Reproductive Health
Vol. 23 No 1 | Autumn 2021
Feature
Male infertility: a clinical approach
Dr Roger Perkin
BSc, MBBS, FRCOG, FRANZCOG

Obstetrics and gynaecology may have had little or no exposure to addressing male infertility disorders. It is estimated that men contribute around 50% to overall infertility.1 Therefore a thorough evaluation of the male partner is important. In particular asking questions regarding symptoms and conducting an examination which may prove confronting.

Nevertheless, an in-depth evaluation of the male partner is important. In many cases it is possible to obtain a diagnosis and commence appropriate treatment in order to improve a couple’s chances of conceiving. It is also important to include the male partner in all discussions and decision making in order to keep him engaged and supported in the couple’s infertility journey.

It is also important to look beyond the semen analysis report as there is increasing awareness that male fertility is an indicator of overall health. Evidence points to increased incidence of co-morbidities such as cardiovascular disease, type 2 diabetes, increased incidence of testicular cancer, and increased mortality in men with semen abnormalities.2 There is increasing evidence that both genetic and non-genetic factors in sperm, for example microRNA’s, have an influence on the health of children.3

Evaluation of the male

The first encounter with the male patient is often the semen report. The accepted reference for semen testing along with laboratory techniques are found in the World Health Organisation (WHO) laboratory manual.4 This manual includes a reference range based on sampling a large population of men with a healthy sperm count.5

It is important to remember that one abnormal parameter on its own is not a predictor of infertility. The presence of multiple abnormalities has more clinical relevance.6 And there is considerable variability in sperm quality between samples in healthy men.7 Therefore it is recommended that at least 2 samples are examined.8 More advanced testing of samples, such as DNA fragmentation has reported effects on conception and miscarriage risk.9

In addition to semen testing, it is important to thoroughly evaluate the male by taking a medical history, conducting an examination, and where appropriate, conducting further investigations. Also many men may volunteer information and confide in having suffered from low libido, and tiredness which may relate to low testosterone.

A surprising number of previously undiagnosed conditions such as undescended testes are detected by the physical examination. It may be helpful to use orchidometer beads to assess testicular volumes. Particularly important is palpation of the vasa deferentia, because congenital absence of the vas deferens (CBAVD) is relatively common. Examination of the scrotum is best performed in the standing position, as this will make detection of varicoceles easier.

Lower reference limits of sperm parameters (5th centile with 95% CI)
Semen volume: 1.5 mL (1.4–1.7)
Total sperm numbers: 39M per ejaculate (33–46)
Sperm concentration: 15M per mL (12–16)
Total motility: 40% (38–42)
Progressive motility: 32% (31–34)
Sperm morphology: 4% normal forms (3.0–4.0)

 

Evaluation of azoospermia

The initial encounter with a patient presenting with azoospermia can seem challenging. However, having a systematic approach and referring to the classification system of causes, will make this task easier.

Classification of azoospermia:

  • Pre-testicular (hypogonadotropic)
  • Testicular
  • Obstruction
  • Retrograde and anejaculation

Clinical clues which help with diagnosis include examination of testicular volumes (typically low in testicular disorders and in early onset hypogonadism) which are very small in Klinefelter syndrome (KS). Around 90% of the ejaculate volume derives from the prostate and seminal vesicles. Semen volume is low in CBAVD, ejaculatory duct obstruction, retrograde ejaculation and chronic hypogonadism. Failure to palpate the vasa deferentia will diagnose CBAVD. Also check for unilateral renal agenesis (URA) and cystic fibrosis gene mutations in these patients. Examination of post ejaculate urine and transrectal prostate ultrasound will help where ejaculatory volume is very low. Elevated follicle–stimulating hormone (FSH) (over 7.5mU/mL) points to testicular causes.10 Low Luteinizing hormone (LH) and low morning testosterone are noted in hypogonadotropic patients. Obstructive causes account for around 40% of patients with azoospermia.11

Causes of obstruction / ejaculatory azoospermia:

  • Post vasectomy
  • CBAVD
  • Ejaculatory duct obstruction
  • Retrograde ejaculation
  • Anejaculation e.g. spinal injury

Management of these patients is relatively straightforward. Needle collection of either sperm or tubule tissue can be used for intracytoplasmic sperm injection (ICSI). In cases of retrograde ejaculation, an alternative is to use sperm from post ejaculation urine. Vasectomy reversal is an option in those men who underwent the vasectomy under 10 years previously.

Testicular sperm extraction (TESE) is a brief outpatient procedure on the awake patient. Local anaesthetic is infiltrated directly into the scrotal skin and testis whilst grasping the testis. A 19 gauge needle is used to extract seminiferous tubule tissue which is examined immediately by the scientist. Occasionally more than one needle pass is needed in order to collect an adequate sample. TESE tissue is usually cryo-stored in straws which may be thawed individually as needed. The technique for percutaneous epididymal sperm aspiration (PESA) is similar, but instead of extracting tubules, free sperm is aspirated, and this is used on the same day as the egg retrieval. Surgically extracted sperm is only suitable in the context of ICSI.

Testicular disorders are sometimes referred to as non-obstructive azoospermia (NOA) and account for around 60% of azoospermia cases.12

Causes of testicular (NOA) azoospermia:

  • Undescended testis
  • Torsion
  • Injury
  • Orchitis
  • Post chemotherapy
  • Klinefelter syndrome
  • Micro Y deletions
  • Other genetic causes
  • Unknown

Included in this group is the relatively common KS. In addition it is important to check for micro–Y deletions.

There is increasing awareness of other genetic causes.13 Unfortunately, in many cases the cause is unknown.14 In patients where spermatogenesis has been stored in isolated tubules, it may be possible to surgically extract sperm. Traditionally, random testicular biopsy, and more recently micro–TESE have been used.

Micro–TESE is an advanced technique used to improve surgical sperm retrieval rates in men with testicular cause azoospermia. A powerful operating microscope is used in order to better identify potential tubules. This procedure is conducted in the operating theatre under general anaesthesia, and may take up to four hours. Typically, two scientists are present in the theatre in order to immediately examine the samples for sperm. This technique has largely replaced random testicular biopsies and is more likely to lead to successful retrieval.15 Sperm retrieval rates are reported in the 40–60% range.16

Pre-testicular (hypogonadotropic) is the least common cause of azoospermia.

Pre-testicular causes of azoospermia:

  • Androgen intake
  • Pituitary tumours (craniopharyngioma)
  • Head trauma, surgery, irradiation
  • Kallmann syndrome
  • Thyroid dysfunction

Management of these cases includes correction of underlying conditions where possible and may include treatment with human chorionic gonadotropin (hCG) and FSH injections. It may take 12 to 18 months for a sufficient quantity of sperm to appear in the ejaculate to allow cryo-storage. The sperm is used for ICSI treatment.

Classification Testicular Obstruction Pre-testicular Retrograde ejaculation
Semen volume Normal Normal or low (depending on the site of obstruction) Normal or reduced Reduced
Testis volume Small Normal Normal or reduced Normal
Vasa Elevated FSH Absent in CBAVD Palpable Palpable
Gonadotrophins Normal or low Normal Reduced FSH and LH Normal
Testosterone Normal or low Normal Reduced Normal
Treatment Micro TESE Needle extraction
(testis or epididymis)
Treatment of cause and gonadotrophin supplements Sperm from urine or needle extraction

 

Reduced semen quality

Sperm quality influences time to pregnancy.17 Since recordings began in the 1930s there have been indications of a decline in sperm quality.18 This decline is also influenced with the increase in male age which in turn increases the risk to pregnancy and offspring.19 20 21 A broad range of influences affect male fertility including a number of rare disorders such as Immotile Cilia Syndrome.

This is the time to discuss measures to improve the man’s health. Checking for co-morbidities which are known to be more common in subfertile men.22 Discussing lifestyle choices, including healthy diet, regular physical activity, and managing obesity23 as well as addressing the use of alcohol, smoking and recreational drugs. This is also an opportunity to encourage testicular self-examination particularly in view of an increased testicular cancer risk.24

There is evidence for benefit in correction of a clinically palpable varicocele.25 Antioxidant supplements have received considerable attention.26

Management of erectile difficulties will increase opportunities for intercourse and reduce the need for IVF. Consideration can be given to prescribing adjunctive medications such as, hCG, in order to improve libido and semen quality.

Adverse environmental conditions affecting male fertility:

  • Aging male
  • Obesity
  • Poor diet
  • Unhealthy lifestyle, including smoking, excessive alcohol and recreational drugs
  • Medical disorders such as diabetes and hypertension
  • Varicocele
  • Infections
  • Exposure to environmental chemicals and toxins
  • Excessive heat

 

Summary

Evaluation of the male partner is an important part of the infertility work up. It is possible in many cases to improve sperm quality in order to facilitate natural conception and to improve health outcomes for the children. It is an excellent opportunity to engage the male partner with health disorders. And it is possible in many cases to induce production and collection of sperm from men with azoospermia for use in assisted reproduction.

Further reading

Sharma R, Agarwal A, Rohra VK, et al. Effects of increasing paternal age on sperm quality, reproductive outcome and associated epigenetic risk to offspring. Reprod Biol Endocrinol. 2015;13:35.

References

  1. Winters BR, Walsh TJ. The epidemiology of male infertility. Urol Clin North Am. 2014; 41(1): 195-204.
  2. Choy TC, Eisenberg ML. Male infertility as a window to health. Fertil Steril. 2018; 110(5): 810-14.
  3. Immler S. The sperm factor: paternal impact beyond genes. Heredity. 2018; 121: 239-47.
  4. World Health Organization. WHO Laboratory manual for the examination and processing of human semen. 5th ed. 2010;286.
  5. Cooper TG, Noonan E, von Eckardstein S, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2009;16(3):231-45.
  6. Schlegel PN, Sigman M, Collura B, et al. Diagnosis and treatment of infertility in men: AUA/American Society Reproductive Medicine Guideline. 2020; Practice Committee Guideline Documents.
  7. Keel BA. Within-and between-subject variation in sperm parameters in infertile men and normal sperm donors. Fertil Steril. 2012; 85: 128-34.
  8. Jarow J, Sigman M, Kolettis PN, et al. Optimal evaluation of the infertile male: American Urological Association best practice statement. 2011.
  9. Schlegel PN, Sigman M, Collura B, et al. Diagnosis and treatment of infertility in men: AUA/American Society Reproductive Medicine Guideline. 2020; Practice Committee Guideline Documents.
  10. Schlegel PN, Sigman M, Collura B, et al. Diagnosis and treatment of infertility in men: AUA/American Society Reproductive Medicine Guideline. 2020; Practice Committee Guideline Documents.
  11. Ghieh F, Mitchell V, Mandon-Pepin B, Vialard F. Genetic defects in human spermatozoa. Basic Clin Androl. 2019;29:4.
  12. Ghieh F, Mitchell V, Mandon-Pepin B, Vialard F. Genetic defects in human spermatozoa. Basic Clin Androl. 2019;29:4.
  13. Ghieh F, Mitchell V, Mandon-Pepin B, Vialard F. Genetic defects in human spermatozoa. Basic Clin Androl. 2019;29:4.
  14. Schlegel PN, Sigman M, Collura B, et al. Diagnosis and treatment of infertility in men: AUA/American Society Reproductive Medicine Guideline. 2020; Practice Committee Guideline Documents.
  15. Deruyver Y, Vanderschueren D, van der Aa F. Outcome of microdissection TESE compared with conventional TESE in non-obstructive azoospermia: a systematic review. Andrology. 2014;2(1):20-4.
  16. Deruyver Y, Vanderschueren D, van der Aa F. Outcome of microdissection TESE compared with conventional TESE in non-obstructive azoospermia: a systematic review. Andrology. 2014;2(1):20-4.
  17. Buck Louis GM, Sundaraman R, Schisterman EF, et al. Semen quality and time to pregnancy, the LIFE Study. Fertil Steril. 2014; 101(2):453-62.
  18. Levine H, Jorgensen N, Anderson M-A, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update. 2017;23(6):646-59.
  19. Buck Louis GM, Sundaraman R, Schisterman EF, et al. Semen quality and time to pregnancy, the LIFE Study. Fertil Steril. 2014; 101(2):453-62.
  20. Levine H, Jorgensen N, Anderson M-A, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update. 2017;23(6):646-59.
  21. Cheung S, Parrella A, Rosenwaks Z, Palermo GD. Genetic and epigenetic profiling of the infertile male. PLoS One. 2019;14(3):e0214275.
  22. Choy TC, Eisenberg ML. Male infertility as a window to health. Fertil Steril. 2018; 110(5): 810-14.
  23. Choy TC, Eisenberg ML. Male infertility as a window to health. Fertil Steril. 2018; 110(5): 810-14.
  24. Hanson HA, Anderson RE, Aston KI, et al. Subfertility increases risk of testicular cancer: evidence from population-based semen samples. Fertil Steril 2915;105(2):322-28.
  25. Asafu-Adjei D, Judge C, Deibert CM, Li G, et al. Systematic review of the impact of varicocele grade on response to surgical management. J Urol. 2020;203(1):48-56.
  26. Smits RM, Mackenzie-Proctor R, Yazdani A, et al. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2019;3(3):CD007411.

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