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To investigate whether the tumor suppressor gene PTEN affects the activity of the androgen receptor (AR), we monitored the expression of the apoptotic gene HA-Bax (inserted in an adenovirus where it is driven by the AR-responsive promoter ARR 2 PB) in the presence or absence of dihydrotestosterone, in PTEN (+) or (−) prostate cancer cell lines, infected with an adenovirus containing wild-type PTEN (Av-CMV-PTEN) or a control LacZ-expressing construct. Our results showed that AR transcriptional activity was antagonized by PTEN expression. This antagonism was not cell line dependent, as it was observed in both LNCaP and LAPC-4 cells, or promoter dependent, as it was observed for a reporter gene (HA-Bax) driven by an exogenous androgen-responsive promoter (the ARR 2 PB promoter), and for a native gene (prostate-specific antigen; PSA) driven by an endogenous AR-responsive promoter. Additional experiments performed with viruses containing constitutively active (Adeno-myrAkt) or dominant negative (Adeno-dnAkt) forms of Akt demonstrated that Akt, a protein kinase whose activation is known to be inhibited by PTEN, mediated the observed antagonism between PTEN and AR transcriptional activity. Recently, two putative Akt phosphorylation sites have been identified in the AR sequence. Site-directed mutagenesis was utilized to convert these two serine into alanine residues. The resulting construct, named CMV-AR S213A&S791A was transfected in AR (−) and PTEN (−) PC-3 cells in the presence or absence of Av-CMV-PTEN and of two reporter plasmids (GRE 2 E1b-Luc and PSA P/E-luc) containing the luciferase gene driven by well-characterized androgen responsive promoters. These experiments demonstrated that, similarly to the wild-type molecule, AR S213A&S791A was transcriptionally inhibited by PTEN, suggesting that Akt does not have an effect on AR transcription by direct phosphorylation, but probably by affecting the availability of a downstream molecule whose main mechanism of action is that of modulating AR transcription. The data presented here suggest that loss of PTEN function may facilitate activation of AR signaling and progression to androgen independence in prostate cancer.

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BackgroundAdding testosterone to hormonal therapy could improve sexual function and general well-being among women during climacteric. We evaluated the effectiveness of testosterone undecanoate on sexual function in postmenopausal women utilizing the standardized questionnaire FSFI score.MethodsPostmenopausal women with sexual complaints and Female Sexual Function Index (FSFI) ≤ 26.5 were enrolled in to this randomized, double-blinded, placebo-controlled trial. Participants were randomly assigned to 8-week treatment with either oral testosterone undecanoate 40 mg or placebo twice weekly with daily oral estrogen. The FSFI scores before and after treatment were compared to assess any improvement of sexual function.ResultsSeventy women were recruited of which each group had 35 participants. The baseline characteristics and baseline FSFI scores were comparable between both groups. After 8 weeks of treatment, the FSFI scores significantly improved in both groups when compared to the baseline but the FSFI scores from the testosterone group were significantly higher than in the placebo group post-treatment (28.6 ± 3.6, 25.3 ± 6.7, respectively, p = 0.04). There was no difference in adverse effect between the two groupsConclusionsThe twice weekly addition of testosterone undecanoate to daily oral estrogen was associated with a significant improvement in sexual function among postmenopausal women than the use of the estrogen alone.Trial registrationClinicalTrials.gov Identifier NCT01724658 (February 17, 2012).

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