Dehydroepiandrosterone-Regulated Testosterone Biosynthesis via Activation of the ERK1/2 Signaling Pathway in Primary Rat Leydig Cells

Abstract

Background: Dehydroepiandrosterone decreases with age and this reduction has been shown to be associated with physical health in human. Some studies have suggested that the effects of DHEA are exerted after it is biotransformed into more biologically-active hormones in peripheral target cells. This study investigated the effects of DHEA on the testosterone biosynthesis and possible signaling pathway mechanism underlying these DHEA effects were also explored in primary rat Leydig cells. Methods: Primary Leydig cells were treated with DHEA and then detected testosterone content by RIA and steroidogenic enzymes, ERK1/2 signal pathway factors protein expression level by Western blot. Results: Incubation of primary Leydig cells with DHEA significantly increased testosterone content and 3β-HSD and 17β-HSD protein expression levels, while aromatase protein expression levels were decreased. Compared with the control group, p-ERK1/2 and p-CREB protein levels were significantly increased in DHEA-treated groups. Testosterone content was significantly decreased in the DHEA-treated group pre-incubated with U0126 (p-ERK1/2 inhibitor). Additionally, the rise in p-ERK1/2, 3β-HSD and 17β-HSD protein levels induced by DHEA was reversed when cells were pre-incubated with U0126. Interestingly, no significant difference was found in aromatase protein expression level in cells pretreated with U0126. Conclusion: These findings demonstrate that (a) exogenous DHEA might preferentially convert to testosterone rather than estradiol due to the up-regulation of 3β-HSD and 17β-HSD protein levels and the down-regulation of aromatase protein level in primary Leydig cells, and (b) the action of DHEA is at least partly associated with the elevation of p-ERK1/2 and p-CREB protein levels.

Androstenedione (a Natural Steroid and a Drug Supplement): A Comprehensive Review of Its Consumption, Metabolism, Health Effects, and Toxicity with Sex Differences

“…Androstenedione can be synthesized from dehydroepiandrosterone and further converted into either testosterone through the action of 17β-hydroxysteroid dehydrogenase, or to estrone via the aromatase enzyme complex [50]. DHEA is converted into androstenedione in the adrenal cortex, where it can be either aromatized to estrone or de-hydrogenated in the liver to yield testosterone [51]. Gene polymorphisms that encode for key enzymes involved in such pathways could have a modulation effect on the endogenous hormone levels; hence, it can influence the risk of hormone-related cancer diseases [52,53], and it can account for different responses to steroids in humans.…”

Nano‐selenium attenuates nickel‐induced testosterone synthesis disturbance through inhibition of MAPK pathways in Sprague‐Dawley rats

“…The mitogen‐activated protein kinases (MAPKs), a family of serine/threonine kinases, mainly include ERK1/2, p38, and JNK, with each MAPK signaling pathway consisting of at least three components . Activation of the MAPK signaling pathways plays a role in steroidogenesis, and multiple exogenous factors can affect the MAPK cascade reactions, affecting the expression of StAR, 3 β ‐HSD and 17 β ‐HSD, to ultimately perturb the levels of testosterone . Importantly, Ni can decrease the expression of StAR, CYP11A1, 3 β ‐HSD, and CYP17A1 via activation of ERK1/2 and p38 MAPK pathways, leading to the suppression of testosterone production in Leydig cells …”

Prostate Cancer: Signal Mechanism of Androgen Receptor

“…Testosteron dışındaki diğer androjenik bileşikler dehidroepiandrosteron (DHEA) ve DHT'dir. DHEA AR üzerinde zayıf agonistik aktiviteye sahipken testosteron ve DHT güçlü bir uyaran olarak majör fizyolojik endojen androjen grubunu oluşturmaktadır (Şekil 2) (14,15). Prostat bezi ve genital dokularda yüksek miktarlarda ifade olan sitokrom p450 ve 5-α redüktaz enzimi AR'ye testosterondan çok daha yüksek bağlanma ilgisine sahip olan DHT dönüşümünü katalize etmektedir (16).…”