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INFERTILITY is a global health issue affecting millions of people of reproductive age worldwide. Available data suggest that male factor infertility contributes to half of the causes of infertility, distributed between male factor as the sole cause in 30% and male combined with female factor in another 20%.
Infertility causes substantial psychological and social distress and imposes a considerable economic burden on patients and health care systems. Early diagnosis and appropriate management can mitigate these factors.
A 1992 meta-analysis confirmed that sperm count had declined by 50% during a 60-year period. Subsequently numerous studies have shown similar declines globally, although some studies have disputed this claim (here, and here).
The saying “it takes two to tango” best describes the unique relationship and interaction between a particular sperm and the mature egg to produce a competent embryo capable of implanting in a receptive endometrium and being maintained until delivery of a healthy live birth.
When a couple has been trying to conceive for 12 months without success, and if the female partner is under 35 years of age, it is time to consult with their GP to start investigations.
Role of the GP in evaluation and management of male subfertility
GPs are not only the first to be consulted for male subfertility evaluation but can also provide support at many different stages:
- Preconception stage – immediate referral to a male fertility specialist for men with risk factors such as Klinefelter syndrome, a fairly common genetic condition, or history of undescended testis or testicular trauma.
- Giving advice regarding lifestyle factors, reversing testosterone abuse, erectile dysfunction, requesting and interpreting semen analysis and making the appropriate referral to fertility specialists.
- During infertility treatment – there is increasing evidence that paternal health at the time of conception can affect the offspring’s metabolic health and reproductive potential through transgenerational transmission of epigenetic modifications. Obesity or diabetes might contribute not only to male subfertility but can also compromise the health of future offspring.
- Following treatment – testosterone replacement therapy for hypogonadal patients.
- Long term treatment and associated long term medical comorbidity.
Semen analysis is the initial and only test required to evaluate male fertility. Unfortunately, it is not a good predictor of fertility as it is not a functional test.
If the semen analysis parameters are not within the normal range according to the 2010 WHO sperm reference values – a semen volume of 1.5 mL, sperm concentration of 15 million/mL, sperm total motility of 40%, and sperm with a normal morphology of 4% – then the test should be repeated, given the inherent changes in semen production and parameters due to regression to the mean. At that point, full history and investigations need to be undertaken.
There are five goals that need to be fulfilled when conducting full investigations of male infertility – an easy mnemonic to help GPs remember is SPERM:
- Systemic disease exclusion – diabetes mellitus, pitiutary adenoma, testicular cancer.
- Paternal genetic disorder – carrier for cystic fibrosis, Yq microdeletion, paternal age.
- Etiology – it is important for the patient to know the cause of male infertility so that specific treatment can be selected.
- Reversible conditions – hypogonadotrophic hypogonadism, steroid misuse.
- Medical problems associated with treating erectile dysfunction or long term testosterone replacement therapy.
After the couple has been evaluated, options for treatment can be specified, ranging from conceiving naturally, to intrauterine insemination, intracytoplasmic injection (ICSI), surgical sperm retrieval, and the last option of sperm donation.
According to the most recent national estimates, 4.9% of all women who gave birth in Australia in 2019 received some form of assisted reproductive technology treatment
How are the most severe cases of male infertility managed?
Severe male factor infertility ranges from the lower range of semen parameters when sperm concentration is less than 5 million/mL with very low motility or morphology, or a combination of the previous parameters. At the extreme of this spectrum lies cases of azoospermia.
After referral to a male fertility specialist, it is paramount to differentiate between obstructive and non-obstructive azoospermia as the sperm retrieval technique and prognosis differ according to the diagnosis. Such cases will need additional testing including karyotype, Yq microdeletion and a hormonal profile. When sperm is available, assisted reproductive technology using ICSI is the only effective method of treatment.
Before the advent of ICSI in 1992, men with severe male factor infertility were deemed sterile and not able to have their own biological children. ICSI is considered to be a breakthrough in the management of severe male factor infertility. There are currently two methods of fertilising the egg in vitro. The first is conventional in vitro fertilisation, which is when hundreds of thousands of sperm are mixed with an egg. The other method is ICSI, where a single viable sperm is injected directly into a mature egg under high magnification using a micromanipulator. ICSI can be used to achieve pregnancy when men have a very low sperm count, or even no sperm in their ejaculate but sperm that can be retrieved surgically.
Soon after the introduction of ICSI, its indication was expanded to include non-male factor infertility such as unexplained infertility, older women, low egg reserve, or poor quality oocytes. This expansion has led to an increasing rate of ICSI worldwide with the consequence of extra cost and laboratory time, without better reproductive outcomes compared to conventional in vitro fertilisation.
Australia has witnessed a small decrease in the use of ICSI (from 62.9% in 2015 to 58.2% in 2019).
In cases without male factor infertility or a history of prior fertilisation failure, the routine use of ICSI for all oocytes is not supported by the current evidence. On the other hand, it is estimated that 33 ICSI procedures would have needed to be completed to prevent one case of total fertilisation failure.
What is new on the horizon of male infertility
Research in the area of male infertility has been less evident than female infertility because ICSI is very effective in bypassing the vast majority of male factor infertility. However, a search for a functional test to select the best sperm for ICSI is still evolving.
New emerging technologies such as microfluidic sperm function tests are developing and being investigated to select the most viable sperm with less DNA damage.
Use of artificial intelligence for sperm selection is another emerging technology for which there are high hopes. With the development of novel genetic testing like whole exome sequencing, we may be able to unravel the mystery of the genetics of male infertility and develop more effective diagnostic and therapeutic options.
There is an ongoing debate about male age effects on sperm quality. Research has shown associations between older age and lower sperm concentration, motility and morphology, and increases in the DNA damage that may be associated with autism, schizophrenia, Apert syndrome, achondroplasia in offspring. Further research needs to be done to confirm these findings, along with preventive measures such as storing sperm at a younger age, and educating men to start a family at a younger age.
Long term consequences of severe male factor infertility
Recent research indicates that male factor infertility is increasingly recognised as a marker for overall male health and can be associated with premature death, cancer and other comorbid medical conditions that can be mitigated by primary health care providers (here, and here).
Finally, there are two important recommendations for GPs.
The first is not to delay referrals in the hope that addressing and managing a lifestyle factor will reverse the problem of male subfertility. The cycle of spermatogenesis takes approximately 74 days to complete and if noticeable improvement is to happen, it will take a long time to achieve with the unwanted consequences of having a poor outcome, especially in the presence of another female factor like age.
The second recommendation is understanding that male infertility is a relative problem to the female egg quality; a young, good quality egg has the machinery to repair poor quality sperm with high DNA fragmentation, while the reverse is difficult to demonstrate.
In conclusion, GPs play a key role in educating men about the importance of leading a healthy lifestyle, effect of age, medication usage and environmental exposures in preparation for parenthood. GPs are the starting point for evaluating male factor subfertility. Collaborating with a reproductive endocrinologist, they can manage short and long term disorders associated with hypogonadism, and can refer to a fertility specialist when appropriate.
Dr Hossam Elzeiny a certified fertility specialist, reproductive endocrinologist, andrologist, reproductive microsurgeon and gynaecologist affiliated with Melbourne IVF. He is also Clinical Director at the Reproductive Services Unit, Royal Women’s Hospital in Melbourne.
The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.