Australasian Science: Australia's authority on science since 1938

The Boys Are Not OK

Credit: alex-mit/iStock

Credit: alex-mit/iStock

By Moira O’Bryan & Rob McLachlan

Not only is male infertility a determining factor in a couple’s ability to start a family, it is also associated with a higher risk of early death.

One in six Australian couples is infertile, and male infertility is the sole or a contributory cause in half of these. Treatment sought by infertile couples leads to 70,000 assisted reproductive technology cycles each year at a cost of $600 million, with each couple paying approximately $4000 per cycle out of pocket.

A less readily quantified cost of infertility is the psychosocial and relationship stress resulting from the inability to father a biological child. Male infertility is a deeply personal affliction for which disclosure to family and friends, or support groups, is often declined or unavailable.

Failure to produce adequate numbers of motile and functional sperm is the most common presentation of male infertility, yet for most men no specific cause can be identified. As such, no effective treatment can be provided.

Our current inability to make a precise diagnosis compounds the sense of frustration for patient and clinician alike. Semen and hormone testing provide insights into the severity of the underlying disorder, but usually not the cause of disease.

In an effort to rectify this situation, studies are underway to identify the genetic causes behind about 50% of infertility cases. A potentially far more challenging task is identifying environmental causes of infertility and the interplay between genetics and environmental exposures.

For many men, assisted reproductive technology approaches, such as intra-cytoplasmic sperm injection, provides a bypass for sperm functional deficits. But assisted reproductive technologies place a disproportionately heavy burden on the female partner, and can carry substantial treatment-associated risks and financial burdens.

Added to this burden is that infertility remains “women’s business” in many countries, with the focus of infertility assessments being the female partner. This apparent gender bias is, however, gradually receding with the Fertility Society of Australia recently mandating the routine evaluation of male partners within all clinical infertility programs.

Despite this overwhelming clinical and social need, relatively little research is conducted on the mechanisms underlying normal or disordered male fertility. This lack of prioritisation is tied up in complex taboos and narrow-minded perceptions that unless you die of something, or patients are openly complaining, it does not deserve funding.

Rather, we would argue that male infertility is such a personal issue it will be the very rare patient who will stand up in public and proclaim themselves to be infertile and become a” crusader” in the way we have seen with several types of cancer. Until infertility is “normalised” as a disease like any other in the community, it will be left to those who know the breadth and depth of this condition to advocate for increased service and research effort.

In constructing the case for an enhanced focus on male reproductive health, we present three perspectives:

  1. male infertility is extraordinarily common, affecting men you know or it could affect you;
  2. male contraception represents a largely untapped means of increasing fertility control options; and
  3. infertile men die younger than their fertile brothers.

Currently men play a major but often under-recognised role in natural family planning through the use of condoms and sterilisation. There is, however, a need for a new male contraceptive for couples for whom existing methods (including female-based methods) are unacceptable. The ideal contraceptive needs to be efficacious, reversible, safe, cheap and easy to use, but ultimately the development of a contraceptive akin to the female pill also involves a business case.

An effective male hormone-based contraceptive strategy has been developed, and several non-hormonally-based methods are in development. The male hormonal contraceptive approach involves the administration of androgens, usually with a progestin every 2–3 months, to suppress pituitary gonadotrophic support for sperm production (this is analogous to the combined female oral contraceptive pill). Data shows that sperm concentration falls to below one million/ml or zero in 95% of men. This approach is reversible within 6–12 months, and it provides similarly effective contraception to female hormonal methods.

However, the viability of this method is undermined by the slow speed of onset of protection (1–6 months), the need to check sperm density given its failure to suppress all men, and the potential for sperm output to rebound if treatment is interrupted. Importantly, the potential side-effects to cardiovascular health and mood require further evaluation.

The development of an effective, consumer-friendly male contraceptive remains challenging as it requires strong co­operation between the public and private sectors. It is now 25 years since the first World Health Organization-sponsored trial showed comparable contraceptive efficacy to female methods, yet all major pharmaceutical companies withdrew from the area a decade ago, and show no signs of returning, because of concerns about safety, market size, patentability, medico-legal dimensions and the prodigious expense of product development and registration. Small-scale publically funded work continues in the USA, but sadly there is no prospect of a marketable product in the foreseeable future.

Finally, at a population level, infertile men die younger than fertile men. While this has only been recently recognised, in hindsight it makes perfect scientific sense and offers a brilliant opportunity for intervention.

Comparisons of lifespan are compounded by many factors, including lifestyle, genetics and psychological factors. It is for this reason that a Danish study of lifespan in men presenting for infertility treatment was so compelling (http://tinyurl.com/pbmwetk). Data from semen analyses from more than 43,000 men presenting for infertility treatment in the greater Copenhagen region was linked to longevity via the Danish central registers. All semen data was obtained from the same laboratory. While undoubtedly not perfect, the selection of this patient group normalises for several factors, including socioeconomic standing (which is undoubtedly a key determinant of life expectancy) and geographical influences. The results of this study showed that men with lower sperm counts were significantly more likely to die younger than men with high sperm counts.

Indeed, a negative linear relationship was observed between sperm count and life expectancy, which levelled off above 40 million sperm per millilitre of semen. A similar correlation was observed between sperm motility, sperm morphology and life expectancy. Interestingly, the presence of children in the man’s home (from his partner, for example) was not protective against early death, suggesting that children per se do not help you live longer.

Across the Atlantic, a similar result was obtained in an American study (http://tinyurl.com/qf5mt8g) that analysed its data in a slightly different way: the chances of death in an 8-year follow-up period. The researchers analysed semen profiles from 12,000 relatively young patients (<50 years) in California and Texas, and linked it to mortality data via the National Death Index or Social Security Death Index. The authors found that any of low semen volume, sperm concentration and count, and the percentage of motile sperm within an ejaculate was associated with higher risk of early death. The authors found that if a man presented with two or more abnormal semen parameters he had a 2.3-fold higher risk of death compared with men with normal semen. This risk was comparable to diabetes or smoking.

But why are infertile men dying younger, and what are they dying of? While the two studies above could not define cause due to a paucity of events within the datasets, other studies have reported links between male infertility and both testicular cancer (http://tinyurl.com/p3qw82p) and high-grade prostate cancer (http://tinyurl.com/ob7qcmj).

Clearly this lack of definitive causation deserves intensive study, and provides a compelling argument for the collection of a detailed medical history at the time of infertility assessment. Such data should be integrated with long-term follow-up of outcomes and data linkage, as occurs in Scandinavia.

There are two possible explanations for the link between male infertility and earlier death. These explanations are linked to the complex and sensitive nature of sperm production and are equivalent to the clinical distinctions of primary and secondary testicular failure.

In primary cases, the origin of the infertility is in the testis, where sperm production occurs. Spermatogenesis is a complex process requiring the coordinated expression of many thousands of individual genes to produce a cell, the sperm, that is ultimately capable of both motility and fertility.

Spermatogenesis involves three major phases:

  • the continuous replication of a stem cell population;
  • the mixing and halving of the genetic complement during meiosis; and
  • a remarkable transformation wherein round spermatid cells are transformed into the highly specialised and streamlined cells we all recognise as sperm.

Spermatogenesis occurs at a frenetic pace across a male’s adult life, leading to a mind-boggling production rate of 1000 sperm per second. To achieve this, many pathways involved in spermatogenesis are running at “full throttle”. If there is a problem with an individual gene required for sperm production, or a pathway is impacted by an environmental insult, sperm production drops off and/or sperm quality is compromised.

Importantly, however, many of these pathways are conserved in other parts of the body, but only come into play at times of biological stress. Notable examples include DNA repair pathways that are absolutely essential for male fertility but also exist to protect the rest of the body against mutations and the development of cancers.

Indeed, spermatogenesis has been a fantastic model system to define pathways of fundamental importance to human health, including the first discovery of stem cells, numerous aspects of DNA repair pathways, and many aspects of the epigenetic pathways that are gaining such attention recently because of their potential to transmit “poor health” across generations.

The second potential link between male infertility and mortality is what is clinically referred to as secondary testicular failure. Simplistically, this is when ill health in another part of the body compromises sperm output. A classic example is when structural or functional defects in the hypothalamo-pituitary axis lead to the shutting down of sperm production, but many more diverse causes exist including obesity, viral infections and environmental pollution. Spermatogenesis is remarkably sensitive.

Regardless of the cause of infertility, the link between male fertility and long-term health offers an opportunity for early intervention. If we as a research community are able to flesh out the links between particular types of male infertility and health, the presentation of a man at an infertility clinic will offer the opportunity to not only provide him and his partner with the children they clearly desire, but it will be an opportunity to predict potentially more deadly and expressive disease at a younger and more treatable age.

The first step in this worthy pathway would be the broad acceptance that male infertility is a both common and serious disease that is deserving of equal importance to some of the more high profile diseases. It should be discussed openly, with semen analysis a standard part of any male health workup.

Moira O’Bryan is Head of the Development and Stem Cells program at the Biomedicine Discovery Institute at Monash University. Rob McLachlan is the Director of Andrology Australia.