Despite the fact that male factors contribute to approximately 50% of all infertility, the mechanisms underlying their origin are unknown. Currently, clinicians rely primarily on semen analyses to predict male reproductive potential and chart treatment success. Even when invasive procedures are performed, the causes of male infertility frequently remain elusive. Recently, the advent of new technologies has spurred the search for novel male infertility biomarkers, and the detection of genes, proteins or metabolites unique to the infertile male holds much promise. The concept that a cost-effective, non-invasive and accurate set of biomarkers can be identified to diagnose male infertility is tantalizing. This review focuses on the various methodologies employed in the discovery of novel biomarkers along with their findings. Specific attention is paid to recent advances in the fields of genetics, proteomics and metabolomics.

ZAP-70, a Syk family cytoplasmic protein tyrosine kinase (PTK), is required to couple the activated T-cell antigen receptor (TCR) to downstream signaling pathways. It contains two tandem SH2 domains that bind to phosphorylated TCR subunits and a C-terminal catalytic domain. The region connecting the SH2 domains with the kinase domain, termed interdomain B, has previously been shown to have striking regulatory effects on ZAP-70 function, presumed to be due to the recruitment of key substrates. Paradoxically, deletion of interdomain B preserves ZAP-70 function. Recent structural studies of several receptor tyrosine kinases (RTKs) revealed that their juxtamembrane regions negatively regulate their catalytic activities. In EphB2 and several other RTKs, this autoinhibition depends upon interaction between the kinase domain and tyrosine residues within the juxtamembrane region. Autoinhibition is released when these tyrosines become phosphorylated following receptor stimulation. Sequence homology suggested analogous regulation for ZAP-70. Based on mutagenesis analysis of ZAP-70 interdomain B, we find that this region downregulates ZAP-70 catalytic activity in a similar manner as the juxtamembrane region of EphB2. Similar regulation was also noted for the related Syk kinase. These findings suggest that a general autoinhibitory mechanism employed by RTKs is also used by some cytoplasmic tyrosine kinases.Stimulation of the T-cell antigen receptor (TCR) leads to a series of signaling events that result in changes in T-cell function and gene expression. Signaling is initiated by two families of protein tyrosine kinases (PTKs) (17). Src-family kinases first phosphorylate specific immunoreceptor tyrosine-based activation motifs (ITAMs) (4) in the cytoplasmic tails of the CD3 and subunits of TCR. Each ITAM is composed of a pair of tyrosines separated by 9 to 11 amino acids which, when phosphorylated, bind the Syk family PTK ZAP-70. In turn, ZAP-70 becomes activated and subsequently phosphorylates a number of key downstream signaling molecules necessary for further signal propagation.ZAP-70 consists of two N-terminal SH2 domains, responsible for binding to doubly phosphorylated ITAMs, and a Cterminal tyrosine kinase domain (6). The SH2 domains are separated by a linker region, termed interdomain A. The region between the SH2 domains and the kinase domain is known as interdomain B.Upon binding to phosphorylated ITAMs of the activated TCR, ZAP-70 itself becomes phosphorylated on multiple tyrosine residues, both by Src family PTKs and via autophosphorylation. It is well established that tyrosine phosphorylation plays an important role in ZAP-70 activation, but the precise mechanism responsible is still incompletely understood. Among the best-studied phosphorylation sites are tyrosines 492 and 493 (Y492 and Y493) in the activation loop of the kinase (5,33,34). A model has been proposed whereby Y493 becomes phosphorylated first by the Src-family PTK Lck. This phosphorylation is then followed by autophosphorylation at Y492 (5). Phosp...

Purpose Testosterone replacement therapy in men with prostate cancer is controversial, with concern that testosterone can stimulate cancer growth. We evaluated the safety and efficacy of testosterone in hypogonadal men with prostate cancer treated with radical prostatectomy. Materials and Methods We performed a review of 103 hypogonadal men with prostate cancer treated with testosterone after prostatectomy (treatment group) and 49 nonhypogonadal men with cancer treated with prostatectomy (reference group). There were 77 men with low/intermediate (nonhigh) risk cancer and 26 with high risk cancer included in the analysis. All men were treated with transdermal testosterone, and serum hormone, hemoglobin, hematocrit and prostate specific antigen were evaluated for more than 36 months. Results Median (IQR) patient age in the treatment group was 61.0 years (55.0–67.0), and initial laboratory results included testosterone 261.0 ng/dl (213.0–302.0), prostate specific antigen 0.004 ng/ml (0.002–0.007), hemoglobin 14.7 gm/dl (13.3–15.5) and hematocrit 45.2% (40.4–46.1). Median followup was 27.5 months, at which time a significant increase in testosterone was observed in the treatment group. A significant increase in prostate specific antigen was observed in the high risk and nonhigh risk treatment groups with no increase in the reference group. Overall 4 and 8 cases of cancer recurrence were observed in treatment and reference groups, respectively. Conclusions Thus, testosterone therapy is effective and, while followed by an increase in prostate specific antigen, does not appear to increase cancer recurrence rates, even in men with high risk prostate cancer. However, given the retrospective nature of this and prior studies, testosterone therapy in men with history of prostate cancer should be performed with a vigorous surveillance protocol.

Introduction: Selective androgen receptor modulators (SARMs) differentially bind to androgen receptors depending on each SARM’s chemical structure. As a result, SARMs result in anabolic cellular activity while avoiding many of the side effects of currently available anabolic steroids. SARMs have been studied in the treatment of breast cancer and cachexia and have also been used as performance enhancing agents. Here, we evaluate and summarize the current literature on SARMs. Aims: To present the background, mechanisms, current and potential clinical applications, as well as risks and benefits of SARMs. Methods: A literature review was performed in MEDLINE using the terms selective androgen receptor modulator, hypogonadism, cachexia, breast cancer, benign prostatic hyperplasia, libido and lean muscle mass. Both basic research and clinical studies were included. Results: While there are currently no FDA-approved indications for SARMs, investigators are exploring the potential uses for these compounds. Basic research has focused on the pharmacokinetics and pharmacodynamics of these agents, demonstrating good availability with a paucity of drug interactions. Early clinical studies have demonstrated potential uses for SARMs in the treatment of cancer-related cachexia, benign prostatic hyperplasia, hypogonadism, and breast cancer, with positive results. Conclusion: SARMs have numerous possible clinical applications, with promise for the safe use in the treatment of cachexia, BPH, hypogonadism, breast cancer, and prostate cancer.