Clinical andrology: from evidence-base to ethics

The `E' quintet in clinical andrology

Frank Comhaire

Ghent University Hospital, Center for Medical and Urological Andrology, De Pintelaan, 185, B-9000 Gent, Belgium. E-mail: Frank.Comhaire{at}rug.ac.be


    Abstract
 Top
 Abstract
 The `E' quintet
 Problems with evidence-based...
 Pitfalls of type II...
 Effective cumulative delivery...
 Ethics and economic aspects
 Conclusions
 References
 
The management of the infertile man should be founded on consensus-based medicine, i.e. the consensual opinion of experts considering evidence-based as well as empirical or experience-based medicine, the effective cumulative rate of successful deliveries, ethical and economic considerations. The apparent contradictions between conclusions from experience-based medicine and evidence-based medicine regarding the efficacy of varicocele treatment and tamoxifen treatment can be explained by scientific reasons. It is argued that the suggestion not to implement these treatments is ill founded because of flawed meta-analyses. The effective cumulative rate of successful deliveries and time to pregnancy as observed in cohort studies should be considered the ultimate touchstone of treatment efficacy. Based on the data of effective cumulative delivery rate, cost per successful delivery, and the known prevalence of aetiological diagnoses in infertile men, it is possible to estimate the number of deliveries that can be attained thanks to an investment of, e.g. 1 million Euro. This number is ~70–80 if IVF (including intracytoplasmic sperm injection) is chosen as first line treatment, and four times higher if conventional treatment (including intrauterine insemination) is applied. It is concluded that the well thought out approach recommended by the World Health Organization should generally be implemented for the management of couples in whom infertility is (mainly) due to a male factor.

Key words: andrology/E quintet/infertility/male factor


    The `E' quintet
 Top
 Abstract
 The `E' quintet
 Problems with evidence-based...
 Pitfalls of type II...
 Effective cumulative delivery...
 Ethics and economic aspects
 Conclusions
 References
 
The value of any therapeutic approach, and of the treatment of male infertility in particular, must be assessed on the basis of five principles that can be summarized as the `E quintet'. The recommendations of evidence-based medicine (conscientious explicit and judicious use of current best evidence) must be compatible with empirical medicine (care based on knowledge acquired from experience and observation). The present trend is for established experts to convene and to consider all available evidence in order to formulate a consensual view (consensus-based medicine). The effect of treatment of infertility must be assessed by means of the effective cumulative delivery rate and time to pregnancy. Ethical considerations are of pivotal importance, and economic aspects are part of ethics. Here, I address specific concerns relating to the implementation of the E quintet in the modern approach to infertility due to a male factor.


    Problems with evidence-based medicine
 Top
 Abstract
 The `E' quintet
 Problems with evidence-based...
 Pitfalls of type II...
 Effective cumulative delivery...
 Ethics and economic aspects
 Conclusions
 References
 
Clinical research in the field of andrological aspects of human reproduction is difficult. The end-point of male infertility treatment can be either the occurrence of pregnancy in the partner, or improvement of semen quality. The former largely depends on the fertility potential of the (usually unique) female partner, which has been found to be impaired in as many as half of the couples with `male factor' infertility [World Health Organization (WHO), 1987]. `Optimizing' the fertility potential of the female will increase the pregnancy rate of those couples. The latter end-point, i.e. change in semen quality, may be difficult to interpret because of poor reproducibility of basic semen analysis. Also, the correlation between sperm quality and fertility potential is not very strong, though it is clearly documented (Bostofte et al., 1990Go; Wichmann et al., 1994Go; Bonde et al., 1998Go).

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, 1999Go). 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., 1999Go), 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): 1.43–3.77, 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., 1995Go), 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., 1983Go; WHO, 1984; Comhaire, 1987Go; Snick et al., 1997Go).

In addition, it is not permissible to simply `add up' the results of trials A and B in meta-analysis (Kamishke and Nieschlag, 1999Go).


    Pitfalls of type II or ß errors
 Top
 Abstract
 The `E' quintet
 Problems with evidence-based...
 Pitfalls of type II...
 Effective cumulative delivery...
 Ethics and economic aspects
 Conclusions
 References
 
Type I or {alpha} error means the coincidental finding of a statistically significant difference, in spite of the absence of a `real' difference. This relates to the chosen limit of statistical significance, e.g. if the limit is set at 0.05, approximately one out of every 20 (5%) of statistical tests may give a significant result. In type II or ß error, a `real' difference remains undetected upon statistical testing, usually because of too few observations. There are many examples of incorrect conclusions because of type II error (Smith, 1994Go; Rolf et al., 1999Go), and caution must be taken not to interpret `no evidence of effect' as `evidence of no effect' (Savulescu et al., 1996Go).

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: 0.99–2.40). The reviewers of the Cochrane group (Vandekerckhove et al., 1999Go) 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., 1998Go) (Figure 1Go). 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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Figure 1. Relationship between fecundability and sperm concentration in a study of first-pregnancy planners (Bonde et al., 1998Go). The effect on fecundability of doubling sperm concentration when starting from different initial concentrations is exemplified.

 
In addition, several controlled and observational studies on the effect of tamoxifen on sperm concentration have remained inconclusive. However, the average number of cases included in these trials is only 18, compared with 68 in the trials revealing a significant increased sperm concentration ({chi}2 for difference between groups: P = 0.029). This suggests that the negative outcome of certain trials is related to the small number of observations rather than to a lack of efficacy, and therefore to type II error.


    Effective cumulative delivery rate (ECDR) and time to pregnancy (TTP)
 Top
 Abstract
 The `E' quintet
 Problems with evidence-based...
 Pitfalls of type II...
 Effective cumulative delivery...
 Ethics and economic aspects
 Conclusions
 References
 
The aim of infertility treatment is to attain delivery of healthy offspring in as many couples as possible and in as short a period of time as possible. In order to investigate these end points, cohort studies and the calculation of the effective number of pregnancies resulting in successful delivery attained after a well-defined period of time is recommended (Figure 2Go). Calculation of the theoretical probability of conception (De Vries et al., 1999Go) does not take into account the proportion of couples that have abandoned treatment, reducing their probability of attaining pregnancy. The discontinuation rate is highly variable between treatment modalities. It is high after failed initial IVF (Stolwijk et al., 1996Go; Roest et al., 1998Go; Osmanagaoglu et al., 1999Go) but low or non-existent during medical treatment with tamoxifen or after varicocele treatment respectively. Also, the time interval between treatment attempts has a major influence on the ECDR (Comhaire et al., 1996Go). Indeed, the time interval between subsequent attempts at IVF is often long, reducing the ECDR in spite of a high success rate per attempt. As a result, the ECDR after 12 months is not significantly different in couples treated by IVF from that of couples treated for varicocele or with tamoxifen (Comhaire et al., 1995Go).



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Figure 2. Effective cumulative delivery rate observed in cohort studies after different modes of treatment of male infertility (Comhaire et al., 1996Go).

 
Furthermore, the time needed to attain a defined number of pregnancies may be different between different modes of treatment, even if the total number of pregnancies that will ultimately occur is similar. This has been documented for different methods of sperm preparation and cycle monitoring of the female partner in intrauterine insemination (IUI) (Depypere et al., 1995Go). Also, in the WHO varicocele trial, the time needed to attain pregnancy in 20% of couples was significantly shorter if varicocele was treated immediately (160 days) compared with 316 days in couples where varicocele treatment was postponed for 12 months. This proves that immediate varicocele treatment is more effective than delayed treatment.


    Ethics and economic aspects
 Top
 Abstract
 The `E' quintet
 Problems with evidence-based...
 Pitfalls of type II...
 Effective cumulative delivery...
 Ethics and economic aspects
 Conclusions
 References
 
Recently, the results of a very large multi-centre trial on IUI have been published (Guzick et al., 1999Go) and discussed (Mastroianni, 1999Go). Patients who were treated by ovulation induction and IUI had a higher pregnancy rate (33%) than those who were treated with IUI only (18%) and those who were treated with ovulation induction and intracervical insemination (19%). Those in the intracervical insemination-only group had the lowest fecundity rate (10%). However, the live birth rate after IUI with or without ovulation induction was not significantly different (Figure 3Go) because of the lower birth rate per pregnancy in the stimulated group. Furthermore, 24 out of 25 multiple pregnancies occurred in the latter group. It is generally accepted that multiple pregnancies must be avoided since they are hazardous to both the mother and the offspring. Therefore, it should be concluded that ovulation induction with or without IUI is ethically unacceptable, but that IUI without ovulation induction is an effective mode of treatment for couples with unexplained infertility.



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Figure 3. Pregnancy rate attained after either intracervical insemination (ICI) or intrauterine insemination (IUI) with or without ovarian stimulation. Open bars show the total pregnancy rates, shaded bars represent the rate of delivery of life offspring. The line joining the square points shows the proportions of live births among pregnant cases (right-hand scale). There was no significant difference in the live birth rate for the IUI/stimulated group and that in the other groups (recalculated from the data of Guzick et al., 1999). NS = not significant.

 
Ethical rules compel medical doctors to prescribe the best available established (standard) treatment in all cases. This implies that new treatment modalities, such as antioxidants (Rolf et al., 1999Go) or recombinant FSH (Kamishke et al., 1998), should only be used in controlled trials if treatment of established effectiveness is also given. Since `counselling' was shown to be a more effective treatment than placebo (vide supra), it may be mandatory to counsel all couples included in double-blind trials. Hence, the implementation of ethical rules makes it extremely difficult to design strictly randomized trials, although there still is an urgent need for such trials based on biologically well-founded hypotheses and designs (Mahmoud and Comhaire, 2000Go).

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 4Go) (Neumann et al., 1994Go; Comhaire et al., 1995Go; Schlegel, 1997Go; Karande et al., 1999Go; Goverde et al., 2000Go). 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., 2000Go). 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 330–350 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., 1995Go) 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., 2000Go). 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., 2000Go), or conventional IVF may be substituted for the more sophisticated and probably less safe ICSI.



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Figure 4. Estimated cost per successful delivery resulting from different modes of treatment of male infertility. TLC = tender loving care (controls, counselling); VAR = varicocele treatment by means of transcatheter embolization or surgery on an outpatient basis; Tamox = treatment with tamoxifen; IUI-Percoll = intrauterine insemination of spermatozoa selected on a density gradient column (1 = first cycle, 2 = second cycle, 3 = third cycle); IVF = conventional in-vitro fertilization; ICSI = IVF with intracytoplasmic sperm injection (Comhaire, 1995Go).

 

    Conclusions
 Top
 Abstract
 The `E' quintet
 Problems with evidence-based...
 Pitfalls of type II...
 Effective cumulative delivery...
 Ethics and economic aspects
 Conclusions
 References
 
While implementation of the rules of evidence-based medicine should be the preferred approach to any medical treatment, this may turn out to be extremely difficult in couple infertility caused by a `male factor'. The (negative) outcome of certain randomized trials or meta-analyses contrasts with the positive evidence empirically collected from carefully performed observational studies. It may be counterproductive simply to reject the empirical evidence as unreliable; rather attempts should be made to explain scientifically the cause of these contradictions. In addition, ethical aspects must play a pivotal role in the approach taken to cure the infertile male and economic factors must also be considered.

It is concluded that the well thought-out andrological approach recommended by WHO (Rowe et al., 2000Go) should be implemented by all doctors who are involved with the management of infertile couples.


    Notes
 
This debate was previously published on Webtrack, July 13, 2000


    References
 Top
 Abstract
 The `E' quintet
 Problems with evidence-based...
 Pitfalls of type II...
 Effective cumulative delivery...
 Ethics and economic aspects
 Conclusions
 References
 
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