Applying mass spectrometric methods to study androgen biosynthesis and metabolism in prostate cancer

Abstract

Recent development of gas chromatography and liquid chromatography-tandem mass spectrometry (GC-MS/MS, LC-MS/MS) has provided novel tools to define sex steroid concentrations. These new methods overcome several of the problems associated with immunoassays for sex steroids. With the novel MS-based applications we are now able to measure small concentrations of the steroid hormones reliably and with high accuracy in both body fluids and tissue homogenates. The sensitivity of the tandem mass spectrometry assays allows us also for the first time to reliably measure picomolar or even femtomolar concentrations of estrogens and androgens. Furthermore, due to a high sensitivity and specificity of MS technology, we are also able to measure low concentrations of steroid hormones of interest in the presence of pharmacological concentration of other steroids and structurally closely related compounds. Both of these features are essential for multiple preclinical models for prostate cancer. The MS assays are also valuable for the simultaneous measurement of multiple steroids and their metabolites in small sample volumes in serum and tissue biopsies of prostate cancer patients before and after drug interventions. As a result, novel information about steroid hormone synthesis and metabolic pathways in prostate cancer has been obtained. In our recent studies, we have extensively applied a GC-MS/MS method to study androgen biosynthesis and metabolism in VCaP prostate cancer xenografts in mice. In the present review, we shortly summarize some of the benefits of the GC-MS/MS and novel LC-MS/ MS assays, and provide examples of their use in defining novel mechanisms of androgen action in prostate cancer. Journal of Molecular Endocrinology(2019) 62, R255-R267

The gut microbiota is a major regulator of androgen metabolism in intestinal contents

“…Also, several of these studies indicated that the sexual dimorphism in serum T levels is attenuated in GF mice (33,49,50). These studies used less specific immunoassay-based techniques for analysis of serum T levels, with known limitations in the lower concentration range (26,30), and different mouse strains, most probably with different GM compositions, at different ages compared with the present study. Interestingly, our study demonstrated elevated tissue DHT levels in the liver and seminal vesicles of male GF mice, with a similar trend in the thymus.…”

CYP19A1 Is Regulated by BRD4 and Suppresses Castration-resistant Prostate Cancer Cell Invasion and Proliferation by Decreasing AR Expression

“…The androgen metabolic pathway is important in androgen synthesis and metabolism. It has been demonstrated that the abnormal function of the androgen metabolic pathway plays key role in the occurrence of CRPC [29]. The androgen metabolic pathway consists of several components, which include cytochromes P450 (CYPs) [30].CYPs are one of the largest and most diverse superfamily of enzymes [6].…”

Effects of dutasteride in a rat model of chemically induced prostatic inflammation—Potential role of estrogen receptor β

“…27,28 Thus, further studies are needed using, for example, a gas chromatography-tandem mass spectrometry, which has been applied for detecting steroid hormones at low concentrations, to detect the upregulation of potential ERβ ligands in the prostate. 29 Second, we evaluated the mRNA expression levels of only a few cytokines, but not underlying inflammatory cascades in the prostate with or without dutasteride administration. While additional studies will be required to fully explain the anti-inflammatory effects of dutasteride in the prostate, the impact of this androgen metabolism inhibitor on the opposing actions of ERα and ERβ, as implicated by our results, will clearly be an important mechanism to decipher.…”

“…Androgen metabolites, such as Δ5‐diol or dehydroepiandrosterone, a precursor of ERβ ligands reportedly stimulate ERβ 27,28 . Thus, further studies are needed using, for example, a gas chromatography‐tandem mass spectrometry, which has been applied for detecting steroid hormones at low concentrations, to detect the upregulation of potential ERβ ligands in the prostate 29 . Second, we evaluated the mRNA expression levels of only a few cytokines, but not underlying inflammatory cascades in the prostate with or without dutasteride administration.…”