Ghent University Hospital, Center for Medical and Urological Andrology, De Pintelaan, 185, B-9000 Gent, Belgium. E-mail: Frank.Comhaire{at}rug.ac.be
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Abstract |
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Key words: andrology/E quintet/infertility/male factor
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The `E' quintet |
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Problems with evidence-based medicine |
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To circumvent these difficulties in evaluating the effectiveness of treatment of the infertile male, several strategies can be adopted. In order to reduce the influence of the `female factor', randomized trials including a large number of couples can be performed. These usually require a multicentre design, which may decrease their reliability due to differences in diagnostic accuracy and therapeutic (e.g. surgical) skills (Mastroianni, 1999). Some large-scale randomized trials have been performed in one single centre. These too should be considered with caution, since inclusion/exclusion criteria may not be strictly adhered to in order to permit recruitment of a sufficient number of cases. Randomization and informed consent may not reach international standards, and external peer review is uncommon. Problems with standardization of semen analysis can be overcome by exchanging video recordings and morphology slides (Giwercman et al., 1999
), but these measures are rarely applied in single centre trials.
An example of contradictory conclusions from apparently similar trials is the effect of varicocele treatment. Recently, the results of several prospective and randomized trials have been published comparing the pregnancy rate after immediate varicocele treatment versus treatment being postponed for 12 months. The single centre trial (Nieschlag et al., 1995, updated in 1998), referred to as trial A, concludes `counselling to be as effective as occlusion of the vena spermatica' for the treatment of varicocele associated infertility. The WHO multi-centre trial on varicocele surgery (Hargreave, 1997, referred to as trial B) concludes immediate varicocele surgery to be an effective mode of treatment. Both studies include a similar number of couples of whom a similar proportion completed the protocol (trial A: 125 out of 203 = 61.6%, trial B: 135 out of 238 = 56.7%, difference between the studies not statistically significant). Also, the success rate in the group of cases randomized to immediate treatment was similar in the two studies: 29.0% in trial A compared with 31.3% in trial B. The difference occurred in the prevalence of pregnancies in the control groups, which was 14.4 % during the 12-month follow-up in trial B, compared with 25.4% in trial A. As a result there was no difference between controls and treated cases in trial A, whereas trial B revealed a significant positive effect of immediate treatment [relative risk (RR): 2.32, confidence interval (CI): 1.433.77, P < 0.01].
All couples in trial A were `counselled', independent of whether the men received immediate treatment or varicocele surgery was postponed. Counselling included `monitoring each partner's reproductive function by the gynaecologists' (Nieschlag et al., 1995), which apparently included optimizing her fertilizing potential. Monitoring of the female seems to have improved the couple's fertility, since the monthly conception rate in the counselled controls (2.6%) was significantly higher (P < 0.01) than that of couples treated with placebo as part of other studies performed in the same centre (0.4%, Kamishke et al., 1998; Rolf et al., 1999). Hence, the conclusion that varicocele treatment is ineffective, which is suggested from the equivalence in trial A is invalid, since application of an effective treatment to the female partner made it impossible to assess the effect of treatment of the man. This conclusion is reinforced by the observation that the relatively high pregnancy rate in the `control group' of trial A was attained in spite of unchanged semen variables, and that the occurrence of conceptions in this group was independent of the duration of infertility. The latter stands in contrast with results of several other publications (Collins et al., 1983
; WHO, 1984; Comhaire, 1987
; Snick et al., 1997
).
In addition, it is not permissible to simply `add up' the results of trials A and B in meta-analysis (Kamishke and Nieschlag, 1999).
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Pitfalls of type II or ß errors |
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A typical example of type II error is the `tamoxifen case'. Meta-analysis of randomized double-blind studies with anti-oestrogen treatment (either clomiphene citrate or tamoxifen) for male infertility taking pregnancy rate as an outcome, gives an odds ratio of 1.54 in favour of treatment. This is not significant at the 5% level, since the 95% CI includes the value 1 (CI: 0.992.40). The reviewers of the Cochrane group (Vandekerckhove et al., 1999) note that `the stronger treatment effect observed in the trials of lower methodological quality seemed not to be due to a higher pregnancy rate in the treated groups, but to the lower pregnancy rate in the controls of these trials compared with the controls of the better quality trials (7.0 versus 12.5%)'. This sentence tends to discredit the conclusions of certain trials. In fact, the finding can be expected on the basis of the hyperbolic regression between sperm concentration and fecundability (Bonde et al., 1998
) (Figure 1
). From these data it can be calculated that doubling sperm concentration, e.g. from 4 to 8x106 spermatozoa/ml multiplies the monthly conception rate by 2.58, from 3.3 to 8.5%. However, doubling sperm concentration from 8 to 16x106 or from 16 to 32x106 spermatozoa/ml increases fecundability from 8.5 to 11.4% and from 11.4 to 15.1% respectively (multiplication factors 1.34 and 1.32). Treatment that doubles sperm concentration (as reported for tamoxifen) will therefore have a stronger effect on the probability of conception when initial sperm count is lower (e.g. geometric mean in our own patient material = 5.1x106/ml) than when initial sperm concentration is higher (mean 13.1x106/ml in 17 published trials). Since a lower initial sperm concentration is correlated with a lower fecundability, it is not surprising that the success rate of tamoxifen treatment in terms of pregnancy rates is stronger in trials with lower treatment-independent pregnancy rate.
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Effective cumulative delivery rate (ECDR) and time to pregnancy (TTP) |
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Ethics and economic aspects |
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Finally, ethics imply that the financial resources available for health care must be employed in the most cost-effective manner. This is particularly the case in providing effective, practical and inexpensive treatments for underprivileged people, or couples who cannot accept assisted reproductive technologies on ethical, medical or religious grounds. In the case of male infertility (excluding cases with irreversible azoospermia), it is the cost per successful delivery that must be taken into account rather than the cost of treatment. Several publications have calculated the cost per delivery for different treatment modalities, taking into account the effective delivery rates (Figure 4) (Neumann et al., 1994
; Comhaire et al., 1995
; Schlegel, 1997
; Karande et al., 1999
; Goverde et al., 2000
). Both the prevalence of different causes of male infertility (WHO, 1987) and the cost per delivery of their treatment are known. Therefore it is possible to compare the cost-effectiveness of, e.g. immediate IVF (plus ICSI), versus the conventional approach to treatment as recommended by WHO (Rowe et al., 2000
). It appears from these calculations that an investment of public funds of, e.g. 1 million Euro will result in between 70 and 80 deliveries if the former approach is implemented, compared with 330350 deliveries if the latter is used. In addition, the cost of perinatal care after IVF is known to be approximately five times higher (Gissler et al., 1995
) than after singleton delivery resulting from conventional treatment. Independently of concerns about the long-term health of offspring born after ICSI, economic aspects should favour the implementation of well-considered conventional treatment as recommended by WHO (Rowe et al., 2000
). In addition, this approach may improve semen quality to such an extent that implementation of artificial reproductive technology can either be avoided or `down-graded'. This implies that IUI may be substituted for IVF (Goverde et al., 2000
), or conventional IVF may be substituted for the more sophisticated and probably less safe ICSI.
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Conclusions |
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It is concluded that the well thought-out andrological approach recommended by WHO (Rowe et al., 2000) should be implemented by all doctors who are involved with the management of infertile couples.
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Notes |
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References |
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