Role of Androgen and Estrogen Receptors for the Action of Dehydroepiandrosterone (DHEA)

Abstract

Dehydroepiandrosterone (DHEA) is an abundant steroid hormone, and its mechanism of action is yet to be determined. The aim of this study was to elucidate the importance of androgen receptors (ARs) and estrogen receptors (ERs) for DHEA function. Orchidectomized C57BL/6 mice were treated with DHEA, DHT, 17β-estradiol-3-benzoate (E2), or vehicle. Orchidectomized AR-deficient (ARKO) mice and wild-type (WT) littermates were treated with DHEA or vehicle for 2.5 weeks. At termination, bone mineral density (BMD) was evaluated, thymus and seminal vesicles were weighted, and submandibular glands (SMGs) were histologically examined. To evaluate the in vivo ER activation of the classical estrogen signaling pathway, estrogen response element reporter mice were treated with DHEA, DHT, E2, or vehicle, and a reporter gene was investigated in different sex steroid-sensitive organs after 24 hours. DHEA treatment increased trabecular BMD and thymic atrophy in both WT and ARKO mice. In WT mice, DHEA induced enlargement of glands in the SMGs, whereas this effect was absent in ARKO mice. Furthermore, DHEA was able to induce activation of classical estrogen signaling in bone, thymus, and seminal vesicles but not in the SMGs. In summary, the DHEA effects on trabecular BMD and thymus do not require signaling via AR and DHEA can activate the classical estrogen signaling in these organs. In contrast, DHEA induction of gland size in the SMGs is dependent on AR and does not involve classical estrogen signaling. Thus, both ERs and ARs are involved in mediating the effects of DHEA in an organ-dependent manner.

Bu-Shen-Ning-Xin decoction suppresses osteoclastogenesis <i>via </i>increasing dehydroepiandrosterone to prevent postmenopausal osteoporosis

“…Accordingly, after menopause all estrogens are made locally from DHEA by the mechanisms of intracrinology (73). DHEA activates ERβ to nearly the same extent as E2 and it activates ERα to a lesser extent (38,66). The current data showed that administration of BSNXD increased the serum concentration of DHEA but not that of E2.…”

Inhibition of Osteoblast Function by Brucella abortus is Reversed by Dehydroepiandrosterone and Involves ERK1/2 and Estrogen Receptor

“…It has been reported that ER and AR are involved in the action of DHEA ( 37 , 38 ). Then, experiments were conducted to determine the expression of ER and AR during B. abortus infection and their modulation by cortisol and DHEA.…”

“…Although the ability of AR and ER to mediate DHEA signaling was described in different cell types ( 37 , 38 ); it has been reported that DHEA seems to act on osteoblast through the MAPK signaling pathway involving ERK1/2 in a way that is mainly modulated by ERβ instead of AR. In concordance, DHEA could reverse the inhibitory effect of B. abortus infection on ERβ expression in osteoblast (Figure 7 B).…”

Adrenal Steroids Modulate Fibroblast-Like Synoviocytes Response During B. abortus Infection

“…In addition, DHEA mediated this effect through ER receptor as evidenced when infections and the treatment with supernatants from B. abortus -infected monocytes were performed in the presence of fulvestrant. The ability of DHEA and its metabolites to signal through androgen receptor (AR) and ER has been previously described (43, 44). However, since the addition of ER antagonist, fulvestrant, completely avoids the effect of DHEA on RANKL expression, we could affirm that the main signaling of DHEA during B. abortus infection in sinoviocytes is via ER.…”