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Safeguarding Men’s Health

The role of sperm counts

By Christopher De Jonge, PhD, HCLD(ABB)

Critical to the sperm count decline argument is the “old standard” manual semen analysis, which seems to be perpetually debated for its modern-day relevance, less than optimal discriminatory power to identify fertile from infertile men, and spotty adherence by testing labs to World Health Organization (WHO) laboratory standards for examination of semen.

It is important to remark that while high quality assessment of semen parameters is essential for contributing to accurate clinical diagnoses, the results are also critical for characterizing the proportion of infertile men in a population. This article will offer a brief overview of male infertility, its relationship with overall health, and some thoughts about ways in which Minnesota providers can contribute to making an even greater public health impact.

The Semen Analysis

Globally, one in six couples is considered infertile after an inability to conceive within one year of unprotected intercourse. In fact, the American Medical Association and WHO classify infertility as a disease because of its impact on normal reproductive function in both men and women. The incidence of infertility is essentially equal in men and women (30% and 35%, respectively), with the remaining 35% attributed to combined or unexplained causes. Infertility is most commonly a couple’s issue, and it is essential that simultaneous evaluation of both partners be done as part of the infertility investigation. Although a male factor is assigned in 30 to 40% of cases, a specific etiology is often missing. This is due to incomplete understanding around the processes of sperm production and functional quality and how lifestyle and environmental factors can influence those processes.

Male infertility may serve as a canary in the coal mine for future general health issues.

When evaluating a male for infertility it is essential that a comprehensive history and physical exam be done accompanied by a semen analysis. The global standard for assessing male reproductive function is the semen analysis. This has been the case since the early 1950s when MacLeod and Gold published on standardized methods for evaluating semen, followed by a series of papers reporting on the semen parameters, i.e., sperm counts, motility and morphology, in a large population of fertile versus infertile couples. Since that time WHO has published six editions of a laboratory manual for the examination of human semen; the latest edition was released in 2021 (www.who.int/publications/i/item/9789240030787). The manual also includes a table with the “Distribution of semen examination results from men in couples starting a pregnancy within one year of unprotected sexual intercourse leading to a natural conception.” The men were selected for data inclusion based on the definition for when a couple is considered as infertile. It is also well known that there is a substantial overlap of semen analysis results between fertile and infertile men. The preceding reinforces the essential need for simultaneous infertility evaluation of the female partner when determining a way forward in therapeutic strategy.

The following semen parameters reflect the fifth percentile values from a global population of almost 3,500 men:

• Semen volume (ml): > 1.4
• Sperm concentration (106 per ml): > 16
• Total sperm number (106 per ejaculate): > 39
• Progressive motility (%): > 30
• Vitality (%): > 54
• Morphology (normal forms %): > 4

It is preferable to refer men for semen analysis testing to a facility that performs semen analyses daily and that abides by current global standards for examination of the ejaculate. Some of the recommended standards are: collection of the specimen by masturbation after an ejaculatory abstinence period of two to seven days because fewer than two days or more than seven days of abstinence may influence semen quality; a sterile specimen collection cup should be used that is nontoxic to sperm as demonstrated by a bioassay; no lubricant should be used unless it is demonstrated to be nontoxic to sperm; off-site specimen collection using a special semen collection condom is acceptable provided the patient receives instructions for use, maintains the specimen at body temperature during transport and delivers it to the lab in less than 60 minutes; and the patient should be asked if the complete specimen was collected because the first fraction is enriched in sperm, and any loss can have an effect on semen analysis results.

The rationale for progression in the male infertility investigation based on semen analysis is:



• If all semen parameter values are above the lower reference limit after the initial analysis (WHO, 2021), then a requirement for a second semen collection is not indicated.
• If one or more semen parameter values fall below the lower reference limit, then a second collection is warranted.
• If semen parameter values fall below the reference range a second time, then referral to a urologist with subspecialty training in male infertility is recommended.
• If semen parameters fall above the lower reference limits, then results from infertility investigation of the female are equally important to help guide the next step, which may likely be referral to a reproductive medicine program for possible assisted reproduction.
• The odds of a man’s being infertile increases as the number of parameters outside WHO reference ranges increases.
  

Quality Metrics

The quality of a man’s ejaculate can be quite variable and it serves to further confound the predictive ability of fertility based solely on semen analysis. Reasons for specimen variability include factors such as anxiety surrounding the specimen collection process, lifestyle, fever and inherent individual variation. An important yet infrequently addressed variable concerns the quality of the laboratory where the test is performed, e.g., requisite qualifications and proficiency of testing personnel, compliance with regulatory standards and adherence to current WHO standard procedures for testing. 

Imbalances in reproductive gonadotrophins (follicle stimulating hormone, luteinizing hormone), genetic defects (e.g., cystic fibrosis and microdeletions in the Y chromosome), and other pathologies (e.g., varicocele) also influence semen quality. Adjunct tests are available for diagnosing most conditions, and in many cases corrective treatments can be offered. The semen analysis plays a key role in determining efficacy of post-treatment therapy.

Unfortunately, the etiology behind one or more abnormal semen parameters often remains elusive because more robust diagnostic tests are lacking. Further, if there is no identifiable cause for the semen’s being abnormal (idiopathic infertility), then there is no evidenced-based rationale for offering an effective treatment – because they simply aren’t available. The consequence is that the female partner in the couple becomes the surrogate for treating male factor infertility, and this highlights a stark example of medical inequity.

To achieve balance in equity requires substantial investments in research funding to decrease the significant gap that exists in our knowledge about the process of sperm production and function. Gaining fundamental knowledge can translate into broader and more accurate diagnostic tests and the development of precision treatment strategies for male infertility. Until then, women will continue to bear the assisted reproduction treatment burden for male factor infertility. 

Lifestyle and General Health

In addition to revealing overall reproductive health, the semen analysis can provide insight into a man’s lifestyle. For example, men using anabolic steroids to increase their muscle mass will also be responsible for the steroid-induced decrease in their sperm production because of testosterone deficiency (hypogonadism) and reduced testicular volume, resulting in severe oligo- and azoospermia (low or no sperm in the ejaculate). If drug use is not discontinued, prolonged exposure can result in complete and irreversible cessation of male reproductive capacity, rendering him sterile. Cannabis is a popular recreational drug used by reproductive age men and women. Men who frequently use cannabis are more likely to have abnormal semen parameters. Further reinforcing the importance that infertility be treated as a couple’s issue, recent findings caution that women should avoid cannabis use during pregnancy to optimize maternal and neonatal outcomes. Moderation is sage advice for many lifestyle issues, for example, hot tubs, alcohol, sleep, nutrition, obesity and stress, which can cause physiological changes to both body and brain, especially when the patient and his partner are starting down a pathway toward conception.

Evidence is accumulating that male infertility may serve as a canary in the coal mine for future general health issues. What does that mean? Recent data have revealed a connection between male reproductive health and overall health. For example, in comparison to fertile men, men with infertility are at a higher risk for testicular and prostate cancer, chronic comorbidities such as cardiovascular and metabolic disease, and higher mortality. Furthermore, male infertility can also impact both maternal and new baby wellness. The growing scientific data are so concerning that an author urged in a publication that “physicians should comprehensively assess men presenting for couple infertility given their higher risk for developing cancer”.

Men who frequently use cannabis are more likely to have abnormal semen parameters.

A Promising Future

Modern technologies for determining the sequence (termed: next generation sequencing) of the whole genome (the entire sequence of DNA coding for the whole of who we are) and whole exome (the protein-encoding region of the DNA) are quickly contributing to advances in male infertility diagnosis. For example, whole exome sequencing is increasing our understanding of what may be genetic causes of ill health and infertility. Epigenetics is another field that is beginning to have a tremendous impact on male reproduction research. The definition of epigenetics can be grossly simplified to mean those factors that are attached to DNA to regulate the activity of genes without changing their sequence. This regulatory process influences the production of proteins, i.e., the “building blocks of life”. Collectively, these new technologies are beginning to reveal that lifestyle, for example, obesity, environmental factors, occupational hazards, can impact the overall and reproductive health of the individual and the health of offspring born to that individual (termed: transgenerational inheritance).

These new areas of translational reproductive health research, while simplistically described here, are likely to transform the understanding of the origin and consequence of infertility, and how such causes might be mitigated by, for example, lifestyle changes. Lastly, for the aforementioned to be fully realized requires a heroic coordinated approach from research centers around the world to generate more quickly the massive datasets necessary to yield clear understanding of cause and effect of lifestyle on both good and ill health. To support research of this magnitude requires significant government policy and funding changes, even across borders.

Anticipated progress in the development of more accurate diagnostic tests contributes directly to the development of better and more effective treatment strategies. These changes can be anticipated to occur more quickly than in the past. Therefore, access to and delivery of health care will also need to evolve to accommodate new diagnostic and therapeutic technologies. This will compel rapid change and adaptation by medical educational programs so that new providers are current on the technologies. Also importantly, social education programs must be updated so that the communities being served are well informed. As the adage goes, “an ounce of prevention is worth a pound of cure”, and this makes financial sense for payers as well, i.e., insurance companies. It goes without saying that a loss of a partner/husband/father/worker to acute or chronic disease negatively impacts not only a household but a community and economy.

Considerations for men’s health and fertility throughout life

Teens (13-17 years old): Timing of puberty marks initiation of spermatogenesis. It also marks a time when teens should be made aware about the connection between reproductive and overall health. Teen males should be educated about the importance of healthy diet and exercise, good sleep habits, and the hazards of alcohol and recreational drug use. The medical community can provide information fact sheets for parents and teens that stress the importance of how establishing a healthy lifestyle routine early in life will yield future benefit.

Young Adults (18-24 years old): This is a period when males often go missing from health care seeking except in acute instances. Thus, the early conversations with teens are essential for reinforcing continuation of annual physical exams in young adult males. It is a critical time to question male patients about any physical changes they might have noticed, such as a lump in the testis or pain in the groin. Reinforce healthy eating habits and maintaining a routine exercise program. Review lifestyle choices that mitigate against toxic habits, such as recreational drug use, alcohol consumption, and inhalation of tobacco products.

With the development of more informative over the counter semen testing kits, suggestion can be made for young adults to consider them. They are inexpensive and the test is done in the privacy of their home. Most often it is not until a man becomes of future father age and trying to conceive with his partner that problems are revealed.

Future fathers (~25 to ~40 years old): In addition to the lifestyle factors that men have been educated about in earlier years, e.g., nutrition, exercise, they are now more likely to need reinforced consultation about other factors that could influence fertility and time to conception, such as diet, prescription and recreational drug use, alcohol and hot tub use. For the latter, prolonged and repetitive exposure of the testes to high temperatures can suppress spermatogenesis.

Men should be encouraged to actively participate in preconception planning with their partner. Healthy parents are more likely to conceive a healthy baby.

Men who have or will engage in occupations associated with exposures that may be hazardous to fertility (for example, firefighters, pilots, armed forces, welders) should be informed of the potential negative effects and be offered semen analysis to establish baseline fertility. Sperm freezing as a means of fertility preservation should be discussed.

Middle age (~40 to ~50 years old): Like women, men too have a biological clock with fertility declining past the age of 40 years. Reduced sperm quality is associated with increased time to conception and increased rates of miscarriage. Reduced fertility can be associated with comorbidities, can be an indicator of poor overall health and cardiovascular disease, and is associated with increased risks of prostate cancer.

Older men (>50 years old): Pregnancies conceived when the father is >50 years old are at a high risk of miscarriage and obstetric complications. Children conceived when their father is older are at an increased risk of autism and schizophrenia.

Summary

The goal of this article was to bring to you, the health care providers of Minnesota who serve as the gatekeepers for future Minnesota fathers, awareness and information about male reproductive health, infertility and correlation with overall health.

Science and medicine are moving rapidly forward hand in hand. Providers will soon benefit from advances in front line diagnostic tests, such as lab on chip devices, that will provide early detection of and reveal the etiology behind reproductive malfunction and any relationship with somatic health. Patients will in turn reap the benefits from early detection because of the opportunity for early targeted intervention and, it is hoped mitigation of the problem. An example of evolving testing that affords the opportunities mentioned comes from the field of epigenetics where changes have been shown to occur in the epigenetic profile of semen when cannabis use is stopped or when healthy foods, e.g., nuts, are supplemented to a regular Western-style diet. This is a scratch at the surface of how science and medicine will be used to evaluate the pre- and post-treatment responses in an individual’s reproductive health profile after lifestyle changes or other therapeutic interventions.

Lastly, women make about 80% of family health care decisions, including those of her male partner. Increased awareness by both men and women of male reproductive health issues can positively affect the future of not only the man’s health but also the health of the woman and their future children’s health. “Men’s health is family health”.

Christopher De Jonge, PhD, HCLD(ABB), is the director of the andrology program at the University of Minnesota Medical Center. He is also an adjunct professor in the department of urology at the University of Minnesota.