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1H NMR-Based Metabonomics for Infertility Diagnosis in Men with Varicocele - Beyond the Abstract

Infertility is a prevalent condition affecting up to 15% of the couples, while a male factor is found in up to 50% of these cases.1 Varicocele is the most common correctable cause of male infertility, with a prevalence of 15% in the male population.2 However, varicocele does not always impair male reproductive function, in fact, only 20% of the men affected by this condition will become infertile (3 Thus, there should be pathophysiological mechanisms that differ between those men who will and those who will not develop varicocele-related male infertility. Several pathways have been proposed to explain the damage to fertility caused by varicocele, but the complete picture, including why most men with varicocele have no apparent fertility issues, remains unclear. Increased testicular temperature, increased testicular oxidative, adrenal metabolites reflux, damage to the blood-testis barrier, and formation of anti-sperm antibodies are the most studied.4

Recently, different “omics” techniques have been used to better understand male infertility conditions, helping the development of new diagnostic, therapeutic, and prognostics tools.5,6 The “omics” methods use high-throughput techniques to study several biological systems in a step-by-step fashion, progressing from the most basic information, the genome, passing through mechanisms that process this information, the epigenome, and the transcriptome, reaching the functional elements, the proteome, and ending in the net effects of their action, the metabolome and the phenome. This integrated approach relies heavily on chemical analytical methods, producing a massive amount of data that should be interpreted using bioinformatics and computational analysis tools in order to deliver clinically useful information.7 The unraveling of the physiopathologic mechanisms of varicocele in both collective and individual levels will definitively provide a precise clinical approach for the men who are affected by this condition, individualizing treatment based on their biological characteristics.

In this way, we applied a metabonomics technique to study the differences in the seminal metabolome among healthy, fertile, and infertile men with and without varicocele. Using hydrogen-1 nuclear magnetic resonance spectroscopy, we aimed to identify metabolites that were differentially expressed in these 3 groups of participants and to create statistical models capable of discriminating the groups. 

We identified 19 metabolites that were important in group segregation. These metabolites were associated with the metabolism of amino acids, energy metabolism, and oxidative stress response. These findings suggest that the degree of damage to spermatogenesis caused by varicocele is associated with the compensatory response capability of each individual. That is, fertile men with varicocele have a better compensatory response to varicocele than infertile. Furthermore, using multivariate statistical tools, we created several metabonomics models that discriminated against the study groups with high accuracy.

We believe that our results will help to understand the metabolic pathways responsible for varicocele-induced male infertility, and will pave the way to the development of a more individualized approach for varicocele diagnosis and treatment.

Written by: Filipe Tenorio Lira Neto, Ronmilson Alves Marques, Alexandre de Freitas Cavalcanti Filho, Leslie Clifford Noronha Araujo, Salvador Vilar Correia Lima, Licarion Pinto, Ricardo Oliveira Silva



Department of Surgery, Universidade Federal de Pernambuco, Rua Guilherme Salazar, n 150, apt 601E, Recife, PE, ZIP 52061-275, Brazil. ., Fundamental Chemistry Department, Universidade Federal de Pernambuco, Av. Jornalista Anibal Fernandes, s/n° Cidade Universitária, Recife, PE, ZIP 50740-560, Brazil., Instituto de Medicina Integral Prof. Fernando Figueira, Rua dos Coelho, 300, Coelhos, Recife, PE, ZIP 50070-902, Brazil., Faculdade de Medicina de Olinda, Rua Dr. Manoel de Almeida Belo, n 1333, Olinda, PE, ZIP 53030-030, Brazil., Department of Surgery, Universidade Federal de Pernambuco, Hospital das Clínicas - Campus UFPE, Av. Prof. Moraes Rego,"s/n° - Bloco "A" - Térreo Cidade Universitária, Recife, PE, ZIP 50670-420, Brazil.

References:

  1. Boivin J, Bunting L, Collins JA, Nygren KG. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod. 2007;22(6):1506-12.
  2. Gorelick JI, Goldstein M. Loss of fertility in men with varicocele. Fertility and sterility.1993;59(3):613-6.
  3. Sigman M. There is more than meets the eye with varicoceles: current and emerging concepts in pathophysiology, management, and study design. Fertility and sterility. 2011;96(6):1281-2.
  4. Kathrins M. The varicocele as related to fertility. Fertility and sterility. 2017;107(1):72-3.
  5. Pontes TA, Barbosa AD, Silva RD, Melo-Junior MR, Silva RO. Osteopenia-osteoporosis discrimination in postmenopausal women by 1H NMR-based metabonomics. PloS one. 2019;14(5):e0217348.
  6. Kovac JR, Pastuszak AW, Lamb DJ. The use of genomics, proteomics, and metabolomics in identifying biomarkers of male infertility. Fertility and sterility. 2013;99(4):998-1007.
  7. Karczewski KJ, Snyder MP. Integrative omics for health and disease. Nature Reviews Genetics. 2018;19(5):299-310.
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