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The use of genomics, proteomics, and metabolomics in identifying biomarkers of male infertility

2013; Elsevier BV; Volume: 99; Issue: 4 Linguagem: Inglês

10.1016/j.fertnstert.2013.01.111

1556-5653

Jason R. Kovac, Alexander W. Pastuszak, Dolores J. Lamb,

Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

Although male factors account for 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 factor 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, noninvasive, and accurate set of biomarkers can be identified to diagnose male factor infertility is tantalizing. This review focuses on the various methodologies used 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. Although male factors account for 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 factor 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, noninvasive, and accurate set of biomarkers can be identified to diagnose male factor infertility is tantalizing. This review focuses on the various methodologies used 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. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/kovacjr-genomics-proteomics-metabolomics-biomarkers/Infertility affects ∼15% of all couples with a male factor involved in ∼50% (1Mosher W.D. Pratt W.F. Fecundity and infertility in the United States: incidence and trends.Fertil Steril. 1991; 56: 192-193Abstract Full Text PDF PubMed Google Scholar, 2De Kretser D.M. Baker H.W. Infertility in men: recent advances and continuing controversies.J Clin Endocrinol Metab. 1999; 84: 3443-3450Crossref PubMed Google Scholar, 3Sabanegh Jr., E. Agarwal A. Male infertility.in: Campbell's urology. Vol. 1. Elsevier Saunders, Philadelphia, PA2012: 616-647Google Scholar). The complex nature of the condition is underscored by the fact that each individual contributes a complex array of genetic, proteomic, and metabolic differences that interact in unpredictable ways. The frustration that couples face is compounded by difficulties that clinicians have in diagnosing and treating infertility, particularly in men. Many causes of male factor infertility are still defined as idiopathic (1Mosher W.D. Pratt W.F. Fecundity and infertility in the United States: incidence and trends.Fertil Steril. 1991; 56: 192-193Abstract Full Text PDF PubMed Google Scholar, 3Sabanegh Jr., E. Agarwal A. Male infertility.in: Campbell's urology. Vol. 1. Elsevier Saunders, Philadelphia, PA2012: 616-647Google Scholar) and as such, most diagnoses tend to be descriptive rather than specific. For example, the simple classification of azoospermia into obstructive or nonobstructive (NOA) simply delineates a physical blockage from testicular failure. However, a more accurate taxonomy is not possible when the very origins of the condition are unknown.Infertility is defined as the inability to conceive after 12 months of regular, unprotected intercourse (4WHO World Health Organization (WHO) manual for the standard investigation and diagnosis of the infertile couple. Cambridge University Press, Cambridge, UK2000Google Scholar). Clinical investigations should not begin until this amount of time has elapsed—with several exceptions including advanced maternal age. Once inquiry begins, medical history and physical examination are performed and specific male factors addressed by semen analysis, karyotyping, Y-microdeletion analysis, and endocrine profiling. Unfortunately, for many men, these tests are normal or inconclusive, leading to a diagnosis of idiopathic infertility. A definitive diagnosis must then be pursued with surgical intervention, in the form of a testicular biopsy, which carries with it inherent complications. As a result, the identification of alternative, noninvasive methods to diagnose specific etiologies of male factor infertility are essential.The use of novel genetic, proteomic, and metabolomic techniques may hold the key to more accurately diagnosing and treating male factor infertility. It is within these categories that the search for potential biomarkers can begin (5Lamb D.J. A look towards the future: advances in andrology expected to revolutionize the diagnosis and treatment of the infertile male.in: Lipshultz L. Howards S. Niederberger C. Infertility in the male. Cambridge University Press, Cambridge2009: 642-653Crossref Google Scholar). A biomarker is a distinctive biological or biologically derived indicator of a process, event, or condition that can be objectively measured, evaluated, and compared (6Merriam-Webster Merriam-Webster dictionary. Merriam-Webster, Springfield, MA2012Google Scholar). The ideal biomarker should identify disease at an early stage, be easily detectable, cost-effective, and accurate, as well as having minimal side effects. The discovery of such noninvasive, highly sensitive and specific biomarkers would be helpful in eliminating the need for invasive testing in the infertile man and allowing an expanded and more specific classification of male factor infertility (7Kovac J.R. Lipshultz L.I. The significance of insulin-like factor 3 as a marker of intratesticular testosterone.Fertil Steril. 2013 Jan 29; https://doi.org/10.1016/j.fertnstert.2012.12.039Abstract Full Text Full Text PDF Google Scholar, 8Roth M.Y. Lin K. Bay K. Amory J.K. Anawalt B.D. Matsumoto A.M. et al.Serum insulin-like factor 3 is highly correlated with intratesticular testosterone in normal men with acute, experimental gonadotropin deficiency stimulated with low-dose human chorionic gonadotropin: a randomized, controlled trial.Fertil Steril. 2013; 99: 132-139Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar).For the purposes of this review, the field of male fertility-related biomarkers is classified into several areas. Basic laboratory analyses are discussed, including semen analysis, endocrine laboratory investigations, and antisperm antibodies, which are currently being used to assist clinicians in categorizing, diagnosing, and treating male factor infertility. This is followed by a summary of the current knowledge underlying state-of-the-art genomics, proteomics, and metabolomics. The difficulty involved with bringing these biomarkers from the bench to the bedside is also discussed. Although these areas are evolving and currently investigational, they have the potential to reinvent how male factor infertility is diagnosed and treated.Basic biomarkersA biomarker is any biological molecule that is measured and evaluated objectively and functions as an indicator of a physiological pathway (6Merriam-Webster Merriam-Webster dictionary. Merriam-Webster, Springfield, MA2012Google Scholar). In the context of male factor infertility, biomarkers have the intent of evaluating, in an accurate and minimally invasive manner, a man's potential for fathering children. At present the most widely used biomarker to predict male fertility potential is the semen analysis.Semen is a complex fluid comprised of a cellular element (i.e., spermatozoa) as well as a plasma element that functions as a nourishing and protective medium for spermatozoa (9Duncan M.W. Thompson H.S. Proteomics of semen and its constituents.Proteomics Clin Appl. 2007; 1: 861-875Crossref PubMed Scopus (8) Google Scholar). Semen is primarily derived from the seminal vesicles (65%–75%) and prostate (25%–30%), and its multifocal origin makes the search for biomarkers more difficult (9Duncan M.W. Thompson H.S. Proteomics of semen and its constituents.Proteomics Clin Appl. 2007; 1: 861-875Crossref PubMed Scopus (8) Google Scholar). Although semen analysis yields basic, yet critical information, it is subject to significant modulation and is an overall poor predictor of male fertility (10Guzick D.S. Overstreet J.W. Factor-Litvak P. Brazil C.K. Nakajima S.T. Coutifaris C. et al.Sperm morphology, motility, and concentration in fertile and infertile men.N Engl J Med. 2001; 345: 1388-1393Crossref PubMed Scopus (390) Google Scholar). Several physiological factors (i.e., duration between ejaculates) as well as pathologies (i.e., diabetes, sarcoidosis [11Kovac J.R. Flood D. Mullen J.B. Fischer M.A. Diagnosis and treatment of azoospermia resulting from testicular sarcoidosis.J Androl. 2012; 33: 162-166Crossref PubMed Scopus (1) Google Scholar]), systemic illnesses (i.e., flu), and environmental factors (i.e., smoking, alcohol) result in significant variability among semen samples (10Guzick D.S. Overstreet J.W. Factor-Litvak P. Brazil C.K. Nakajima S.T. Coutifaris C. et al.Sperm morphology, motility, and concentration in fertile and infertile men.N Engl J Med. 2001; 345: 1388-1393Crossref PubMed Scopus (390) Google Scholar). This leads to difficulties in the interpretation and management of men with abnormal findings (10Guzick D.S. Overstreet J.W. Factor-Litvak P. Brazil C.K. Nakajima S.T. Coutifaris C. et al.Sperm morphology, motility, and concentration in fertile and infertile men.N Engl J Med. 2001; 345: 1388-1393Crossref PubMed Scopus (390) Google Scholar).To provide further utility to semen analysis, the components are broken down into macroscopic and microscopic factors (12Turek P.J. Male reproductive physiology.in: Campbell-Walsh urology. Vol. 1. Elsevier-Saunders, Philadelphia2012: 591-615Google Scholar). Coagulation, color, viscosity, pH, and volume are classified as macroscopic components, whereas agglutination, sperm counts and concentration, motility, morphology, and viability are microscopic (12Turek P.J. Male reproductive physiology.in: Campbell-Walsh urology. Vol. 1. Elsevier-Saunders, Philadelphia2012: 591-615Google Scholar). Sperm counts and concentration are primarily useful in the classification of male factor infertility into either azoospermic (absence of sperm) or oligospermic ( 1,000 known cystic fibrosis transmembrane regulator mutations that have yet to be explored (54Yu J. Chen Z. Ni Y. Li Z. CFTR mutations in men with congenital bilateral absence of the vas deferens (CBAVD): a systemic review and meta-analysis.Hum Reprod. 2012; 27: 25-35Crossref PubMed Scopus (5) Google Scholar).Higher resolution assessment of a sperm's genetic complement can be achieved using fluorescence in situ hybridization, a technique that uses fluorescently labeled DNA to identify specific genetic sequences (55Landegent J.E. Jansen in de Wal N. van Ommen G.J. Baas F. de Vijlder J.J. van Duijn P. et al.Chromosomal localization of a unique gene by non-autoradiographic in situ hybridization.Nature. 1985; 317: 175-177Crossref PubMed Scopus (19) Google Scholar). Although not a first-line investigation in the United States, fluorescence in situ hybridization of sperm is used in cases of severe teratospermia or oligoasthenoteratospermia. In addition, in situations of recurrent pregnancy loss, it defines meiotic defects in the form of aneuploid sperm (56Bernardini L.M. Costa M. Bottazzi C. Gianaroli L. Magli M.C. Venturini P.L. et al.Sperm aneuploidy and recurrent pregnancy loss.Reprod Biomed Online. 2004; 9: 312-320Abstract Full Text PDF PubMed Google Scholar). Its primary disadvantage as an investigative tool is that the sequence of interest must be known before determining whether a region of interest exists in a specific patient.Microarray technologies, which evaluate men for copy number variations, gene expression levels, and single nucleotide polymorphisms (SNPs) hold great promise for identifying highly sensitive and specific genetic biomarkers. Comparative genomic hybridization, a technique used to assess the relative quantities of DNA