. J Bone Miner Res 2008;23:400-8.
|
| 52. | Duan Y, Beck TJ, Wang XF, Seeman E. Structural and biomechanical basis of sexual dimorphism in femoral neck fragility has its origins in growth and aging. J Bone Miner Res 2003;18:1766-74.
|
| 53. | Riggs BL, Melton Iii LL 3 rd , Robb RA, Camp JJ, Atkinson EJ, et al. Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites. J Bone Miner Res 2004;19:1945-54.
|
| 54. | Szulc P, Seeman E. Thinking inside and outside the envelopes of bone: dedicated to PDD. Osteoporos Int 2009;20:1281-8.
|
| 55. | Szulc P, Boutroy S, Vilayphiou N, Chaitou A, Delmas PD, et al. Cross-sectional analysis of the association between fragility fractures and bone microarchitecture in older men: the STRAMBO study. J Bone Miner Res 2011;26:1358-67.
|
| 56. | Peacock M, Buckwalter KA, Persohn S, Hangartner TN, Econs MJ, et al. Race and sex differences in bone mineral density and geometry at the femur. Bone 2009;45:218-25.
|
| 57. | Srinivasan B, Kopperdahl DL, Amin S, Atkinson EJ, Camp J, et al. Relationship of femoral neck areal bone mineral density to volumetric bone mineral density, bone size, and femoral strength in men and women. Osteoporos Int 2011;23:155-62.
|
| 58. | Riggs BL, Khosla S, Melton LJ 3 rd . A unitary model for involutional osteoporosis: estrogen deficiency causes both type i and type ii osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 1998;13:763-73.
|
| 59. | Khosla S, Melton LJ 3 rd , Riggs BL. The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed? J Bone Miner Res 2011;26:441-51.
|
| 60. | Manolagas SC. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev 2010;31:266-300.
|
| 61. | Szulc P, Joly-Pharaboz MO, Marchand F, Delmas PD. Insulin-like growth factor i is a determinant of hip bone mineral density in men less than 60 years of age: MINOS study. Calcif Tissue Int 2004;74:322-9.
|
| 62. | Ohlsson C, Mellstrom D, Carlzon D, Orwoll E, Ljunggren O, et al. Older men with low serum igf-1 have an increased risk of incident fractures: the MROS sweden study. J Bone Miner Res 2011;26:865-72.
|
| 63. | Boonen S, Pye SR, O'neill TW, Szulc P, Gielen E, et al. EMAS Group. Influence of bone remodelling rate on quantitative ultrasound parameters at the calcaneus and dxa bmda of the hip and spine in middle-aged and elderly european men: The European Male Ageing Study (EMAS). Eur J Endocrinol 2011;165:977-86.
[PUBMED] |
| 64. | Pye SR, Almusalam B, Boonen S, Vanderschueren D, Borghs H, et al. EMAS Study Group. Influence of insulin-like growth factor binding protein (igfbp)-1 and igfbp-3 on bone health: results from the European Male Ageing Study. Calcif Tissue Int 2011;88:503-10.
|
| 65. | Curtis JR, Ewing SK, Bauer DC, Cauley JA, Cawthon PM, et al. Association of intact parathyroid hormone levels with subsequent hip BMD loss: The Osteoporotic Fractures in men (MROs) study. J Clin Endocrinol Metab 2012;97:1937-44.
|
| 66. | Grundberg E, Lau EM, Pastinen T, Kindmark A, Nilsson O, et al. Vitamin d receptor 3' haplotypes are unequally expressed in primary human bone cells and associated with increased fracture risk: The MROS study in Sweden and Hong Kong. J Bone Miner Res 2007;22:832-40.
|
| 67. | Vanderschueren D, Pye SR, O'neill TW, Lee DM, Jans I, et al. EMAS Study Group. Active vitamin d (1,25-dihydroxyvitamin d) and bone health in middle-aged and elderly men: The European Male Aging Study (EMAS). J Clin Endocrinol Metab 2013;98:995-1005.
[PUBMED] |
| 68. | Roef G, Lapauw B, Goemaere S, Zmierczak H, Fiers T, et al. thyroid hormone status within the physiological range affects bone mass and density in healthy men at the age of peak bone mass. Eur J Endocrinol 2011;164:1027-34.
|
| 69. | Waring AC, Harrison S, Fink HA, Samuels MH, Cawthon PM, et al. Osteoporotic Fractures in Men (MrOS) Study. A prospective study of thyroid function, bone loss, and fractures in older men: The MROS study. J Bone Miner Res 2013;28:472-9.
|
| 70. | Rolland T, Boutroy S, Vilayphiou N, Blaizot S, Chapurlat R, et al. Poor trabecular microarchitecture at the distal radius in older men with increased concentration of high-sensitivity c-reactive protein: The STRAMBO study. Calcif Tissue Int 2012;90:496-506.
|
| 71. | Roshandel D, Holliday KL, Pye SR, Boonen S, Borghs H, et al. EMAS Study Group. Genetic variation in the rankl/rank/opg signaling pathway is associated with bone turnover and bone mineral density in men. J Bone Miner Res 2010;25:1830-8.
|
| 72. | Roshandel D, Holliday KL, Pye SR, Ward KA, Boonen S, et al. EMAS Study Group. Influence of polymorphisms in the RANKL/RANK/OPG signaling pathway on volumetric bone mineral density and bone geometry at the forearm in men. Calcif Tissue Int 2011;89:446-55.
|
| 73. | Roshandel D, Thomson W, Pye SR, Boonen S, Borghs H, et al. EMAS Study Group. Polymorphisms in genes involved in the NF-kB signalling pathway are associated with bone mineral density, geometry and turnover in men. Plos One 2011;6:e28031.
|
| 74. | Liu CT, Estrada K, Yerges-Armstrong LM, Amin N, Evangelou E, et al. Assessment of gene-by-sex interaction effect on bone mineral density. J Bone Miner Res 2012;27:2051-64.
|
| 75. | Van Caenegem E, Wierckx K, Taes Y, Dedecker D, Van De Peer F, et al. Bone mass, bone geometry, and body composition in female-to-male transsexual persons after long-term cross-sex hormonal therapy. J Clin Endocrinol Metab 2012;97:2503-11.
|
| 76. | Taes Y, Lapauw B, Vandewalle S, Zmierczak H, Goemaere S, et al. Estrogen-specific action on bone geometry and volumetric bone density: longitudinal observations in an adult with complete androgen insensitivity. Bone 2009;45:392-7.
|
| 77. | Han TS, Goswami D, Trikudanathan S, Creighton SM, Conway GS. Comparison of bone mineral density and body proportions between women with complete androgen insensitivity syndrome and women with gonadal dysgenesis. Eur J Endocrinol 2008;159:179-85.
|
| 78. | Almeida M, Han L, Martin-Millan M, Plotkin LI, Stewart SA, et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem 2007;282:27285-97.
|
| 79. | Bellido T, Jilka RL, Boyce BF, Girasole G, Broxmeyer H, et al. Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor. J Clin Invest 1995;95:2886-95.
|
| 80. | Hofbauer LC, Ten RM, Khosla S. The anti-androgen hydroxyflutamide and androgens inhibit interleukin-6 production by an androgen-responsive human osteoblastic cell line. J Bone Miner Res 1999;14:1330-7.
|
| 81. | Callewaert F, Venken K, Kopchick JJ, Torcasio A, van Lenthe GH, et al. Sexual dimorphism in cortical bone size and strength but not density is determined by independent and time-specific actions of sex steroids and IGF-1: evidence from pubertal mouse models. J Bone Miner Res 2010;25:617-26.
|
| 82. | Perry RJ, Farquharson C, Ahmed SF. The role of sex steroids in controlling pubertal growth. Clin Endocrinol (Oxf) 2008;68:4-15.
|
| 83. | Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994;331:1056-61.
|
| 84. | Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997;337:91-5.
|
| 85. | Bilezikian JP, Morishima A, Bell J, Grumbach MM. Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 1998;339:599-603.
|
| 86. | Bouillon R, Bex M, Vanderschueren D, Boonen S. Estrogens are essential for male pubertal periosteal bone expansion. J Clin Endocrinol Metab 2004;89:6025-9.
|
| 87. | Merlotti D, Gennari L, Stolakis K, Nuti R. Aromatase activity and bone loss in men. J Osteoporos 2011;2011:230671.
|
| 88. | Borjesson AE, Windahl SH, Karimian E, Eriksson EE, Lagerquist MK, et al. The role of estrogen receptor-alpha and its activation function-1 for growth plate closure in female mice. Am J Physiol Endocrinol Metab 2012;302:E1381-9.
|
| 89. | Zachmann M, Prader A, Sobel EH, Crigler JF Jr, Ritzen EM, et al. pubertal growth in patients with androgen insensitivity: indirect evidence for the importance of estrogens in pubertal growth of girls. J Pediatr 1986;108:694-7.
|
| 90. | Callewaert F, Venken K, Ophoff J, De Gendt K, Torcasio A, et al. Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-alpha. FASEB J 2009;23:232-40.
|
| 91. | Albright F, Smith PH, Richardson AM. Postmenopausal osteoporosis. JAMA 1941;116:2465-74.
|
| 92. | Finkelstein JS, Klibanski A, Neer RM, Greenspan SL, Rosenthal DI, et al. Osteoporosis in men with idiopathic hypogonadotropic hypogonadism. Ann Intern Med 1987;106:354-61.
[PUBMED] |
| 93. | Swartz CM, Young MA. Male hypogonadism and bone fracture. N Engl J Med 1988;318:996.
|
| 94. | Slemenda CW, Longcope C, Zhou L, Hui SL, Peacock M, et al. Sex steroids and bone mass in older men. Positive Associations with serum estrogens and negative associations with androgens. J Clin Invest 1997;100:1755-9.
|
| 95. | Khosla S, Melton LJ 3 rd , Atkinson EJ, O'fallon WM, Klee GG, et al. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab 1998;83:2266-74.
|
| 96. | Khosla S, Melton LJ 3 rd , Atkinson EJ, O'fallon WM. Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab 2001;86:3555-61.
|
| 97. | Szulc P, Munoz F, Claustrat B, Garnero P, Marchand F, et al. Bioavailable estradiol may be an important determinant of osteoporosis in men: the MINOS study. J Clin Endocrinol Metab 2001;86:192-9.
|
| 98. | Gennari L, Merlotti D, Martini G, Gonnelli S, Franci B, et al. Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men. J Clin Endocrinol Metab 2003;88:5327-33.
|
| 99. | Szulc P, Uusi-Rasi K, Claustrat B, Marchand F, Beck TJ, et al. Role of sex steroids in the regulation of bone morphology in men. The MINOS study. Osteoporos Int 2004;15:909-17.
|
| 100. | Goderie-Plomp HW, van der Klift M, De Ronde W, Hofman A, de jong FH, et al. Endogenous sex hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: The Rotterdam Study. J Clin Endocrinol Metab 2004;89:3261-9.
|
| 101. | Khosla S, Melton LJ 3 rd , Robb RA, Camp JJ, Atkinson EJ, et al. Relationship of volumetric bmd and structural parameters at different skeletal sites to sex steroid levels in men. J Bone Miner Res 2005;20:730-40.
|
| 102. | Vandenput L, Labrie F, Mellstrom D, Swanson C, Knutsson T, et al. Serum levels of specific glucuronidated androgen metabolites predict bmd and prostate volume in elderly men. J Bone Miner Res 2007;22:220-7.
|
| 103. | Kuchuk NO, van Schoor NM, Pluijm SM, Smit JH, de Ronde W, et al. the association of sex hormone levels with quantitative ultrasound, bone mineral density, bone turnover and osteoporotic fractures in older men and women. Clin Endocrinol (Oxf) 2007;67:295-303.
|
| 104. | Araujo AB, Travison TG, Leder BZ, Mckinlay JB. Correlations between serum testosterone, estradiol, and sex hormone-binding globulin and bone mineral density in a diverse sample of men. J Clin Endocrinol Metab 2008;93:2135-41.
|
| 105. | Vanderschueren D, Pye SR, Venken K, Borghs H, Gaytant J, et al. EMAS Study Group. Gonadal sex steroid status and bone health in middle-aged and elderly european men. Osteoporos Int 2010;21:1331-9.
[PUBMED] |
| 106. | Mellstrom D, Vandenput L, Mallmin H, Holmberg AH, Lorentzon M, et al. Older men with low serum estradiol and high serum shbg have an increased risk of fractures. J Bone Miner Res 2008;23:1552-60.
|
| 107. | Ward KA, Pye SR, Adams JE, Boonen S, Vanderschueren D, et al. EMAS Study Group. Influence of age and sex steroids on bone density and geometry in middle-aged and elderly european men. Osteoporos Int 2011;22:1513-23.
|
| 108. | Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, et al. EMAS Group. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010;363:123-35.
|
| 109. | Vandenput L, Boonen S, Van Herck E, Swinnen JV, Bouillon R, et al. Evidence from the aged orchidectomized male rat model that 17beta-estradiol is a more effective bone-sparing and anabolic agent than 5alpha-dihydrotestosterone. J Bone Miner Res 2002;17:2080-6.
|
| 110. | Limer KL, Pye SR, Thomson W, Boonen S, Borghs H, et al. EMAS Study Group. Genetic variation in sex hormone genes influences heel ultrasound parameters in middle-aged and elderly men: results from the European Male Aging Study (EMAS). J Bone Miner Res 2009;24:314-23.
|
| 111. | Holliday KL, Pye SR, Thomson W, Boonen S, Borghs H, et al. EMAS Study Group. The ESR1 (6q25) locus is associated with calcaneal ultrasound parameters and radial volumetric bone mineral density in European men. Plos One 2011;6:e22037.
|
| 112. | Huhtaniemi IT, Pye SR, Holliday KL, Thomson W, O'Neill TW, et al. European Male Aging Study Group. Effect of polymorphisms in selected genes involved in pituitary-testicular function on reproductive hormones and phenotype in aging men. J Clin Endocrinol Metab 2010;95:1898-908.
|
| 113. | Huhtaniemi IT, Pye SR, Limer KL, Thomson W, O'Neill TW, et al. European Male Aging Study Group. Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats. J Clin Endocrinol Metab 2009;94:277-84.
|
| 114. | Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352:154-64.
|
| 115. | Smith MR, Goode M, Zietman AL, Mcgovern FJ, Lee H, et al. Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition. J Clin Oncol 2004;22:2546-53.
|
| 116. | Sieber PR, Keiller DL, Kahnoski RJ, Gallo J, Mcfadden S. Bicalutamide 150 mg maintains bone mineral density during monotherapy for localized or locally advanced prostate cancer. J Urol 2004;171:2272-6.
|
| 117. | Wadhwa VK, Weston R, Mistry R, Parr NJ. Long-term changes in bone mineral density and predicted fracture risk in patients receiving androgen-deprivation therapy for prostate cancer, with stratification of treatment based on presenting values. BJU Int 2009;104:800-5.
|
| 118. | Burnett-Bowie SA, Mckay EA, Lee H, Leder BZ. Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels. J Clin Endocrinol Metab 2009;94:4785-92.
|
| 119. | Falahati-Nini A, Riggs BL, Atkinson EJ, O'Fallon WM, Eastell R, et al. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 2000;106:1553-60.
|
| 120. | Yu E, Taylor A, Wulcyzn K, Webb M, Perros N, et al. Hypogonadism with estrogen removal (Her): differential effects of androgens and estrogens on bone microarchitecture in adult men. J Bone Mineral Res 2012;27:S66.
|
| 121. | Vandenput L, Ederveen AG, Erben RG, Stahr K, Swinnen JV, et al. Testosterone prevents orchidectomy-induced bone loss in estrogen receptor-alpha knockout mice. Biochem Biophys Res Commun 2001;285:70-6.
|
| 122. | Mellstrom D, Johnell O, Ljunggren O, Eriksson AL, Lorentzon M, et al. Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MROS Sweden. J Bone Miner Res 2006;21:529-35.
|
| 123. | Meier C, Nguyen TV, Handelsman DJ, Schindler C, Kushnir MM, et al. Endogenous sex hormones and incident fracture risk in older men: The Dubbo Osteoporosis Epidemiology Study. Arch Intern Med 2008;168:47-54.
|
| 124. | van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab 2000;85:3276-82.
|
| 125. | Tajar A, Huhtaniemi IT, O'Neill TW, Finn JD, Pye SR, et al. EMAS Group. Characteristics of androgen deficiency in late-onset hypogonadism: results from the european male aging study (EMAS). J Clin Endocrinol Metab 2012;97:1508-16.
[PUBMED] |
| 126. | Amin S, Zhang Y, Felson DT, Sawin CT, Hannan MT, et al. Estradiol, testosterone, and the risk for hip fractures in elderly men from the framingham study. Am J Med 2006;119:426-33.
|
| 127. | Vandenput L, Swinnen JV, Boonen S, Van Herck E, Erben RG, et al. Role of the androgen receptor in skeletal homeostasis: the androgen-resistant testicular feminized male mouse model. J Bone Miner Res 2004;19:1462-70.
|
| 128. | Rochira V, Zirilli L, Madeo B, Aranda C, Caffagni G, et al. skeletal effects of long-term estrogen and testosterone replacement treatment in a man with congenital aromatase deficiency: evidences of a priming effect of estrogen for sex steroids action on bone. Bone 2007;40:1662-8.
|
| 129. | Leblanc ES, Nielson CM, Marshall LM, Lapidus JA, Barrett-Connor E, et al. Osteoporotic Fractures in Men Study Group. The effects of serum testosterone, estradiol, and sex hormone binding globulin levels on fracture risk in older men. J Clin Endocrinol Metab 2009;94:3337-46.
|
| 130. | Cauley JA, Ewing SK, Taylor BC, Fink HA, Ensrud KE, et al. Osteoporotic Fractures in Men Study (MrOS) Research Group. Sex steroid hormones in older men: longitudinal associations with 4.5-year change in hip bone mineral density--the osteoporotic fractures in men study. J Clin Endocrinol Metab 2010;95:4314-23.
|
| 131. | Vanbillemont G, Lapauw B, Bogaert V, Goemaere S, Zmierczak HG, et al. Sex hormone-binding globulin as an independent determinant of cortical bone status in men at the age of peak bone mass. J Clin Endocrinol Metab 2010;95:1579-86.
|
| 132. | Lorentzon M, Swanson C, Andersson N, Mellstrom D, Ohlsson C. Free testosterone is a positive, whereas free estradiol is a negative, predictor of cortical bone size in young swedish men: The GOOD study. J Bone Miner Res 2005;20:1334-41.
|
| 133. | Eriksson AL, Lorentzon M, Mellstrom D, Vandenput L, Swanson C, et al. SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density. J Clin Endocrinol Metab 2006;91:5029-37.
|
| 134. | Center JR, Nguyen TV, Sambrook PN, Eisman JA. Hormonal and biochemical parameters and osteoporotic fractures in elderly men. J Bone Miner Res 2000;15:1405-11.
|
| 135. | Khosla S. Editorial: sex hormone binding globulin: inhibitor or facilitator (or both) of sex steroid action? J Clin Endocrinol Metab 2006;91:4764-6.
|
| 136. | Swanson C, Lorentzon M, Vandenput L, Labrie F, Rane A, et al. Sex steroid levels and cortical bone size in young men are associated with a uridine diphosphate glucuronosyltransferase 2B7 polymorphism (H268Y). J Clin Endocrinol Metab 2007;92:3697-704.
|
| 137. | Lorentzon M, Eriksson AL, Mellstrom D, Ohlsson C. The COMT Val158met polymorphism is associated with peak BMD in men. J Bone Miner Res 2004;19:2005-11.
|
| 138. | Eriksson AL, Mellstrom D, Lorentzon M, Orwoll ES, Redlund-Johnell I, et al. The COMT Val158met polymorphism is associated with prevalent fractures in swedish men. Bone 2008;42:107-12.
|
| 139. | Lorentzon M, Eriksson AL, Nilsson S, Mellstrom D, Ohlsson C. Association between physical activity and BMD in young men is modulated by catechol-o-methyltransferase (COMT) genotype: The GOOD study. J Bone Miner Res 2007;22:1165-72.
|
| 140. | Stolk L, van Meurs JB, Jhamai M, Arp PP, van Leeuwen JP, et al. The catechol-o-methyltransferase met158 low-activity allele and association with nonvertebral fracture risk in elderly men. J Clin Endocrinol Metab 2007;92:3206-12.
|
| 141. | Issa S, Schnabel D, Feix M, Wolf L, Schaefer HE, et al. Human osteoblast-like cells express predominantly steroid 5alpha-reductase type 1. J Clin Endocrinol Metab 2002;87:5401-7.
|
| 142. | Tollin SR, Rosen HN, Zurowski K, Saltzman B, Zeind AJ, et al. Finasteride therapy does not alter bone turnover in men with benign prostatic hyperplasia--a Clinical Research Center Study. J Clin Endocrinol Metab 1996;81:1031-4.
|
| 143. | Matsumoto AM, Tenover L, Mcclung M, Mobley D, Geller J, et al. Pless Study Group. The long-term effect of specific type ii 5alpha-reductase inhibition with finasteride on bone mineral density in men: results of a 4-year placebo controlled trial. J Urol 2002;167:2105-8.
|
| 144. | Amory JK, Watts NB, Easley KA, Sutton PR, Anawalt BD, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 2004;89:503-10.
|
| 145. | Amory JK, Anawalt BD, Matsumoto AM, Page ST, Bremner WJ, et al. The effect of 5α-reductase inhibition with dutasteride and finasteride on bone mineral density, serum lipoproteins, hemoglobin, prostate specific antigen and sexual function in healthy young men. J Urol 2008;179:2333-8.
|
| 146. | Jacobsen SJ, Cheetham TC, Haque R, Shi JM, Loo RK. Association between 5-alpha reductase inhibition and risk of hip fracture. JAMA 2008;300:1660-4.
|
| 147. | Vestergaard P, Rejnmark L, Mosekilde L. Risk of fractures associated with treatment for benign prostate hyperplasia in men. Osteoporos Int 2011;22:731-7.
|
| 148. | Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, et al. Exogenous testosterone (t) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 2005;90:1502-10.
|
| 149. | Windahl SH, Andersson N, Borjesson AE, Swanson C, Svensson J, et al. Reduced bone mass and muscle strength in male 5alpha-reductase type 1 inactivated mice. Plos One 2011;6:e21402.
|
| 150. | Andriole GL, Kirby R. Safety and tolerability of the dual 5alpha-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia. Eur Urol 2003;44:82-8.
|
| 151. | Bhasin S, Travison TG, Storer TW, Lakshman K, Kaushik M, et al. Effect of testosterone supplementation with and without a dual 5alpha-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial. JAMA 2012;307:931-9.
|
| 152. | Meier C, Liu PY, Ly LP, De Winter-Modzelewski J, Jimenez M, et al. Recombinant human chorionic gonadotropin but not dihydrotestosterone alone stimulates osteoblastic collagen synthesis in older men with partial age-related androgen deficiency. J Clin Endocrinol Metab 2004;89:3033-41.
|
| 153. | Idan A, Griffiths KA, Harwood DT, Seibel MJ, Turner L, et al. Long-term effects of dihydrotestosterone treatment on prostate growth in healthy, middle-aged men without prostate disease: a randomized, placebo-controlled trial. Ann Intern Med 2010;153:621-32.
|
| 154. | Moverare S, Venken K, Eriksson AL, Andersson N, Skrtic S, et al. Differential effects on bone of estrogen receptor alpha and androgen receptor activation in orchidectomized adult male mice. Proc Natl Acad Sci U S A 2003;100:13573-8.
|
| 155. | Tivesten A, Moverare-Skrtic S, Chagin A, Venken K, Salmon P, et al. Additive protective effects of estrogen and androgen treatment on trabecular bone in ovariectomized rats. J Bone Miner Res 2004;19:1833-9.
|
| 156. | Venken K, De Gendt K, Boonen S, Ophoff J, Bouillon R, et al. Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model. J Bone Miner Res 2006;21:576-85.
|
| 157. | Sims NA, Dupont S, Krust A, Clement-Lacroix P, Minet D, et al. Deletion of estrogen receptors reveals a regulatory role for estrogen receptors-beta in bone remodeling in females but not in males. Bone 2002;30:18-25.
|
| 158. | Maclean HE, Moore AJ, Sastra SA, Morris HA, Ghasem-Zadeh A, et al. DNA-binding-dependent androgen receptor signaling contributes to gender differences and has physiological actions in males and females. J Endocrinol 2010;206:93-103.
|
| 159. | Windahl SH, Vidal O, Andersson G, Gustafsson JA, Ohlsson C. Increased cortical bone mineral content but unchanged trabecular bone mineral density in female erbeta(-/-) mice. J Clin Invest 1999;104:895-901.
|
| 160. | Sims NA, Clement-Lacroix P, Minet D, Fraslon-Vanhulle C, Gaillard-Kelly M, et al. A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice. J Clin Invest 2003;111:1319-27.
|
| 161. | Kawano H, Sato T, Yamada T, Matsumoto T, Sekine K, et al. Suppressive function of androgen receptor in bone resorption. Proc Natl Acad Sci U S A 2003;100:9416-21.
|
| 162. | Chiang C, Chiu M, Moore AJ, Anderson PH, Ghasem-Zadeh A, et al. Mineralization and bone resorption are regulated by the androgen receptor in male mice. J Bone Miner Res 2009;24:621-31.
|
| 163. | Notini AJ, Mcmanus JF, Moore A, Bouxsein M, Jimenez M, et al. Osteoblast deletion of exon 3 of the androgen receptor gene results in trabecular bone loss in adult male mice. J Bone Miner Res 2007;22:347-56.
|
| 164. | Wiren KM, Zhang XW, Toombs AR, Kasparcova V, Gentile MA, et al. Targeted overexpression of androgen receptor in osteoblasts: unexpected complex bone phenotype in growing animals. Endocrinology 2004;145:3507-22.
|
| 165. | Wiren KM, Semirale AA, Zhang XW, Woo A, Tommasini SM, et al. Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis: a model for compartment-specific androgen action in the skeleton. Bone 2008;43:440-51.
|
| 166. | Sinnesael M, Claessens F, Laurent M, Dubois V, Boonen S, et al. Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: evidence from targeted AR disruption in mouse osteocytes. J Bone Miner Res 2012;27:2535-43.
|
| 167. | Abu EO, Horner A, Kusec V, Triffitt JT, Compston JE. The localization of androgen receptors in human bone. J Clin Endocrinol Metab 1997;82:3493-7.
|
| 168. | Turner AG, Notini AJ, Chiu WS, Hodge J, Nicholson G, et al. Androgen receptor expression and function in osteoclasts. Open Physiol J 2008;1.
|
| 169. | Huber DM, Bendixen AC, Pathrose P, Srivastava S, Dienger KM, et al. Androgens suppress osteoclast formation induced by rankl and macrophage-colony stimulating factor. Endocrinology 2001;142:3800-8.
|
| 170. | Pederson L, Kremer M, Judd J, Pascoe D, Spelsberg TC, et al. Androgens regulate bone resorption activity of isolated osteoclasts in vitro. Proc Natl Acad Sci U S A 1999;96:505-10.
|
| 171. | Michael H, Harkonen PL, Vaananen HK, Hentunen TA. Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption. J Bone Miner Res 2005;20:2224-32.
|
| 172. | Nakamura T, Watanabe T, Nakamichi Y, Fukuda T, Matsumoto T, et al. Genetic evidence of androgen receptor function in osteoclasts: generation and characterization of osteoclast-specific androgen receptor knockout mice. J Bone Miner Res 2004;19:S3.
|
| 173. | Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of fas ligand in osteoclasts. Cell 2007;130:811-23.
|
| 174. | Martin-Millan M, Almeida M, Ambrogini E, Han L, Zhao H, et al. The estrogen receptor-alpha in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol Endocrinol 2010;24:323-34.
|
| 175. | Sjogren K, Lagerquist M, Moverare-Skrtic S, Andersson N, Windahl SH, et al. Elevated aromatase expression in osteoblasts leads to increased bone mass without systemic adverse effects. J Bone Miner Res 2009;24:1263-70.
|
| 176. | Almeida M, Iyer S, Martin-Millan M, Bartell SM, Han L, et al. Estrogen receptor-alpha signaling in osteoblast progenitors stimulates cortical bone accrual. J Clin Invest 2013;123:394-404.
|
| 177. | Maatta JA, Buki KG, Gu G, Alanne MH, Vaaraniemi J, et al. Inactivation of estrogen receptor alpha in bone-forming cells induces bone loss in female mice. FASEB J 2013;27:478-88.
|
| 178. | Windahl SH, Borjesson AE, Farman HH, Engdahl C, Moverare-Skrtic S, et al. Estrogen receptor-alpha in osteocytes is important for trabecular bone formation in male mice. Proc Natl Acad Sci U S A 2013;110:2294-9.
|
| 179. | Lee K, Jessop H, Suswillo R, Zaman G, Lanyon L. Endocrinology: bone adaptation requires oestrogen receptor-alpha. Nature 2003;424:389.
|
| 180. | Callewaert F, Bakker A, Schrooten J, Van Meerbeek B, Verhoeven G, et al. Androgen receptor disruption increases the osteogenic response to mechanical loading in male mice. J Bone Miner Res 2010;25:124-31.
|
| 181. | MacLean HE, Chiu WS, Notini AJ, Axell AM, Davey RA, et al. Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice. FASEB J 2008;22:2676-89.
|
| 182. | Ophoff J, Van Proeyen K, Callewaert F, De Gendt K, De Bock K, et al. Androgen signaling in myocytes contributes to the maintenance of muscle mass and fiber type regulation but not to muscle strength or fatigue. Endocrinology 2009;150:3558-66.
|
| 183. | Chambon C, Duteil D, Vignaud A, Ferry A, Messaddeq N, et al. Myocytic androgen receptor controls the strength but not the mass of limb muscles. Proc Natl Acad Sci U S A 2010;107:14327-32.
|
| 184. | Dubois V, Laurent M, Boonen S, Vanderschueren D, Claessens F. Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions. Cell Mol Life Sci 2012;69:1651-67.
|
| 185. | Gielen E, Verschueren S, O'Neill TW, Pye SR, O'connell MD, et al. Musculoskeletal frailty: a geriatric syndrome at the core of fracture occurrence in older age. Calcif Tissue Int 2012;91:161-77.
|
| 186. | Verschueren S, Gielen E, O'Neill TW, Pye SR, Adams JE, et al. Sarcopenia and its relationship with bone mineral density in middle-aged and elderly european men. Osteoporos Int 2013;24:87-98.
|
| 187. | Ohlsson C, Engdahl C, Borjesson AE, Windahl SH, Studer E, et al. Estrogen receptor-alpha expression in neuronal cells affects bone mass. Proc Natl Acad Sci U S A 2012;109:983-8.
|
| 188. | Raskin K, de Gendt K, Duittoz A, Liere P, Verhoeven G, et al. Conditional inactivation of androgen receptor gene in the nervous system: effects on male behavioral and neuroendocrine responses. J Neurosci 2009;29:4461-70.
|
| 189. | Olson LE, Ohlsson C, Mohan S. The role of GH/IGF-I-mediated mechanisms in sex differences in cortical bone size in mice. Calcif Tissue Int 2011;88:1-8.
|
[Figure 1], [Figure 2], [Figure 3]
[Table 1]
| This article has been cited by | | 1 |
Critical Role of Estrogens on Bone Homeostasis in Both Male and Female: From Physiology to Medical Implications |
|
| Noirrit-Esclassan Emmanuelle,Valera Marie-Cécile,Trémollieres Florence,Arnal Jean-François,Lenfant Françoise,Fontaine Coralie,Vinel Alexia | | International Journal of Molecular Sciences. 2021; 22(4): 1568 | | [Pubmed] | [DOI] | | | 2 |
Age and Sex Differences in Load-Induced Tibial Cortical Bone Surface Strain Maps |
|
| Alessandra Carriero,Behzad Javaheri,Neda Bassir Kazeruni,Andrew A Pitsillides,Sandra J Shefelbine | | JBMR Plus. 2021; | | [Pubmed] | [DOI] | | | 3 |
Sex estimation using scapular measurements: discriminant function analysis in a modern Italian population |
|
| Steffi Vassallo,Catriona Davies,Lucie Biehler-Gomez | | Australian Journal of Forensic Sciences. 2021; : 1 | | [Pubmed] | [DOI] | | | 4 |
Sex determination by radiographic localization of the inferior alveolar canal using cone-beam computed tomography in an Egyptian population |
|
| Arwa Mousa,Sahar El Dessouky,Dina El Beshlawy | | Imaging Science in Dentistry. 2020; 50(2): 117 | | [Pubmed] | [DOI] | | | 5 |
Morphology and serum and bone tissue calcium and magnesium concentrations in the bones of male rats chronically treated with letrozole, a nonsteroidal cytochrome P450 aromatase inhibitor |
|
| Anna Pilutin,Kamila Misiakiewicz-Has,Agnieszka Kolasa-Wolosiuk,Grzegorz Trybek,Fabian Urban,Mariola Marchlewicz,Bartosz Leszczynski,Andrzej Wróbel,Barbara Wiszniewska | | Connective Tissue Research. 2020; : 1 | | [Pubmed] | [DOI] | | | 6 |
Identification of osteogenic progenitor cell-targeted peptides that augment bone formation |
|
| Min Jiang,Ruiwu Liu,Lixian Liu,Alexander Kot,Xueping Liu,Wenwu Xiao,Junjing Jia,Yuanpei Li,Kit S. Lam,Wei Yao | | Nature Communications. 2020; 11(1) | | [Pubmed] | [DOI] | | | 7 |
Boneæs Response to Mechanical Loading in Aging and Osteoporosis: Molecular Mechanisms |
|
| Valeria Carina,Elena Della Bella,Viviana Costa,Daniele Bellavia,Francesca Veronesi,Simona Cepollaro,Milena Fini,Gianluca Giavaresi | | Calcified Tissue International. 2020; | | [Pubmed] | [DOI] | | | 8 |
Bone Development in Transgender Adolescents Treated With GnRH Analogues and Subsequent Gender-Affirming Hormones |
|
| Sebastian E E Schagen,Femke M Wouters,Peggy T Cohen-Kettenis,Louis J Gooren,Sabine E Hannema | | The Journal of Clinical Endocrinology & Metabolism. 2020; 105(12) | | [Pubmed] | [DOI] | | | 9 |
OPG-Fc treatment partially rescues low bone mass phenotype in mature Bgn/Fmod deficient mice but is deleterious to the young mouse skeleton |
|
| Vardit Kram,Priyam Jani,Tina M. Kilts,Li Li,Emily Y. Chu,Marian F. Young | | Journal of Structural Biology. 2020; : 107627 | | [Pubmed] | [DOI] | | | 10 |
Late-onset Hypogonadism: Bone health |
|
| Vincenzo Rochira | | Andrology. 2020; | | [Pubmed] | [DOI] | | | 11 |
Factors of mineral homeostasis impairment and bone mineral density loss in women with central hypogonadism |
|
| I. Ilovayskaya,V. Zektser,L. Lazebnik | | Climacteric. 2020; : 1 | | [Pubmed] | [DOI] | | | 12 |
Androgen action on renal calcium and phosphate handling: Effects of bisphosphonate treatment and low calcium diet |
|
| Rougin Khalil,Ioannis Simitsidellis,Na Ri Kim,Ferran Jardi,Dieter Schollaert,Ludo Deboel,Philippa Saunders,Geert Carmeliet,Frank Claessens,Dirk Vanderschueren,Brigitte Decallonne | | Molecular and Cellular Endocrinology. 2020; : 110891 | | [Pubmed] | [DOI] | | | 13 |
Sex determination from dimensions of distal tibiae in adult Kenyans: A discriminant function analysis |
|
| Musa K. Misiani,Thomas Amuti,Shane Darbar,Pamela Mandela,Emily Maranga,Moses Obimbo | | Translational Research in Anatomy. 2020; : 100075 | | [Pubmed] | [DOI] | | | 14 |
Evaluation of the auricular surface method for non-adult sex estimation on the Lisbon documented collection |
|
| Álvaro M. Monge Calleja,Claudia M. Aranda,Ana Luísa Santos,Leandro H. Luna | | American Journal of Physical Anthropology. 2020; | | [Pubmed] | [DOI] | | | 15 |
Bone gain following loading is site-specifically enhanced by prior and concurrent disuse in aged male mice |
|
| Gabriel L. Galea,Peter J. Delisser,Lee Meakin,Joanna S. Price,Sara H. Windahl | | Bone. 2020; : 115255 | | [Pubmed] | [DOI] | | | 16 |
Estrogen receptor alpha signaling in extrahypothalamic neurons during late puberty decreases bone size and strength in female but not in male mice |
|
| Na Ri Kim,Ferran Jardí,Rougin Khalil,Leen Antonio,Dieter Schollaert,Ludo Deboel,G. Harry van Lenthe,Brigitte Decallonne,Geert Carmeliet,Jan-Åke Gustafsson,Frank Claessens,Claes Ohlsson,Marie K. Lagerquist,Vanessa Dubois,Dirk Vanderschueren | | The FASEB Journal. 2020; | | [Pubmed] | [DOI] | | | 17 |
Bone Health in the Transgender Population |
|
| Micol S. Rothman,Sean J. Iwamoto | | Clinical Reviews in Bone and Mineral Metabolism. 2019; | | [Pubmed] | [DOI] | | | 18 |
Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS) |
|
| Lucia Lanciotti,Marta Cofini,Alberto Leonardi,Mirko Bertozzi,Laura Penta,Susanna Esposito | | International Journal of Environmental Research and Public Health. 2019; 16(7): 1268 | | [Pubmed] | [DOI] | | | 19 |
Involvement of Bone in Systemic Endocrine Regulation |
|
| I. ZOFKOVA | | Physiological Research. 2018; : 669 | | [Pubmed] | [DOI] | | | 20 |
Manipulation of the Alternative NF-?B Pathway in Mice Has Sexually Dimorphic Effects on Bone |
|
| Allahdad Zarei,Chang Yang,Jesse Gibbs,Jennifer L Davis,Anna Ballard,Rong Zeng,Linda Cox,Deborah J Veis | | JBMR Plus. 2018; | | [Pubmed] | [DOI] | | | 21 |
Sex-Differences in Skeletal Growth and Aging |
|
| Jeri W. Nieves | | Current Osteoporosis Reports. 2017; | | [Pubmed] | [DOI] | | | 22 |
Small leucine rich proteoglycans, a novel link to osteoclastogenesis |
|
| Vardit Kram,Tina M. Kilts,Nisan Bhattacharyya,Li Li,Marian F. Young | | Scientific Reports. 2017; 7(1) | | [Pubmed] | [DOI] | | | 23 |
Inhibition of CaMKK2 reverses age-associated decline in bone mass |
|
| Zachary J. Pritchard,Rachel L. Cary,Chang Yang,Deborah V. Novack,Michael J. Voor,Uma Sankar | | Bone. 2015; 75: 120 | | [Pubmed] | [DOI] | | | 24 |
Effect of the Combined Extracts of Herba Epimedii and Fructus Ligustri Lucidi on Sex Hormone Functional Levels in Osteoporosis Rats |
|
| RenHui Liu,Xue Kang,LiPing Xu,HongLei Nian,XinWei Yang,HaoTian Shi,XiuJuan Wang | | Evidence-Based Complementary and Alternative Medicine. 2015; 2015: 1 | | [Pubmed] | [DOI] | | | 25 |
The Endocrine Role of Estrogens on Human Male Skeleton |
|
| Vincenzo Rochira,Elda Kara,Cesare Carani | | International Journal of Endocrinology. 2015; 2015: 1 | | [Pubmed] | [DOI] | | | 26 |
Bone Tissue as a Systemic Endocrine Regulator |
|
| I. ZOFKOVA | | Physiological Research. 2015; : 439 | | [Pubmed] | [DOI] | | | 27 |
Osteoporosis and Low Bone Mineral Density in Men with Testosterone Deficiency Syndrome |
|
| Christopher D. Gaffney,Matthew J. Pagano,Adriana P. Kuker,Doron S. Stember,Peter J. Stahl | | Sexual Medicine Reviews. 2015; 3(4): 298 | | [Pubmed] | [DOI] | | | 28 |
Estrogens, the be-all and end-all of male hypogonadal bone loss? |
|
| M. R. Laurent,E. Gielen,D. Vanderschueren | | Osteoporosis International. 2014; | | [Pubmed] | [DOI] | | | 29 |
Sex Steroid Actions in Male Bone |
|
| Dirk Vanderschueren,Michaël R. Laurent,Frank Claessens,Evelien Gielen,Marie K. Lagerquist,Liesbeth Vandenput,Anna E. Börjesson,Claes Ohlsson | | Endocrine Reviews. 2014; 35(6): 906 | | [Pubmed] | [DOI] | | | 30 |
Mitochondrial maintenance failure in aging and role of sexual dimorphism |
|
| John Tower | | Archives of Biochemistry and Biophysics. 2014; | | [Pubmed] | [DOI] | | | 31 |
Sex, Eyes, and Vision: Male/Female Distinctions in Ophthalmic Disorders |
|
| Alvin Eisner | | Current Eye Research. 2014; : 1 | | [Pubmed] | [DOI] | |
|
 |
|
|
|
Search Pubmed for