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The Cost-Effectiveness of Treatments for Male Infertility

Mehran Movassaghi, MD, Paul J. Turek, MD Expert Rev Pharmacoeconomics Outcomes Res. 2008;8(2):197-206.

Abstract and Introduction

Abstract

The medical management of human infertility is a unique area of clinical medicine. In responding to a biological need, this realm of healthcare has typically grasped new reproductive technology as it develops, and is just now beginning to evolve with the help of rigorous, evidence-based research in cost and efficacy. This review will discuss medical and surgical treatments currently available for male factor infertility and compare their cost-benefit and cost-effectiveness with assisted reproductive technology. The lack of substantive data regarding medical treatments is emphasized, as is the application of decision analysis models to assess the value of complex and costly surgical treatments for male infertility.
Introduction

The management of male infertility has undergone a reformation since the advent of intracytoplasmic sperm injection as an adjunct to in vitro fertilization (IVF) in 1992.[1] With its ability to bypass even the severest forms of male infertility, the spectacular success of IVF-intracytoplasmic sperm injection has set the bar high for classic medical and surgical treatments offered for this condition. In addition, the increased delay in childbearing by reproductive age women has led to re-evaluation of the overall effectiveness of male infertility treatments, as it introduces a newfound urgency into the reproductive equation. This review will discuss the medical and surgical treatments currently available for male factor infertility and how they fare with assisted reproductive technology (ART) from cost-benefit and cost-effectiveness viewpoints. With this analysis, we hope to convey an understanding that male-specific treatments play a larger role than ever in the care of the infertile couple.

Medical Therapy
The first consideration in the male-specific treatment of infertility is the response time to therapy. From an older kinetic analysis in 1963, the length of a human cycle of spermatogenesis had been estimated to be 64 days.[2] To arrive at this figure, sequential testis biopsies and radiography were taken from men who had undergone testicular injections of 3H-thymidine. From other studies, epididymal transit time has been estimated to be 5.5 days.[3] This forms the foundation for the general belief that human spermatogenesis requires 2-3 months to complete and has guided the care of infertile men for 40 years. More recent data, however, suggest that this timeline may in fact be shorter.[4] Using a noninvasive method to assess germ cell turnover time accurately in vivo with stable isotope labeling (2H20) and gas chromatography mass spectrometric analysis, we observed that a cycle of sperm production (from production to ejaculation) occurs in a mean 64 8 days (range: 42-76 days). Medical therapy for male infertility seeks to treat conditions with clearly defined (specific) or ill-defined (empirical) causes. These range from hormonal imbalances, which can alter testosterone, gonadotropins and spermatogenesis, to autoimmune disorders or infections that inhibit fertilization or implantation of an embryo. Much of medical therapy for male infertility is empirical in nature, and true efficacy requires further investigation.[5-9] The variety of current medical therapies for male infertility are reviewed here.
Hormonal Management

Our understanding of the hypothalamic-pituitary-gonadal (HPG) axis has benefited most from experiments performed in the 1950s in which hormones were purified from the brains of animals and used for bioassays. In the 1970s, the development of radioimmunoassays allowed hormone measurement without the need for living tissue and bioassays. It is now clear that HPG hormones play a critical role in the phenotypic development of the embryo, sexual maturation at puberty, endocrine testis function (testosterone production) and exocrine testis function (sperm production). These advances form the basis for the endocrine evaluation and management of the infertile male. Sigman and Jarow published a large retrospective study of 1035 patients to define the prevalence of endocrine disorders among infertile men.[10] In general, 20% of men had an abnormal hormone level on initial testing, but only 9.6% harbored a hormone abnormality on repeat testing. If follicle-stimulating hormone (FSH) elevations are excluded, the incidence of clinically significant endocrinopathies in infertile men is 1.7%. outlines the spectrum of endocrine abnormalities observed in infertile men from this study.
Table 1. Specific Hormonal Disorders in Infertile Men (n = 1035)

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Testosterone

Exogenous testosterone replacement and withdrawal therapy was thought for years to improve semen quality after first reducing it and then letting it rebound on withdrawal of therapy. This technique has been abandoned as a form of therapy for male infertility. Testosterone must be endogenously made to be effective for male infertility. Endogenous testosterone can be increased in patients with secondary hypogonadism, such as diabetics, with the use of antiestrogens as described below.

Gonadotropins (Follicle Stimulating Hormone & Luteinizing Hormone)

In men with hypogonadotrophic hypogonadism (<1% of infertile men), injectable medications with properties of FSH and luteinizing hormone (LH) are available and have been shown to improve sperm count, motility, morphology and testicular volume. In a study of 24 such men, 92% became fertile after gonadotropin therapy, resulting in 40 pregnancies. Interestingly, 71% of these men had low sperm concentrations (<20 million/ml), suggesting that normal semen quality is not necessary for fertility with this condition.[11] Correcting hyperprolactinemia with dopamine antagonists and adding gonadotropins, if the prolactin-induced central hypogonadism does not resolve, can also be considered for male infertility due to prolactinomas. Less well demonstrated is the ability of FSH administration to improve semen quality in men with severe oligospermia (very low sperm counts) or unexplained male infertility, or the ability of FSH to improve intracytoplasmic sperm injection (ICSI) fertilization rates, embryo quality and implantation rates in couples with severe oligospermia.[12-14]

Antiestrogens

The logic underlying the use of antiestrogens lies in their ability to favorably alter the intrinsic HPG hormone axis. The most popular of these drugs is clomiphene citrate, a selective estrogen receptor modulator. By reducing hypothalamic and pituitary sensitivity to estrogens, antiestrogens increase pituitary output of LH and FSH, thus stimulating both testosterone production and spermatogenesis. Despite at least 20 clinical trials with clomiphene citrate for male infertility in the last 30 years, there is still debate about the value of antiestrogens for male infertility. A WHO study of 190 couples found clomiphene to have no significant effect on pregnancy rates or semen characteristics,[15] while an older Cochrane meta-analysis of ten controlled studies involving 738 men showed beneficial hormonal effects, but no effect on pregnancy rates.[16] However, there is emerging literature to suggest that clomiphene citrate may play an important role in a subgroup of infertile patients to overcome acquired hypogonadotropic hypogonadism at the pituitary level due to prolactinoma, sickle cell disease, diabetes mellitus and thalassemias.[17] Other selective estrogen receptor modulator drugs, including tamoxifen citrate, act in a similar fashion to clomiphene citrate.

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Corticosteroids

Because of their well-established anti-inflammatory effects, corticosteroids have been used to treat male immunological infertility due to antisperm antibodies. Despite claims of success from several randomized trials using corticosteroids in this autoimmune condition, no significant improvement in fertility was noted in a meta-analysis of four randomized controlled studies.[18] Indeed, this conclusion, in combination with the significant side-effect profile of this therapy, has rendered their use almost obsolete.

Antibiotics

While infections can increase the risk of infertility in women, secondary to pelvic inflammatory disease and its sequelae, a direct link in men is much more difficult to demonstrate. Indeed, it is well recognized that 54% of men with elevated levels of seminal white blood cells (leukocytospermia) have no evidence of infection and that 83% of healthy men have positive semen cultures. Nonetheless, infections involving Chlamydia trachomatis, Mycoplasm hominis, Ureaplasma urealticum, Escherichia colt, Neisseria gonorrhoea, Treponema pallidum, Mycobacterium tuberculosis, Haemophilus ducrey, herpes simplex virus I and II, polio myelitis virus, and Trichomonas vaginalis have been shown to reduce sperm motility and also sperm function.[19-23] However, controlled studies evaluating the effect of antibiotic treatment of these infectious agents on pregnancy rates are lacking. Despite this, the treatment of well-documented infections with these agents will continue to be recommended.
-sympathomimetics

When infertility is due to mechanical dysfunction in the male reproductive tract, notably retrograde ejaculation, sympathomimetics can help tighten the bladder neck and encourage antegrade ejaculation. In a third of diabetic men with retrograde ejaculation, these agents can increase ejaculate volume. This therapy is less effective in cases of retrograde ejaculation associated with pelvic nerve (hypogastric plexus) damage and surgical scarring at the level of the bladder neck.
Alternative Therapy

Given recent healthcare trends and the incorporation of Eastern medicine into Western medicine, many patients opt for the natural, homeopathic or nutraceutical approaches to treating male infertility in lieu of, or in addition to, traditional medical or surgical therapy.

Antioxidants

The best-studied fertility supplements are the antioxidants, notably vitamins E and C, acetylcysteine and glutathione. In small studies, vitamin E (tocopherol) has been shown to improve sperm function[24] and IVF success rates.[25] Ascorbic acid (vitamin C) has been reported to protect sperm DNA from the damage induced by exogenous oxidative stress in vitro.[26] Other studies have also shown that higher levels of sperm DNA fragmentation, a marker of oxidative stress and possibly reduced fertility, are associated with lower levels of seminal ascorbic acid.[27] In animal studies, acetylcysteine has been shown to improve fertility.[28] Furthermore, combination therapy with essential fatty acids has been shown to improve sperm concentration in men with low sperm counts and significantly reduce reactive oxygen species (ROS).[29] Sperm membranes play an important role in fertilization capacity. Sperm membranes harbor a higher concentration of polyunsatured fatty acids (PUFA) than other human cells. Sperm with the highest concentration of PUFA are thought to have the most normal morphology.[30] ROS can cause instability in membrane permeability through effects on PUFA, as these fatty acids are extremely sensitive to oxidative stress. Indeed, the most protective antiperoxidative mechanism protecting PUFA uses thiol- or glutathione-dependent enzymes. For these reasons, ROS scavengers, such as glutathione, are thought to maintain cell membrane stability.[31] Currently, antioxidant supplements are used empirically in cases of low sperm motility and to reduce levels of fragmented DNA in sperm.

Folic Acid

Folic acid is an important micronutrient that is well studied for its effects on preventing neural tube defects in the developing embryo. Folate also plays a role in RNA and DNA synthesis during spermatogenesis and has antioxidant properties. While older studies have shown no benefit for folic acid supplementation on the semen quality of infertile men, newer studies suggest that there may be benefit, especially for tobacco users. Most recently, when combined with zinc, folate supplementation was shown to increase sperm concentration in infertile men in a blinded, randomized, controlled trial.[32]

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Zinc

As a cofactor for more than 80 metalloenzymes, the trace element zinc plays an important role in testicular development, spermatogenesis and sperm motility. In fact, the zinc level in male genital organs is considerably higher than that in other tissues. It is predominantly secreted by the prostate and is also found in maturing spermatozoa. Clinical studies evaluating dietary zinc deficiency have shown a direct relationship between testosterone production by testicular Leydig cells and adequate dietary zinc intake.[33] This relationship may be explained in that zinc is important for the conversion of testosterone into its more active derivative, 5--dihydrotestosterone. Among infertile men, one study found a significant increase in testosterone levels after 40-50 days administration of zinc.[34] Zinc deficiency has also been linked to oligozoospermia (very low sperm counts) in men. In a small study, 80% of subjects experienced oligozoospermia after zinc restriction for 24-40 weeks, which subsequently resolved after zinc supplementation.[35] While the biochemical role of zinc in testis physiology is clear, large randomized clinical studies of zinc supplementation in infertile men are lacking.

L-carnitine

L-carnitine and acetyl-L-carnitine are highly concentrated in the epididymis and are important for sperm metabolism and maturation. In a double-blind, crossover trial of 100 infertile patients, receiving either L-carnitine or placebo, a significant improvement in sperm quality (sperm concentration and forward motility) was observed in the L-carnitine group. In addition, the largest improvements were noted in men with the poorest semen quality.[36] In another study by the same investigators, combination therapy with both L-carnitine and acetyl-L-carnitine was given to 60 infertile men and similar outcomes were observed.[37] Whether or not this form of supplementation can result in significant improvements in pregnancy rates remains unproven.

Surgical Therapy
Surgical therapy for male infertility seeks to improve semen quality through relief of obstruction, by reversal of iatrogenic problems, or through treating varicoceles, which have been linked to infertility. Through surgical procedures, sperm can also be obtained for use with assisted reproductive techniques.
Varicocele Repair

A varicocele is dilation and enlargement of the pampiniform plexus of scrotal veins that drain the testis. Defective valves within the vessels or compression of the vein by a nearby structure can cause dilatation of the veins, leading to the formation of a varicocele. Although constantly debated, varicoceles are clearly linked to male infertility.[5] They occur in 15-20% of all males, in 40% of primarily infertile men and in 80% of secondarily infertile men.[6] Although a Cochrane review of eight randomized studies concluded that there is no evidence that varicocele treatment for unexplained infertility will improve conception, there were flaws in the review methodology.[38] In retrospective cohort studies, improvement of semen quality is seen in 51-78% of men after varicocele repair, with an associated pregnancy rate of 24-60%.[39] In randomized, controlled trials of varicocele repair in men with clinically palpable lesions and abnormal semen analyses, a doubling of baseline pregnancy rates has been observed with varicocele treatment ( ).
Table 2. Controlled Trials Addressing the Treatment of Clinically Palpable Varicoceles in Men with Infertility and Abnormal Semen Analyses

Ejaculatory Duct Obstruction

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Ejaculatory duct obstruction occurs in 5% of azoospermic men. Causes include seminal vesicle stones, Miillerian or Wolffian duct cysts or scar tissue from inflammation or surgery. It typically presents with low ejaculate volume in combination with either no or low sperm concentration and motility, and the diagnosis is aided by transrectal ultrasound (TRUS). Surgical intervention and relief of obstruction results in a 70-80% improvement in semen quality and a 20-30% natural pregnancy rate.[40,41]
Vasovasostomy & Vasoepididymostomy

In cases of infertility secondary to vasectomy, vasectomy reversal surgery is proved successful in 80-99% of cases. Depending on the findings at the time of surgery, either a vasovasostomy or vasoepididymostomy is performed. Both of these microsurgical techniques are technically challenging and success is directly proportional to the surgeons skill and judgment. With a healthy female partner, natural pregnancy rates after a vasovasostomy can reach 60-65%. After vasoepididymostomy, a 30-55% natural pregnancy rate can be expected.[42]
Sperm Retrieval

Microsurgical epididymal sperm aspiration is a surgical technique commonly used to provide sperm for IVF-ICSI in men who have obstruction as a cause of infertility. This method is suitable for men with congenital absence of the vas deferens or a prior vasectomy.[43] Testis sperm retrieval by biopsy or needle aspiration is also commonly used in cases of obstruction. In men with nonobstructive azoospermia, or testis failure, testis sperm retrieval by biopsy is most successful.[44] A recent Cochrane meta-analysis determined that there is insufficient data from randomized trials to recommend any particular surgical sperm retrieval technique for either obstructive or non-obstructive azoospermia.[45] In cases of nonobstructive azoospermia, a recent systematic review analyzed 24 descriptive studies reporting results of sperm retrieval for nonobstructive azoospermia and concluded that there may be advantages to certain strategies in terms of sperm retrieval success, but there is no relationship between the technique used to find sperm and clinical pregnancy or live birth rates obtained with testis sperm.[46]

Cost-effectiveness of Nonsurgical Male Infertility Treatments Treatment

There is virtually no literature that specifically addresses the cost-effectiveness of medical treatments for male infertility. There are randomized clinical trials, case-cohort studies and retrospective reviews, as well as best-practice guidelines and expert consensus reports that help to define the efficacy of medical treatments, but the inclusion of cost data is rare.[47] In addition, with particular treatments, cost-effectiveness data may not be necessary to improve care, such as with cases of infertility due to treatable infections. The dearth of literature in this area is due to: The empirical nature of many medical treatments for infertility

Insufficient numbers of male reproductive urologists available to treat men with infertility

The widespread belief that male infertility is not truly a disease that needs specific treatment

The increasing effectiveness of assisted reproduction techniques to help couples overcome infertility

Cost-effectiveness of Surgical Male Infertility Treatments

Substantially more literature has addressed Pregnancy the cost-benefit and cost-effectiveness of surgical treatments for male infertility. Indeed, the advent of very effective assisted reproductive techniques such as intrauterine insemination (IUI), IVF and ICSI has led to a critical re-examination infertility.
Varicocele-related Infertility

Schlegel performed the first cost-benefit analysis of surgical treatment and assisted reproduction (IVF-ICSI) for varicocele-related male infertility.[48] This analysis of cost per delivery used published and contemporary results for IVF-ICSI in the USA for male factor infertility and compared it against surgical varicocelectomy results derived from controlled trials. Cost estimates were based on prevailing nationwide charges in 1994. The study found that the cost per delivery with IVF-ICSI was $89,091 (95% confidence interval: $78,720-99,462), whereas that of varicocelectomy was $26,268 (confidence interval: $19,138-44,656). He concluded that specific treatment of varicocele-associated male factor infertility with varicocelectomy is more cost-effective than primary treatment

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with assisted reproduction. In a subsequent study, Penson et al. extended the cost-benefit analysis of varicocele-associated infertility to include four treatment arms.[49] The authors compared the following options for men with varicoceles: observation, surgical varicocelectomy followed by IVF if unsuccessful, gonadotropin-stimulated IUI followed by IVF if unsuccessful, and immediate IVF. They proposed a hypothetical 2-year model and applied published pregnancy rates for each of the groups: 14.4% for varicocelectomy, 11.9% for gonadotropin-IUI and 25.4% for IVF. Costs of complications were included. The main study outcome was cost per live delivery regardless of number of newborns. The cost per live delivery was lowest with observation alone ($13,863), next lowest with varicocelectomy-IVF ($44,562), and rose to $49,757 for the IUI-IVF group and $64,422 for the immediate IVF cohort. Interestingly, since varicocelectomy can cure the male factor infertility problem, but assisted reproduction does not, they also analyzed the marginal cost for a second live delivery after an initial one. Remarkably, the cost of a second live delivery in the varicocelectomy-IVF group was fairly equivalent to that for a first delivery ($52,152), but the cost in IUI-IVF group was $561,423. They suggested infertile couples with varicoceles consider either varicocelectomy or IUI before proceeding to IVF. Given the finding that the cost-benefit of varicocele treatment can vary depending on whether IUI or IVF is the alternative, Meng et al. applied decision analysis modeling to further investigate this issue.[50] Decision models are constructed with predefined assumptions and serve as useful tools for estimating outcomes when multiple complex medical treatments are available (Figure 1). In this study, outcome probabilities applied to the model were derived from institutional and published sources, and costs of interventions were calculated from institutional data. Sensitivity analyses were applied to determine which elements were most important and were used to calculate threshold values. For the analysis, theoretical subjects were dichotomized into different levels of assisted reproduction (IUI vs IVF-ICSI) based on presenting semen quality. Varicocelectomy was assigned an overall pregnancy rate of 36.6%, but this rate varied with presenting semen quality. Overall, varicocele surgery was found to be more cost-effective than IVF as long as pregnancy rates of more than 14% could be obtained with surgery. It was also determined that IUI can be more cost-effective than varicocelectomy, depending on the presenting semen quality of the patient ( ). Thus, whether or not varicocele repair is more cost-effective than ART depends, in large part, on the clinical characteristics that define the individual couple.
Table 3. Cost per Pregnancy for Male Infertility due to Varicocele

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Figure 1.

Decision analysis algorithm for pregnancy and male factor infertility due to varicocele. The decision node is the choice between surgical varicocelectomy and assisted reproduction. ART: Assisted reproductive technology; ICSI: Intracytoplasmic sperm injection; IUI: Intrauterine insemination; TMC: Total motile sperm count (volume sperm concentration motile fraction). Reproduced with permission from.[50] Taking a different analytical approach, Cayan et al. examined the value of varicocelectomy from a shift-of-care perspective.[39] The cost of IVF-ICSI is generally approximately $10,000-12,000 per attempted cycle; however, the cost of IUI is much less expensive at approximately $500-1200 per attempted cycle. What Cayan et al. demonstrated was that roughly 50% of couples who would only be candidates for IVF or IVF-ICSI due to varicocele and low semen quality could be rescued from the need to undergo these procedures and conceive naturally or with only IUI after varicocelectomy. In essence, it makes good economic sense to repair varicoceles if ART costs are prohibitively expensive for couples.
Vasectomy-related Infertility

Several cost-benefit analyses have addressed the relationship between vasectomy reversal and IVF-ICSI with sperm retrieval as alternative ways to conceive in vasectomy-related male infertility.[51,52] In a study from Cornell that considered direct and indirect costs (e.g., lost work days) and used live delivery rate as an outcome, vasectomy reversal resulted in a $25,475 cost per delivery, while IVF-ICSI and sperm retrieval was $72,520.[52] One of the most significant factors in this cost difference was the added cost of multiple births associated with IVF-ICSI that is not observed with vasectomy reversal. Another study drew a similar conclusion when even the most complicated vasectomy reversal technique with the least likely associated success rate is required (e.g., vasoepididymostomy) to reconstruct vasectomy-related male infertility.[51] In this study, vasectomy reversal resulted in a $31,100 cost per delivery and IVF-ICSI with sperm retrieval resulted in a $51,024 cost per delivery. Two other studies from Europe and South America have confirmed these cost-benefit analysis findings.[53,54] In the European study, vasectomy reversal was four- to fivefold more cost effective than IVF-ICSI and sperm retrieval.[53] In the South American study, the benefit of vasectomy reversal was most apparent in couples with no obvious female infertility issues and where the interval for vasectomy obstruction was less than 15 years.[54] The ideal way to study the issue of vasectomy reversal or ART (e.g., IVF-ICSI) cost-effectiveness would be to perform a randomized clinical trial. This will likely never be done, certainly not is the USA, where insurance coverage for such procedures lacks uniformity around the country. We took an alternative approach to analyzing this problem using the tools of decision science.[50] For a patient seeking fertility after vasectomy, the first decision is the choice between vasectomy reversal and ART. In this model, the cost per pregnancy was the end point for comparing outcomes of the two branches. The assumptions inherent in the model were that:

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Fecundity is dependent on female age, but is independent of treatment modality

Pregnancy rates were stable and did not decrease with subsequent treatments

The fraction of couples that pursue additional therapy after initial treatment failure is the same for both arms of the decision algorithm The decision algorithm we applied for theoretical patients is given in Figure 2. From an analysis of costs and success, we found that vasectomy reversal is often more cost-effective than ART and that the vasectomy reversal patency rate (the rate of return of sperm to the ejaculate after the procedure) has a large impact on the cost-effectiveness equation. A sensitivity analysis also determined that if vasectomy reversal patency rates are less than 79%, then ART is almost always more cost-effective than vasectomy reversal. From this study, then, we learned that urologists who perform vasectomy reversals need to be good at what they do to keep vasectomy reversal more cost-effective than ART.[50]

Figure 2.

Treatment algorithm for pregnancy after vasectomy. The decision node is the choice between surgical reconstruction and assisted reproductive technology. IC: Intercourse; ICSI: Intracytoplasmic sperm injection. Reproduced with permission from.[50] Since the vasectomy reversal patency rate, and indirectly the age of the vasectomy, was observed to drive cost-effectiveness in our decision model, we then performed a more sophisticated analysis to further investigate the effects of patency rate and maternal age

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on cost-effectiveness.[55] Clinically, the decision to choose vasectomy reversal or ART is more complex in the setting of the older vasectomy (obstructive interval >14 years) or with advanced maternal age (>38 years old). Indeed, the relative impact of these clinical variables is very real to the many couples affected by them, but has not been well studied. To evaluate these two clinical variables over time, we used Markov modeling, a form of decision analysis in which hypothetical patients proceed through health states over time based on predefined probabilities and costs. As patients are cycled, outcomes, including incurred costs and events, are tracked. Male infertility resulting from vasectomy is suitable for this form of analysis because the condition entails discrete states (i.e., obstruction or patency) that can change with time as interventions are performed. In this study, 50,000 theoretical patients were simulated in treatment arms that involved ART or vasectomy reversal. Cost-effectiveness was defined as the ratio of out-of-pocket costs to pregnancy rate, with lower ratios being more desirable. Cost-effectiveness was also referenced against willingness to pay, which represents the highest increase in costs that patients are willing to pay per unit increase in pregnancy rate. Using associated costs, willingness to pay and effectiveness, the net health benefit was calculated and compared for each treatment protocol. Not unexpectedly, the impact of female partner age on cost-effectiveness was large. Somewhat unexpectedly, however, the impact of female partner age was observed to carry much more weight than vasectomy reversal patency rate in influencing cost-effectiveness (Figure 3). Thus, the use of sophisticated decision models for this issue demonstrates that when cost-effectiveness is considered over time, female age (and indirectly female reproductive potential) has a greater influence on outcomes than the age of the vasectomy.

Figure 3.

Tornado diagram of female partner age, vasectomy obstructive interval, and other clinical parameters that affect cost-effectiveness of vasectomy-related male infertility. Widths of horizontal bars indicate magnitude of impact on net health benefits. The wider the bar, the greater the impact. Dark vertical bars indicate threshold values at which reversal and assisted reproductive technology switch being more cost-effective. For this analysis patient, WTP was set at $100,000. IVF: In vitro fertilization; WTP: Willingness to pay. Reproduced with permission from.[55]

Expert Commentary
Classic medical and surgical treatments for male infertility have been used for 50 years. For better or worse, the intrinsic value of these treatments has recently been challenged by advances in assisted reproduction. With the rapid acceptance of new assisted reproduction techniques, research in the field of male infertility treatment has focused intensely on its cost-benefit and cost-effectiveness. Cost-benefit analyses, decision analysis paradigms and Markov models have all been constructed to this end. Interestingly, this research has almost uniformly demonstrated that classic treatments for male infertility still retain huge value. What is most surprising is that no research to date has ever demonstrated that ART is more cost-effective than established medical or surgical therapy for male infertility. Given that the downside risk to offspring from the use of assisted reproduction, including birth defects, chromosomal issues, developmental delay and epigenetic alterations, is not yet fully delineated, we are now witnessing a patient-driven trend toward less technology and more home-conception friendly therapies that have classically been used to manage

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male infertility.

Five-year View
It is our belief that, over the next 5 years, there will be a resurgence of clinical research focused on classical and new medical and surgical therapies for male infertility. This will be driven by the realization by patients and providers that IVF-ICSI, although a powerful reproductive tool, is not necessary to treat the vast majority of infertility due to male factor issues. IVF-ICSI is expensive, involved and has many potential complications for offspring, the details of which are simply not yet clarified. These include a potentially higher risk of chromosomal abnormalities, developmental delay (e.g., autism), birth defects such as hypospadias, and issues surrounding altered epigenetics. Further research into the efficacy and cost-effectiveness of male infertility treatment is necessary and important, as most treatments lack sufficient evidence for their use. As the burgeoning field of reproductive toxicology also gains a foothold in the scientific literature, it is likely that much more of currently undefined male infertility will be explained and potentially treatable in the future.

Sidebar: Key Issues

Medical therapy of male infertility includes both empirical and disease-specific treatments, none of which have undergone rigorous evaluations for cost-effectiveness.

The value of classical medical and surgical therapy for male infertility has recently been challenged by effective developments in assisted reproduction.

In the absence of randomized, controlled clinical trials, the cost-benefit and cost-effectiveness of surgical therapy for male infertility relative to assisted reproductive techniques has been demonstrated in recent literature from several centers.

Numerous individual clinical, cultural and socioeconomic variables, including the important role of the female partner reproductive potential, determine the cost-effectiveness of male infertility treatments.

In this realm of healthcare, computer modeling of complex treatment algorithms will likely continue to inform the value of specific infertility treatments.

References

Papers of special note have been highlighted as:

of interest of considerable interest

1. Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 340 (8810), 17-18 (1992). 2. Clermont Y, Heller C. Spermatogenesis in man: an estimate of its duration. Science (140), 184-185 (1963). 3. Franca LR, Avelar GF, Almeida FFL. Spermatogenesis and sperm transit through the epididymis with emphasis on

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Reprint Address Paul J Turek, Departments of Urology, Obstetrics, Gynecology & Reproductive Sciences, University of California San Francisco, 1600 Divisidero Street, Rm A633, San Francisco, CA 94143-1695, USA. pturek@urology.ucsf.edu Expert Rev Pharmacoeconomics Outcomes Res. 2008;8(2):197-206. 2008 Expert Reviews Ltd.

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