The significance of sperm morphology

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Anthony P. Cheung, MB BS, MPH, MBA, FRANZCOG, FRCSC

Research Director, Division of Reproductive Endocrinology and Infertility

Former Medical Director, UBC IVF Program

In our clinical practice, we constantly receive semen analysis reports from laboratories in our province showing a low percentage of normal sperm morphology, together with annotated comments on the potential causes. In the absence of other relevant information, many of these patients could be misclassified, and this, in turn, could lead to unnecessary anxiety among infertile couples and inappropriate utilization of health care resources. Indeed, some men have received controversial treatment such as a varicocele ligation, on the assumption that this was the cause of decreased sperm morphology, when improvement in sperm parameters has rarely been found on follow-up testing. Other men have been referred for the more invasive and costly assisted reproductive technology of in vitro fertilization (IVF) combined with intracytoplasmic sperm injection (ICSI). It is therefore important to interpret a low percentage of normal sperm morphology in perspective.

Standardization

Following the first report in 1929¹ to identify the value of sperm count, and the subsequent work of McLeod and Gold in 1951,² semen analysis has remained the benchmark measurement of male fertility. Increasing recognition of the need to objectively determine male fertility factors brought about the standardization of quantity, quality and functional characteristics of spermatozoa, which subsequently led to the World Health Organization guidelines.³ However, standardization does not imply a cause-and-effect relationship between sperm count and male infertility, but only makes it easier to communicate and compare information between research centres, while serving as a basis for further validation. For example, some subfertile men produce ten times the amount of semen considered normal according to WHO criteria, while others can father children by natural intercourse despite semen counts of 1.5 million/ml (WHO criteria define a normal concentration as over 20 million/ml). Thus, a given sperm count merely indicates the likelihood of fertility, rather than giving a definite “yes” or “no” answer.

Apart from sperm counts, we also have to take into account other sperm parameters, such as motility and morphology. In order to make these standards useful in predicting fertility, each centre should ideally revise them according to their own experience of the correlation between semen analysis results and subsequent fertility. When appropriate, we should also adjust for any concurrent female factors (such as age) by appropriate statistical methods. However, reliable data in this regard are difficult to obtain, given the many interrelated factors.

Nevertheless, the need for more reliable reference points has been heightened by the claim that, compared to men in the past, the output of total sperm per ejaculate in healthy men may have decreased by as much as 50 percent over the last few decades. This claim, which is based on a meta-analysis of 61 observational studies,⁴ has been disputed and criticized on various methodological grounds.⁵ Subsequent studies within single centres over time have reported increased, decreased or unchanged sperm outputs. Others have reported regional variation among geographically separated groups of men⁶ or bias of self-selected sperm donors for comparison.⁷ Further, there has been an increasing emphasis placed on the relation between abnormal sperm morphology and poor IVF rates, using the stricter Kruger criteria to classify sperm morphology and incorporating these criteria into the recent WHO guidelines for semen evaluation.

Sperm morphology

Clinicians, until recently, have generally ignored sperm morphology because interpretations of individual sperm as “normal” varied widely among different observers, even using atlases of sperm morphology as guides. Then investigators introduced overlays to use with video microscopy, which allowed a more standardized assessment of morphology.⁸ With this method, variation between observers was markedly reduced. In a series of articles, T. F. Kruger and his colleagues championed morphology assessment as the best indicator for predicting successful fertilization following IVF treatment.⁹ Using strict criteria, they shifted many sperm out of the earlier WHO “normal” category by including, as abnormal, sperm with even minor abnormalities, as well as those with abnormalities of the acrosome (in addition to the usual head and tail abnormalities). The acrosome is the pocket of enzymes that are released from the tip of sperm head after binding of the sperm to the oocyte; it is thought these acrosome enzymes are important in sperm penetration of the oocyte.

Despite some limited data correlating sperm morphology and fertilization rates following IVF treatment, others have not confirmed these findings, including the use of computer-assisted morphometric evaluation to minimize differences between observers.¹⁰ More importantly, field data using WHO or Kruger criteria in predicting general fertility (rather than IVF), have been limited. In particular, such a correlation may not be valid in the absence of a concurrent group of fertile males as controls. Even the scoring of morphology poses a problem, because multiple defects involving multiple sites can be present in the same sperm. Existing criteria consider mainly the overall percentages of sperm with abnormal forms without attention to the number and sites of the defects on each sperm. Some investigators have therefore suggested combining all these sperm abnormalities as an overall score in addition. An example is the multiple anomalies index (MAI) or teratozoospermia index (TZI), calculated as the mean number of defects per abnormal sperm which might be useful in predicting fertility among infertile men.¹¹ However, it has not yet been validated with simultaneous fertile controls, while others have not found a correlation between sperm morphology or TZI with fertilization rates, embryo scores or pregnancy rates following IVF or ICSI treatment.¹²

Significance of sperm morphology

Although many studies have been devoted to fertility estimation using semen analysis, very few have involved fertile controls. D. S. Guzick and his colleagues, by assessing both fertile and infertile men, have concluded that while threshold values for sperm concentration, motility, and morphology can be used to classify men as subfertile, of indeterminate fertility, or fertile, none of the measures are diagnostic of infertility.¹³ 

TABLE 1. SPERM THRESHOLD VALUES

Adapted from Guzick et al., “Sperm  Morphology, Motility and Concentration,” NEJM 345 (2001)

As the authors pointed out, “Although low values for each measurement increase the likelihood that a male factor contributes to infertility, there was substantial overlap in the frequency distributions in our study. Thus, values ... that are in the subfertile range do not exclude the possibility of normal fertility.” <!--[if !supportFootnotes]-->[*]<!--[endif]--> Indeed, this study showed that over 5% of fertile males had <5% of normal sperm morphology and over 20% of fertile males had between 5 to <9% of normal sperm morphology. Correspondingly, over 25% of subfertile males had >12 to 18% of normal sperm morphology. In our own study comparing fertile and subfertile males, we have found sperm morphology a poor predictor of fertility.¹⁴ Similar findings were noted in a subset of couples going through clomiphene citrate with intrauterine insemination (IUI)¹⁵ or superovulation using FSH with IUI.¹⁶

Conclusion

It is important to remember that semen analysis is only a screening test. A reference range for standardization does not necessarily rule out the chance of pregnancy. In the initial fertility workup, a low percentage of normal sperm morphology in isolation in the semen analysis has a poor predictive value for pregnancy success and does not warrant immediate urological consultation. It is certainly not an immediate indication for IVF/ICSI as normal pregnancy, whether spontaneous or following “low tech” fertility treatment, can occur. Rather than taking the isolated finding of a low percentage of normal sperm morphology on face value, it is important to consider the couple’s history, prior pregnancy, duration of infertility, and exclusion of other female factors such as age before attributing a male factor as the cause of infertility.

[FOOTNOTES – SET AS TRUE FOOTNOTES, i.e. AT BOTTOM OF THE COLUMNS IN WHICH THEIR RESPECTIVE NOTE CITATION CUES OCCUR. SET AT LEAST 1 POINT SMALLER THAN TEXT.]

[SVP PLACEZ LES NOTES DE BAS DE PAGE AU FOND DE LA COLONNE-MEME OU LA NOTATION SE TROUVE, EN REDUISANT LA TAILLE PAR 1 POINT MINIMUM]

1. D. Macomber and M. B. Sanders, “The spermatozoa count: Its value in the diagnosis, prognosis, and treatment of sterility,” New England Journal of Medicine 200, no. 19 (1929).

2. J. MacLeod and R. Z. Gold, “The male factor in fertility and infertility, II:  Spermatozoon counts in 1000 men of unknown fertility and in 1000 cases of infertile marriage,” Journal of Urology 66 (1951); “The male factor in fertility and infertility, IV: Sperm morphology in fertile and infertile marriage,” Fertility and Sterility 2, no. 5 (September–October 1951).

3. WHO Laboratory Manual for the Examination of Human Semen and Semen-cervical Mucus Interaction, 2nd ed. (Cambridge University Press 1987); 4th ed. (Cambridge University Press, 1999).

4. E. Carlsen, A. Giwercman, N. Keiding and N. Skakkeback, “Evidence for decreasing quality of semen during past 50 years,” British Medical Journal 305, no. 6854 (September 12, 1992).

5. P. Bromwich, J. Cohen, I. Stewart and A. Walker, “Decline in sperm counts: An artifact of changed reference range of ‘normal’?” British Medical Journal 309, no. 6946 (July 2, 1994); G.W. Olsen, K. M.Bodner, J. M. Ramlow et al., “Have sperm counts been reduced 50% in 50 years? A statistical model revisited,” Fertility and Sterility 63, no 4 (April 1995).

6. H. Fisch and E.T. Goluboff, “Geographic variations in sperm counts: A potential cause of bias in studies of semen quality,” Fertility and Sterility 65, no. 5 (1996); CECOS, “Evidence for regional differences of semen quality among fertile French men,” Human Reproduction 12, no. 4 (April 1997).

7. D. J. Handelsman, “Sperm output of healthy men in Australia: Magnitude of bias due to self-selected volunteers,” Human Reproduction 12, no. 12 (December 1997).

8. D. F. Katz, L. Diel and J. W. Overstreet, “Differences in the movement of morphologically normal and abnormal human seminal spermatozoa,” Biology of Reproduction 26, no. 4 (May 1982).

9. T. F. Kruger, A. A. Acosta, K. F, Simmons et al., “Predictive value of abnormal sperm morphology in in vitro fertilization,” Fertility and Sterility 49, no. 1 (January 1988).

10. N. Sukcharoen, T. Sithipravej, S. Promviengchai et al., “sperm morphology evaluated by computer (IVOS) cannot predict the fertilization rate in vitro after intracytoplasmic sperm injection,” Fertility and Sterility 69, no. 3 (March 1998).

11. P. Jouannet, B. Ducot, D. Feneux and A. Spira, “Male factors and the likelihood of pregnancy in infertile couples, I: Study of sperm characteristics,” International Journal of Andrology  11, no. 5 (October 1988).

12. E. Host, E. Ernst,  S. Lindenberg and S. Smidt-Jensen, “Morphology of spermatozoa used in IVF and ICSI from oligozoospermic men,” Redproductive Biomedicine Online,  vol. 3,  no. 3 (2001).

13. D. S. Guzick, J. W. Overstreet, P. Factor-Litvak et al., “Sperm morphology, motility, and concentration in fertile and infertile men,” New England Journal of Medicine 345, no. 19 (November 8, 2001).

14. A. P. Cheung, W. S. Geary, S. Wilson et al., “Sperm morphology in predicting male infertility” (paper presented at the 49th Annual Meeting of the Canadian Fertility and Andrology Society, Victoria, BC, November 5–8, 2003).

15. A. P. Cheung, M. Odulio and C. Nair, “The value of sperm morphology in predicting pregnancy success following clomiphene citrate and intrauterine insemination for idiopathic infertility” (paper presented at the 49th Annual Meeting of the Canadian Fertility and Andrology Society, Victoria, BC, November 5–8, 2003).

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16. A. P. Cheung et al., “The value of sperm morphology in predicting pregnancy success following superovulation and intrauterine insemination for idiopathic infertility” (paper presented at the 50^th Annual Meeting of the Canadian Fertility and Andrology Society, Jasper, Alberta, November 23–27, 2004).