Guidelines for the management of male infertility

Evaluation

The goals of male infertility evaluation include:

• Identifying a reversible cause which, if treated, may improve a man’s fertility potential
• Identifying an irreversible cause which may be effectively bypassed using ART
• Diagnosing associated health conditions that may affect the man and/or his offspring

Initial evaluation 

The clinician should offer an assessment of male fertility to concerned men and/or couples experiencing infertility. Initial evaluation of fertility should be performed in both male and female partners to avoid delays in accessing fertility care. A parallel assessment of the female partner’s fertility status, including ovarian reserve, is necessary to inform decisions on timing and type of intervention. 

An initial evaluation of the man includes history, physical examination and a semen analysis. 

Physical examination is considered mandatory because some causes of male infertility may only be detected by examination (such as a clinically significant varicocele or a testicular mass) and is preferable to performing an initial routine ultrasound. Semen analysis should be performed but antisperm antibody testing is not required for initial examination. Abnormal semen analysis requires confirmation and should be considered alongside other clinical assessments. Men should also be advised to undertake regularly testicular self-examination until the age of 55.

After baseline evaluation in a primary care setting, the infertile man should be further evaluated by a specialist in male reproduction.

Further evaluation 

Further evaluation of a man with suspected infertility should be guided by a specialist practitioner (urologist, endocrinologist or obstetrician/gynaecologist). Given the prevalent use of ART, such clinicians should have a working knowledge of ART practice. 

General

When a man exhibits a low total motile sperm count on repeated semen analyses, he should be advised that in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) is likely to be more effective than intrauterine insemination (IUI).

Testicular volume should be estimated by physical examination or an orchidometer and an ultrasound examination should be performed where physical examination is suboptimal or not possible (e.g. telehealth). 

A hormonal evaluation should be performed in men if there is male factor infertility, including abnormal semen parameters, small testes or symptoms of androgen deficiency. Blood should be collected before 10:00am and ideally under fasting conditions, as serum testosterone levels peak in the early morning and glucose consumption suppresses production. 

Re-evaluation of male fertility should be considered where the couple has experienced multiple failed ART cycles or two or more pregnancy losses (recurrent pregnancy loss).

Azoospermia

Azoospermia affects 1% of men and accounts for 10-15% of male infertility. It is the most severe form of male infertility. 

Differentiating between obstructive azoospermia (OA) and non-obstructive azoospermia (NOA) is essential because it guides further investigation and management. The evaluation of azoospermia is based initially on semen volume and pH, scrotal examination and serum FSH. A diagnostic testis biopsy should not be routinely performed because it may compromise future sperm retrieval and results can be difficult to interpret due to tubule heterogeneity and sampling bias. 

Men with NOA should be comprehensively assessed to identify the underlying aetiology and associated comorbidities. In irreversible cases or idiopathic NOA, surgical management will be required for sperm retrieval.  

Men with suspected OA should be considered for further imaging with MRI or transrectal ultrasound to identify the nature and location of obstruction.

Sperm DNA fragmentation testing

Sperm DNA fragmentation (SDF) testing is recommended where it may guide interventions, such as if the man has a clinical varicocele and in couples with unexplained infertility or RPL. In these settings, sperm DNA fragmentation may contribute to difficulties conceiving an ongoing pregnancy.

Genetic testing 

Australian clinical practice varies in terms of types of genetic tests offered and thresholds for testing. Genetic testing can be costly for the health care system, and for the patient when there are significant out-of-pocket costs. However, some genetic conditions, such as karyotypic anomalies and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations may have serious implications for offspring.

Karyotype testing should be offered to men where the couple has experienced recurrent pregnancy loss and in men with unexplained azoospermia or moderate oligospermia (<10 million/mL). Testing for Y chromosome microdeletions should be offered to men with severe oligospermia (<5 million/mL) but should be considered mandatory for men with very severe oligospermia (<1 million/mL). These genetic tests should not be offered to men with obstructive azoospermia.

Men with structural abnormalities of the vas deferens (including congenital bilateral absence of the vas deferens (CBAVD)) or idiopathic obstructive azoospermia should be offered CFTR gene testing. If initial genetic testing is negative for men with CBAVD, the couple should be referred to a genetic counsellor and/or clinical geneticist to discuss extended CFTR testing of both members of the couple.

Imaging

Scrotal ultrasound is recommended under various circumstances, including in the further evaluation of men with identified structural or anatomical abnormalities and men with a history of cryptorchidism or testis cancer. Imaging of the genitourinary tract is recommended for men with clinical features of obstruction. 

Scrotal ultrasound should be considered for men with repeated abnormal semen analyses, as they have an elevated risk of testicular cancer.

Infection

Pyospermia can have multiple causes, including infection, and further evaluation should be considered. Men with a genitourinary tract infection should be treated and their partners referred for evaluation, if sexually transmitted. In the absence of infection, antibiotics and antioxidants do not improve live birth rates and are not recommended.

Cryptorchidism

Males with untreated unilateral or bilateral cryptorchidism should be referred to a urologist for surgical consideration. Hormonal interventions to aid testicular descent should not be used in post-pubertal men with cryptorchidism.

Management and therapeutic considerations 

Male infertility is managed by a variety of health professionals, including urologists, endocrinologists and obstetrician/gynaecologists through ART. The following guideline statements provide advice to medical practitioners regarding the management of men with fertility concerns, those with clinically diagnosed infertility and men receiving treatment for cancer. 

Counselling 

Men with fertility concerns should be counselled about optimisation of potentially modifiable risk factors to improve fertility potential. Men with abnormal semen parameters should be informed about associated health conditions. Men aged >40 years should be informed of the increased risk of adverse health outcomes in offspring. 

Referral to a genetic counsellor is necessary for couples with an identified genetic condition and for men with a known inheritable disease. Couples need to be informed that Y chromosome microdeletions in the male partner will be passed on to any sons, who will then have a higher risk of spermatogenic impairment in adulthood.

Varicocele

Varicoceles are detected in 10-15% of the general male population but in one third of infertile men.  

Scrotal examination and Valsalva manoeuvre should be performed to identify palpable varicoceles. A varicocele is considered clinically significant when it is palpable on examination and not exclusively detected by ultrasound. Abdominal imaging is not recommended for an isolated small or moderate right varicocele. 

It is important to identify a clinical varicocele because it can cause or contribute to abnormal semen parameters, sperm DNA fragmentation, recurrent pregnancy loss and poor ART outcomes. 

Surgical repair of a clinical varicocele is recommended in adolescents and men under a defined range of circumstances but is not recommended in adolescents or men who have sub-clinical varicoceles.

Surgical management

The following guideline statements provide information on the surgical management of men with infertility. 

General sperm retrieval

Various options exist for sperm retrieval from men with anejaculation or retrograde ejaculation. 

Surgical sperm retrieval is recommended for men with obstructive azoospermia (OA) where surgical repair is not an option or as an adjunct to surgical repair.

Routine diagnostic biopsies are not recommended, as they may compromise future surgical sperm retrieval efforts.

Obstructive azoospermia

Vasectomy is the most common cause of obstructive azoospermia (OA) in Australian men. Approximately one quarter of Australian men aged >40 years have had vasectomies (Yusuf and Siedlecky, 2009) and ~3-6% of vasectomised men consider a vasectomy reversal (Uvin et al, 2018). For men seeking fertility after vasectomy, options include surgical reversal or surgical sperm retrieval for use in ART. The choice will depend on a number of factors, but all options should be discussed with the patient

Surgical reconstruction may be considered in OA men seeking natural fertility post-vasectomy and in men with other vasal or epididymal obstructions. Surgical options for men with ejaculatory duct obstruction (EDO) include transurethral resection of ejaculatory ducts (TURED) or surgical sperm retrieval.

It is recommended that men consider cryopreservation of ejaculated sperm following successful surgical reconstruction, given the risk of delayed anastomotic fibrosis (Farber et al, 2019).  

Non-obstructive azoospermia

Non-obstructive azoospermia is observed in ~60% of men with azoospermia (Flannigan et al, 2017) and, for these men, surgical sperm retrieval offers a chance to father a child. However, there are no reliable predictors for successful sperm retrieval in NOA. 

In Australia, micro testicular sperm extraction (TESE) can be performed with results comparable to world literature (Lantsberg et al, 2022) and has the highest rates of success compared to other methods (Bernie et al, 2015). However, conventional TESE may be used where micro-TESE is not available. Fine needle aspiration (FNA)/testicular sperm aspiration (TESA) is not recommended for this purpose.

Surgical sperm retrieval should not be performed in men with complete AZFa or AZFb microdeletions, as there is effectively no chance of successful sperm retrieval. 

A diagnostic biopsy prior to surgical sperm retrieval is not required and indeed may compromise future sperm retrieval efforts (Deruyver et al, 2014). The routine use of medical therapies in NOA prior to TESE to improve the chance of successful retrieval is not supported by current evidence but may be considered in select cases (Tharakan et al, 2022).

Non-surgical management

Non-surgical management of male infertility includes the consideration of treatment of hypogonadotrophic hypogonadism (HH) or idiopathic infertility. 

Hypogonadotrophic hypogonadism

Hypogonadotrophic hypogonadism (HH) is a rare cause of male infertility and may be congenital or acquired. HH results in the inability of the testes to adequately produce sperm and androgens, as a consequence of hypothalamic and/or pituitary dysfunction.

Hormone treatments

Testosterone therapy should not be prescribed for men with reproductive intent, due to negative feedback on the hypothalamus and pituitary that decreases gonadotrophin production and results in impaired sperm production (Patel et al, 2018).

It should be noted that gender-affirming hormone therapy (GAHT) for transwomen inhibits spermatogenesis but it can recover after cessation of GAHT (de Nie et al, 2023).

The routine use of aromatase inhibitors (AIs), human chorionic gonadotropin (hCG) or selective oestrogen receptor modulators (SERMs) to improve sperm counts in men with idiopathic infertility is not supported by current evidence. 

FSH therapy may be considered to improve sperm parameters in men with idiopathic oligozoospermia and normal gonadotrophins because some evidence suggests improved semen parameters and pregnancy rates. However it is not recommended in men with non-obstructive azoospermia prior to surgical sperm retrieval. FSH treatment is exceedingly expensive and is not supported by the PBS except in the setting of confirmed HH.

Hyperprolactinaemia

Hyperprolactinaemia, characterised by excess production of prolactin by the pituitary gland, can inhibit GnRH production by the hypothalamus leading to reduced pituitary gonadotrophin production, and subsequently testosterone deficiency and impaired spermatogenesis. 

Men with HH and hyperprolactinaemia should be evaluated to identify the underlying cause and establish effective treatment strategies. 

Supplements

The use of supplements to improve male fertility is popular but data from well‐designed randomised-controlled trials is lacking and thus specific recommendations on the routine use of such supplements cannot be made.

Klinefelter syndrome

Klinefelter syndrome (KS) is the most frequent genetic cause of male infertility and results from one or more extra X chromosomes in males, with the classic 47,XXY genotype accounting for most cases. For men with KS, it is important to establish their desire for paternity and its timing, as this influences management. 

Men with KS who desire paternity should be offered a semen analysis and cryopreservation of sperm if present. For men with KS and azoospermia, an informed discussion on timing of surgical sperm retrieval and androgen replacement is recommended. 

Men with KS require long-term follow-up for androgen replacement and management of associated comorbidities.

Cancer and male infertility

Men with infertility have an increased risk of testicular cancer. Not all testicular lesions are malignant and some may be suitable for surveillance, facilitated by a multidisciplinary case discussion. 

For men with testis cancer undergoing orchidectomy, it is essential that sperm cryopreservation is offered prior to surgery, noting that sperm parameters are often abnormal. Oncotesticular sperm extraction at the time of radical orchidectomy should be considered for men with azoospermia or severe semen abnormalities.

All males, from mid-puberty onwards, who are about to embark on cancer treatments with potential to compromise fertility should be offered fertility preservation, especially prior to the commencement of gonadotoxic therapy.

Men desiring paternity after completing gonadotoxic therapy should be advised that there are multiple factors to consider before advising on appropriate timing of conception and expert individualised guidance is recommended. After treatment cessation, men seeking paternity should undergo a semen analysis, noting that the time for the return of sperm to the ejaculate varies widely depending on the type of cancer treatment (Yumura et al, 2023). Further assessment of these men should include measurement of serum gonadotrophins and testosterone (Burney and Garcia, 2012). For those men who remain azoospermic after treatment cessation, surgical sperm retrieval, preferably via micro-TESE, is an option (Hsiao et a, 2011). Surgical retrieval success rates will depend on the underlying cancer, the type, dose and duration of cancer treatment, and the presence of other risk factors for infertility.