Male infertility may be due to problems with sperm production or transport and also sexual dysfunction, and in some cases a combination of all or few of these. The underlying cause in most cases is unexplained and male factors alone account for up to 30% of subfertile couples undergoing in vitro fertilisation.
Gonadotrophin deficiency (Hypothalamic/ Pituitary disease) examples; Kallman syndrome, tumours, radiation, surgery,
Hyperprolactinaemia, hyper‐or hypothyroidism, Hormones Intake (anabolic steroids, glucocorticoid excess).
Most of these can be treated with hormone manipulation
Testicular (Majority of Causes):
Idiopathic: (almost 50%)
Congenital: Chromosomal (Kleinfelter syndrome 47, XXY), Y chromosome microdeletions, Noonan syndrome (male Turner syndrome 45, XO), Undescended Tests (Cryptorchidism)
Acquired: Infection/Injury (orchitis, torsion, trauma), Varicocele*, Severe systemic disease (renal failure, liver failure), Testicular tumours, Chemotherapy, radiotherapy
*Varicoceles, a collection of dilated refluxing veins in the spermatic cord, are found twice commonly in men with abnormal semen compared to those with normal semen. (25% vs 12%). It is believed that increased scrotal heating and altered testicular steroidogenesis affects semen quality, but the evidence is limited.
These conditions are largely irreversible but can be treated with assisted reproductive technology (ART), if sperm is retrievable. The diagnosis is based on reduction in testicular size and elevation of serum FSH levels and in the majority of cases (66%) the cause is unknown.
Post‐testicular (anatomical or functional obstruction):
Excluding Vasectomy, 40% of azospermia cases are due to obstruction, and with ART these men can achieve pregnancy after sperm retrieval.
Congenital: Cystic fibrosis, congenital absence of the vas deferens (CAVD), Young’s syndrome
Acquired: Infection (chlamydia, gonorrhoea), Vasectomy, Iatrogenic vasal injury
Disorders of sperm function or motility: Globozoospermia (100% round heads), Maturation defects, Immunological infertility, Immotile cilia syndrome
The diagnosis is based on normal serum FSH levels, normal testicular volume and evidence of complete spermatogenesis on biopsy.
These conditions can be treated with microsurgery or with ART
Erectile/ ejaculatory dysfunction, Inappropriate timing and frequency of intercourse. Diabetes mellitus, multiple sclerosis, spinal cord/pelvic injuries.
A UK study has shown that paternal age of >35 years halves the chance of achieving a pregnancy compared with a paternal age of <25 years and drop in fertility is worse after the age of 50. There are also studies showing increase in adverse outcome in the offspring.
Environmental, occupational and lifestyle factors: Obesity, Alcohol, Tobacco, Oxidative stress,
Through an imbalance of reproductive hormone (reduced sex hormone binding globulin and elevated oestrogen levels), amongst others, obesity is associated with poor semen quality. In addition, sexual dysfunction is also more common in obese men possibly from altered metabolism of environmental toxins, and sedentary lifestyle.
Heavy alcohol consumption affects sexual and reproductive performance in a reversible fashion.
Tobacco smoking and cannabis consumption have been shown to reduce semen parameters and men with suboptimal semen quality may benefit from quitting smoking and this should be strongly encouraged. Other recreational drugs such as cocaine, amphetamines and opiates may adversely affect reproductive performance due to decreased libido and erectile dysfunction.
There is limited evidence for, sperm DNA damage secondary to oxidative stress may be the cause of between 30% and 80% of male subfertility cases. Recent evidence suggests that antioxidant supplementation in subfertile males, including carnitines, vitamin C, vitamin E, selenium, zinc and coenzyme Q10, improves semen quality and live birth rates in couples undergoing fertility treatment.
More than 104 000 such chemicals and physical agents (environmental, occupational) have been identified that can affect semen quality; heat, X‐rays, heavy metals (lead, mercury), glycol ethers (highly volatile compounds used as solvents) and pesticides. The level of environmental estrogens would not appear to be a threat to male reproductive health.
Recent observational studies support a dose‐dependent decrease in semen parameters related to exposure to electromagnetic waves emitted from mobile phones, but there is still no clear clinical significance of this.
There is evidence that a sedentary lifestyle, Testicular hyperthermia, can affect sperm production and semen quality, but no clear proof that wearing loose‐fitting underwear improves fertility.
Usage of Anabolic‐androgenic steroids severely affects sperm quality and testosterone production and therefore can lead to azoospermia and erectile dysfunction, by interfering with the hypothalamic‐pituitary‐gonadal (HPG) axis. Azoospermia may be reversed by conservative management when the drugs are discontinued for 4-12 months and in some cases by administration of human chorionic gonadotrophin and human menopausal gonadotrophin.
A lot of ‘steroid‐free’ dietary supplements have been reported to be contaminated with traces of hormones.
History, physical examination together with the semen analysis is standard initial evaluation of most men, followed by special tests in selected cases.
Fertility history: Previous pregnancies – with current and previous partners, Duration of infertility, Previous infertility treatments
Sexual history: Erection or ejaculation problems & Frequency and timings of intercourse
Social history: Alcohol, smoking, usage of anabolic steroids, recreational drugs, Exposure to ionising radiation (X-Rays), Chronic heat exposure, Aniline dyes, Pesticides and Lead exposure
Medical history: Recent pyrexia/ illness, Systemic illness – diabetes mellitus, cancer, infection. Genetic disorders – cystic fibrosis, Klinefelter syndrome
Surgical history: Undescended testes, orchidopexy, Hernia repair, Testicular trauma, torsion, Pelvic, bladder or retroperitoneal surgery
Medication: Nitrofurantoin, cimetidine, sulfasalazine, spironolactone, α‐blockers, methotrexate, colchicine, amiodarone, antidepressants, phenothiazines, chemotherapy
Signs of decreased body hair or gynaecomastia, the height, weight, BMI and blood pressure should be noted.
Scrotal examination in the standing position should establish presence of normal, size (mean volume of 20 ml) and firm consistency testes on both sides, with non- tender and un-distended epididymis, and presence of vas difference, and absence of “bag of worms” suggestive of varicoceles during Valsalva manoeuvre.
Micro Penis, hypospadias should be looked for. And a rectal examination will provide clues on prostate abnormalities or seminal vesicle enlargement.
Semen analysis is the most important investigation of male and is a guide for minimal standards of adequacy fertility (5th percentile of semen characteristics of men initiating natural conception within 12 months of unprotected intercourse: WHO 2010). These minimum values do not imply proof of male fertility.
|Parameter||Reference limit||95% confidence interval|
|Semen volume (ml)||1.5||1.4-1.7|
|Sperm concentration (106/ml)||15.0||12-16|
|Total number (106/ejaculate)||39.0||33-46|
|Total Motility (PR+NP,%)
PR=Progressive motility NP=Non-progressive motility
Progressive motility (PR,%)
|Normal forms (%)||4.0||3.0-4.0|
Semen analysis must be done at a qualified lab after 3-5 days abstinence and if an abnormality is detected a repeat semen analysis should be performed after 3 months, or sooner if the initial test shows azoospermia. The entire ejaculate should be collected, and the sample should be analysed within an hour of collection because sperm motility decreases after ejaculation. If produced at home, the sample should be kept at body temperature during transport.
Fresh semen is coagulated and liquefies 15–30 minutes after ejaculation. Low ejaculate volumes of <1.5 ml may not buffer against vaginal acidity sufficiently and may indicate retrograde ejaculation, obstruction, androgen deficiency, incomplete collection or anejaculation.
In men with Oligospermia (sperm counts of <5 × 106 ml) and or impaired sexual function (erectile dysfunction, reduced libido, symptomatic hypothyroid, endocrine evaluation should include, FSH, LH, testosterone and prolactin in an early morning blood sample to assess normality of Hypothalamic-pituitary-gonadal (HPG). FSH reflects sperm production. Low testosterone levels with high FSH and LH indicate primary testicular failure whereas low testosterone levels in combination with low LH and FSH levels indicate a central defect with secondary hypogonadism. Azoospermia in combination with normal hormone levels suggests an obstructive cause.
A karyotype is indicated in cases of severe oligospermia (<1 × 106 ml) or azoospermia to identify Klinefelter syndrome (47, XXY) microdeletions on the long arm of the Y chromosome (Yq). This region includes the Azoospermia Factor (AZF) locus, which contains three subregions: AZFa, AZFb, and AZFc. AZFc micro‐deletions have a good prognosis for surgical sperm recovery whereas the prognostic value for sperm recovery in AZFa and AZFb micro‐deletions is poor. All men with idiopathic obstructive azoospermia and those with non‐palpable vas deferens (CBAVD) should be tested for mutations in the cystic fibrosis gene as they can be associated with cystic fibrosis carrier status.
Scrotal ultrasound should be performed if an abnormality such as a testicular tumour is detected on physical examination. Ultrasound can also be useful in the clinical diagnosis of varicocele, especially with the use of colour flow Doppler and demonstration of retrograde blood flow with a Valsalva manoeuvre. If an absent vas is detected on examination, a renal ultrasound scan is recommended, as up to 30% of such men may have a renal abnormality.
Testicular biopsy can aid the diagnosis of azoospermia and facilitate sperm recovery for intracytoplasmic sperm injection (ICSI) use. Biopsy can be done by an open/microscopic or percutaneous needle approach and is used to obtain a small piece of testicular tissue for histological examination and if sperm found for ICSI or cryopreservation. Testicular biopsy specimens can be classified histologically:
- normal (appropriate number of cells with complete spermatogenesis)
- hypo-spermatogenesis (all cell types present and in correct ratio but at reduced cell numbers)
- maturation arrest (failure of spermatogenesis beyond a certain stage; can be ‘early’ or ‘late’)
- sertoli cell‐only (del Castillo) syndrome (no germ cells).
In some cases, complex mixtures of pathological patterns may be present.
Other sperm function tests
Routine semen analysis provides information about spermatogenesis and sperm delivery, but the functional ability of sperm is difficult to ascertain. Sperm DNA fragmentation has been shown to be a robust predictor of assisted reproductive outcomes. Sperm DNA tests such as the sperm chromatin structure assay (SCSA), the comet assay and the TUNEL (terminal deoxynucleotidyl transferase‐mediated dUTP nick end‐labelling) assay, which assess sperm DNA integrity, show promise both as diagnostic tests for male infertility and prognostic tests for the outcome of assisted reproductive technologies. Their clinical application, however, needs further evaluation and improvement.
Specific hormonal treatments are effective for hyperprolactinaemia, hypothyroidism and congenital adrenal hyperplasia. Hypo-gonadotrophic hypogonadism can be treated successfully with GnRH or exogenous gonadotrophins. However medical treatments have a limited role in idiopathic male infertility as there is no treatable cause in over 50% of these cases.
Primary testicular failure
There is no effective treatment to restore fertility in primary testicular failure. Men undergoing treatments that contribute to infertility, such as chemotherapy, should be offered the opportunity to cryopreserve semen. Alternatively, surgical sperm retrieval with assisted reproduction can be attempted and the prognosis depends on the underlying pathology and the quality of sperm that can be found even with microscopic sperm retrieval.
Reversal of vasectomy
The success rates for vasectomy reversal depend on the skill of the operating surgeon, surgical technique and the time from the initial surgery. Patency rates seem to decline with increasing time due to the increasing rates of anti‐sperm antibody development and secondary epididymal obstruction.
Surgical sperm retrieval
Techniques for sperm retrieval from the testes include testicular sperm aspiration (TESA), testicular sperm extraction (TESE) and microsurgical TESE (micro‐TESE) performed under local combined with regional or general anaesthesia. The results of a single biopsy may not be indicative of the spermatogenic process in the whole of the testis and multiple biopsies may be necessary both to find treatment suitable sperm and or to diagnose testicular pathology.
Sperm from the epididymis can be retrieved by microsurgical (MESA) or percutaneous (PESA) epididymal sperm aspiration under local anaesthetic.
Sperm can be retrieved from the testes or the epididymis for use in IVF/ICSI. Common indications include obstructive causes, severe male factor infertility or ejaculatory failure (sperm retrieval by Rectal Electro Ejaculation). Testicular biopsy should be done in a tertiary centre with facilities for sperm cryopreservation.
Success rates for surgical sperm retrieval of almost 100% have been reported in obstructive cases, with lower rates of approximately 50% in non‐obstructive cases. A meta‐analysis of the use of surgical sperm retrieval in azoospermic men, showed the outcome of ICSI cycles in terms of fertilisation rates and clinical pregnancy rates to be significantly higher with the use of sperm from men with obstructive azoospermia as compared with non‐obstructive azoospermia.
Recent evidence from a randomised control trial indicates that varicocelectomy in infertile men with impaired semen quality and palpable varicoceles (clinically evident bilateral), significantly improves semen characteristics and the chances of pregnancy within 1 year of follow‐up. Varicocelectomy may also correct the serum testosterone deficit in men with varicocele and low testosterone levels.
Intrauterine insemination (IUI)
IUI involves the placement of a washed pellet of ejaculated sperm within the uterine cavity, thus bypassing the cervical barrier. It can be performed with or without ovarian stimulation. Indications include mild male factor infertility, immunologic infertility and mechanical problems of sperm delivery such as erectile dysfunction or hypospadias.
National Institute for Clinical Excellence (NICE), United Kingdom recommends that IUI is used in mild forms of oligozoospermia (reduced number of sperms) usually no less than 5 million motile sperm. Monthly conception rates of 8–16% have been reported for IUI and therefore, NICE currently recommends the use of up to six cycles of unstimulated IUI in mild cases of male factor infertility to optimize chances of successful pregnancy and reduce the risk of multiple pregnancies.
In vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI)
Although IVF can be used to treat milder forms of sperm abnormalities, more severe forms require ICSI. ICSI was originally described in 1988 and has since revolutionised the treatment of male factor infertility. It involves the micromanipulation and injection of a single human sperm into the cytoplasm of the oocyte. ICSI requires ovarian stimulation, oocyte retrieval and sperm preparation as for IVF. It is used for un‐correctable severe forms of male factor infertility including oligospermia and asthenoteratozoospermia (OATS), or following fertilisation failure in a previous IVF cycle. Average pregnancy rates of 33.0% per embryo transfer have been reported after ICSI.
Recent data suggest that offspring born to infertile couples using ICSI have a higher incidence of chromosomal anomalies than do children who are naturally conceived.
Possible mechanism for this could be that ICSI bypasses the natural barriers to fertilisation and therefore there is the potential risk of propagation of genetic defects that may re‐surface in the male offspring of treatable infertile men. This could potentially lead to the creation of a population of subfertile men and couple are to be fully counselled on this concern.
‘Artificial’ haploid gametes have been successfully created in vitro from embryonic stem cells in animal models. These gametes have been used to create live offspring in mice. Human trials is unlikely to progress due to strong ethical reasons.
Male infertility is a common problem that requires appropriate specialist referral. Assessment should include full clinical history and careful examination. Semen analysis remains the main initial investigation that guides further assessment of the infertile male. Advances in research have increased the treatment options available for male infertility. The potential for ICSI to propagate genetic abnormalities warrants thorough counselling for couples regarding the possible implications of its use, prior to treatment starting. The health and wellbeing of children following ICSI requires long‐term follow‐up.
In the future, a better understanding of the causes of male infertility and new reproductive technologies may offer the possibility of novel treatments, but these need to be carried out within the appropriate ethical framework.