The first Australian evidence‐based guidelines on male infertility

Infertility, defined as the inability to achieve a spontaneous pregnancy despite at least 12 months of regular intercourse without contraception, affects about one in six couples.1 In Australia, one in three assisted reproductive technology (ART) cycles are used because of male factor infertility,2 and male factors solely explain 20–30% of cases and contribute to 50% cases of couple infertility overall.3

Male infertility is characterised by quantitative and/or qualitative defects in spermatogenesis arising from primary spermatogenic failure in most cases, genital tract obstruction, sexual dysfunction, or rarely hypogonadotrophic hypogonadism (HH). Despite thorough investigation, a specific cause is unknown in 77% of cases.1 Male infertility is also a biomarker for overall health and its assessment presents an opportunity for remedial and/or preventative health interventions.4 The male contribution to couple infertility has been recognised by international clinical practice guidelines for more than two decades but, until recently, Australian‐based guidelines did not exist.

In Australia, male infertility is managed by a variety of medical specialists, including general practitioners, urologists, endocrinologists, and particularly obstetricians and gynaecologists through the use of ART. Therefore, there is a need for a unifying set of guidelines which are endorsed by key stakeholder organisations, relevant to the Australian context, to support clinical practice.

The terms male, men and man are used throughout this article to refer to individuals with a biological sex of male (cis males). The aim of the guidelines that we describe in this article is to inform and support Australian clinicians in the management of all major aspects of male infertility.

Methods

A modified version of the ADAPTE process5 was used to develop Australian guidelines on male infertility. The target audience for the guidelines is broad, encompassing general practitioners, gynaecologists who frequently provide services to men with infertility and who sometimes lack formal andrology training, and endocrinologists and urologists who provide care to men before or during fertility intent.

A multidisciplinary panel of experts was formed by one of us (RIM, the named recipient of grant funding for the production of the guidelines) to include representatives from various professional organisations, including a urologist with a special interest in male infertility, reproductive endocrinologists with expertise in andrology, and a reproductive endocrinologist and gynaecologist with expertise in ART. Consumer representation was from Healthy Male, a not‐for‐profit organisation that provides male health information, education and advocacy. Conflicts of interest were disclosed and a timeframe was agreed.

The goal of developing the first comprehensive guidelines on male infertility applicable to the Australian setting was established. The panel of experts recognised the existence of two recently published, well established and refined evidence‐based guidelines on male infertility from the European Association of Urology and from the American Urological Association and American Society for Reproductive Medicine.6,7,8 Both guidelines are comprehensive, with much overlap, but nuanced for their different populations, cultures and health systems. The European guidelines used the strength rating from accepted methods which were modified from the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.9 The American guidelines were similarly designated grading strengths with assistance from the Emergency Care Research Institute’s Evidence‐based Practice Center team.

Each statement within each guideline from the European and American guidelines was examined and discussed over a series of meetings from July 2022 to November 2024. Where concordance was found, the panel of experts discussed whether the statement was applicable to the Australian setting with considerations such as regional disparities in access to care, approved funding through Medicare, and different ethnicities of the Australian population including Indigenous people. Statements were modified by all members of the group stating agreement or dissent, providing caveats and making comments. Following group discussion, consensus was reached with the establishment of 80 revised guideline statements (hereafter referred to as GS1 to GS80) tailored to the Australian context. Wherever possible, pragmatic considerations relevant to Australian clinical practice were valued and, where applicable, references to studies of the Australian population were incorporated into the narrative.

Each of the guideline statements were rated as mandatory, recommended or suggested, based on level of evidence and the panel of experts’ perceived importance of adhering to the recommendation. The panel of experts further stratified each guideline statement according to the level of evidence, using the GRADE evidence rating system (high, moderate or low–very low).9 For all statements, each member wrote their opinion or comments for the group to consider. At the time of meeting, each comment was discussed and a decision was reached by consensus.

Following development of the draft guidelines, relevant Australian professional organisations were contacted to formally review the guidelines, and feedback was integrated. The finalised guidelines have been endorsed by Healthy Male, the Urological Society of Australia and New Zealand, the Endocrine Society of Australia and the Fertility Society of Australia and New Zealand.

Funding for administrative support in formulating the guidelines was provided by Healthy Male under contract from a grant to UNSW Sydney from the Medical Research Future Fund’s Emerging Priorities and Consumer‐Driven Research initiative (EPCD000007).

Recommendations

The guidelines are freely available at https://healthymale.org.au/projects/male‐infertility‐guidelines¹⁰ and the guideline statements are provided in Box 1, arranged into categories to facilitate ease of use. In this summary article, we highlight key guideline statements within each category and subcategory. There is overlap between certain subcategories because some recommendations are pertinent to more than one.

Initial evaluation

The goals of the evaluation of infertile men include: identifying a reversible cause which, if treated, may improve a man’s fertility potential; identifying an irreversible cause which may be overcome with ART; and diagnosing associated health conditions that may affect the man and/or their offspring.

An overview of the initial evaluation of male fertility, together with other information used for discriminating male infertility subtypes, is provided in Box 2. The first guideline statement (GS1) (Box 1) instructs clinicians to offer an assessment of male fertility to concerned men and/or couples experiencing infertility, which includes taking general and reproductive history, conducting a physical examination and performing a semen analysis. A detailed history with a focus on identifying risk factors and potential causes of infertility is crucial. A physical examination to identify signs of systemic disease and androgen deficiency, testicular volume and scrotal pathology is considered mandatory. Importantly, some causes of male infertility may be detected by clinical examination — for example, a varicocele or a testicular mass requiring immediate evaluation. A routine scrotal ultrasound is not recommended in the initial evaluation of male infertility (GS8). An ultrasound may be required for measurement of testicular volume if physical examination is not possible or suboptimal (eg, owing to assessment via telehealth or limitations due to body habitus) (GS12). Testicular volume assessed with a Prader orchidometer or by ultrasound correlates with testicular function in infertile men,12 and men with testicular volumes of less than 12 mL (as assessed by ultrasound) have poorer semen parameters.13

Semen analysis is the most important laboratory investigation for male partners in infertile couples. A standard semen analysis provides total sperm count, assesses sperm concentration, motility and morphology, and evaluates parameters such as semen volume, pH and viscosity. A sample is ideally provided after masturbation on site to avoid delays in processing and extreme temperatures that may interfere with results, but otherwise delivery of the sample to the laboratory within 1 hour of collection is acceptable.11 Abstinence from ejaculation for 2 to 7 days before sample collection is recommended. If the results of an initial semen analysis are abnormal, a second analysis should be performed about 6 weeks afterwards (GS4).11 The World Health Organization has published reference values for human semen parameters that are commonly used as defining thresholds for male infertility,11 but they require interpretation alongside a clinical assessment and other investigations. These reference values have changed over time and were most recently updated in 2021 (Box 2).11 Although a confirmed abnormal result from a semen analysis may provide evidence of male contribution to a couple’s infertility, it does not identify an underlying cause and further evaluation is required.

Routine use of antisperm antibody and sperm DNA fragmentation testing is not recommended in the initial evaluation (GS6, GS17). Antisperm antibody testing very rarely helps in the management of infertility; sperm DNA fragmentation testing can be considered as part of further evaluation.14

The initial evaluation should be performed in parallel with evaluation of the female partner’s fertility to avoid delays in accessing appropriate and timely fertility care (GS2). Simultaneous assessment of partners may also obviate the need for unnecessary tests if a cause has been found and possibly treated in either partner.

Given that male infertility is often diagnosed by a primary health care practitioner, it is recommended that once male infertility is identified, the patient should be further evaluated by a specialist in male reproduction (GS5).

Further evaluation

General

In general, recommendations for further evaluation relate to management of patients requiring detailed evaluation by specialists in male reproduction (GS9‐GS33). GS9–GS12 describe more general recommendations in this context. GS10 highlights the need for the man to be thoroughly reassessed in cases in which there are multiple failed ART cycles or recurrent pregnancy losses. Diagnoses such as a clinically significant varicocele or a high rate of sperm DNA fragmentation may be important to address before commencing further ART cycles.15,16

Hormonal evaluation is recommended if there is suspicion of male factor infertility and/or androgen deficiency based on abnormal semen parameters or clinical findings (GS11). Serum testosterone levels peak in the early morning and glucose consumption suppresses testosterone production, so blood for measurement of hormonal profiles should be collected before 10:00 am and ideally under fasting conditions.17 Isolated elevation of serum follicle stimulating hormone (FSH) level suggests primary spermatogenic failure, whereas elevated serum FSH and luteinising hormone (LH) levels associated with a low testosterone level is consistent with primary testicular failure (the most useful FSH value for the upper limit of normal in a young man is 8.4 IU/L18). Low or inappropriately normal FSH and LH levels together with a low testosterone level is consistent with HH.

Azoospermia

Azoospermia is the most severe form of infertility, accounting for about 10–15% of male infertility.19 It is crucial to differentiate between obstructive azoospermia (OA) and non‐obstructive azoospermia (NOA), as this guides further investigations and management. Application of a standardised assessment framework should permit differentiation in most circumstances (GS13) (Box 2). Features suggestive of OA include a low volume ejaculate with normal testicular volumes and a normal serum FSH level. Obstruction distal to the seminal vesicles, such as ejaculatory duct obstruction or bilateral absence of the vas deferens (usually associated with hypoplastic or absent seminal vesicles), characteristically causes an acidic ejaculate owing to impaired passage of alkaline seminal vesicle fluid. Conversely, men with NOA typically have normal volume and normal pH seminal fluid with reduced testicular volumes and either an elevated serum FSH level (in primary testicular failure) or a normal or low FSH level (in HH).

Routine diagnostic testicular biopsy is not recommended because it may compromise future sperm retrieval, especially in cases of NOA (GS14).20 It is important to perform a comprehensive assessment of men with NOA to identify the underlying cause and associated comorbidities (GS15). Similarly, additional imaging (eg, magnetic resonance imaging) in cases of OA may be indicated to identify the nature and location of obstruction (GS16).21

Sperm DNA fragmentation testing

Sperm DNA fragmentation testing is only recommended in specific circumstances for which it may guide management, such as to determine whether varicoceles should be treated or decide whether testicular sperm should be used for ART (GS17).16,22

Genetic testing

The availability of genetic testing varies between health services. Genetic testing can be costly for the health care system and may generate significant out‐of‐pocket costs for patients. Therefore GS18–GS23 offer evidence‐based approaches to genetic testing in a cost‐effective and targeted manner,23 noting that some results (eg, karyotypic anomalies and cystic fibrosis transmembrane conductance regulator gene mutation) may have serious implications for offspring.

Y‐chromosome microdeletions are present in 5% and 10% of men with severe oligozoospermia (sperm concentration less than 5 million/mL) and NOA, respectively.24 The frequency of Y‐chromosome microdeletions in men with a sperm concentration of between 1 million/mL and 5 million/mL is very low (about 0.8%).25,26,27 As such, it is recommended that screening for Y‐chromosome microdeletions be offered to men with a sperm concentration of less than 5 million/mL but it should be mandatory for those with a sperm concentration of less than 1 million/mL (GS20).

Imaging

The guideline statements on imaging include detailed recommendations regarding the indications for scrotal ultrasound (GS25, GS26). Importantly, GS26 addresses advice from the European guidelines, which state that testicular cancer likely arises from testicular dysgenesis and that male infertility is a risk factor for testicular cancer.6

Infection

While pyospermia may be caused by infection, hence necessitating further assessment (GS28), there are other causes. Routine use of antibiotics (and antioxidants) is not recommended, as this does not improve live birth rates (GS30).28

Cryptorchidism

Patients with untreated cryptorchidism need to be referred to a urologist (GS32) because they may benefit from surgery, both from a fertility perspective and to permit self‐surveillance owing to the increased risk of testicular malignancy.29 Some patients with cryptorchidism may need an orchidectomy.

Management and therapeutic considerations

Counselling

The guideline statements on counselling focus on general advice and genetic counselling for infertile men. Some medical practitioners managing infertility may not be skilled in genetic counselling, so professional genetic counselling must be offered when abnormalities are found (GS34).

Medical practitioners will be aware that patients should be counselled about optimisation of potentially modifiable factors to improve fertility potential (GS36).30 The association of male factor infertility with non‐gonadal health conditions is likely less well known, thus necessitating a distinct guideline statement (GS37). Comorbidities of male infertility include cancer, cardiovascular disease, metabolic disease and premature mortality.7,31 As such, it is advisable that clinicians perform a cardiometabolic assessment to identify comorbidities such as obesity, obstructive sleep apnoea, hypertension, and undiagnosed or poorly controlled diabetes. In obesity, sustained weight loss improves sperm count, and regular physical activity and a diet rich in nutrients improve sperm quality. It is important to appreciate that sperm quality deteriorates with age, with increased risks of autism spectrum disorder and some autosomal dominant diseases in offspring (GS38).32

Varicocele

Varicoceles are present in one‐third of infertile men and in 10–15% of men in the general population, but their causative role in male infertility is contentious.33 Varicoceles that are palpable on examination (not exclusively ultrasound detected) are considered clinically significant (GS40).34

Clinically significant varicoceles can cause or contribute to abnormal semen parameters, sperm DNA fragmentation, recurrent pregnancy loss and poor ART outcomes (GS41) and, as such, are important to identify.15,35,36 Treatment for a varicocele should be considered in these contexts. A microsurgical varicocelectomy may improve pregnancy rates compared with other surgical treatments, and has the lowest complication rate, but other interventions (surgery or embolisation) may need to be considered in the context of availability.37,38 The evidence supporting a varicocelectomy before micro testicular sperm extraction (TESE) in NOA is mixed, therefore it is not recommended and should only be considered in select cases (GS42).39

Surgical management

Sperm retrieval: The potential role for surgically retrieved sperm extends beyond the classic context of azoospermia. After addressing any reversible factors, clinicians may consider using surgically retrieved sperm in non‐azoospermic men who have high sperm DNA fragmentation in ejaculated sperm or cryptozoospermia, particularly those in couples who have experienced previous failure of intracytoplasmic sperm injection using ejaculated sperm (GS49). Current evidence suggests that using surgically retrieved sperm for intracytoplasmic sperm injection in the such situations may improve pregnancy and live birth rates, but high quality data are lacking.40,41,42,43 The optimal method of surgical sperm retrieval will depend on spermatogenic function; fine needle aspiration or testicular sperm aspiration may be appropriate in those with high sperm DNA fragmentation and normal sperm concentration or mild oligozoospermia, while TESE (possibly with microsurgical assistance if needed) is recommended in men with cryptozoospermia.

Obstructive azoospermia: The most common cause of OA is a vasectomy, with about 25% of Australian men older than 40 years having undergone the procedure.44 About 3–6% of men consider having another child after a vasectomy.45 There are two options in this situation: a vasectomy reversal to restore natural fertility, or extraction of sperm for use in ART. Practitioners should discuss both options with patients, and highlight factors to consider in reaching a decision (GS51, GS52). If reconstructive surgery has been successful after vasectomy, then cryopreservation of ejaculated sperm should be considered given the risk of delayed anastomotic fibrosis, which can occur in about 10% of men who initially have sperm return to the ejaculate (GS54).46 A rare cause of OA is ejaculatory duct obstruction, for which transurethral resection of ejaculatory ducts may restore fertility (GS55).47

Non‐obstructive azoospermia: The gold standard for sperm retrieval in NOA is micro‐TESE because it has higher sperm retrieval rates than other techniques (GS56).48 A diagnostic biopsy is not necessary because every potential histology finding in NOA may still be associated with sperm production owing to heterogeneity between tubules (GS57).49 Furthermore, there is a risk of compromising future sperm retrieval.49 There are no known clinical or endocrine markers which can reliably predict sperm retrieval rates (GS58).50

In Australia, micro‐TESE can be performed with results comparable to those from overseas.51 If micro‐TESE is not available, a conventional random open TESE can be used. Fine needle aspiration should not be used as the definitive technique in NOA (GS59).

Routine use of medical therapy such as human chorionic gonadotrophin (hCG), FSH, antioestrogens or aromatase inhibitors before TESE in NOA due to primary spermatogenic failure is not supported by current evidence but may be considered in select cases (GS60).52 If a patient has complete AZFa or AZFb deletions, then any attempt at sperm retrieval is futile and should not be undertaken (GS61).53

Non‐surgical management

Hypogonadotrophic hypogonadism and hyperprolactinaemia: HH is a rare cause of male infertility, but diagnosis is critical because natural fertility may be restored and the underlying cause could have serious health implications. It is essential to evaluate remaining pituitary function, including prolactin level, and to consider magnetic resonance imaging of the pituitary gland. If clinically significant hyperprolactinaemia is identified, then a thorough assessment for the cause must ensue to target treatment (GS68). Dopamine agonists are unlikely to be helpful in cases of mild idiopathic hyperprolactinaemia with normal serum gonadotrophin and testosterone levels (GS69).

It is important to determine whether HH is congenital or acquired, as this will guide further investigations, management and expectations around fertility potential (GS62). The genetic basis of congenital HH is complex, with variability in inheritance, penetrance and expressivity; more than 60 genes underlie congenital HH,54 so genetic testing is appropriate in these cases.

Congenital and acquired HH due to irreversible hypothalamic–pituitary disease may be treated with hCG, as an LH substitute, thereby restoring intratesticular testosterone levels and promoting spermatogenesis. This may be sufficient in many cases of HH with post‐pubertal onset (GS63).55 In congenital or pre‐pubertal onset cases, optimal sperm output will typically require the addition of FSH. While simultaneous hCG and FSH therapy, or sequential therapy with unopposed FSH followed by hCG, have been suggested in severe cases of congenital HH, such as absence of spontaneous puberty (testicular volume < 4 mL) and/or cryptorchidism, the optimal approach to spermatogenesis induction is yet to be established.

Hormone treatments and supplements for idiopathic infertility: While frequently used in Australia,56 the routine use of hCG, antioestrogens and aromatase inhibitors in men with idiopathic infertility is not strongly supported by available evidence (GS65) and they are not approved for this indication. Weak evidence indicates that clomiphene may be beneficial to sperm output and motility in normogonadotrophic and hypogonadal men with idiopathic oligozoospermia,57 but improved fertility outcomes are unproven. Current evidence for aromatase inhibitor use in idiopathic male infertility is weak and there are concerns about adverse effects.58 Some evidence suggests that semen parameters and pregnancy rates improve after FSH therapy in normogonadotrophic idiopathic male infertility (GS66).59,60 A recent meta‐analysis demonstrated improved sperm concentration, total sperm count and progressive sperm motility after FSH therapy compared with placebo or no treatment in men with idiopathic oligozoospermia and normal gonadotrophin levels; however, due to the heterogeneity of the data, further studies are needed.59 Exogenous testosterone suppresses the hypothalamic–pituitary–gonadal axis and is contraindicated in men seeking fertility (GS64).61

Data from prospective controlled studies of the use of antioxidants in male infertility are poor, owing to the use of different antioxidants in different combinations and dosages for varying durations.62 An additional challenge in this area of research is the lack of consensus regarding methods of detecting oxidative stress and subsequent difficulty in identifying patients most likely to benefit from antioxidant treatment.63 Without results from well designed randomised controlled trials, specific recommendations on routine use of antioxidants cannot be made (GS70).

Klinefelter syndrome

For men diagnosed with Klinefelter syndrome (KS), it is necessary to assess their desire for paternity and its timing. For men with KS who are seeking imminent paternity and have NOA, a micro‐TESE (where available) is recommended (GS72). If paternity is considered some time into the future, a detailed, personalised and informed discussion about micro‐TESE and testosterone replacement should be undertaken by a suitably qualified specialist. KS is a non‐heritable chromosomal disorder and so does not confer an elevated risk of transmission to offspring. It is paramount to assess, treat and monitor the androgen status of men with KS after fertility has been addressed. Men with KS experience high rates of various diseases, and therefore regular surveillance and management is critical (GS73).64

Cancer and male infertility

Risk of testicular cancer is increased in men with infertility. However, not all intratesticular lesions are malignant27 and some indeterminate lesions may be amenable to surveillance, with decision making facilitated by a multidisciplinary case discussion (GS74). In men who have a suspicious testicular tumour, an orchidectomy is standard of care.65,66 Sperm cryopreservation should be attempted before orchidectomy for all men; some may be unable to provide an adequate sample at the first attempt of collection, and may therefore require repeated collections. Semen quality is often impaired in men with testicular cancer,67 so concomitant extraction of sperm from testicular tissue at the time of orchidectomy should be discussed (GS76).68

All males from mid‐puberty onwards who are about to embark on cancer treatment should be considered for fertility preservation, especially before commencing gonadotoxic therapy (GS77). Multiple factors affect decisions about appropriate timing of attempted conception after gonadotoxic therapies, so expert individualised guidance is recommended (GS78), but a specific timeframe is not prescribed.69 After gonadotoxic treatment, a semen analysis is recommended for men seeking fertility, appreciating the variability in the potential recovery of semen parameters (GS79).69 Further assessment by hormonal profiling may be necessary (GS79).70 Some men have residual NOA that requires surgical sperm retrieval, ideally using micro‐TESE (GS80).71

Conclusion

To our knowledge, these 80 guideline statements are the first set of evidence‐based recommendations for management of male infertility in Australia. The comprehensive and broad scope of the guidelines serves as a framework for managing male infertility. The guidelines have been endorsed by key stakeholder organisations. We hope that this article will aid in raising awareness of this common condition.

Box 2 – Overview of the initial evaluation of male fertility and information used for discriminating male infertility subtypes

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