Differential effects on bone of estrogen receptor   and androgen receptor activation in orchidectomized adult male mice

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

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Androgen receptor activation alleviates airway hyperresponsiveness, inflammation, and remodeling in a murine model of asthma

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00441.2020 ◽

2021 ◽

Vol 320 (5) ◽

pp. L803-L818

Author(s):

Rama Satyanarayana Raju Kalidhindi ◽

Nilesh Sudhakar Ambhore ◽

Premanand Balraj ◽

Taylor Schmidt ◽

M. Nadeem Khan ◽

...

Keyword(s):

Androgen Receptor ◽

Murine Model ◽

Airway Hyperresponsiveness ◽

Epidemiological Studies ◽

Receptor Activation ◽

Male Mice ◽

Beneficial Role ◽

Male Hormones ◽

Inflammatory Changes ◽

Androgen Receptor Activation

Epidemiological studies demonstrate an apparent sex-based difference in the prevalence of asthma, with a higher risk in boys than girls, which is reversed postpuberty, where women become more prone to asthma than men, suggesting a plausible beneficial role for male hormones, especially androgens as a regulator of pathophysiology in asthmatic lungs. Using a murine model of asthma developed with mixed allergen (MA) challenge, we report a significant change in airway hyperresponsiveness (AHR), as demonstrated by increased thickness of epithelial and airway smooth muscle layers and collagen deposition, as well as Th2/Th17-biased inflammation in the airways of non-gonadectomized (non-GDX) and gonadectomized (GDX) male mice. Here, compared with non-GDX mice, MA-induced AHR and inflammatory changes were more prominent in GDX mice. Activation of androgen receptor (AR) using 5α-dihydrotestosterone (5α-DHT, AR agonist) resulted in decreased Th2/Th17 inflammation and remodeling-associated changes, resulting in improved lung function compared with MA alone challenged mice, especially in GDX mice. These changes were not observed with Flutamide (Flut, AR antagonist). Overall, we show that AR exerts a significant and beneficial role in asthma by regulating AHR and inflammation.

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