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Are worldwide sperm counts declining?

2021; Elsevier BV; Volume: 116; Issue: 6 Linguagem: Inglês

10.1016/j.fertnstert.2021.10.020

1556-5653

Niels Jørgensen, Dolores J. Lamb, Hagai Levine, Alexander W. Pastuszak, John T. Sigalos, Shanna H. Swan, Michael L. Eisenberg,

Assisted Reproductive Technology and Twin Pregnancy

“Are sperm counts (SCs) declining?” This question touches on a myriad of scientific and social issues. A declining SC has implications for birth rates, male reproductive health and overall health, societal and economic trends, and even men’s self-identity. Addressing a decline can have profound consequences for the multiple lifestyle and chemical risk factors implicated. Some of this controversy is genuine and scientific. Unfortunately, some may also be artifactual, manufactured by industries suspected of contributing to these declines, as has happened, for example, with respect to lead and tobacco (1Michaels D. The triumph of doubt. Oxford University Press, Oxford2020Google Scholar). In 1992, Carlsen et al. (2Carlsen E. Giwercman A. Keiding N. Skakkebaek N.E. Evidence for decreasing quality of semen during past 50 years.BMJ. 1992; 305: 609-613Crossref PubMed Google Scholar) published a significant article on this issue, which concluded, “There has been a genuine decline in semen quality over the past 50 years.” This article was widely critiqued, and the dataset was reanalyzed and enlarged (in part by us) (3Swan S.H. Elkin E.P. Fenster L. Have sperm densities declined? A reanalysis of global trend data.Environ Health Perspect. 1997; 105: 1228-1232Crossref PubMed Google Scholar, 4Swan S.H. Elkin E.P. Fenster L. The question of declining sperm density revisited: an analysis of 101 studies published 1934-1996.Environ Health Perspect. 2000; 108: 961-966Crossref PubMed Google Scholar). However, it should be noted that the overall conclusion remained unchanged. Our 2017 meta-analysis, reaching a similar conclusion, was able to make use of methods developed in the interim (such as progress in systematic literature searches and meta-analytic statistical techniques) as well as heightened awareness of the need for transparency in research. As a result, there is now a much broader consensus regarding the decline in SCs. This can be seen in both the scarcity of published challenges to our results and statements by official organizations, such as that issued by the United Nations (5United Nations Human Rights Office of the High CommissionerOpening Remarks, United Nations Special Rapporteur on human rights and hazardous substances and wastes, Baskut Tuncak 74th Session of the U.N. General Assembly, Third Committee.https://www.ohchr.org/EN/NewsEvents/Pages/DisplayNews.aspx?NewsID=25232&LangID=EDate accessed: October 22, 2021Google Scholar). Male reproductive health is a sensitive issue that has been largely neglected, stemming in part from the traditional assumption that a couples’ failure to conceive was the woman’s “fault.” Therefore, the signal that SCs (and male reproductive function) are in decline triggers a wide range of responses, including some that are emotional, defensive, and nonscientific. The ideal study cannot be conducted, particularly on the global level (6Smarr M.M. Sapra K.J. Gemmill A. Kahn L.G. Wise L.A. Lynch C.D. et al.Is human fecundity changing? A discussion of research and data gaps precluding us from having an answer.Hum Reprod. 2017; 32: 499-504PubMed Google Scholar). Such a study would require consistent, population-wide records of SCs in comparable populations across time and space, as are collected for the number of births, the sex of the offspring, birth weight, or age at death, which are universally and reliably recorded across time in most countries. There is some consistent recording of significant health endpoints such as cancers and birth defects, but these are far from universal. There is no such practice or legal requirement for the widespread recording of any measure of reproductive health as, perhaps, there should be. In fact, the semen quality of most men is unknown, even to the men themselves. Indeed, we and others have called for the development of a surveillance system for reproductive indicators (7Le Moal J. Sharpe R.M. Jϕrgensen N. Levine H. Jurewicz J. Mendiola J. et al.Toward a multi-country monitoring system of reproductive health in the context of endocrine disrupting chemical exposure.Eur J Public Health. 2016; 26: 76-83Crossref PubMed Scopus (27) Google Scholar). Because these data are not routinely recorded, any analysis of trends in semen quality must rely on published reports in isolated times and locations and in relatively small subsets of men. Unless there are resources devoted to collecting this data, using standard methods, data will necessarily be subject to selection factors. These include the availability of necessary medical and laboratory facilities to conduct testing, social attitudes toward sperm testing, and motivation for participation. Since any analysis must rely on published results, publication in the peer review literature introduces additional selection factors, such as the ability to write a manuscript that passes peer review and is suitable for inclusion in a bibliographic database, such as PubMed. These are challenges to studying time trends for most physiologic variables. They do not, of course, doom the enterprise to failure but increase the demand for extreme rigor, attention to potential confounding, and transparency of methods. If, however, semen quality were accepted as a significant health indicator (as for blood pressure and cholesterol), this would not only provide consistently collected data for epidemiologic analysis but also provide men with a measure of their overall health (8Eisenberg M.L. Li S. Behr B. Cullen M.R. Galusha D. Lamb D.J. et al.Semen quality, infertility and mortality in the USA.Hum Reprod. 2014; 29: 1567-1574Crossref PubMed Scopus (123) Google Scholar). This question is compound in several ways. First, semen quality is measured by multiple parameters, including count, concentration, morphology, and motility. Second, the term variation includes both true (biologic) variation between populations and methodological (nonbiologic) variations. If, hypothetically, semen parameters could be assessed in multiple populations using comparable methods of population selection and analysis (and confounding factors such as age and time since last ejaculation could be reliably controlled for), the remaining variability would reflect the true biologic variation. This was the rationale for several studies that examined semen parameters in men from diverse environments. In these, selection criteria were identical across locations, and rigorous quality control measures and comparable instrumentation minimized methodological variation (9Redmon J.B. Thomas W. Ma W. Drobnis E.Z. Sparks A. Wang C. et al.Semen parameters in fertile US men: the study for future families.Andrology. 2013; 1: 806-814Crossref PubMed Scopus (41) Google Scholar, 10Jørgensen N. Andersen A.G. Eustache F. Irvine D.S. Suominen J. Petersen J.H. et al.Regional differences in semen quality in Europe.Hum Reprod. 2001; 16: 1012-1019Crossref PubMed Google Scholar). Short of this, most comparisons across locations and time are also subject to methodological variation. In the study by Levine et al. (11Levine H. Jørgensen N. Martino-Andrade A. Mendiola J. Weksler-Derri D. Mindlis I. et al.Temporal trends in sperm count: a systematic review and meta-regression analysis.Hum Reprod Update. 2017; 23: 646-659Crossref PubMed Scopus (501) Google Scholar), we were acutely aware of this challenge and introduced selection criteria to minimize these sources of variation. For example, we required the use of a hemocytometer and excluded any study in which men were selected by factors that were plausibly related to fertility and semen parameters. It has been suggested that an alternative hypothesis to a significant decline in SC and concentration is “biovariation,” which is not supported by the available data. If the declines we and several others report merely reflect biovariability, we would expect that, on average, half of these publications would show an increase and half would show a decrease in SC. In fact, a quick review of studies listed in PubMed that report trends in SC and total sperm concentration (TSC) reveals a few that report no significant change and a majority that report significant declines. It is striking that few (if any) report a significant increase across the study period in either sperm parameter. We may speculate that publication bias has led to a greater likelihood that studies showing a decrease would be published. However, given the debate on this issue over the past 25 years, this is an unlikely explanation for the absence of studies reporting an increase in SC. Therefore, although we agree that SC and TSC can vary widely on an individual level, SC biovariation does not appear to explain the population-wide trends that we report. Based on extensive animal and human data, it is now widely accepted that exposures occurring during the male programming window in early gestation have the most profound influence on adult semen quality. Although we cannot perform clinical studies to demonstrate this, it is illustrated by the strongly negative and irreversible effect of maternal smoking during pregnancy in contrast to the less marked and reversible effect of a man’s smoking in adulthood. Although we cannot assign harmful exposure at random, there are other valid study designs that can be used to examine the causes of altered semen quality. In the occupational setting, there are several historical examples of this. For example, the pesticide dibromochloropropane was found to drastically lower SCs. When its use was halted, SCs recovered (12Goldsmith J.R. Dibromochloropropane: epidemiological findings and current questions.Ann N Y Acad Sci. 1997; 837: 300-306Crossref PubMed Google Scholar). Industrial disasters also provide “experiments” in which a population is inadvertently poisoned by a massive accident, such as the dioxin accident in Seveso, Italy, in 1976, with profound effects on semen quality (13Mocarelli P. Gerthoux P.M. Patterson Jr., D.G. Milani S. Limonta G. Bertona M. et al.Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality.Environ Health Perspect. 2008; 116: 70-77Crossref PubMed Scopus (220) Google Scholar). Studies of semen quality in occupationally exposed workers, such as lead battery workers, also provide convincing causal evidence of effects of chemical exposure on semen quality (14Naha N. Chowdhury A.R. Inorganic lead exposure in battery and paint factory: effect on human sperm structure and functional activity.J UOEH. 2006; 28: 157-171Crossref PubMed Scopus (39) Google Scholar). In addition, the effect of environmental exposures on semen quality can be demonstrated through intervention studies, such as removing a suspect exposure from a man’s usual practice and comparing his semen quality with that of a random sample of men performing “business as usual.” Finally, in vitro studies coupled with animal studies demonstrating reproductive toxicity can inform well-conducted population-based epidemiologic studies. A consistent “weight of evidence” across these three sources of data is convincing evidence of causality (15Hardy A. Benford D. Halldorsson T. Jeger M.J. Knutsen H.K. More S. et al.EFSA Scientific CommitteeGuidance on the use of the weight of evidence approach in scientific assessments.EFSA J. 2017; 15 (Available at https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/j.efsa.2017.4971. Accessed November 14, 2021)e04971Crossref Google Scholar). The dangers of neglecting a true decline in SCs are far more serious than reporting a decline that does not exist. Ignoring the potential decline and its causes can lead to irreversible damage to human and planetary health, which, at some point, could become an existential threat, even if odds seem currently low. Environmental agents capable of altering semen quality could have long-term, even transgenerational, impact. Action to improve semen quality such as decreasing unhealthy lifestyle behaviors such as smoking, poor diet, or lack of physical activity and eliminating toxic environmental chemicals will only serve to improve general health and sustainability. The cost of delayed action is high, whereas that of investment in research and precautionary measures is minimal in comparison to that potential damage. Since the 1970s and 1980s, there has been concern that SCs are declining compared with those in the early to mid-20th century (16Nelson C.M. Bunge R.G. Semen analysis: evidence for changing parameters of male fertility potential.Fertil Steril. 1974; 25: 503-507Abstract Full Text PDF PubMed Google Scholar, 17Bostofte E. Serup J. Rebbe H. Has the fertility of Danish men declined through the years in terms of semen quality? A comparison of semen qualities between 1952 and 1972.Int J Fertil. 1983; 28: 91-95PubMed Google Scholar, 18Murature D.A. Tang S.Y. Steinhardt G. Dougherty R.C. Phthalate esters and semen quality parameters.Biomed Environ Mass Spectrom. 1987; 14: 473-477Crossref PubMed Google Scholar). This discussion was ignited in 1992 after a meta-analysis by Carlsen et al. (2Carlsen E. Giwercman A. Keiding N. Skakkebaek N.E. Evidence for decreasing quality of semen during past 50 years.BMJ. 1992; 305: 609-613Crossref PubMed Google Scholar) reported that the average semen volume had decreased from 3.4 to 2.75 mL between 1940 and 1990 and that the average sperm concentrations dropped from 113 to 66 million sperm per milliliter. To date, this study has been cited 3,800 times. These conclusions are patently false. There are no high-quality data that support a decline in semen parameters over time. The debate exists because of the subpar data and interpretations that were used over the past century. More reliable contemporary data provide a stronger signal that neither semen parameters nor male fertility have changed over the last century. Although semen analysis (SA) was used since the 1930s in the workup of male infertility, the precision and accuracy changed significantly from 1938 to 1990 (19Neuwinger J. Behre H.M. Nieschlag E. External quality control in the andrology laboratory: an experimental multicenter trial.Fertil Steril. 1990; 54: 308-314Abstract Full Text PDF PubMed Google Scholar, 20Andrade-Rocha F.T. On the origins of the semen analysis: a close relationship with the history of the reproductive medicine.J Hum Reprod Sci. 2017; 10: 242-255Crossref PubMed Scopus (8) Google Scholar). The development of improved sperm counting chambers, standardization of the assays, and development of proficiency programs to allow interlaboratory comparisons of accuracy led to improved accuracy of semen testing since its inception. The Carlsen article, in addition to making an incorrect assumption regarding SA standardization, also reported few data during the first 30 years of the analysis, as 10% of the studies represented 40% of the time analyzed and contained only 184 (1.2%) men evaluated (21Pastuszak A.W. Lamb D.J. Counting your sperm before they fertilize: are sperm counts really declining?.Asian J Androl. 2013; 15: 179-183Crossref PubMed Scopus (8) Google Scholar). Farrow et al. (22Farrow S. Falling sperm quality: fact or fiction?.BMJ. 1994; 309: 1-2Crossref PubMed Google Scholar), in his 1994 critique of this article, noted significant patient selection bias because men were evaluated under heterogeneous scenarios. Multiple studies took issue with not only the methodology of data collection but also the data analysis (21Pastuszak A.W. Lamb D.J. Counting your sperm before they fertilize: are sperm counts really declining?.Asian J Androl. 2013; 15: 179-183Crossref PubMed Scopus (8) Google Scholar, 22Farrow S. Falling sperm quality: fact or fiction?.BMJ. 1994; 309: 1-2Crossref PubMed Google Scholar, 23Olsen G.W. Bodner K.M. Ramlow J.M. Ross C.E. Lipshultz L.I. Have sperm counts been reduced 50 percent in 50 years? A statistical model revisited.Fertil Steril. 1995; 63: 887-893Abstract Full Text PDF PubMed Google Scholar). Sperm concentrations do not follow a normal distribution; therefore, reporting of the mean sperm concentration is inferior to reporting of the medians, and the data should have used geometric or logarithmic transformation. Olsen et al. (23Olsen G.W. Bodner K.M. Ramlow J.M. Ross C.E. Lipshultz L.I. Have sperm counts been reduced 50 percent in 50 years? A statistical model revisited.Fertil Steril. 1995; 63: 887-893Abstract Full Text PDF PubMed Google Scholar) reanalyzed the Carlsen data using four different statistical models (linear, quadratic, spline fit, and stairstep). Only the linear model, which was the original analysis method used in the Carlsen article, was consistent with a hypothesis of a constant continuous decline in SCs. The quadratic and spline fit models (with an equally good or better fit of the data) were consistent with a catastrophic drop in sperm concentration in the 1960s followed by an increase since the 1970s, with the stairstep model showing no change in SCs (23Olsen G.W. Bodner K.M. Ramlow J.M. Ross C.E. Lipshultz L.I. Have sperm counts been reduced 50 percent in 50 years? A statistical model revisited.Fertil Steril. 1995; 63: 887-893Abstract Full Text PDF PubMed Google Scholar). When larger, better controlled studies evaluated equivalent study populations from similar geographies, with the same indications for semen parameter assessment and the same laboratories over time, no changes in SCs were observed. Macleod and Wang (24MacLeod J. Wang Y. Male fertility potential in terms of semen quality: a review of the past, a study of the present.Fertil Steril. 1979; 31: 103-116Abstract Full Text PDF PubMed Google Scholar) in 1979 reported no change in semen parameters in the assessment of approximately 15,000 men from 1951 and 1966–1977 (24MacLeod J. Wang Y. Male fertility potential in terms of semen quality: a review of the past, a study of the present.Fertil Steril. 1979; 31: 103-116Abstract Full Text PDF PubMed Google Scholar). When a homogeneous group of 4,867 Danish men from the Copenhagen area were evaluated from 1996 to 2010, the median sperm concentration increased from 43 to 48 million/mL, and the TSC increased from 132 to 151 million over the 15-year study period (25Jørgensen N. Joensen U.N. Jensen T.K. Jensen M.B. Almstrup K. Olesen I.A. et al.Human semen quality in the new millennium: a prospective cross-sectional population-based study of 4867 men.BMJ Open. 2012; 2 (Available at https://bmjopen.bmj.com/content/bmjopen/2/4/e000990.full.pdf. Accessed November 14, 2021.)e000990Crossref PubMed Scopus (200) Google Scholar). In a Canadian study of approximately 48,000 men presenting to infertility clinics over a 13-year period from 1984 to 1996, the linear regression analysis of the means of each center for each year showed no significant trend (26Younglai E.V. Collins J.A. Foster W.G. Canadian semen quality: an analysis of sperm density among eleven academic fertility centers.Fertil Steril. 1998; 70: 76-80Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). Since the 1990s, studies of varying quality across a number of geographic locations were published, which investigated changes in semen parameters over time. Between 1992 and 2013, 35 studies examining changes in semen parameters over time were published. Of these, 8 studies including 18,109 men suggested a decline in semen parameters, whereas 21 studies including 112,386 men showed either no change or improvements in semen quality (27Fisch H. Braun S.R. Trends in global semen parameter values.Asian J Androl. 2013; 15: 169-173Crossref PubMed Scopus (22) Google Scholar). The debate over semen parameters was reignited in 2017 after a meta-analysis was published in Human Reproduction Update that garnered lay public and scientific attention. The investigators observed a 50%–60% decline in SCs between 1973 and 2011 (99.0 million/mL in 1973 to 47.1 million/mL in 2011) among men from Western populations. These results were in contrast to the results of the “other” populations from South America, Asia, and Africa, where SC did not change (11Levine H. Jørgensen N. Martino-Andrade A. Mendiola J. Weksler-Derri D. Mindlis I. et al.Temporal trends in sperm count: a systematic review and meta-regression analysis.Hum Reprod Update. 2017; 23: 646-659Crossref PubMed Scopus (501) Google Scholar). To prevent some of the methodological shortcomings of previous meta-analyses, the investigators limited included data to those that used equivalent SC measurement techniques and excluded men with known infertility and exposures that may cause infertility. The investigators attempted to control for potential confounders, implemented quality control protocols, and performed sensitivity analyses. Despite these best efforts, differences in SA technique, quality control, and training changed over the studied time period, making comparisons between results inaccurate (28Pacey A.A. Are sperm counts declining? Or did we just change our spectacles?.Asian J Androl. 2013; 15: 187-190Crossref PubMed Scopus (14) Google Scholar, 29Boulicault M. Perret M. Galka J. Borsa A. Gompers A. Reiches M. et al.The future of sperm: a biovariability framework for understanding global sperm count trends.Hum Fertil (Camb). 2021; : 1-15Crossref PubMed Scopus (6) Google Scholar). Limitations in the completeness of the datasets included in the analysis also limit the conclusions (29Boulicault M. Perret M. Galka J. Borsa A. Gompers A. Reiches M. et al.The future of sperm: a biovariability framework for understanding global sperm count trends.Hum Fertil (Camb). 2021; : 1-15Crossref PubMed Scopus (6) Google Scholar). There is an implicit assumption in the data analysis by Carlson et al. (2Carlsen E. Giwercman A. Keiding N. Skakkebaek N.E. Evidence for decreasing quality of semen during past 50 years.BMJ. 1992; 305: 609-613Crossref PubMed Google Scholar) and the studies described earlier that the SA values reported are accurate and precise, that the abstinence period was controlled, and that comparing results obtained from several laboratories in different areas would allow for reliable pooling of data. Thus, there is a lack of standardization and accuracy in SA performance. The results can be precise and not be accurate. Keel et al. (30Keel B.A. Quality control, quality assurance, and proficiency testing in the andrology laboratory.Arch Androl. 2002; 48: 417-431Crossref PubMed Scopus (20) Google Scholar, 31Keel B.A. Quinn P. Schmidt Jr., C.F. Serafy Jr., N.T. Serafy Sr, N.T. Schalue T.K. Results of the American Association of Bioanalysts national proficiency testing programme in andrology.Hum Reprod. 2000; 15: 680-686Crossref PubMed Google Scholar, 32Keel B.A. Stembridge T.W. Pineda G. Serafy Sr N.T. Lack of standardization in performance of the semen analysis among laboratories in the United States.Fertil Steril. 2002; 78: 603-608Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar) showed that SA results are unreliable from several laboratories—an observation also made by others on the basis of interlaboratory comparisons (reviewed in Keel et al. [30–32]). The results from different laboratories on the same specimen varied by as much as two orders of magnitude (not twofold!) (31Keel B.A. Quinn P. Schmidt Jr., C.F. Serafy Jr., N.T. Serafy Sr, N.T. Schalue T.K. Results of the American Association of Bioanalysts national proficiency testing programme in andrology.Hum Reprod. 2000; 15: 680-686Crossref PubMed Google Scholar, 33Mallidis C. Cooper T.G. Hellenkemper B. Lablans M. Ückert F. Nieschlag E. Ten years' experience with an external quality control program for semen analysis.Fertil Steril. 2012; 98: 611-616.e4Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). A multicenter study in Europe showed that overall, <8% of clinical laboratories truly followed the World Health Organization (WHO) guidelines (33Mallidis C. Cooper T.G. Hellenkemper B. Lablans M. Ückert F. Nieschlag E. Ten years' experience with an external quality control program for semen analysis.Fertil Steril. 2012; 98: 611-616.e4Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). From a methodological perspective, several clinical andrology laboratories now use disposable counting chambers using undiluted semen with sperm actively swimming in and out of the field of view. Counting motile sperm makes the SC less reliable, in particular when several sperm are present. The WHO specifies that semen should be diluted before counting, rendering the sperm immotile and permitting counting precision. The use of different counting chambers other than the hemocytometer impacts the SC, whether manual analysis or computer-assisted SA is performed (34Seaman E.K. Goluboff E. BarChama N. Fisch H. Accuracy of semen counting chambers as determined by the use of latex beads.Fertil Steril. 1996; 66: 662-665Abstract Full Text PDF PubMed Google Scholar, 35Dardmeh F. Heidari M. Alipour H. Comparison of commercially available chamber slides for computer-aided analysis of human sperm.Syst Biol Reprod Med. 2021; 67: 168-175Crossref PubMed Scopus (2) Google Scholar). The criteria for sperm morphology according to the WHO have changed as the definitions to described normal sperm morphology became increasingly strict. Without standardization of every step of the sample collection and abstinence and due to the lack of reliable interlaboratory results, it is impossible to interpret the data. This controversy continues to provoke interest and scientific discussion today, as in the last year four groups published articles examining the question of SCs with two groups finding evidence for decline and two showing no decline (36Rosa-Villagrán L. Barrera N. Montes J. Riso C. Sapiro R. Decline of semen quality over the last 30 years in Uruguay.Basic Clin Androl. 2021; 31 (Available at https://doi.org/10.1186/s12610-021-00128-6. Accessed November 14, 2021.): 8Crossref PubMed Scopus (2) Google Scholar, 37Cannarella R. Condorelli R.A. Gusmano C. Barone N. Burrello N. Aversa A. et al.Temporal trend of conventional sperm parameters in a Sicilian population in the decade 2011-2020.J Clin Med. 2021; 10 (Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957883/pdf/jcm-10-00993.pdf. Accessed November 14, 2021.): 993Crossref PubMed Scopus (3) Google Scholar, 38Barrera N. Ordoqui R. Montes J.M. Canepa M. Bonelli C. Surka C. et al.The Uruguayan semen donor population: a twenty-eight-year retrospective study.Andrologia. 2020; 52e13502Crossref Scopus (4) Google Scholar, 39Liu J. Dai Y. Li Y. Yuan E. Wang Q. Wang X. et al.A longitudinal study of semen quality among Chinese sperm donor candidates during the past 11 years.Sci Rep. 2020; 10: 10771Crossref PubMed Scopus (2) Google Scholar). The abundance of conflicting data on the topic continues to makes this debate controversial. Regardless, when the best controlled and methodologically sound studies are examined, these data support no change in SCs over time. To unequivocally answer the question of whether semen parameters are declining over time, one would need to enroll men in a study or studies that satisfy several conditions. The study would have to be prospective, with thousands of participants providing multiple semen samples across several years and geographic distributions/climates, and involve a comprehensive multinational effort (40Santi D. Magnani E. Michelangeli M. Grassi R. Vecchi B. Pedroni G. et al.Seasonal variation of semen parameters correlates with environmental temperature and air pollution: a big data analysis over 6 years.Environ Pollut. 2018; 235: 806-813Crossref PubMed Scopus (50) Google Scholar). Even within each geography, robust efforts to adequately sample different environments would be vital because diets, weather patterns, and environmental exposures vary greatly with differing locations even within one nation. Additionally, the study would need to accrue men across the life span, with the collection of a wide variety of social and biologic measures needed to identify potential confounders and causal variables in sperm variation, such as smoking and body mass index. Strict sample collection and processing requirements to ensure that abstinence times remain consistent and that laboratory assays are standardized with quality control and ongoing proficiency testing would also be required (28Pacey A.A. Are sperm counts declining? Or did we just change our spectacles?.Asian J Androl. 2013; 15: 187-190Crossref PubMed Scopus (14) Google Scholar). There exists baseline variability in semen parameters even among fertile males, which makes obtaining reliable, repeatable conclusions challenging. The SA results are variable both within a population and within single individuals. Indeed, in animal models and agriculturally important species, high SC and larger testis size are genetic traits that can be achieved through breeding. This is true for prize bulls, race horses, and other financially valuable animals. Accordingly, semen parameters can vary markedly between different countries where there are very different lineages of people—for example, Denmark and Finland—geographically close but with very different genetic backgrounds between the populations. Differences in temperature gradients between northern and southern regions of a country and changes in seasons can alter semen parameters, as can abstinence times and arousal methods, as well as myriad environmental factors, chemicals, and medications. Because several factors can alter semen parameters, accounting for these is a challenge when approaching semen parameters from a population level over time (21Pastuszak A.W. Lamb D.J. Counting your sperm before they fertilize: are sperm counts really declining?.Asian J Androl. 2013; 15: 179-183Crossref PubMed Scopus (8) Google Scholar). The best way to account for variations in study design is repetition with several samples across time from each individual and large numbers of individuals generally across a diversity of environmental settings. The logistical practicalities of this approach have limited its adoption in the current literature. There are significant and challenging requirements in completing a study that would definitively shed light on the discussion around declining SCs. Preclinical models in this context are useful for preliminary hypothesis generation and evaluation but do not faithfully recapitulate human physiology of the sperm production. However, preclinical models may help guide optimal study design in humans to investigate pertinent environmental factors. Ultimately, preclinical models are inadequate to draw definitive conclusions on the effects of environmental factors on human spermatogenesis. Significant differences exist between spermatogonial subtypes and subtype amplification in mice, nonhuman primates, and human subjects (41Boitani C. Di Persio S. Esposito V. Vicini E. Spermatogonial cells: mouse, monkey and man comparison.Semin Cell Dev Biol. 2016; 59: 79-88Crossref PubMed Scopus (28) Google Scholar). Despite these differences in spermatogenesis, translating conclusions drawn from preclinical models in a laboratory environment to human spermatogenesis response in a real-world environment would be inadequate as the laboratory environment would be insufficient to replicate the exact environmental milieu of the real world, which varies from location to location and across several cultural and socioeconomic factors in humans. In the scientific community, hypotheses are tested against the null hypothesis, which states that there is no difference between groups unless proven otherwise. The danger in reporting inaccurate positive findings is the ability for those results to impact how a population is treated, how healthcare is delivered, and how a line of investigation is approached. It is dangerous to report a decline in SCs when none exists due to the inaccurate assumptions and conclusions about what a decline in semen concentration contextually represents. These reports have led to projections of widespread male infertility in the near future, without any evidence supporting the increased rates of male infertility (42Inhorn M.C. Patrizio P. Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century.Hum Reprod Update. 2015; 21: 411-426Crossref PubMed Scopus (616) Google Scholar, 43Mascarenhas M.N. Flaxman S.R. Boerma T. Vanderpoel S. Stevens G.A. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys.PLoS Med. 2012; 9e1001356Crossref PubMed Scopus (358) Google Scholar, 44Meacham R.B. Joyce G.F. Wise M. Kparker A. Niederberger C. Urologic Diseases in America Project. Male infertility.J Urol. 2007; 177: 2058-2066Crossref PubMed Scopus (43) Google Scholar, 45Bowles N. The dawning of sperm awareness. The New York Times, 2018Google Scholar). Semen parameters are also considered a metric for male health more generally. Abnormal semen parameters may reflect a harbinger for disease across the male population (8Eisenberg M.L. Li S. Behr B. Cullen M.R. Galusha D. Lamb D.J. et al.Semen quality, infertility and mortality in the USA.Hum Reprod. 2014; 29: 1567-1574Crossref PubMed Scopus (123) Google Scholar, 11Levine H. Jørgensen N. Martino-Andrade A. Mendiola J. Weksler-Derri D. Mindlis I. et al.Temporal trends in sperm count: a systematic review and meta-regression analysis.Hum Reprod Update. 2017; 23: 646-659Crossref PubMed Scopus (501) Google Scholar). Although there is little evidence to support the conclusion that sperm concentration alone is a valid holistic appraisal of male health (29Boulicault M. Perret M. Galka J. Borsa A. Gompers A. Reiches M. et al.The future of sperm: a biovariability framework for understanding global sperm count trends.Hum Fertil (Camb). 2021; : 1-15Crossref PubMed Scopus (6) Google Scholar), studies show modest associations between lifestyle factors that affect longevity and individual semen parameters (46Verón G.L. Tissera A.D. Bello R. Beltramone F. Estofan G. Molina R.I. et al.Impact of age, clinical conditions, and lifestyle on routine semen parameters and sperm kinematics.Fertil Steril. 2018; 110: 68-75.e4Abstract Full Text Full Text PDF PubMed Google Scholar, 47Povey A.C. Clyma J.A. McNamee R. Moore H.D. Baillie H. Pacey A.A. et al.Modifiable and non-modifiable risk factors for poor semen quality: a case-referent study.Hum Reprod. 2012; 27: 2799-2806Crossref PubMed Scopus (63) Google Scholar). Concluding that semen parameters are in decline can result in concern across the lay population that male health is deteriorating. These practical concerns regarding male fertility and general health have been stretched by men’s rights and alt right groups to fit a narrative that postulates declining SCs in developed nations is due to the liberalization, feminization, and decline of Western man (29Boulicault M. Perret M. Galka J. Borsa A. Gompers A. Reiches M. et al.The future of sperm: a biovariability framework for understanding global sperm count trends.Hum Fertil (Camb). 2021; : 1-15Crossref PubMed Scopus (6) Google Scholar). These erroneous assumptions regarding a decline in semen concentration, therefore, psychologically harm men who view semen parameters as marker of health, fertility, or masculinity. We prefer the framework proposed by Boulicault et al. (29Boulicault M. Perret M. Galka J. Borsa A. Gompers A. Reiches M. et al.The future of sperm: a biovariability framework for understanding global sperm count trends.Hum Fertil (Camb). 2021; : 1-15Crossref PubMed Scopus (6) Google Scholar) that espouses the SC biovariation hypothesis. This framework recognizes “male infertility is a complex biologic and social phenomenon that is not predicted by the single metric of sperm count and that the connection between sperm count and health is mediated by the individual’s recent experience and prior life history. The short time scales for sperm regeneration make sperm non-ideal for tracking health status” (29Boulicault M. Perret M. Galka J. Borsa A. Gompers A. Reiches M. et al.The future of sperm: a biovariability framework for understanding global sperm count trends.Hum Fertil (Camb). 2021; : 1-15Crossref PubMed Scopus (6) Google Scholar). To preserve the trust of general society, the scientific community cannot jump to conclusions regarding the decline of SCs because the data do not support this conclusion and sensationalized reports will cause undesired harm. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34082