Why Do We Need New Markers for Male Hypogonadism and How Seminal Proteomics Might Solve the Problem?

Author(s): Giuseppe Grande*, Domenico Milardi, Silvia Baroni, Andrea Urbani, Alfredo Pontecorvi

Journal Name: Protein & Peptide Letters

Volume 27 , Issue 12 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Male hypogonadism is “a clinical syndrome that results from failure of the testis to produce physiological concentrations of testosterone and/or a normal number of spermatozoa due to pathology at one or more levels of the hypothalamic– pituitary–testicular axis”. The diagnostic protocol of male hypogonadism includes accurate medical history, physical exam, as well as hormone assays and instrumental evaluation. Basal hormonal evaluation of serum testosterone, LH, and FSH is important in the evaluation of diseases of the hypothalamus-pituitary-testis axis. Total testosterone levels < 8 nmol/l profoundly suggest the diagnosis of hypogonadism. An inadequate androgen status is moreover possible if the total testosterone levels are 8-12 nmol/L. In this “grey zone” the diagnosis of hypogonadism is debated and the appropriateness for treating these patients with testosterone should be fostered by symptoms, although often non-specific. Up to now, no markers of androgen tissue action can be used in clinical practice. The identification of markers of androgens action might be useful in supporting diagnosis, Testosterone Replacement Treatment (TRT) and clinical follow-up. The aim of this review is to analyze the main findings of recent studies in the field of discovering putative diagnostic markers of male hypogonadism in seminal plasma by proteomic techniques. The identified proteins might represent a “molecular androtest” useful as a seminal fingerprint of male hypogonadism, for the diagnosis of patients with moderate grades of testosterone reduction and in the follow-up of testosterone replacement treatment.

Keywords: Male hypogonadism, testosterone, seminal plasma, proteins, marker, TRT.

[1]
Bhasin, S.; Brito, J.P.; Cunningham, G.R.; Hayes, F.J.; Hodis, H.N.; Matsumoto, A.M.; Snyder, P.J.; Swerdloff, R.S.; Wu, F.C.; Yialamas, M.A. Testosterone therapy in men with hypogonadism: An endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab., 2018, 103(5), 1715-1744.
[http://dx.doi.org/10.1210/jc.2018-00229] [PMID: 29562364]
[2]
Behan, L.A.; Agha, A. Endocrine consequences of adult traumatic brain injury. Horm. Res., 2007, 68(5)(Suppl. 5), 18-21.
[http://dx.doi.org/10.1159/000110466] [PMID: 18174698]
[3]
Kelberman, D.; Dattani, M.T. Hypopituitarism oddities: Congenital causes. Horm. Res., 2007, 68(5)(Suppl. 5), 138-144.
[http://dx.doi.org/10.1159/000110610] [PMID: 18174732]
[4]
Lenzi, A.; Balercia, G.; Bellastella, A.; Colao, A.; Fabbri, A.; Foresta, C.; Galdiero, M.; Gandini, L.; Krausz, C.; Lombardi, G.; Lombardo, F.; Maggi, M.; Radicioni, A.; Selice, R.; Sinisi, A.A.; Forti, G. Epidemiology, diagnosis, and treatment of male hypogonadotropic hypogonadism. J. Endocrinol. Invest., 2009, 32(11), 934-938.
[http://dx.doi.org/10.1007/BF03345775] [PMID: 19955846]
[5]
Arver, S.; Lehtihet, M. Current Guidelines for the Diagnosis of Testosterone Deficiency. In: Advances in the Management of Testosterone Deficiency; Jones, T.H. Ed.; KARGER: Basel, 2008, Vol. 37, pp. 5-20.
[http://dx.doi.org/10.1159/000175839]
[6]
La Vignera, S.; Condorelli, R.A.; Cimino, L.; Russo, G.I.; Morgia, G.; Calogero, A.E. Late-onset hypogonadism: The advantages of treatment with human chorionic gonadotropin rather than testosterone. Aging Male, 2016, 19(1), 34-39.
[http://dx.doi.org/10.3109/13685538.2015.1092021] [PMID: 26488941]
[7]
Matsumoto, A.M. Hormonal therapy of male hypogonadism. Endocrinol. Metab. Clin. North Am., 1994, 23(4), 857-875.
[http://dx.doi.org/10.1016/S0889-8529(18)30072-0] [PMID: 7705324]
[8]
Corona, G.; Rastrelli, G.; Vignozzi, L.; Maggi, M. Emerging medication for the treatment of male hypogonadism. Expert Opin. Emerg. Drugs, 2012, 17(2), 239-259.
[http://dx.doi.org/10.1517/14728214.2012.683411] [PMID: 22612692]
[9]
Yılmazel, F.K.; Karabulut, İ.; Yılmaz, A.H.; Keskin, E.; Bedir, F.; Özbey, İ. A review of hypogonadotropic hypogonadism cases followed up in our clinic in the last decade. Urologia, 2019, 391560319882231.
[http://dx.doi.org/10.1177/0391560319882231] [PMID: 31622170]
[10]
Alshahrani, S.; McGill, J.; Agarwal, A. Prostatitis and male infertility. J. Reprod. Immunol., 2013, 100(1), 30-36.
[http://dx.doi.org/10.1016/j.jri.2013.05.004] [PMID: 23938147]
[11]
Brooks, D.E. Influence of androgens on the weights of the male accessory reproductive organs and on the activities of mitochondrial enzymes in the epididymis of the rat. J. Endocrinol., 1979, 82(2), 293-303.
[http://dx.doi.org/10.1677/joe.0.0820293] [PMID: 490085]
[12]
Green, S.M.; Mostaghel, E.A.; Nelson, P.S. Androgen action and metabolism in prostate cancer. Mol. Cell. Endocrinol., 2012, 360(1-2), 3-13.
[http://dx.doi.org/10.1016/j.mce.2011.09.046] [PMID: 22453214]
[13]
Ma, C.; Yoshioka, M.; Boivin, A.; Gan, L.; Takase, Y.; Labrie, F.; St-Amand, J. Atlas of dihydrotestosterone actions on the transcriptome of prostate in vivo. Prostate, 2009, 69(3), 293-316.
[http://dx.doi.org/10.1002/pros.20883] [PMID: 19023869]
[14]
Barrachina, F.; Jodar, M.; Delgado-Dueñas, D.; Soler-Ventura, A.; Estanyol, J.M.; Mallofré, C.; Ballescà, J.L.; Oliva, R. Stable-protein pair analysis as a novel strategy to identify proteomic signatures: Application to seminal plasma from infertile patients. Mol. Cell. Proteomics, 2019, 18(Suppl. 1), S77-S90.
[http://dx.doi.org/10.1074/mcp.RA118.001248] [PMID: 30518674]
[15]
Cayer, D.M.; Nazor, K.L.; Schork, N.J. Mission critical: The need for proteomics in the era of next-generation sequencing and precision medicine. Hum. Mol. Genet., 2016, 25(R2), R182-R189.
[http://dx.doi.org/10.1093/hmg/ddw214] [PMID: 27439388]
[16]
Milardi, D.; Grande, G.; Vincenzoni, F.; Castagnola, M.; Marana, R. Proteomics of human seminal plasma: Identification of biomarker candidates for fertility and infertility and the evolution of technology. Mol. Reprod. Dev., 2013, 80(5), 350-357.
[http://dx.doi.org/10.1002/mrd.22178] [PMID: 23559416]
[17]
Milardi, D.; Grande, G.; Vincenzoni, F.; Giampietro, A.; Messana, I.; Castagnola, M.; Marana, R.; De Marinis, L.; Pontecorvi, A. Novel biomarkers of androgen deficiency from seminal plasma profiling using high-resolution mass spectrometry. J. Clin. Endocrinol. Metab., 2014, 99(8), 2813-2820.
[http://dx.doi.org/10.1210/jc.2013-4148] [PMID: 24796927]
[18]
Michalski, A.; Damoc, E.; Lange, O.; Denisov, E.; Nolting, D.; Mü, M.; Viner, R.; Schwartz, J.; Remes, P.; Belford, M. Ultra High Resolution Linear Ion Trap Orbitrap Mass Spectrometer (Orbitrap Elite) Facilitates Top Down LC MS/MS and Versatile Peptide Fragmentation Modes. Mol. Cell. Proteomics, 2011, 11(3) O111.013698.
[http://dx.doi.org/10.1074/mcp.O111.013698.]
[19]
Baldwin, M.A. Protein identification by mass spectrometry: Issues to be considered. Mol. Cell. Proteomics, 2004, 3(1), 1-9.
[http://dx.doi.org/10.1074/mcp.R300012-MCP200] [PMID: 14608001]
[20]
Grande, G.; Vincenzoni, F.; Mancini, F.; Barrachina, F.; Giampietro, A.; Castagnola, M.; Urbani, A.; Oliva, R.; Milardi, D.; Pontecorvi, A. Quantitative analysis of the seminal plasma proteome in secondary hypogonadism. J. Clin. Med., 2019, 8(12)E2128
[http://dx.doi.org/10.3390/jcm8122128] [PMID: 31816910]
[21]
Behre, H.M.; Kliesch, S.; Schädel, F.; Nieschlag, E. Clinical relevance of scrotal and transrectal ultrasonography in andrological patients. Int. J. Androl., 1995, 18(Suppl. 2), 27-31.
[PMID: 8719855]
[22]
Tomar, A.K.; Sooch, B.S.; Raj, I.; Singh, S.; Yadav, S. Interaction analysis identifies semenogelin I fragments as new binding partners of PIP in human seminal plasma. Int. J. Biol. Macromol., 2013, 52, 296-299.
[http://dx.doi.org/10.1016/j.ijbiomac.2012.10.011] [PMID: 23085372]
[23]
Hassan, M.I.; Waheed, A.; Yadav, S.; Singh, T.P.; Ahmad, F. Prolactin inducible protein in cancer, fertility and immunoregulation: Structure, function and its clinical implications. Cell. Mol. Life Sci., 2009, 66(3), 447-459.
[http://dx.doi.org/10.1007/s00018-008-8463-x] [PMID: 18854942]
[24]
Martínez-Heredia, J.; de Mateo, S.; Vidal-Taboada, J.M.; Ballescà, J.L.; Oliva, R. Identification of proteomic differences in asthenozoospermic sperm samples. Hum. Reprod., 2008, 23(4), 783-791.
[http://dx.doi.org/10.1093/humrep/den024] [PMID: 18281682]
[25]
Yadav, V.K.; Kumar, V.; Chhikara, N.; Kumar, S.; Manral, P.; Kashav, T.; Saini, S.; Srinivasan, A.; Singh, S.; Singh, T.P.; Yadav, S. Purification and characterization of a native zinc-binding high molecular weight multiprotein complex from human seminal plasma. J. Sep. Sci., 2011, 34(9), 1076-1083.
[http://dx.doi.org/10.1002/jssc.201000842] [PMID: 21404442]
[26]
Ban, R.W.; Cooper, J.F.; Imfeld, H.; Foti, A. Hormonal effects on prostatic acid phosphatase synthesis in tissue culture. Invest. Urol., 1974, 11(4), 308-311.
[PMID: 4129202]
[27]
Wichmann, L.; Vaalasti, A.; Vaalasti, T.; Tuohimaa, P. Localization of lactoferrin in the male reproductive tract. Int. J. Androl., 1989, 12(3), 179-186.
[http://dx.doi.org/10.1111/j.1365-2605.1989.tb01302.x] [PMID: 2767778]
[28]
Milardi, D.; Grande, G.; Vincenzoni, F.; Messana, I.; Pontecorvi, A.; De Marinis, L.; Castagnola, M.; Marana, R. Proteomic approach in the identification of fertility pattern in seminal plasma of fertile men. Fertil. Steril., 2012, 97(1), 67-73.e1.
[http://dx.doi.org/10.1016/j.fertnstert.2011.10.013] [PMID: 22088208]
[29]
Piomboni, P.; Gambera, L.; Serafini, F.; Campanella, G.; Morgante, G.; De Leo, V. Sperm quality improvement after natural anti-oxidant treatment of asthenoteratospermic men with leukocytospermia. Asian J. Androl., 2008, 10(2), 201-206.
[http://dx.doi.org/10.1111/j.1745-7262.2008.00356.x] [PMID: 18097513]
[30]
Morelli, A.; Corona, G.; Filippi, S.; Ambrosini, S.; Forti, G.; Vignozzi, L.; Maggi, M. Which patients with sexual dysfunction are suitable for testosterone replacement therapy? J. Endocrinol. Invest., 2007, 30(10), 880-888.
[http://dx.doi.org/10.1007/BF03349232] [PMID: 18075293]
[31]
Wang, C.; Nieschlag, E.; Swerdloff, R.; Behre, H.M.; Hellstrom, W.J.; Gooren, L.J.; Kaufman, J.M.; Legros, J-J.; Lunenfeld, B.; Morales, A.; Morley, J.E.; Schulman, C.; Thompson, I.M.; Weidner, W.; Wu, F.C. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur. J. Endocrinol., 2008, 159(5), 507-514.
[http://dx.doi.org/10.1530/EJE-08-0601] [PMID: 18955511]
[32]
Corona, G.; Maggi, M. The role of testosterone in erectile dysfunction. Nat. Rev. Urol., 2010, 7(1), 46-56.
[http://dx.doi.org/10.1038/nrurol.2009.235] [PMID: 19997070]
[33]
Morley, J.E.; Charlton, E.; Patrick, P.; Kaiser, F.E.; Cadeau, P.; McCready, D.; Perry, H.M.3rd. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism, 2000, 49(9), 1239-1242.
[http://dx.doi.org/10.1053/meta.2000.8625] [PMID: 11016912]
[34]
Heinemann, L.A.; Saad, F.; Heinemann, K.; Thai, D.M. Can results of the Aging Males’ Symptoms (AMS) scale predict those of screening scales for androgen deficiency? Aging Male, 2004, 7(3), 211-218.
[http://dx.doi.org/10.1080/13685530400004223] [PMID: 15669540]
[35]
Smith, K.W.; Feldman, H.A.; McKinlay, J.B. Construction and field validation of a self-administered screener for testosterone deficiency (hypogonadism) in ageing men. Clin. Endocrinol. (Oxf.), 2000, 53(6), 703-711.
[http://dx.doi.org/10.1046/j.1365-2265.2000.01152.x] [PMID: 11155092]
[36]
Rosen, R.C.; Araujo, A.B.; Connor, M.K.; Gerstenberger, E.P.; Morgentaler, A.; Seftel, A.D.; Miner, M.M.; Shabsigh, R. The NERI Hypogonadism Screener: Psychometric validation in male patients and controls. Clin. Endocrinol. (Oxf.), 2011, 74(2), 248-256.
[http://dx.doi.org/10.1111/j.1365-2265.2010.03925.x] [PMID: 21114509]
[37]
Corona, G.; Mannucci, E.; Petrone, L.; Balercia, G.; Fisher, A.D.; Chiarini, V.; Forti, G.; Maggi, M. ANDROTEST: A structured interview for the screening of hypogonadism in patients with sexual dysfunction. J. Sex. Med., 2006, 3(4), 706-715.
[http://dx.doi.org/10.1111/j.1743-6109.2006.00262.x] [PMID: 16839327]
[38]
Rastrelli, G.; Corona, G.; Bandini, E.; Strada, C.; Maseroli, E.; Ricca, V.; Faravelli, C.; Mannucci, E.; Maggi, M. Investigation on psychological symptoms improves ANDROTEST accuracy in predicting hypogonadism in subjects with sexual dysfunction. Int. J. Impot. Res., 2013, 25(1), 34-39.
[http://dx.doi.org/10.1038/ijir.2012.33] [PMID: 22992755]
[39]
Millar, A.C.; Lau, A.N.C.; Tomlinson, G.; Kraguljac, A.; Simel, D.L.; Detsky, A.S.; Lipscombe, L.L. Predicting low testosterone in aging men: A systematic review. CMAJ, 2016, 188(13), E321-E330.
[http://dx.doi.org/10.1503/cmaj.150262] [PMID: 27325129]


open access plus

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 27
ISSUE: 12
Year: 2020
Page: [1186 - 1191]
Pages: 6
DOI: 10.2174/0929866527666200505214021

Article Metrics

PDF: 25
HTML: 2