Abstract
Despite the growing body of knowledge showing that testosterone (T) may not significantly affect tumor progression in hypogonadal patients treated for prostate cancer (Pca), the use of this hormone in this population still remains controversial. The effects of continuous or pulsed T stimulation were tested in vitro and in vivo on androgen-sensitive Pca cell lines in order to assess the differential biological properties of these two treatment modalities. Pulsed T treatment resulted in a greater inhibition than continuous T supplementation of tumor growth in vitro and in vivo. The effects of pulsed T treatment on tumor growth inhibition, G0/G1 cell cycle arrest, and tumor senescence was more pronounced than those obtained upon continuous T treatments. Mechanistic studies revealed that G0/G1 arrest and tumor senescence upon pulsed T treatment were associated with a marked decrease in cyclin D1, c-Myc and SKp2, CDK4 and p-Rb levels and upregulation of p27 and p-ERK1/2. Pulsed, but not continuous, T supplementation decreased the expression levels of AR, p-ARser81 and CDK1 in both cellular models. The in vitro results were confirmed in an in vivo xenografts, providing evidence of a greater inhibitory activity of pulsed supraphysiological T supplementation than continuous treatment, both in terms of tumor volume and decreased AR, p-ARser81, PSA and CDK1 staining. The rapid cycling from hypogonadal to physiological or supra-physiological T intraprostatic concentrations results in cytostatic and senescence effects in preclinical models of androgen-sensitive Pca. Our preclinical evidence provides relevant new insights in the biology of Pca response to pulsed T supplementation.
Highlights
The number of subjects requiring Testosterone Replacement Therapy (TRT) secondary to aging or to pathological conditions is dramatically increasing [1]
It has been previously shown that continuous T treatment exerts a biphasic effect on the proliferative responses of prostatic cancer cell lines in vitro, inducing proliferation at concentrations corresponding to those in the cultured medium supplemented with 10% heat-inactivated fetal bovine serum (10% FBS), and inhibition at higher concentrations [15]
To investigate whether pulsed T treatment could affect the growth of androgen sensitive prostate cancer (Pca) cells, cultures were treated for 48 h with pulsed T (5.3 nM or 17.2 nM)
Summary
The number of subjects requiring Testosterone Replacement Therapy (TRT) secondary to aging or to pathological conditions is dramatically increasing [1]. Morgentaler proposed the “saturation theory” to explain why T does not directly affect Pca progression during TRT [9] According to this theory, Pca growth may become insensitive to changes at physiological androgen levels due to saturation of the androgen receptor (AR) by circulating androgens. When the effect of increasing doses of exogenous T on the concentrations of intraprostatic androgens was investigated in a randomized double blind placebo controlled trial (RCT), it was evident that the average serum T concentrations during treatment positively correlated with both intraprostatic DHT and T after 12 weeks of treatment [14] These clinical data may be of interest in the light of biological evidence that suggests that prostate cancers have a biphasic response to tumor cell growth in androgen-sensitive Pca cells [15,16,17,18]. Our preclinical study was built to investigate whether the rapid cycling from intraprostatic T concentrations typical of hypogonadism to physiological or supra-physiological concentrations may affect some biological parameters associated with aggressive behavioral properties of preclinical models of prostate cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
