Evaluation of infertile men: Mini-review

Mohannad AbuFaza, Ibrahim A. Abdelazim2*, Hossam S. Othman, Dareen A. Alsharif

1Department of Obstetrics and Gynecology, Ahmadi Hospital, Ahmadi, Kuwait

2Department of Obstetrics and Gynecology, Ain Shams University, Cairo, Egypt

Evaluation of infertile men: Mini-review

Mohannad AbuFaza1, Ibrahim A. Abdelazim12*, Hossam S. Othman1, Dareen A. Alsharif1

1Department of Obstetrics and Gynecology, Ahmadi Hospital, Ahmadi, Kuwait

2Department of Obstetrics and Gynecology, Ain Shams University, Cairo, Egypt

ARTICLE INFO

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Received

Received in revised form

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Men

Objective: Evaluation of infertile couple indicated because of failure of conception for one year of unprotected intercourse, and indicated for the infertile couple because of failure of conception for 6 months of unprotected intercourse if the female partner is above 35 years. Initial male partner evaluation includes: 1) thorough reproductive history, and at least one semen analysis. If the initial male partner evaluation showed any abnormality, complete assessment needed. Initial assessment of the infertile male include; thorough reproductive history, and at least one semen examination. Endocrine assessment indicated for males with abnormal semen analysis. Post-ejaculatory urine analysis performed in males having ＜1 mL ejaculation volume, except in congenital bilateral absent vasa deferentia (CBAVD), and hypogonadism. Genetic testing for cystic fibrosis transmembrane conductance regulator (CFTR) mutations offered to male with CBAVD before IVF. Males with severe oligozoospermia and/or non-obstructive azoospermia are at risk of genetic abnormality, and must offered karyotype and Y-chromosome testing before IVF.

1. Introduction

A previously fertility male, may acquire a secondary disease causing secondary infertility. Initial male partner evaluation include; thorough reproductive history and at least one semen analysis. If the initial male evaluation showed any abnormality, complete male assessment needed [1-2].

Methods of complete male evaluation include; 1) complete history, examination, and semen analysis by a male reproduction specialist; 2) endocrine evaluation; 3) post-ejaculatory urine analysis; 4) ultrasound; 5) specific semen and sperm tests; 6) genetic testing [1-2].

History and examination of the male partner include; 1) coital frequency; 2) duration of infertility; 3) medical disorders (upper respiratory diseases, diabetes mellitus); 4) previous surgery, and drug allergies; 5) previous sexually transmitted infections; 6) exposures to environmental or chemical gonadal-toxins.

2. Semen analysis

Semen analysis is a basic step in infertile male assessment, and the physician should provide the male partner with the proper instructions for semen collection such as pre-examination abstinence interval [3].

Semen should collected at the laboratory or at home by intercourse or by masturbation using special condoms not containing toxic sperm materials. If the semen sample collected at home, the sample should transferred to the laboratory for examination within 1 hour, and kept at body temperature during transfer [4].

Semen examination report should provides information about the volume of the semen sample, the concentration of the sperm, viability, motility, and the morphology of the sperms in the sample. According to world health organization definitions, lower limit of normal semen sample should contains: 1.5 mL volume, 15 106 spermatozoa/mL (total sperm number 39 106 spermatozoa/ ejaculate), 40% of the sperms of the sample motile (32% forward progressive motility), 4% of the sperms of the sample with normal morphology with absent of agglutination in the sample [5].

Detailed sperm morphology is not needed except after failed invitro-fertilization (IVF) and before intra-cytoplasmic injection (ICSI) [6].

Sperm concentration 48 million/mL, motility 63%, and morphology 12% usually seen in normal fertile male. Sperm concentration ＜13.5 million/mL, motility＜32%, and morphology＜9% normal usually seen in sub-fertile male [7].

3. Complete assessment of the infertile male

If the initial assessment of the male partner showed abnormality in the semen sample a complete male assessment needed. The complete assessment of the male partner includes; 1) Thorough reproductive history and thorough examination performed by male reproduction specialist; 2) endocrine evaluation; 3) post-ejaculatory urine analysis; 4) ultrasound; 5) specific semen and sperm tests; and 6) genetic testing.

3.1. Thorough reproductive history and thorough examination performed by male reproduction specialist

Thorough history should includes; 1) Thorough evaluation of the whole body systems; 2) family history of infertility; 3) use of anabolic steroids.

General physical examination includes; 1) Thorough genital examination; penis, testes, epididymides, and both vasa; 2) the reproduction specialist examining an infertile male should comment on presence or absence secondary sexual character and/or varicocele and perform per rectal examination if needed.

The reproduction specialist can diagnose the congenital bilateral absent vasa deferentia (CBAVD) by general and scrotal examinations.

3.2. Endocrine evaluation

Endocrine disorders are uncommon in males with normal semen analysis. Endocrine evaluation is needed for male with; 1) ＜10 million/mL sperm concentarion; 2) sexual dysfunction; 3) history or examination findings suggestive of endocrinopathy.

The initial hormonal evaluation includes: serum follicle stimulating hormone, and total serum testosterone (T). If the total serum T level is ＜300 ng/mL, more evaluation is needed, and includes morning total serum testosterone and free serum testosterone, prolactin, and luteinizing hormone, to identify the source of abnormal total testosterone level [8]. Carter, et al., suggests that the serum inhibinB level are lower in infertile male, and related with the sperm parameters better than the follicle stimulating hormone [9].

3.3. Post-ejaculatory urine analysis

Low volume or absence of the semen in the sample suggests incomplete collection, obstruction of the ejaculatory duct, retrograde ejaculation, or CBAVD. In order to exclude the possibility of retrograde ejaculation; a post-ejaculatory urine analysis performed in males having ＜ 1 mL ejaculation volume, except in CBAVD and hypogonadism.

3.4. Ultrasound

The male genital tract can easily and accurately imaged using ultrasound. Ultrasound can detect male genital tract abnormalities that may cause infertility. Trans-rectal ultrasound can diagnose seminal vesicles, prostatic and ejaculatory ducts abnormalities. Scrotal ultrasound can diagnose varicocele, absent vasa and testicular lesions [10].

3.5. Specific semen and sperm tests

Specific semen and sperm tests include: 1) Identification of leukocytes in the semen sample; increased white blood cells (WBCs) count in semen associated with decreased motility, and function of the sperms. The immature germ cells and WBCs appear as round cells under microscopic wet-mount examination. WBCs cells can differentiated from the immature germ cells by the immuno-histochemical staining [11].

2) Antisperm antibodies (ASA); Infertile couple due to ASA typically treated with ICSI. ASA suspected when there is isolated asthenospermia with normal semen parameters, and normal sperm concentration. ASA developed after break in blood-testis barrier as after trauma, testicular biopsy or vasectomy. ASA in the serum or in the seminal fluid detected using indirect antibody agglutination test. ASA bound to the sperms detected using immuno-bead test [12-13]. 3). Sperm viability. Assessed by mixing semen with eosin dye (eosin dye test). Viable sperm remain colorless after mixing with eosin dye, while non-viable sperm will take up the eosin stain [14-15]. 4). Sperm DNA fragmentation; The term “DNA fragmentation”means no repairable damage of the DNA of the sperm. This damage of the sperm DNA detected by 1) Direct tests, including single-cell electrophoresis (Comet), and terminal deoxy-nucleotide transferasemediated dUTP nick-end labeling (TUNEL) [16-18]. 2) Indirect tests, including sperm chromatin structure, to identify the abnormal structure of the chromatin, and increased liability of DNA of the sperms to denaturation.

DNA damage of the sperms is common in infertile males, and males with decreased reproductive ability. ICSI with retrieved sperms through testicular aspiration or testicular biopsy is the best treatment for males with abnormal ejaculated sperm DNA integrity [19-20].

3.6. Genetic testing

Males with severe oligozoospermia and/or non-obstructive azoospermia are at risk of genetic abnormality, and must offered karyotype and Y-chromosome testing before IVF [21].

Cystic fibrosis transmembrane conductance regulator (CFTR)gene mutations seen in eighty perecnt (80%) of the males diagnosed as CBAVD. CFTR gene mutations increased among azoospermia males, CBAVD, and men with vasa agenesis

Chromosomal abnormalities seen in 10%-15% of the azoospermic males. Sex chromosomal abnormalities (Klinefelter syndrome) constitutes 2/3 of chromosomal abnormalities found in infertile males. Balanced chromosomal translocation is also high in infertile males [21].

Males with non-obstructive azoospermia, or severe oligozoospermia should have chromosomal study before using their sperm for IVF [22].

Y-chromosome micro-deletions seen in 16% of infertile males with azoospermia or severe oligospermia. Y-chromosome micro-deletion detected with PCR testing to visualize the whole Y chromosome length. Most deletions causing oligozoospermia or azoospermia occur in the Y-chromosome long arm known as the azoospermia factor; identified as proximal, central and distal. Sixteen percent (16%) of men with Y-chromosome micro-deletion had short-staturehomeo-box abnormalities. Short-stature-homeo-box abnormalities mean short stature males with arm and wrist deformities, and mental retardation. Y-chromosome micro-deletions rarely found in male who has children [23-25].

4. Conclusion

Initial assessment of the infertile male include; thorough reproductive history, and at least one semen examination. Endocrine assessment indicated for males with abnormal semen analysis. Post-ejaculatory urine analysis performed in males having ＜1 mL ejaculation volume, except in CBAVD and hypogonadism. Genetic testing for CFTR mutations should offered to male with CBAVD before IVF. Males with severe oligozoospermia and/or nonobstructive azoospermia are at risk of genetic abnormality, and must offered karyotype and Y-chromosome testing before IVF.

Statement of conflict interest

The authors declare that they have no competing interest.

[1] Stephen EH, Chandra A. Declining estimates of infertility in the United States: 1982-2002. Fertil Steril 2006; 86: 516-523.

[2] Practice Committee of American Society for Reproductive M. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008; 90: S60.

[3] Marshburn PB, Alanis M, Matthews ML, Usadi R, Papadakis MH, Kullstam S, et al. A short period of ejaculatory abstinence before intrauterine insemination is associated with higher pregnancy rates. Fertil Steril 2010; 93: 286-288.

[4] Jurema MW, Vieira AD, Bankowski B, Petrella C, Zhao Y, Wallach E, et al. Effect of ejaculatory abstinence period on the pregnancy rate after intrauterine insemination. Fertil Steril 2005; 84: 678-681.

[5] Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update 2010; 16: 231-245.

[6] Raziel A, Friedler S, Schachter M, Kaufman S, Omanski A, Soffer Y, et al. Influence of a short or long abstinence period on semen parameters in the ejaculate of patients with nonobstructive azoospermia. Fertil Steril 2001; 76: 4850-4490.

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[7] Guzick DS, Overstreet JW, Factor-Litvak P, Brazil CK, Nakajima ST, Coutifaris C, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001; 345: 1388-1393.

[8] Kumanov P, Nandipati K, Tomova A, Agarwal A. Inhibin B is a better marker of spermatogenesis than other hormones in the evaluation of male factor infertility. Fertil Steril 2006; 86: 332-338.

[9] Carter SS, Shinohara K, Lipshultz LI. Transrectal ultrasonography in disorders of the seminal vesicles and ejaculatory ducts. Urol Clin North Am 1989; 16: 773-790.

[10] Practice Committee of American Society for Reproductive M. Report on varicocele and infertility. Fertil Steril 2008; 90: S247-S249.

[11] Wolff H, Anderson DJ. Immunohistologic characterization and quantitation of leukocyte subpopulations in human semen. Fertil Steril 1988; 49: 497-504.

[12] Check ML, Check JH, Katsoff D, Summers-Chase D. ICSI as an effective therapy for male factor with antisperm antibodies. Arch Androl 2000; 45: 125-130.

[13] Lee R, Goldstein M, Ullery BW, Ehrlich J, Soares M, Razzano RA, et al. Value of serum antisperm antibodies in diagnosing obstructive azoospermia. J Urol 2009; 181: 264-269.

[14] Liu J, Tsai YL, Katz E, Compton G, Garcia JE, Baramki TA. High fertilization rate obtained after intracytoplasmic sperm injection with 100% nonmotile spermatozoa selected by using a simple modified hypoosmotic swelling test. Fertil Steril 1997; 68: 373-375.

[15] de Mendoza MV, Gonzalez-Utor AL, Cruz N, Gutierrez P, Cascales F, Sillero JM. In situ use of pentoxifylline to assess sperm vitality in intracytoplasmic sperm injection for treatment of patients with total lack of sperm movement. Fertil Steril 2000; 74: 176-177.

[16] Evenson DP, Jost LK, Marshall D, Zinaman MJ, Clegg E, Purvis K, et al. Utility of the sperm chromatin structure assay as a diagnostic and prognostic tool in the human fertility clinic. Hum Reprod 1999; 14: 1039-1049.

[17] Larson-Cook KL, Brannian JD, Hansen KA, Kasperson KM, Aamold ET, Evenson DP. Relationship between the outcomes of assisted reproductive techniques and sperm DNA fragmentation as measured by the sperm chromatin structure assay. Fertil Steril 2003; 80: 895-902.

[18] Henkel R, Hajimohammad M, Stalf T, Hoogendijk C, Mehnert C, Menkveld R, et al. Influence of deoxyribonucleic acid damage on fertilization and pregnancy. Fertil Steril 2004; 81: 965-972.

[19] Collins JA, Barnhart KT, Schlegel PN. Do sperm DNA integrity tests predict pregnancy with in vitro fertilization? Fertil Steril 2008; 89: 823-831.

[20] Practice Committee of American Society for Reproductive M. The clinical utility of sperm DNA integrity testing. Fertil Steril 2008; 90: S178-S180.

[21] McCallum T, Milunsky J, Munarriz R, Carson R, Sadeghi-Nejad H, Oates R. Unilateral renal agenesis associated with congenital bilateral absence deferens: phenotypic findings and genetic considerations. Hum Reprod 2001; 16: 282-288.

[22] Ravel C, Berthaut I, Bresson JL, Siffroi, JP. Prevalence of chromosomal abnormalities in phenotypically normal and fertile adult males: largescale survey of over 10 000 sperm donor karyotypes. Hum Reprod 2006; 21: 1484-1489.

[23] Oates RD, Silber S, Brown LG, Page DC. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y-chromosome, and of 18 children conceived via ICSI. Hum Reprod 2002; 17: 2813-2824.

[24] Krausz C, Quintana-Murci L, McElreavey K. Prognostic value of Y deletion analysis: what is the clinical prognostic value of Y-chromosome microdeletion analysis? Hum Reprod 2000; 15: 1431-1434.

[25] Jorgez CJ, Weedin JW, Sahin A, Tannour-Louet M, Han S, Bournat JC, et al. Aberrations in pseudoautosomal regions (PARs) found in infertile men with Y-chromosome microdeletions. J Clin Endocrinol Metab 2011; 96: E674-E679.

[26] Carrell DT. The clinical implementation of sperm chromosome aneuploidy testing: pitfalls and promises. J Androl 2008; 29: 124-133.

[27] Carrell DT, Wilcox AL, Lowy L, Peterson CM, Jones KP, Erickson L, et al. Elevated sperm chromosome aneuploidy and apoptosis in patients with unexplained recurrent pregnancy loss. Obstet Gynecol 2003; 101: 1229-1235.

[28] Petit FM, Frydman N, Benkhalifa M, Le Du A, Aboura A, Fanchin R, et al. Could sperm aneuploidy rate determination be used as a predictive test before intracytoplasmic sperm injection? J Androl 2005; 26: 235-241.

[29] Tempest HG, Martin RH. Cytogenetic risks in chromosomally normal infertile men. Curr Opin Obstet Gynecol 2009; 21: 223-227.

ment heading

10.1016/j.apjr.2016.10.006

*Corresponding author: Ibrahim A. Abdelazim, Obstetrics and Gynecology, Ain Shams University, Egypt and Consultant at Ahmadi Hospital, Kuwait Oil Company (KOC), Kuwait.

Tel: (+965)-66551300.

E-mail: dr.ibrahimanwar@gmail.com

ORCID: http://orcid.org/0000-0002-7241-2835

Infertility

Review