Androgens and estrogens in skeletal sexual dimorphism

Laurent, Michaël; LʼAbbate, Antonio; Sinnesael, Mieke; Dubois, Vanessa; Gielen, Evelien; Classens, Frank; Vanderschueren, Dirk

doi:10.4103/1008-682x.122356

Cited by 60 publications

(60 citation statements)

References 194 publications

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“…Earlier studies in androgen-resistant, AR/ERα knockout and overexpressing rodent models and in vitro studies suggest a dual mode of action by which both AR and ERα play a direct role in restraining male bone turnover and stimulating periosteal bone formation; there is even some animal evidence for a similar effect of both AR and ERα in muscle and fat [3,11,12]. However, these conclusions were reached in ubiquitous AR/ERα knockout models.…”

Section: Preclinical Studiesmentioning

confidence: 51%

“…However, these conclusions were reached in ubiquitous AR/ERα knockout models. In more recent conditional, cellspecific knockdown mouse models, male cortical and trabecular bone is directly regulated by ERα in osteoprogenitor cells, osteoblasts and osteocytes [11], while AR in these bone cells has only a mild effect which is limited to trabecular bone. Nevertheless, AR overexpression in osteoblasts stimulates periosteal bone in the calvaria [13], which is unlikely to be explained by bone-muscle interactions.…”

Section: Preclinical Studiesmentioning

confidence: 99%

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Estrogens, the be-all and end-all of male hypogonadal bone loss?

2014

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Gender is one of the strongest predictors of osteoporotic fracture risk, second only to ageing. A recent systematic review of worldwide epidemiology revealed that hip fracture incidence is about twofold lower in men compared to women, despite greater than tenfold variation between geographic regions [1]. This lower fracture incidence occurs despite persisting underdiagnosis and undertreatment of osteoporosis in men, which probably explains why hip fracture incidence may be decreasing in women but not men [2][3][4][5]. It is well known that men generally have a more robust body composition; even after correction for an average 10 % greater height and bone length, men at the age of peak bone mass have 25 % greater bone mineral content [6], almost 50 % greater muscle mass and power and half the fat mass of women [7]. Conversely, late-onset male hypogonadism increases the risk of bone loss, muscle atrophy and fat accumulation [3,8]. Understanding the underlying mechanisms involved in this gender dimorphism in body composition may thus identify additional therapeutic targets not only for osteoporosis, but also for sarcopenia and obesity. Female sex steroids on a male genetic backgroundEmbryonically, we are all destined for female development, unless SRY (sex-determining region on the Y chromosome) and other transcription factors turn the bipotential gonads into testes capable of testosterone (T) production. Studies on bone health in sexual medicine provide unique opportunities to examine whether sexual dimorphism is ultimately determined by sex chromosomes (genetic determinism) or sex steroids (endocrine regulation).Van Caenegem et al. [9] are the first to study changes in areal and volumetric bone mineral density (aBMD, vBMD) and bone geometry in a representative, sizeable cohort (compared to the small number of subjects treated for gender dysphoria) of 49 male-to-female transsexual persons. The strength of this research paradigm is evident to anyone closely familiar with the spectacular bodily transformations experienced by subjects under cross-gender hormonal therapy. In a previous cross-sectional study by Van Caenegem et al., female-to-male transsexual persons had normal female body composition at baseline, but those on long-term T therapy exhibited increased lean body mass and grip strength, decreased fat mass with android distribution and increased radial cortical bone size with lower cortical vBMD [10]. The prospective design of their current study is however important because, compared to male controls, these male-to-female transsexual persons had baseline low aBMD due to somewhat lower periosteal circumference and lower trabecular vBMD, lower lean body mass, lower grip strength and muscle crosssectional area. This was probably related to lifestyle differences, as evidenced by less sports activities and lower serum 25-OH-vitamine D levels.

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Section: Preclinical Studiesmentioning

confidence: 51%

Section: Preclinical Studiesmentioning

confidence: 99%

Estrogens, the be-all and end-all of male hypogonadal bone loss?

2014

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“…However, androgen deficiency does indeed lead to lower bone mineral density and thereby increased risk of osteoporosis. Although a degree of direct impact of testosterone on bone mineralization has been shown, 46-49 most of the androgenic effects on the bone are mediated through the estrogens to which the male sex hormone is converted through the action of aromatase.…”

Section: Hypogonadism and Osteoporosismentioning

confidence: 99%

Hypogonadism in young men treated for cancer

Giwercman¹,

Giwercman²

2015

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An ever-increasing proportion of young males treated for cancer are cured. Therefore, one of the major challenges of modern Clinical Oncology is to ensure good quality of life. Cancer disease per se as well as cancer treatment may have a negative impact on androgen production, thereby leading to subclinical or clinically overt hypogonadism. Since the symptoms of androgen deficiency are rather unspecific, it is important that reproductive hormone levels be checked in young men who have been treated for cancer. As androgen deficiency in men is associated with increased long-term risk of osteoporosis as well as cardiovascular and metabolic disease, those cancer survivors who present with signs of insufficient androgen production should be followed and preventive as well as therapeutic measures, including androgen replacement therapy, should be applied according to the current guidelines.

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“…and Bertelloni, 2009;Rochira and Carani, 2009;Callewaert et al, 2010;Laurent et al, 2014]. Therefore, the skeletal phenotype of the 2 sexes and bone health are influenced by an adequate sex steroid production and metabolism during life as well as an optimal response to their peripheral actions.…”

mentioning

confidence: 99%

Bone Mineral Density in Women Living with Complete Androgen Insensitivity Syndrome and Intact Testes or Removed Gonads

Bertelloni

Meriggiola²,

Dati

et al. 2017

Sex Dev

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Complete androgen insensitivity syndrome (CAIS) is due to complete androgen resistance in androgen-dependent tissues. Since androgens are involved in growth, development, and mass maintenance of the skeleton, bone health may be a relevant clinical issue for improving quality of life of women living with CAIS. Bone mineral density (BMD) in women with CAIS and intact gonads has been reported in a normal range, although exceptions are known showing a low BMD mainly at the lumbar level. In women with CAIS and removed gonads, BMD is usually reduced at both the lumbar spine and femoral neck. However, the fracture risk remains largely unknown. In women with CAIS, hormonal replacement therapy may improve BMD, but it does not normalize it. Several factors may be operative (e.g., loss of AR signaling at the bone level, gonadal removal, and age at surgery [before or after attainment of the peak bone mass], inadequate sex steroid replacement therapy, poor compliance with hormonal treatment, high serum FSH levels, lack of testicular protein hormones after gonadal removal), but they are poorly evaluated. In conclusion, the maintenance of testes may represent a strategy to improve bone health in women with CAIS, but a strict follow-up to monitor the cancer risk is mandatory mainly from their 20s onwards. Optimal sex steroid substitutive therapy in adolescence and adulthood is a key factor to improve BMD status in women with CAIS and removed gonads, but conclusive data on optimal management are lacking.

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Androgens and estrogens in skeletal sexual dimorphism

Cited by 60 publications

References 194 publications

Estrogens, the be-all and end-all of male hypogonadal bone loss?

Estrogens, the be-all and end-all of male hypogonadal bone loss?

Hypogonadism in young men treated for cancer

Bone Mineral Density in Women Living with Complete Androgen Insensitivity Syndrome and Intact Testes or Removed Gonads

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