Approach

Male factor infertility should be suspected in the presence of normal ovulation and patent tubes in the female partner of an infertile opposite-sex couple. The main goal of evaluating male factor infertility is to find a correctable cause.

Initial evaluation includes a careful history (including reproductive and lifestyle factors), physical examination, and semen analysis. Endocrine tests, genetic testing, and imaging can be helpful.

History

Most men with abnormal semen analysis are asymptomatic and have a normal physical examination and normal sexual function. A careful medical and surgical history including the duration of infertility, previous pregnancies, frequency of intercourse, previous treatments, and lifestyle identifies clues to the aetiology of male infertility in less than one half of the cases.

​Risk factors include varicocele, cryptorchidism, prior chemotherapy or radiotherapy, current medications, cystic fibrosis and congenital bilateral absence of vas deferens, Y chromosome abnormalities, Klinefelter syndrome (47,XXY), endocrinopathy, previous infertility, smoking, alcohol intake, use of marijuana, and use of a hot tub or sauna.[6][8][9][10][12][13][14][15][16][22]

Physical examination

Should include the evaluation of secondary sexual characteristics; examination of the penis, spermatic cord, and vas deferens; and evaluation of the testicular volume, consistency, and irregularity in the volume. Rectal examination may identify prostatic pathology.

Recommended investigations based on semen analysis

The clinical evaluation of an infertile man should include at least one semen analysis. Because semen parameters are highly variable biological measures, it is recommended that at least two semen analyses are performed, at least 1 month apart, particularly if abnormalities are noted on the first analysis.

The specimen is collected after the patient has abstained from any ejaculation for at least 2 days (but not >7), through masturbation without any lubricants as they may contaminate the sample. An alternative to masturbation is the use of a semen collection device (a specialised condom kit made from non-toxic materials) during coitus.

1. Oligozoospermia (<16 million sperm/mL)[33]

  • May indicate a disruption of spermatogenesis at many different levels.

  • Morning endocrine evaluation is indicated, particularly in men with sperm counts <10 million sperm/mL.

  • Physical examination or Doppler imaging may show the presence of a varicocele.

2. Azoospermia

  • Defined by the absence of sperm in the semen after centrifugation of the sample and analysis of the pellet.

  • Indicative of primary or secondary testicular failure, presence of cystic fibrosis transmembrane regulator (CFTR) mutation, or blockage of the reproductive tract.

  • The semen volume should be noted, and the specimen may be assayed for the presence of fructose to determine whether the seminal vesicles are contributing.

  • Cases of non-obstructive azoospermia and severe oligozoospermia (≤5 million sperm/mL) have an increased likelihood of Y chromosomal microdeletions or chromosomal aberrations.[15][34] Further testing with chromosomal analysis is indicated.

Men with azoospermia should have an evaluation to determine obstructive aetiologies versus non-obstructive aetiologies.[2][24]​​

The presence of azoospermia in men with small-volume testes (testicular longitudinal axis [TLA] <4.6 cm), elevated follicle-stimulating hormone (FSH [>7.6 mIU/mL]), and normal semen volume will typically indicate non-obstructive azoospermia (i.e., azoospermia due to impaired sperm production).[24][34]​ Obstructive azoospermia is associated with low or normal semen volume, and normal testicular size and hormonal parameters.[24] It may be associated with congenital bilateral absence of vas deferens (CBAVD), or obstruction of the ejaculatory duct, epididymis, or vas deferens as a result of a previous infection or surgery.[24] This may be a clinical diagnosis if the vasa deferentia are absent or if the proximal epididymis was enlarged on physical examination.[24] Men with obstructive azoospermia and CBAVD should have testing for the CFTR mutation.[24]

3. Abnormal sperm motility (<42% total motility, <30% progressive motility)[33]

  • If the sperm motility is less than the normal value, sperm viability and membrane function may be tested. Anti-sperm antibody testing may also be considered, but only if the results will affect management.[24]

  • Kartagener syndrome and microtubule abnormalities with electron microscopy may be checked for if the above are all negative.

4. Abnormal sperm morphology (<4% normal forms - Kruger strict morphology)[33]

5. Aspermia (absence of ejaculate)

  • Low volume, decreased pH, or aspermia indicates reproductive tract disorders and should be followed up with prostate examination, transrectal ultrasound, and/or post-ejaculatory urine analysis. The specimen may be assayed for the presence of fructose to determine whether the seminal vesicles are contributing.

Endocrine evaluation

Assessment of FSH, luteinising hormone (LH), free and total testosterone, estradiol, sex hormone-binding globulin, albumin (the latter two to calculate bioavailable testosterone), and prolactin levels is indicated in infertile men with impaired libido, erectile dysfunction, oligozoospermia or azoospermia, atrophic testes, or evidence of hormonal abnormality on physical evaluation.[24][35] Low testosterone indicates hypogonadism. Increased FSH in the presence of low testosterone is a sign of testicular failure. Increased prolactin may be due to a pituitary tumour. Thyroid-stimulating hormone (TSH) can be ordered in cases of failed IVF among men >40 years or if there is association with erectile dysfunction.[36][37][38]

Magnetic resonance imaging of the brain is indicated to rule out pituitary or hypothalamic tumours or other disorders in the setting of hypogonadotrophic hypogonadism (low LH and low testosterone).

Testicular biopsy

Diagnostic testicular biopsies are not routinely performed because laboratory and clinical findings may accurately predict obstructive versus non-obstructive aetiology.[24] 

Microdissection testicular sperm extraction (micro-TESE) is recommended in males with non-obstructive azoospermia who are undergoing sperm retrieval (and subsequent cryopreservation for use with ICSI).[24] Micro-TESE allows examination of multiple regions of testicular tissue.

Further laboratory tests

Anti-sperm antibody testing

Do not perform anti-sperm antibody (ASA) testing in the initial evaluation of male infertility.[24]​ While ASA testing may have a role in confirming obstruction, only consider it if the results will affect management of the patient.[24]​ If intracytoplasmic sperm injection is planned, ASA testing is unnecessary.

Sperm function testing

Do not perform advanced sperm function testing, such as sperm penetration or hemizona assays. Studies have found these tests to be highly variable and they have been shown not to be cost-effective.[39]

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