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A short period of ejaculatory abstinence before intrauterine insemination is associated with higher pregnancy rates

2009; Elsevier BV; Volume: 93; Issue: 1 Linguagem: Inglês

10.1016/j.fertnstert.2009.07.972

1556-5653

Paul B. Marshburn, Mark Alanis, Michelle L. Matthews, Rebecca Usadi, M.H. Papadakis, Susan Kullstam, Bradley S. Hurst,

Ovarian function and disorders

An ejaculatory abstinence period of ≤2 days before IUI produced the highest pregnancy rates per cycle compared with longer intervals of ejaculatory abstinence. This higher conception rate occurred despite a lower total number of motile spermatozoa inseminated. An ejaculatory abstinence period of ≤2 days before IUI produced the highest pregnancy rates per cycle compared with longer intervals of ejaculatory abstinence. This higher conception rate occurred despite a lower total number of motile spermatozoa inseminated. Ovulation induction with intrauterine insemination (IUI) produces a significantly higher conception rate compared with timed intercourse (1Verhulst S.M. Cohlen B.J. Hughes E. Heineman M.J. Velde E.T. Intra-uterine insemination for unexplained subfertility.Cochrane Database Syst Rev. 2006; (Oct 18;(4):CD001838)PubMed Google Scholar). The timing of IUI proximate to the time of ovulation and the delivery of an optimum fraction of motile sperm are important factors in achieving the highest pregnancy rates (PRs) per cycle. The total number of motile sperm (TMS) inseminated has been cited as the index most predictive of conception in IUI cycles. A minimum TMS of 1 million for insemination was reported to be a requirement for conception after IUI (2Horvath P.M. Bohrer M. Shelden R.M. Kemmann E. The relationship of sperm parameters to cycle fecundity in superovulated women undergoing intrauterine insemination.Fertil Steril. 1989; 52: 288-294Abstract Full Text PDF PubMed Scopus (115) Google Scholar). With levels of TMS exceeding 10 million for IUI, no further improvement in conception rates was noted (3Van Voorhis B.J. Barnett M. Sparks A.E. Syrop C.H. Rosenthal G. Dawson J. Effect of the total motile sperm count on the efficacy and cost-effectiveness of intrauterine insemination and in vitro fertilization.Fertil Steril. 2001; 75: 661-668Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar).The recommendation for 3–4 days of ejaculatory abstinence (EA) before producing semen for IUI has been based on an EA interval that maximizes the TMS count in the ejaculate (4Freund M. Effect of frequency of emission on semen out-put and an estimate of daily sperm production in man.J Reprod Fertil. 1963; 6: 269-273Crossref PubMed Scopus (61) Google Scholar). An EA period of greater than 4 days produces an increase in sperm density but a reduction in the percentage of motile cells in those ejaculates (5Magnus O. Tollefsrud A. Abyholm T. Purvis K. Effects of varying the abstinence period in the same individuals on sperm quality.Arch Androl. 1991; 26: 199-203Crossref PubMed Scopus (35) Google Scholar). Instructing patients on a specific period of EA before IUI is complicated, because the date of ultimate follicular maturity is not known in advance. Couples might not have intercourse before semen collection for IUI, because they do not wish to compromise their TMS count for IUI. Jurema et al. (6Jurema M.W. Vieira A.D. Bankowski B. Petrella C. Zhao Y. Wallach E. et al.Effect of ejaculatory abstinence period on the pregnancy rate after intrauterine insemination.Fertil Steril. 2005; 84: 678-681Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar) reported that the highest pregnancy rate following IUI was achieved following an EA period of ≤3 days. In this study, the higher PR following IUI with EA periods of ≤3 days was not correlated with variations in the number of TMS in the IUI specimen. Optimal pregnancy rates have been reported to follow IUI performed 30–36 hours after hCG administration (7Testart J. Artificial insemination.Rev Prat. 1990; 40: 2711-2715PubMed Google Scholar). The day and time of hCG administration is clearly defined, but intercourse on the day of hCG administration might cause concern about a lower recovery of TMS with an EA of ≤2 days.Our goal was to assess the effects of EA on pregnancy rates following IUI and to determine whether conception after these EA periods was correlated with the TMS of the inseminating specimen.We performed an institutional review board–approved, retrospective analysis of 866 IUI cycles (372 couples) performed during 2003–2005 at the Carolinas Medical Center Women's Institute (Charlotte, NC). The period of EA before IUI, semen analysis parameters of the ejaculate and the insemination specimen for IUI, and pregnancy rate (PR) following ovulation induction and IUI were prospectively recorded. Donor insemination cycles, cycles with an absence of TMS in the ejaculate for IUI, and incompletely documented cycles were excluded. Couples who were considered candidates for IUI were included if they had documentation of at least one patent fallopian tube by hysterosalpingogram and/or laparoscopy. We counseled couples to pursue assisted reproduction with intracytoplasmic injection if we expected that the TMS for insemination would be less than 5 million. These couples, however, were permitted to proceed with IUI if no other infertility factors would have precluded IUI. The infertility diagnosis for all couples was known before the entry of the study. Cycles of ovulation induction with clomiphene citrate (84%) or gonadotropins (16%) were included. Clomiphene citrate was administered for 5 days beginning on the 3rd or 5th days of the menstrual cycle, and follicular size was monitored by ultrasound beginning on days 10 or 12 of the menstrual cycle. Gonadotropin cycles initiated ultrasound follicular monitoring on days 5 or 7 of the menstrual cycle. A single IUI was performed 30–36 hours after hCG administration when the leading follicle measured a mean diameter of 18 mm. The whole ejaculate was prepared for insemination using a technique of density gradient separation with centrifugation. Clinical pregnancies were documented with normally increasing quantitative serum beta-hCG levels, and the presence of an intrauterine pregnancy by ultrasound. Logistic and linear regression analysis with generalized estimating equations was performed for correlation of the period of EA, with semen parameters of the ejaculate and the inseminating specimen, and with pregnancy rates following IUI. Mann-Whitney and Kruskal-Wallace analyses were used for comparisons of variable means.Paradoxically, an EA duration of 0–2 days before IUI was associated with a higher PR when compared with intervals greater than 2 days (P < 0.02; Table 1). There was an association between higher PR after IUI with an EA of ≤2 days, despite the insemination of fewer numbers of motile sperm cells from semen specimens following shorter periods of EA (P < 0.001). The duration of abstinence significantly affected the semen analysis parameters. Increasing the duration of EA increased the sample volume (P < 0.0001), sperm concentration (P < 0.0001), the total motile sperm count (P < 0.0001), and the numbers of dead sperm (P < 0.0001). A reduction was seen in the percentage of motile sperm cells with an increasing EA period (P < 0.0003). The TMS count decreased in the ejaculate and the insemination specimen with shortening the EA period (Fig. 1). In 71% of the cycles (n = 603), men produced ejaculates for the IUI, indicating normospermia (≥20 sperm cells/mL), and in 29% of the cycles (n = 243), men demonstrated oligozoospermia (<20 million sperm cells/mL). There was no statistical difference between the EA period groupings in regard to a woman's age, infertility diagnosis, type of ovulation induction cycle, or the number of cycles with normospermic or oligozoospermic inseminations.Table 1Pregnancy Rate per IUI Cycle in Relation to the Period of Ejaculatory AbstinenceP- ValuesGroupEA (days)Pregnancy Rate (%)ABC1≤ 211.27<0.02 57.25A = Group 1 vs. Group 2; B = Group 1 vs. Group 2 + 3; C = Group 2 vs. Group 3 Open table in a new tab This report is in accordance with the findings of Jurema et al. (6Jurema M.W. Vieira A.D. Bankowski B. Petrella C. Zhao Y. Wallach E. et al.Effect of ejaculatory abstinence period on the pregnancy rate after intrauterine insemination.Fertil Steril. 2005; 84: 678-681Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar), who evaluated couples with unexplained infertility and found an association between an EA interval of ≤3 days and higher PR following IUI. Our study group, however, might reflect a more general infertility population than the group evaluated by Jurema et al. (6Jurema M.W. Vieira A.D. Bankowski B. Petrella C. Zhao Y. Wallach E. et al.Effect of ejaculatory abstinence period on the pregnancy rate after intrauterine insemination.Fertil Steril. 2005; 84: 678-681Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar), because we offer ovulation induction with IUI to some couples with male factor infertility. In fact, we observed a clinical pregnancy in a cycle in which the inseminating specimen contained only 200,000 TMS after an EA period of 2 days. As mentioned, we found no difference in the proportion of normospermic or oligozoospermic insemination cycles in the different EA interval groups, and so differences in results between these two groups should be normalized.Our results suggest that a shorter period of EA (≤2 days) is associated with a higher PR following IUI, although an EA of ≤2 days was associated with the insemination of fewer numbers of TMS. Our findings do not indicate that the TMS count of the IUI specimen is unimportant. Rather, other factors must be involved to explain an enhancement in PR provided by shortening the EA period. Shortening the residence time of sperm in the male excurrent ductal system might remove sperm from an environment harmful to their viability. A prolonged exposure of sperm to damaging reactive oxygen species (free radicals) from leukocytes, dying spermatozoa, and/or from deficient antioxidant defense systems has been cited as a significant cause of male factor infertility (8Aitken R.J. Clarkson J.S. Hargreave T.B. Irvine D.S. Wu F.C. Analysis of the relationship between defective sperm function and the generation of reactive oxygen species in cases of oligozoospermia.J Androl. 1989; 10: 214-220Crossref PubMed Scopus (276) Google Scholar, 9Agarwal A. Saleh R.A. Bedaiway M.A. Role of reactive oxygen species in the pathophysiology of human reproduction.Fertil Steril. 2003; 79: 829-843Abstract Full Text Full Text PDF PubMed Scopus (1079) Google Scholar). Documentation that shortening the EA period would lessen these potentially harmful influences will require further study.Couples having intercourse on the day of hCG administration might experience an improvement in PR independent of the EA period before IUI. Perhaps intercourse on the day of hCG enhances fertilization in women who ovulate earlier than expected after hCG administration. Studies of intercourse frequency in natural cycles indicate that conception is possible as a result of intercourse 5 days before ovulation, but drops to a low likelihood 1 day after ovulation (10Wilcox A.J. Weinberg C.R. Baird D.D. Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby.N Engl J Med. 1995; 333: 1517-1521Crossref PubMed Scopus (832) Google Scholar). Furthermore, reports suggest but do not prove that uterine and cervical exposure to seminal fluid on the day of egg retrieval for IVF improves pregnancy rates (11Bellinge B.S. Copeland C.M. Thomas T.D. Mazzucchelli R.E. O'Neil G. Cohen M.J. The influence of patient insemination on the implanatation rate in an in vitro fertilization and embryo transfer program.Fertil Steril. 1986; 46: 252-256Abstract Full Text PDF PubMed Scopus (69) Google Scholar, 12von Wolff M. Rosner S. Thone C. Pinheiro R.M. Jaukus J. Bruckner T. et al.Intravaginal and intracervical application of seminal plasma in in vitro fertilization of intracytoplasmic sperm injection treatment cycles–a double-blind, placebo-controlled, randomized pilot study.Fertil Steril. 2009; 91: 167-172Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). These hypothetical benefits of intercourse for improving the PR after IUI could be tested by evaluating a population with an EA period of ≤2 days less and randomizing one group to having intercourse on the day of hCG administration, while in the other group men would ejaculate independent of intercourse.A weakness of our study is that we did not prospectively allocate couples to different EA intervals, nor did we have information on ejaculatory frequency before the period of EA preceding IUI. We also did not determine the percentage of normal sperm morphology for the inseminating specimen. Other reports, however, do not suggest that the EA period has a significant effect on sperm morphology.We conclude that an EA period of ≤2 days was associated with higher PR after ovulation induction with IUI, and this improvement was seen despite a lower TMS in the insemination specimen. On the basis of these results, the standard practice in our clinic is to recommend intercourse on the day of hCG administration to maintain an EA period of ≤2 days before IUI. Furthermore, we encourage patients to have intercourse on the day of IUI if possible. We did not present data to indicate the optimum intercourse frequency during an IUI cycle; however, there may be no need to restrict intercourse before IUI. Ovulation induction with intrauterine insemination (IUI) produces a significantly higher conception rate compared with timed intercourse (1Verhulst S.M. Cohlen B.J. Hughes E. Heineman M.J. Velde E.T. Intra-uterine insemination for unexplained subfertility.Cochrane Database Syst Rev. 2006; (Oct 18;(4):CD001838)PubMed Google Scholar). The timing of IUI proximate to the time of ovulation and the delivery of an optimum fraction of motile sperm are important factors in achieving the highest pregnancy rates (PRs) per cycle. The total number of motile sperm (TMS) inseminated has been cited as the index most predictive of conception in IUI cycles. A minimum TMS of 1 million for insemination was reported to be a requirement for conception after IUI (2Horvath P.M. Bohrer M. Shelden R.M. Kemmann E. The relationship of sperm parameters to cycle fecundity in superovulated women undergoing intrauterine insemination.Fertil Steril. 1989; 52: 288-294Abstract Full Text PDF PubMed Scopus (115) Google Scholar). With levels of TMS exceeding 10 million for IUI, no further improvement in conception rates was noted (3Van Voorhis B.J. Barnett M. Sparks A.E. Syrop C.H. Rosenthal G. Dawson J. Effect of the total motile sperm count on the efficacy and cost-effectiveness of intrauterine insemination and in vitro fertilization.Fertil Steril. 2001; 75: 661-668Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). The recommendation for 3–4 days of ejaculatory abstinence (EA) before producing semen for IUI has been based on an EA interval that maximizes the TMS count in the ejaculate (4Freund M. Effect of frequency of emission on semen out-put and an estimate of daily sperm production in man.J Reprod Fertil. 1963; 6: 269-273Crossref PubMed Scopus (61) Google Scholar). An EA period of greater than 4 days produces an increase in sperm density but a reduction in the percentage of motile cells in those ejaculates (5Magnus O. Tollefsrud A. Abyholm T. Purvis K. Effects of varying the abstinence period in the same individuals on sperm quality.Arch Androl. 1991; 26: 199-203Crossref PubMed Scopus (35) Google Scholar). Instructing patients on a specific period of EA before IUI is complicated, because the date of ultimate follicular maturity is not known in advance. Couples might not have intercourse before semen collection for IUI, because they do not wish to compromise their TMS count for IUI. Jurema et al. (6Jurema M.W. Vieira A.D. Bankowski B. Petrella C. Zhao Y. Wallach E. et al.Effect of ejaculatory abstinence period on the pregnancy rate after intrauterine insemination.Fertil Steril. 2005; 84: 678-681Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar) reported that the highest pregnancy rate following IUI was achieved following an EA period of ≤3 days. In this study, the higher PR following IUI with EA periods of ≤3 days was not correlated with variations in the number of TMS in the IUI specimen. Optimal pregnancy rates have been reported to follow IUI performed 30–36 hours after hCG administration (7Testart J. Artificial insemination.Rev Prat. 1990; 40: 2711-2715PubMed Google Scholar). The day and time of hCG administration is clearly defined, but intercourse on the day of hCG administration might cause concern about a lower recovery of TMS with an EA of ≤2 days. Our goal was to assess the effects of EA on pregnancy rates following IUI and to determine whether conception after these EA periods was correlated with the TMS of the inseminating specimen. We performed an institutional review board–approved, retrospective analysis of 866 IUI cycles (372 couples) performed during 2003–2005 at the Carolinas Medical Center Women's Institute (Charlotte, NC). The period of EA before IUI, semen analysis parameters of the ejaculate and the insemination specimen for IUI, and pregnancy rate (PR) following ovulation induction and IUI were prospectively recorded. Donor insemination cycles, cycles with an absence of TMS in the ejaculate for IUI, and incompletely documented cycles were excluded. Couples who were considered candidates for IUI were included if they had documentation of at least one patent fallopian tube by hysterosalpingogram and/or laparoscopy. We counseled couples to pursue assisted reproduction with intracytoplasmic injection if we expected that the TMS for insemination would be less than 5 million. These couples, however, were permitted to proceed with IUI if no other infertility factors would have precluded IUI. The infertility diagnosis for all couples was known before the entry of the study. Cycles of ovulation induction with clomiphene citrate (84%) or gonadotropins (16%) were included. Clomiphene citrate was administered for 5 days beginning on the 3rd or 5th days of the menstrual cycle, and follicular size was monitored by ultrasound beginning on days 10 or 12 of the menstrual cycle. Gonadotropin cycles initiated ultrasound follicular monitoring on days 5 or 7 of the menstrual cycle. A single IUI was performed 30–36 hours after hCG administration when the leading follicle measured a mean diameter of 18 mm. The whole ejaculate was prepared for insemination using a technique of density gradient separation with centrifugation. Clinical pregnancies were documented with normally increasing quantitative serum beta-hCG levels, and the presence of an intrauterine pregnancy by ultrasound. Logistic and linear regression analysis with generalized estimating equations was performed for correlation of the period of EA, with semen parameters of the ejaculate and the inseminating specimen, and with pregnancy rates following IUI. Mann-Whitney and Kruskal-Wallace analyses were used for comparisons of variable means. Paradoxically, an EA duration of 0–2 days before IUI was associated with a higher PR when compared with intervals greater than 2 days (P < 0.02; Table 1). There was an association between higher PR after IUI with an EA of ≤2 days, despite the insemination of fewer numbers of motile sperm cells from semen specimens following shorter periods of EA (P < 0.001). The duration of abstinence significantly affected the semen analysis parameters. Increasing the duration of EA increased the sample volume (P < 0.0001), sperm concentration (P < 0.0001), the total motile sperm count (P < 0.0001), and the numbers of dead sperm (P < 0.0001). A reduction was seen in the percentage of motile sperm cells with an increasing EA period (P < 0.0003). The TMS count decreased in the ejaculate and the insemination specimen with shortening the EA period (Fig. 1). In 71% of the cycles (n = 603), men produced ejaculates for the IUI, indicating normospermia (≥20 sperm cells/mL), and in 29% of the cycles (n = 243), men demonstrated oligozoospermia (<20 million sperm cells/mL). There was no statistical difference between the EA period groupings in regard to a woman's age, infertility diagnosis, type of ovulation induction cycle, or the number of cycles with normospermic or oligozoospermic inseminations. A = Group 1 vs. Group 2; B = Group 1 vs. Group 2 + 3; C = Group 2 vs. Group 3 This report is in accordance with the findings of Jurema et al. (6Jurema M.W. Vieira A.D. Bankowski B. Petrella C. Zhao Y. Wallach E. et al.Effect of ejaculatory abstinence period on the pregnancy rate after intrauterine insemination.Fertil Steril. 2005; 84: 678-681Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar), who evaluated couples with unexplained infertility and found an association between an EA interval of ≤3 days and higher PR following IUI. Our study group, however, might reflect a more general infertility population than the group evaluated by Jurema et al. (6Jurema M.W. Vieira A.D. Bankowski B. Petrella C. Zhao Y. Wallach E. et al.Effect of ejaculatory abstinence period on the pregnancy rate after intrauterine insemination.Fertil Steril. 2005; 84: 678-681Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar), because we offer ovulation induction with IUI to some couples with male factor infertility. In fact, we observed a clinical pregnancy in a cycle in which the inseminating specimen contained only 200,000 TMS after an EA period of 2 days. As mentioned, we found no difference in the proportion of normospermic or oligozoospermic insemination cycles in the different EA interval groups, and so differences in results between these two groups should be normalized. Our results suggest that a shorter period of EA (≤2 days) is associated with a higher PR following IUI, although an EA of ≤2 days was associated with the insemination of fewer numbers of TMS. Our findings do not indicate that the TMS count of the IUI specimen is unimportant. Rather, other factors must be involved to explain an enhancement in PR provided by shortening the EA period. Shortening the residence time of sperm in the male excurrent ductal system might remove sperm from an environment harmful to their viability. A prolonged exposure of sperm to damaging reactive oxygen species (free radicals) from leukocytes, dying spermatozoa, and/or from deficient antioxidant defense systems has been cited as a significant cause of male factor infertility (8Aitken R.J. Clarkson J.S. Hargreave T.B. Irvine D.S. Wu F.C. Analysis of the relationship between defective sperm function and the generation of reactive oxygen species in cases of oligozoospermia.J Androl. 1989; 10: 214-220Crossref PubMed Scopus (276) Google Scholar, 9Agarwal A. Saleh R.A. Bedaiway M.A. Role of reactive oxygen species in the pathophysiology of human reproduction.Fertil Steril. 2003; 79: 829-843Abstract Full Text Full Text PDF PubMed Scopus (1079) Google Scholar). Documentation that shortening the EA period would lessen these potentially harmful influences will require further study. Couples having intercourse on the day of hCG administration might experience an improvement in PR independent of the EA period before IUI. Perhaps intercourse on the day of hCG enhances fertilization in women who ovulate earlier than expected after hCG administration. Studies of intercourse frequency in natural cycles indicate that conception is possible as a result of intercourse 5 days before ovulation, but drops to a low likelihood 1 day after ovulation (10Wilcox A.J. Weinberg C.R. Baird D.D. Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby.N Engl J Med. 1995; 333: 1517-1521Crossref PubMed Scopus (832) Google Scholar). Furthermore, reports suggest but do not prove that uterine and cervical exposure to seminal fluid on the day of egg retrieval for IVF improves pregnancy rates (11Bellinge B.S. Copeland C.M. Thomas T.D. Mazzucchelli R.E. O'Neil G. Cohen M.J. The influence of patient insemination on the implanatation rate in an in vitro fertilization and embryo transfer program.Fertil Steril. 1986; 46: 252-256Abstract Full Text PDF PubMed Scopus (69) Google Scholar, 12von Wolff M. Rosner S. Thone C. Pinheiro R.M. Jaukus J. Bruckner T. et al.Intravaginal and intracervical application of seminal plasma in in vitro fertilization of intracytoplasmic sperm injection treatment cycles–a double-blind, placebo-controlled, randomized pilot study.Fertil Steril. 2009; 91: 167-172Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). These hypothetical benefits of intercourse for improving the PR after IUI could be tested by evaluating a population with an EA period of ≤2 days less and randomizing one group to having intercourse on the day of hCG administration, while in the other group men would ejaculate independent of intercourse. A weakness of our study is that we did not prospectively allocate couples to different EA intervals, nor did we have information on ejaculatory frequency before the period of EA preceding IUI. We also did not determine the percentage of normal sperm morphology for the inseminating specimen. Other reports, however, do not suggest that the EA period has a significant effect on sperm morphology. We conclude that an EA period of ≤2 days was associated with higher PR after ovulation induction with IUI, and this improvement was seen despite a lower TMS in the insemination specimen. On the basis of these results, the standard practice in our clinic is to recommend intercourse on the day of hCG administration to maintain an EA period of ≤2 days before IUI. Furthermore, we encourage patients to have intercourse on the day of IUI if possible. We did not present data to indicate the optimum intercourse frequency during an IUI cycle; however, there may be no need to restrict intercourse before IUI.