A CLINICAL INVESTIGATION OF TIlE ROLE OF TIlE SEMEN ANALYSIS AND POSTCOITAL TEST IN TIlE EVALUATION OF MALE INFERTILITY

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1 F'ERTllJTY AND STERILITY Copyright 1972 by The Williams & Wilkins Co. Vol. 23, No.4, April 1972 Printed in U.SA. A CLINICAL INVESTIGATION OF TIlE ROLE OF TIlE SEMEN ANALYSIS AND POSTCOITAL TEST IN TIlE EVALUATION OF MALE INFERTILITY ANTHONY G. SANTOMAURO, M.D., JOHN J. SCIARRA, M.D., PH.D., * AND ANDRE O. VARMA, M.D. Departments of Obstetrics and Gynecology, and Preventive and Administrotive Medicine (Biostatistics), Columbia University College of Physicians and Surgeons, Sloane Hospital for Women, Columbia-Presbyterian Medical Center, New York, New York, and Department of Obstetrics and Gynecology, University of Minnesota Medical School, Minneapolis, Minnesota The interpretation of the routinely reported semen analysis is important in the evaluation of male fertility potential 1-6 A possible male factor has been identified by investigators in over 40% of infertile couples 1 and many of the investigators have attempted to correlate semen quality with fertility potential. The present study attempts to review the extent of male infertility in an infertility clinic population, to define the parameters of the semen analysis and postcoital test in this group, and to examine the relationship of these parameters to subsequent fertility. MATERIALS AND METHODS Three hundred fifty-eight couples were studied. These couples were involuntarily infertile for at least 1 year at the time of presentation to the Infertility Clinic of the Sloane Hospital for Women, Columbia Presbyterian Medical Center, New York City, from January, 1960 through December, On the basis of physical examinations and standard laboratory and radiographic procedures, potential female fertility was determined. In this study, the fertility potential of only those 175 males married to potentially fertile females was investigated. Sufficient criterion for fe'male infertility was untreated Received October 21, * Presently at the Department of Obstetrics and Gynecology, University of Minnesota Medical School, Minneapolis, Minnesota. anovulation or oligo-ovulation, bilateral tubal closure, or local factors such as untreated cervicitis with unfavorable cervical mucus. In this population of 358 infertile couples, the fertile male subgroup (96 couples) was defined as that subgroup of males whose wives eventually conceived. The remaining 79 males comprised the infertile subgroup. These males were unable to produce a pregnancy when paired with a female whose physiologic status would classify her as potentially fertile. For male subgroups, female age, the preclinical infertility period and the followup period were tabulated along with the following parameters of the semen analysis: sperm density, per cent motility, total motile count, and volume of ejaculate. Statistical comparison of the infertile and fertile male subgroups was done by the Kalmogorov-Smirnov test. 7 The same test was used to compare the distribution of motility and density in this fertile population and in 2 normal fertile male populations reported by MacLeod,4 and Page and Houlding. 6 The semen analysis was performed in a manner previously described. 1 Where multiple analyses were performed for 1 individual, the values contained in the report of the highest density were used. Per cent motility was determined between the 1st and 4th hr. after ejaculation. The total motile count (TMC) was calculated from the sperm 245

2 246 SANTOMAURO ET AL. Vol. 23 density, the volume of ejaculate, and the in vitro motility. The quality of sperm progression and per cent normal sperm morphology were reported, but were not compared because of the subjectivity with which they were determined in our laboratory. The relationship of the results of the postcoital test to subsequent fertility was investigated in both male subgroups by a statistical analysis of 68 postcoital tests read within 17 hr. after coitus at midcycle. The only variable of the postcoital test which could be satisfactorily quantitated was the number of motile sperm per high power field (S/HPF-400x). The distributions of SIHPF in the fertile and infertile subgroups were compared by a x 2 test. An additional statistical analysis of 100 postcoital tests was performed to determine the rank correlation coefficients between density and S/HPF, motility and S/HPF, and TMC and SIHPF. RESULTS Of the 358 couples studied, 79 were fertile (22.1%), 16.5% conceiving in the 1st year of followup. Among the remaining 279 infertile couples, female or male-female infertility was identified in 183 (65.6%) of the cases. Consequently, the incidence of the male as the sole cause of infertility was 34.4% as shown in Table 1 (96 couples). The average female age was 28.1 years with no significant difference between the ages of wives of fertile and infertile males. TABLE 1. Distribution of 358 Couples by the Clinical Status of the Female and Fertility Status at the End of Followup Potential of female Infertile Fertile Pregnant Not pregnant No Ages were not consistently available for males, but were assumed comparable to those of the female. 5 The mean preclinical infertility period for the entire population was 44.2 months (3.5 years). However, the average for the infertile subgroup (49.1 months) was significantly longer (t test: p < 0.001) than for the fertile subgroup (38.2 months). Ninety per cent of the couples in the infertile subgroup compared to 62% of those in the fertile subgroup had a preclinical infertility period of at least 2 years. There was no significant difference between the clinical followup of the two subgroups (11.1 and 13.2 months on the average) and no couple was followed for less than 6 months (Table 2). The distribution of sperm density in the infertile and fertile male subgroups was significantly different (Kalmogorov test: p < 0.001) as shown in Table 3. Forty- TABLE 2. Anamnestic Preclinical Infertility Period and Followup Periods of 175 Potentially Fertile Fe males by the Status at the End of Followup Pregnant Not pregnant Average preceding infer mos mos. tility period Median preceding infer mos mos. tility Per cent with preceding 62% 90% infertility period of at least 2 years Average followup period 11.1 mos mos. TABLE 3. Sperm Density of Fertile and Infertile Male Subgroups Density in millions/ceo Fertile males Infertile males * No. % No. % s * Five azospermic males.

3 April 1972 EVALUATION OF MALE INFERTll..ITY 247 three per cent of infertile males compared to 10% of fertile males had a sperm density lower than 20 million/cc. The greatest difference in distribution occurred in the 0-10 million/cc. range where the ratio of infertile to fertile males was 11. The median densities for the infertile and fertile subgroups were 26 and 52 million/cc., respectively (Fig. 1). In this and subsequent figures the quartiles of the populations are shown for comparison and these quartiles are summarized in Table 4. Likewise, the distribution of sperm motility in the two subgroups was significantly different (Kalmogorov test: p < 0.01) as shown in Table 5. Approximately 38% of the infertile males compared to 13% of the fertile males showed less than 40% motility. The medians for the infertile and fertile subgroups were 50 and 65%, respectively (Fig. 2). The volume of ejaculate in the infertile. 30 '0 'c 20 :::> Q ;j! Sperm Density in 10' Iml Q ;Ouorliles Infertile Moles O'=Ouarfiles Fertile Males FIG. 1. Percentage distribution of sperm density in subgroups by 79 fertile and 96 infertile males. TABLE 4 Density in Per cent motile mil- motility count in lions/ceo millions A. Fertile male subgroups 25th percentile Median th percentile B. Infertile male subgroups 25th percentile Median th percentile male subgroup was not significantly different from that in the fertile male subgroup (t test: p > 0.7). However, the difference in distribution of the total motile count (TMC) in these two groups was significant (Kalmogorov test: p < 0.001) as shown in Table 6. A TMC less than or equal to 10 million sperm was calculated for 40.6% of the infertile and 5.0% of the fertile males. The medians of TMC for the infertile and fertile subgroups were 26 and 74 million sperm, respectively (Fig. 3). The distribution of sperm density for the fertile population was significantly different from that of two populations of nor- TABLE 5. Per Cent Motile Spermatozoa of Fertile and Infertile Male Subgroups Per cent motile Fertile males Infertile males No. % No. % s :g -0.l!! 'c ::::> q Q) a. 0 Q I =15 Q2=50 d =45 Q'=65 o = Quarliles Infertile Males I i 2 Q 3 =70 5 rq 1 =80 I, 3 :,''''-r"\ I \ : \ \ \,{ERTILE '. INFERTILE Percent Motility FIG. 2. Percentage distribution of motility in subgroups of 79 fertile and 96 infertile males.

4 248 SANTOMAURO ET AL. Vol. 23 TABLE 6. Estimated Number of Spermatozoa (TMC) in the Ejaculates of the Fertile and Infertile Male Subgroups* No. of Fertile male. Infertile male. motile sperm in millions No. % No. % loa s * Calculated as motility x density x volume. infertile males differed significantly (x 2 = 11.42: p < 0.001). The median S/HPF was 5 for these couples; 72.2% of counts for infertile males; and 31.3% of counts for fertile males fell below the median (Table 7). In a random sample of 100 postcoital tests, the mean time following coitus at which tests were read was 13.3 hr. The temporal distribution of this series is shown in Fig. 4. There was a positive correlation between S/HPF and the following semen analysis parameters: density, motility, and TMC. Rank correlation coefficients were 0.52, 0.37, and 0.52, respectively. Eighty-nine per cent of males with a density of 20 million/cc. or less produced postcoital tests with at most 5 S/HPF (Table 8). DISCUSSION Although numerous infertile male popu- TABLE 7. Correlation of Motile Sperm and Fertility of 68 Couples* c Q1=1 0 u 40.!! :g ::;: 30 "0 J!! 20 Q ;;e 0 / 0:=42 o : Quartile's Infertile Moles 0' = Ouortiles Ferlile Moles Q 1!2 I : I Motile Count in 10! INFERTILE FIG. 3. Percentage distribution of the total motile count (TMC) in subgroups of 79 fertile and 96 infertile males. mal fertile males reported elsewhere 4. 8 (Kalmogorov test: p < 0.01). However, there was no significant difference between the distributions of motility reported for these three populations. In the subgroup of 68 couples whose postcoital tests were subjected to statistical analysis, the number of S/HPF found in the wives of fertile males compared to S/HPF No. in- fertile No. fertile Male status Per cent fertile * x' = (p < 0.001). If) en 30 $! '0 U 20 en &.... Ql E z '" o rli Hours Following Coitus Test Performed FIG. 4. Temporal distribution of 100 postcoital tests.

5 April 1972 EVALUATION OF MALE INFERTILITY 249 TABLE 8. Correlation of Sperm Density and S/HPF in 100 Postcoital Tests Sperm/ HPF Sperm density in I06/ce Per cent lations have been differentiated with statistical validity from normal fertile male populations on the basis of parameters of the semen analysis, as Hartman, 9 Freund,10 Charny,2 and Getzhoff3 have separately pointed out, no study has provided means of predicting with any meaningful certainty the infertility of a particular problematic male. By choosing a late referral infertility population, in which the mean infertility period was 3.5 years, and eliminating from consideration all couples in which a female infertility factor was probably contributory, it was possible to evaluate the male infertility factor with more certainty than in previous studies in which potentially fertile males married to infertile females were incorporated in the calculations.1, 4, 6, 9, 11 The 34.4% incidence of a sole male cause of infertility is 1.7 greater than that reported by Buxton and Southam, 1 and Simmons and Layman. 12 This may reflect a more adequate treatment of female infertility during the period of this study. It is possible, however, that if it had been feasible to discriminate infertility of combined etiology in this study, the incidence of male infertility might even be higher. Since no bias was introduced by artifically creating a category of unexplained cases, it is also possible that some potentially fertile males whose wives were infertile from causes which are not as yet clinically detectable were included in the infertile group. The significant difference between the distributions of density, motility, and the TMC in this infertile and fertile male population agrees with reports of most investigators. However, a comparison of the per cent distribution of this infertile population to those of two other infertile populations indicates that the infertile male is characterized by lower semen quality than previously evidenced,4, 6 as shown in Table 9. The discrepancy results from previously defining the infertile male as a male in an infertile marriage, and thereby including in the data analyses of fertile males married to infertile females. The difference between the per cent distribution of the fertile and infertile male population for all semen parameters studied was large only for extremely low values. This is particularly evident when the joint distribution of density and motility of infertile and fertile males is compared (Table 10). From the data pre- TABLE 9. Per Cent Distribution of Motility and Density in 3 Infertile and 1 Fertile Male Population Density in millions/ceo Motility less than 40% Less Less than than Infertile males MacLeod-infertile males Page and Houlding-infertile males Fertile males TABLE 10. A Comparison of the Per Cent Distribution of 79 Fertile and 96 Infertile Male Subgroups for Density and Motility Combined Density in millions/ceo Corresponding motility Per cent distribution Infertile Fertile % < 10 < <60 < <60 > >60 < >60 >

6 250 SANTOMAURO ET AL. Vol. 23 sented in this study, it can, therefore, be concluded that approximately 90% of all males whose semen analyses persistently show a density of less than 10 million/cc., a motility of less than 40%, and a TMC of less than 10 million are infertile. In no higher subdivision was such discrimination possible. However, these data and the comparisons discussed in the next paragraph also suggest that prognosis is guarded when a density of million/ cc. with a motility of less than 40% exists. Although it is highly probable that any male whose semen analysis parameters fall within these lower ranges is infertile, it is not possible to conclude from these data the statistical probability of infertility for a particular individual. There are too many factors affecting fertility potential which are not measured by the semen analysis. To attempt to evaluate the role of sperm motility in male fertility potential, the distributions of this parameter in the fertile subgroup were compared with distributions of motility in the infertile subgroup and in 2 normal fertile male populations.4, 6 In these five comparisons only the infertile male subgroup differed. Only 9-13% of the fertile males in these populations compared to 38% of infertile males had a motility of less than 40%. Therefore, these data support previously reported findings that a motility of greater than 40% is an important condition for fertility.1, 2, 5, The usefulness of the postcoital test in infertility evaluation has been a controversial matter.12, 13, 16, 17 Numerous in vivo studies have documented that spermatozoa traverse the cervix and reach the fundus in less than 1 hr. 8, 18 Botella Llusia 18 postulates that the cervix acts as a filter permiting only sperm with a proper motility configuration to pass since no morphologically abnormal sperm are recovered from the fundus. This questions the prognostic validity of the postcoital tests, as it is rarely performed within the 1st hr. postcoitus. Despite the late readings of postcoital tests in this study, there was a significant difference between the quality of the test for the infertile and fertile populations. This probably reflects a difference in semen quality and supports findings by Danezis, Sujan, and Sobrero 13 and Lubke 16 that "better" semen produces "better" postcoital tests. Although the rank correlation coefficients calculated between semen parameters and postcoital test results were positive, they were not high. This probably reflects the time at which tests were read rather than a lack of correlation. Since V3 of the fertile males in this study produced persistently poor coital tests under optimal conditions, it is doubtful whether this test, as. presently performed, is of use in the evaluation of fertility potential. However, it is useful in determining adequacy of semen deposition and in assessing the possibility of cervical mucus-sperm incompatibility. SUMMARY From a late infertility population of 358 couples, 175 infertile and fertile males married to potentially fertile females were studied. The male was the sole cause of infertility in 34.4% of the cases. The distribution of density, motility, and total motile count reported in the semen analyses of infertile males was significantly different from that of fertile males. However, the infertile male was characterized by lower semen quality than previously reported. A density of less than 10 million/cc. and a motility of less than 40% indicates a semen which is suboptimal for conception. Good motility is probably more important than high density for conception. The infertile male produced over twothirds as many poor postcoital tests as the fertile male. This probably reflects the

7 April 1972 EVALUATION OF MALE INFERTILITY 251 higher incidence of poor semen quality in the former group. Acknowledgment. The authors wish to acknowledge the helpful suggestions of Dr. John MacLeod, Department of Anatomy, Cornell University Medical College, during the preparation of this manuscript. REFERENCES 1. BUXTON, C. L., AND SOUTHAM, A. Human Infertility. Hoeber, New York, CHARNY, C. Male infertility as a concern of the gynecologist. J Amer Med Ass 186:842, GETZHOFF, P. L. Application of current research data in the diagnosis and clinical management of male subfertility. Fertil Steril 16:632, MACLEOD, J. Semen quality in 1000 men of known fertility and 800 cases of infertile marriage. Fertil Steril 2:115, MAcLEOD, J. GOLD, R. Z., AND McLANE, C. M. Correlation of the male and female infertility factors in human infertility. Fertil Steril 6:112, PAGE, E., AND HOULDING, F. The clinical interpretation of 1000 semen analyses among applicants for fertility studies. Fertil Steril 2:141, SIEGEL, S. Nonparametric Statistics for the Behavioral Sciences. McGraw-Hill, New York, RUBENSTEIN, B. B., STAUSS, H., LAZARUS, M. L., AND HANKIN, H. Sperm survival in women. Fertil SteriI2:15, HARTMAN, H. G. Correlations among criteria of semen quality. Fertil SteriI16:632, FREUND, M. Interrelations among the characteristics of human semen and factors affecting semen specimen quality. J Reprod Fertil 4:143, MACLEOD, J., AND GOLD, R. A., III. An analysis of the motile activity in the spermatozoa of 1000 fertile men and 1000 men in infertile marriage. Fertil Steril 2:187, SIMMONS, F. A., AND LAYMAN, M. L. Failure of conception in 100 completely studied couples; analysis of factors in infertility. Fertil Steril 6: 320, DANEZIS, J., SUJAN, S., AND SOBRERO, A. J. Evaluation of the postcoital test. Fertil Steril 13:559, DARuGNA, D. "The Clinical Significance of Sperm Motility and Its Relation to the Volume of Ejaculate, the Number, and Morphology of Sperm Cells." In Proceedings of the Fifth World Congress on Fertility and Sterility. Exerpta Medica Foundation, Amsterdam, DOEPFMER, R. "Clinical Causes of Disturbances in Sperm Motility." In Proceedings of the Fifth World Congress on Fertility and Sterility. Exerpta Medica Foundation, Amsterdam, LUBKE, F. "Correlation between Cervical Penetration and Semen Tests." In Proceedings of the Fifth World Congress on Fertility and Sterility. Exerpta Medica Foundation, Amsterdam, SOUTHAM, A., AND BUXTON, L. Seventy postcoital tests made during the conception cycle. Fertil Steril 7:133, BOTELLA-LLUSIA, J. "Methods for Determining Type and Degree of Spermatic Motility." In Proceedings of the Fifth World Congress on Fertility and Sterility. Exerpta Medica Foundation, Amsterdam, 1967.