Male Factor Infertility

Clinical Context

Infertility is a disease of the reproductive system, defined as the failure to achieve a pregnancy after 12 months of regular unprotected sexual intercourse.² Subfertility describes reduced fertility with prolonged time to conception.

Male factors are responsible for around half of infertility cases in opposite-sex couples and are the sole identifiable cause in 20-30%. US data suggests 18-27% of men in an infertile relationship are never evaluated.⁵

The global incidence is rising, attributed to factors such as obesity and exposure to environmental endocrine disruptors. Most cases are idiopathic, and for many conditions the value of medical or surgical treatment remains uncertain.⁵

Risk Factors

Pathophysiology

Normal physiology

Fertility requires normal sperm production, transport and sexual function.

Leydig cells produce testosterone under luteinising hormone (LH), while spermatogenesis is driven by intratesticular testosterone and follicle-stimulating hormone (FSH) acting on Sertoli cells.

Hypothalamic GnRH controls pituitary FSH/LH release, with negative feedback from testosterone (and its aromatisation to oestradiol) and from Sertoli-cell inhibin.

Hyperprolactinaemia suppresses GnRH.

Mechanisms of infertility (no formal classification)

• Primary spermatogenic failure – reduced or absent sperm production not caused by hypothalamic-pituitary disease. Frequently idiopathic.
• Hypogonadism:
  • Primary – hypergonadotropic hypogonadism from testicular failure (reduced testosterone, compensatory raised FSH/LH).
  • Secondary – hypogonadotropic hypogonadism from reduced GnRH and/or FSH/LH.
  • Androgen insensitivity – end-organ resistance despite adequate hormones.
• Obstructive azoospermia – bilateral obstruction of the seminal ducts causing total absence of sperm in semen, despite normal spermatogenesis. Causes include absent vas deferens, post-infective or post-surgical scarring.
• Endocrine disruption:⁵
  • Obesity – increases aromatisation of testosterone to oestrogen.
  • Environmental toxins/endocrine disruptors.
  • Raised local testicular heat impairs sperm production.
• Immunological/transport factors – anti-sperm antibodies, impaired motility, or ejaculatory/erectile dysfunction preventing sperm delivery.

Clinical Features

History

• Duration trying to conceive, frequency and type of sexual intercourse
• Any prior children (with same or different partner)
• Erectile or ejaculatory dysfunction
• Previous STIs, testicular torsion, or trauma
• Prior chemotherapy, radiotherapy or other gonadotoxic treatment
• Prior surgery, e.g. orchidopexy, hernia repair or vasectomy
• Systemic disease, e.g. diabetes, liver cirrhosis, chronic renal failure, thyrotoxicosis
• Family history of genetic disorders, e.g. cystic fibrosis
• Medication history including anabolic steroids and recreational drugs
• Social history: smoking, alcohol, occupational exposures, and stress

Examination findings

• Calculate BMI – obesity contributes to infertility
• Varicocele – palpable, dilated testicular veins
• Penile abnormalities or abnormal urethral meatus position
• Testicular atrophy (volume <20 cm³) or masses suggesting malignancy
• Signs of hypogonadism – reduced muscle mass, reduced body hair, gynaecomastia
• Headaches, galactorrhoea, or visual disturbance – may suggest pituitary tumour

Signs of congenital disorders:

• Anosmia – Kallmann syndrome
• Absent vasa or epididymis – congenital bilateral absence of vas deferens; frequent respiratory infections may suggest immotile cilia syndrome, e.g. Kartagener’s syndrome

Investigations and Screening

Semen analysis – WHO reference values¹⁰

If the first analysis is abnormal, offer a confirmatory repeat test, ideally 3 months later, to allow a full spermatogenic cycle. If gross deficiency (azoospermia or severe oligozoospermia) is found, repeat as soon as possible.^1,3

After two abnormal analyses:

• Examine the scrotum and testes and consider measuring serum testosterone and gonadotrophins.³
• Low testosterone indicates hypogonadism
• Raised FSH with low testosterone suggests testicular failure
• Raised prolactin may suggest a pituitary tumour

Reserve endocrine evaluation (FSH, LH, testosterone, prolactin +/- oestradiol/SHBG) for men with impaired libido, erectile dysfunction, oligo-/azoospermia, or atrophic testes.

Imaging:³

• Varicocele – scrotal/Doppler ultrasound
• Pituitary MRI if hypogonadotrophic hypogonadism
• Post-ejaculatory urinalysis for suspected retrograde ejaculation

Targeted genetic testing:^2,3

• Y-chromosome microdeletion testing for idiopathic azoospermia or sperm concentration <1 million/mL
• Karyotyping if idiopathic azoospermia; consider if persistent sperm concentration <5 million/mL
• CFTR testing where obstructive azoospermia or a vasal abnormality is suspected
• Offer genetic counselling, as chromosomal defects can be inherited

Do not routinely request anti-sperm antibodies, sperm DNA-fragmentation testing, advanced sperm-function testing or diagnostic testicular biopsy.

Referral to secondary care:¹

• Refer both partners after 12 months of regular unprotected intercourse without conception, or after 6 cycles of artificial insemination
• Refer at presentation where male-factor infertility is known or suspected, e.g. abnormal genital examination, significant varicocele, prior urogenital surgery or infection, ejaculatory dysfunction, endocrine disease or previous gonadotoxic treatment
• Persistent abnormal semen analyses
• Refer promptly for azoospermia or severe oligozoospermia
• Expedite referral before cancer treatment or another treatment likely to impair fertility
• NICE does not require two abnormal analyses before referral when a cause or predisposing factor is already suspected

Management

General Measures

• Optimise co-morbidities and address potentially reversible causes
• Smoking cessation, and advise that excessive alcohol impairs semen quality
• Support weight management where BMI is 30 kg/m² or above
• Review prescribed, over-the-counter and recreational drugs, including testosterone, anabolic steroids, finasteride and cannabis
• Offer counselling and psychological support if required

Medical Management

• Offer gonadotrophin therapy for hypogonadotrophic hypogonadism. For impaired semen parameters without hypogonadotrophic hypogonadism, gonadotrophins or anti-oestrogens should only be considered within a clinical trial
• Do not offer androgens to treat semen abnormalities
• Treat confirmed infection, but do not prescribe antibiotics solely for leucocytes in semen
• The effectiveness of corticosteroids for anti-sperm antibodies is uncertain
• Do not offer supplements, antioxidants or medical treatments aimed at reducing sperm DNA fragmentation

Surgical/Radiological Management

• Obstructive azoospermia – surgical correction or sperm retrieval, taking into account female fertility factors, risks and patient preference
• Non-obstructive azoospermia – offer surgical sperm retrieval (PESA/TESA); consider microsurgical sperm extraction from the testicle (micro-TESE)⁴
• Do not offer retrieval where AZFa or AZFb Y-chromosome microdeletions are present, as retrieval is unlikely to succeed. An AZFc microdeletion does not reduce success and retrieval should be offered
• Varicocele – treat only where a varicocele is clinically detected, semen parameters are reduced and natural conception is intended
• Ejaculatory failure – usually multifactorial, e.g. medications, psychological, retrograde ejaculation; cause must be identified and managed

Assisted Reproduction Techniques (ART):⁸

• Intrauterine insemination (IUI) – superior to timed intercourse in male factor infertility
• In-vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) – offer ICSI when surgically retrieved sperm are used
• Donor insemination – consider for azoospermia, severe semen impairment where ICSI is declined, or significant genetic or infectious transmission risk

Complications and Follow-up

Repeat semen analysis after 3 and 6 months of treatment.

Arrange genetic counselling where Y-chromosome, karyotype or CFTR abnormalities are identified, particularly before sperm retrieval or ICSI.

Psychological effects:² infertility, investigations and unsuccessful treatment can cause distress, reduced libido and relationship difficulties. Counselling should be offered throughout treatment, regardless of the outcome.

Procedure-related risks

Surgical sperm retrieval:⁴ complications include scrotal bruising or swelling, pain, bleeding, infection and, rarely, chronic testicular pain, atrophy or reduced testosterone production.

Varicocele treatment: surgery/embolisation may cause pain, bleeding, infection or haematoma, and possible recurrence.

Testicular cancer:¹¹ male factor infertility is a marker as well as a disease outcome. Men with abnormal semen analysis have a 20 times higher risk of developing testicular cancer. Examination suggesting a testicular mass warrants urgent investigation.

IVF/ICSI:⁸ ICSI may damage a small number of oocytes and does not ensure fertilisation. A small risk of genetic or developmental abnormalities in children conceived through IVF or ICSI cannot be excluded.⁷ Male offspring may inherit Y-linked causes of infertility.

Equity, Safety and Professionalism

Under-recognition and access:⁶ male factors contribute to around half of infertility cases, yet assessment remains female-focused. Both partners should be investigated concurrently to prevent delayed diagnosis and unnecessary treatment.

Safety and consent:⁸ before ICSI or sperm retrieval, discuss uncertain success, procedural risks and possible genetic transmission. Offer genetic counselling where a specific defect is identified. Avoid ICSI without a recognised indication, and explain the limited evidence, cost and uncertainty surrounding fertility add-ons.⁹

Recent Changes and Controversies

Updated NICE guidance:¹ NICE NG257, published in March 2026, standardises male-factor infertility care. It recommends targeted genetic testing, including Y-chromosome microdeletion testing when sperm concentration is below 1 million/mL. Androgens should not be used to treat semen abnormalities, and the guidance supports surgical sperm retrieval for non-obstructive azoospermia.

De-implementation of low-value tests:^1,2 routine anti-sperm antibody and sperm DNA fragmentation testing are not recommended. This reduces unnecessary investigation, cost and anxiety without compromising care.

Testosterone replacement therapy (TRT):⁵ exogenous testosterone suppresses gonadotrophins and intratesticular testosterone, potentially causing severe oligozoospermia or azoospermia. Men wishing to conceive should not receive testosterone monotherapy. Recovery after stopping may take months and can be incomplete.

References

1. National Institute for Health and Care Excellence. Fertility problems: assessment and treatment. Management of male factor fertility problems. NG257. 2026. Available from: https://www.nice.org.uk/guidance/ng257/chapter/Management-of-male-factor-fertility-problems [Accessed 02 Aug 2026].

2. National Institute for Health and Care Excellence. Infertility. Clinical Knowledge Summaries. 2026. Available from: https://cks.nice.org.uk/topics/infertility/assessment/initial-assessment-of-men-concerned-about-infertility/ [Accessed 02 Aug 2026].

3. BMJ Best Practice. Male infertility: epidemiology. 2026. Available from: https://bestpractice.bmj.com/topics/en-gb/497/epidemiology [Accessed 02 Aug 2026].

4. British Association of Urological Surgeons. Sperm retrieval. 2026. Available from: https://www.baus.org.uk/_userfiles/pages/files/Patients/Leaflets/Sperm%20retrieval.pdf [Accessed 02 Aug 2026].

5. European Association of Urology. Sexual and reproductive health: male infertility. 2026. Available from: https://uroweb.org/guidelines/sexual-and-reproductive-health/chapter/male-infertility [Accessed 02 Aug 2026].

6. Winters BR, Walsh TJ. The epidemiology of male infertility. Urol Clin North Am. 2014;41(1):195-204.

7. Tournaye H. Evidence-based management of male subfertility. Curr Opin Obstet Gynecol. 2006;18(3):253-9.

8. Cissen M, Bensdorp A, Cohlen BJ, Repping S, de Bruin JP, van Wely M. Assisted reproductive technologies for male subfertility. Cochrane Database Syst Rev. 2016;(2):CD000360.

9. Human Fertilisation and Embryology Authority. Treatment add-ons with limited evidence. 2025. Available from: https://www.hfea.gov.uk/treatments/treatment-add-ons/ [Accessed 02 Aug 2026].

10. World Health Organization. WHO laboratory manual for the examination and processing of human semen. 6th ed. Geneva: World Health Organization; 2021. Available from: https://www.who.int/publications/i/item/9789240030787 [Accessed 02 Aug 2026].

11. Raman JD, Nobert CF, Goldstein M. Increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis. J Urol. 2005;174(5):1819-1822.

Recommended Reading

NICE Guideline (NG257) – Fertility problems: assessment and treatment

NICE CKS – Infertility

BMJ Best Practice – Male Infertility

EAU Guidelines on Sexual and Reproductive Health 2026

BAUS – Fertility Problems