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

Abstract

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.

The androgen receptor has no direct antiresorptive actions in mouse osteoclasts

“…Although non-aromatizable androgens can prevent bone resorption in rodent models, it remains controversial whether this is also the case in humans. Several experimental studies (Falahati-Nini et al, 2000;Idan et al, 2010;Laurent et al, 2015) have demonstrated that androgens were unable to prevent bone resorption in the face of estrogen deficiency and although they may selectively influence bone formation (Falahati-Nini et al, 2000), this has not been shown to translate into preservation of bone mass in aging men.…”

“…Because in aging, men maintain their sex steroid levels better than women, they do not experience the accelerated phase of bone loss observed after menopause in women. However a slow decline in the levels of bioavailable androgens and therefore also in E2, since androgens are the substrate for the aromatase enzyme and production of estrogens, could contribute to osteoporosis in aging men (Laurent et al, 2015). Although non-aromatizable androgens can prevent bone resorption in rodent models, it remains controversial whether this is also the case in humans.…”

Sex hormones and quantitative ultrasound parameters at the heel in men and women from the general population

“…Sex hormones and sex hormone-binding globulin has been shown to be correlated with loss of bone mineral density (BMD) ( Hsu et al, 2015 , Park et al, 2017 ), but not in all studies ( Paller et al, 2009 , Kuchuk et al, 2007 , Araujo et al, 2008 , Gennari et al, 2003 ). Previous studies revealed association between sex hormones and fracture risk ( Ohlsson et al, 2017 , Cauley et al, 2017 , Shahinian et al, 2005 ), particularly for estradiol ( Mellstrom et al, 2008 , Amin et al, 2006 , Garnero et al, 2000 , Laurent et al, 2015 , Cauley et al, 2010 , Khosla et al, 2008 , LeBlanc et al, 2009 ). Furthermore, previous research in men related testosterone (TT) and DHEAS to markers of bone turnover ( Kyvernitakis et al, 2013 ).…”

Role of Estrogens and Androgens in Osteoporosis

“…Whether inducible AR deletion at later age has any direct detrimental skeletal effects in skeletally mature mice, remains yet unanswered. This is an important topic for future research because a direct role of androgens in the development of osteoporosis in older men has not been confirmed Idan et al, 2010;Laurent et al, 2015). However, some epidemiological studies suggest that the combination of low serum E2 and T may be associated with higher fracture risk than low E2 alone (Amin et al, 2006;Woo et al, 2012).…”