Analysis of semen from patients chronically treated with low or moderate doses of aspirin-like drugs

Several studies indicate that substances interfering with prostaglandin (PG) metabolism, such as nonsteroidal anti-inflammatory drugs (NSAIDs), also called aspirin-like drugs, may affect male reproductive functions (1Porat-Soldin O. Soldin S.J. Preliminary studies on the in vitro and in vivo effect of salicylate on sperm motility.Thera Drug Mon. 1992; 14: 366-370Crossref PubMed Scopus (10) Google Scholar, 2Joyce C.L. Nuzzo N.A. Wilson Jr, L. Zaneveld L.J.D. Evidence for a role of cyclooxygenase (prostaglandin synthetase) and prostaglandins in the sperm acrosome reaction and fertilization.J Androl. 1987; 8: 74-82Crossref PubMed Scopus (59) Google Scholar, 3Seeley R.R. Effect of indomethacin on reproduction under laboratory and field conditions in deermice (Perymyscus maniculatus).Biol Reprod. 1983; 28: 148-153Crossref PubMed Scopus (6) Google Scholar). The deleterious effects of these drugs on male reproductive ability have been frequently reported but always in the context of toxic doses and/or acute or short-term administration (1Porat-Soldin O. Soldin S.J. Preliminary studies on the in vitro and in vivo effect of salicylate on sperm motility.Thera Drug Mon. 1992; 14: 366-370Crossref PubMed Scopus (10) Google Scholar, 2Joyce C.L. Nuzzo N.A. Wilson Jr, L. Zaneveld L.J.D. Evidence for a role of cyclooxygenase (prostaglandin synthetase) and prostaglandins in the sperm acrosome reaction and fertilization.J Androl. 1987; 8: 74-82Crossref PubMed Scopus (59) Google Scholar, 4Didolkar A.K. Gurjar A. Joshi U.M. Sheth A.R. Roychowdhury D. Effects of aspirin on blood plasma levels of testosterone, LH and FSH in maturing male rats.Int J Androl. 1980; 3: 312-318Crossref PubMed Scopus (18) Google Scholar). Self-medication is a very frequent habit in Argentina. In this paper, we retrospectively evaluate the sperm quality of male patients attending an infertility clinic who admitted that they self-medicated with aspirin and/or other NSAIDs in different frequencies and doses and not because of illness or medical prescription. Semen samples were obtained (January 2000 to December 2001) from patients (20–60 years old) attending the Andrology and Reproduction Laboratory (LAR; Córdoba, Argentina). Patients voluntarily filled out a form containing data on drug consumption and genitourinary or other diseases. Those who reported parotiditis, diabetes, hypothyroidism, azoospermia, varicocele, cryptorchidism, and/or other diseases (including chronic inflammatory ones) were excluded from the study; 1,376 semen analyses (one per patient) and the respective forms about toxic habits were considered. Semen collection and analysis were done according to World Health Organization recommendations (5World Health OrganizationWHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. Cambridge University Press, Cambridge1999Google Scholar), except for sperm morphology, which was assessed according to Kruger’s strict criteria (6Kruger T.F. Menkveld R. Stander F.S.H. Lombard C.J. van der Merwe J.P. van Zyl J.A. et al.Sperm morphologic feature as a prognostic factor in in-vitro fertilization.Fertil Steril. 1986; 46: 1118-1123Crossref PubMed Scopus (1063) Google Scholar). Nuclear sperm maturation and plasma seminal concentrations of neutral α-glucosidase, fructose, and citric acid were also assessed. The patients were grouped according to NSAID doses consumed by self-medication as follows: control group, no NSAID consumption; group A, 1–4 NSAID pills/month; group B, 5–9 NSAID pills/month; group C, 10–20 NSAID pills/month; group D, ≥30 NSAID pills/month (at least 1 pill/day). The patients included in the study reported taking the medication for no less than 6 months immediately before semen analysis (this period covers at least two spermatogenic cycles). Because this is a retrospective study, the semen PG content was not evaluated, so it can only be assumed that PG synthesis inhibition may be the main underlying mechanism that explains the following findings. Although inter- and intraindividual variations in seminal parameters must be taken into account, a significant decrease in seminal volume in group D with respect to the control group, group A, or group B was found (Table 1). Seminal vesicles, the principal PG source, are particularly important in this matter, since their secretion in the total volume of ejaculate ranges between 60% and 70% (7Aumüler G. Riva A. Morphology and functions of the human seminal vesicle.Andrologia. 1992; 24: 183-196Crossref PubMed Scopus (109) Google Scholar). Although we found a 16% decrease in sperm concentration in group D with respect to controls (Table 1), differences did not reach statistical significance. Nevertheless, because of the diminished seminal volume, we found a 35% decrease in the total number of spermatozoa in this group.TABLE 1Seminal parameters from patients chronically self-medicated with low or moderate doses of nonsteroidal anti-inflammatory drugs.Seminal parameterControlsGroup AGroup BGroup CGroup DVolume (mL)3.2 ± 0.1a3.3 ± 0.2b3.5 ± 0.3c2.8 ± 0.32.5 ± 0.3a,b,c(1,211)(81)(30)(23)(31)Sperm concentration (× 106/mL)43.9 ± 1.238.1 ± 3.240.6 ± 8.342.8 ± 7.036.8 ± 6.1(1,167)(80)(27)(23)(31)Motile spermatozoa (%)49.0 ± 0.6a48.8 ± 2.6b44.4 ± 5.046.1 ± 4.438.5 ± 4.1a,b(1,167)(80)(27)(23)(31)Dead spermatozoa (%)21.3 ± 0.3a21.8 ± 1.524.5 ± 3.121.9 ± 2.625.4 ± 2.5a(1,167)(80)(27)(23)(31)Spermatozoa with normal morphology (%)10.4 ± 0.2a11.3 ± 1.0b9.6 ± 1.48.4 ± 1.38.5 ± 1.4a,b(956)(69)(24)(21)(29)Spermatozoa with a mature nucleus (%)65.0 ± 0.665.0 ± 3.558.2 ± 4.360.4 ± 5.462.5 ± 3.5(409)(26)(13)(10)(16)Note: Control, no NSAIDs; group A, 1–4 NSAID pills/month; group B, 5–9 NSAID pills/month; group C, 10–20 NSAID pills/month; group D, 1 or more NSAID pills/day. Results are expressed as mean ± SEM. The number of samples is in parentheses. In each line, identical superscripts indicate significant differences (P<.05).Martini. Effects of NSAIDs drugs on human serum. Fertil Steril 2003. Open table in a new tab Note: Control, no NSAIDs; group A, 1–4 NSAID pills/month; group B, 5–9 NSAID pills/month; group C, 10–20 NSAID pills/month; group D, 1 or more NSAID pills/day. Results are expressed as mean ± SEM. The number of samples is in parentheses. In each line, identical superscripts indicate significant differences (P<.05). Martini. Effects of NSAIDs drugs on human serum. Fertil Steril 2003. We did find a decrease in the percentage of motile sperm in group D with respect to the controls and group A (Table 1), characterized by a decrease in rapid spermatozoa and an increase in viable immotile gametes (data not shown). In agreement with our findings, the administration of 2,600 mg/day for 3 days of salicylic acid to healthy donors significantly decreased the sperm motility (50%) with respect to control values (1Porat-Soldin O. Soldin S.J. Preliminary studies on the in vitro and in vivo effect of salicylate on sperm motility.Thera Drug Mon. 1992; 14: 366-370Crossref PubMed Scopus (10) Google Scholar). It should be kept in mind that acetyl salicylic acid irreversibly inhibits cyclooxigenase (8Goodman G.A. Rall T.W. Nies A.S. Taylor P. Goodman y Gilman. Las bases farmacológicas de la terapéutica. Panamericana, México1991Google Scholar) and that 73% of men from our study stated they take only aspirin. In our study, we found a decrease of the viable spermatozoa population in group D when compared with the control group. This observation does not agree with that of other investigators (1Porat-Soldin O. Soldin S.J. Preliminary studies on the in vitro and in vivo effect of salicylate on sperm motility.Thera Drug Mon. 1992; 14: 366-370Crossref PubMed Scopus (10) Google Scholar), who reported that the same aspirin treatment that affected sperm motility did not alter the gamete viability. The long-term treatment of patients included in our study could explain a strongly enhanced deleterious effect. With respect to sperm morphology, we found a decrease in the percentage of normal spermatozoa in group D with respect to the controls and group A. We believe that our finding is well supported by the positive correlation found between normal morphology and motile sperm population (r = 0.3, P <.001). A reduced fructose concentration was detected in group D with respect to the controls (253.9 ± 22.1 mg/100 mL, n = 29; and 320.7 ± 4.9 mg/100 mL, n = 966, respectively; P<.05). When the “corrected fructose level” (log [motile spermatozoa] × [seminal fructose]) is used, the differences increased from 21% to 30%. Since this index is considered to reflect mainly the seminal vesicular function (9Gonzalez G.F. Function of seminal vesicles and their role on male fertility.Asian J Androl. 2001; 3: 251-258PubMed Google Scholar), it is logical to assume that the NSAIDs are able to impair the secretion of PG and, additionally, that of fructose. We did not find significant differences in seminal levels of neutral α-glucosidase and citrate in group D versus controls. We did find a slight but significant positive correlation between α-glucosidase and sperm motility (r = 0.27, P<.05). Previous reports emphasize the role of this enzyme as a marker of human epididymal function (10Fourie M.H. du Toit T. Bornman M.S. Wolmarans L. du Plessis D.J. Epididymal markers in andrology clinic.Arch Androl. 1993; 31: 209-215Crossref PubMed Scopus (14) Google Scholar, 11Viljoen M.H. Bornman M.S. van der Merwe M.P. du Plessis D.J. Alpha-glucosidase activity and sperm motility.Andrologia. 1990; 22: 205-208Crossref PubMed Scopus (26) Google Scholar). Finally, our data suggest a deleterious effect of NSAIDs (mainly aspirin) when chronically administered in low or moderate doses on some male reproductive functions as reflected by the linear regression analysis; there is a positive correlation between increasing NSAID doses and the percentage of dead cells (r = +0.14, P = .0320) and a negative correlation among NSAIDs doses and seminal volume (r = −0.18, P = .0065), sperm motility (r = −0.19, P = .0041), morphology (r = −0.18, P = .0115), and α-glucosidase concentration (r = −0.29, P = .0059). Comparing these findings with previous reports, it is clear that this damage depends, among other factors, on the duration of exposure, doses, type of drug, etc. Further and more detailed studies are necessary.