Bye-bye urinary gonadotrophins?

The conflict between effective and affordable health care—a perspective from the developing world

S.J. Dyer

Andrology Laboratory MB118 First Floor, Maternity Centre, Observatory 7925, South Africa. E-mail: sdyer{at}uctgsh1.uct.ac.za


    Abstract
 Top
 Abstract
 Introduction
 References
 
The recent introduction of recombinant FSH into the clinical management of patients suffering from infertility appears to be associated with several treatment benefits when compared with urinary human menopausal gonadotrophin. However, from the perspective of the developing world the associated increase in cost is a cause for concern—particularly if the ‘cheaper’ urinary gonadotrophins are no longer marketed. The need for infertility care in Africa is significant, but health resources are very limited. The commonest cause of infertility in Africa is tubal disease, so that assisted reproductive techniques, and therefore exogenous gonadotrophins, are central to effective management. The conflict between affordable and effective health care is addressed.

Key words: assisted reproductive technology/developing countries/infertility care/recombinantFSH/urinary gonadotrophins


    Introduction
 Top
 Abstract
 Introduction
 References
 
The ongoing development of more effective and safer pharmacological compounds is driving fundamental changes in medicine (Anonymous, 2001Go). In the field of reproductive medicine this is demonstrated by the pharmacological development of gonadotrophin preparations. The time between the first discovery of gonadotrophic hormones (Zondek and Aschheim, 1927) to the clinical availability of recombinant (r)FSH spans just over six decades. These 60 years have seen the development of the use of exogenous gonadotrophins which were initially extracted from animals, then from the human pituitary and finally from human menopausal urine.

The advent of rFSH has made urinary (u)HMG redundant, or so it seems. Before we bid farewell to HMG let us remember that the therapeutic availability of HMG revolutionized treatment options for ovulatory dysfunction and was an essential component in the development of assisted reproductive techniques. The demand for the latter increased towards the end of the last century to such a degree, that in several developed countries >1% of live births are directly attributed to this technology (ESHRE, 2001Go). This rising demand on a limited resource (human menopausal urine) was one, if not the driving motive for the development of rFSH. In the article ‘Gonadotropic preparations – lessons learned’, (Lunenfeld and Lunenfeld, 1997Go) it was calculated that >100x106 litres of urine would be required to facilitate the treatment of infertile women in the developed world between 1996 and 2000. Interestingly, no reference is made to possible requirements in the developing world.

To date two rFSH preparations are available (Gonal-F®, Serono International and Puregon®, NV Organon). The most significant advantage attributed to this technology is the constant availability of a biochemically highly pure product which is independent of urine collection (Frydman et. al., 2000Go). Careful consideration of this statement and other reports in the literature (Coelingh Bennink et al., 1998Go; Daya and Gunby, 1999Go) allows the conclusion that there are indeed two main advantages of this new technology. Firstly, it provides a more convenient source for exogenous gonadotrophins, an advantage which accrues first and foremost to the pharmaceutical industry although clinicians and patients benefit if an otherwise world-wide shortage of the product can be avoided. Secondly, greater purity of the product is attained (>99% pure FSH with a specific activity of >10 000 IU FSH/mg) which, unlike HMG, does not contain LH or other urinary protein contaminants.

It has been suggested that rFSH is associated with better treatment results in assisted reproduction when compared with urinary (u)FSH or HMG, although the demonstration of statistically increased pregnancy rates (PR) is based on meta-analyses. According to these meta-analyses this increase in PR is in the order of 5%. In the meta-analysis by Daya and Gunby twelve trials including a total of 2875 cases demonstrated a 3.7% risk difference in clinical PR per cycle started in favour of rFSH when compared with uFSH (95%CI, 0.5–6.9%) (Daya and Gunby, 1999Go). Out et al. analysed three randomized controlled trials, which compared the efficacy of rFSH with uFSH and HMG (Out et al., 1997Go). The result was a 5% difference in the ongoing PR (95%CI, 0.2–9.7) in favour of rFSH. However, these findings were not confirmed in a meta-analysis by Agrawal et al. (Agrawal et al., 2000Go). Following the evaluation of 11 randomized controlled trials on the use of FSH versus HMG in assisted reproductive technologies the authors concluded that both preparations yielded similar PR in cycles utilizing GnRH agonists for pituitary desensitization (both long and short protocol). FSH was associated with a higher PR only in the absence of pituitary desensitization (95%CI, 1.01–7.72). A number of subsequent studies addressed the question of treatment benefits secondary to the use of rFSH when compared with HMG but failed to demonstrate an effect on oocyte quality, embryo quality and pregnancy rates(Ng et al., 2001Go; Strehler et al., 2001Go; Westergaard et al., 2001Go).

Recombinant FSH may carry other treatment benefits including both a reduction in the number of ampoules required per treatment cycle as well as the number of days of FSH treatment, although statistical significance may be based on as little a difference as 1.7 ampoules and 0.8 days (Schats et al., 2000Go). The notion that rFSH is associated with a lower risk of ovarian hyperstimulation syndrome still needs further investigation. The absence of contaminating urinary, non-hormonal proteins reduces the (albeit rare) complication of local reactions to exogenous gonadotrophins at the injection site (Albano et al., 1996Go). Most recently the concern has been raised that the urine of humans affected with transmissible spongiform encephalopathies (prion diseases) may contain infective prion proteins. Although the clinical relevance of this finding with regard to disease transmission is currently unclear it has been recommended in this debate on urinary gonadotrophins that their use be discouraged (Matorras and Rodriguez-Escudero, 2002Go).

However, this new technology comes at a cost. In South Africa the difference in cost between rFSH (75 IU) and HMG (75IU) is nearly 100%. Trying to establish the overall increase in cost per assisted reproductive treatment cycle is difficult as the reported requirements for rFSH (dosage and duration treatment) vary considerably. Furthermore, the relative contribution of the cost of medication to the overall cost of assisted reproduction is likely to vary not only between countries but between individual centres. Suffice it to say that the increased cost associated with rFSH is significant and from the perspective of the developing world a cause for grave concern—a concern which tempers the enthusiasm surrounding this new technology. In order to appreciate this concern it is perhaps necessary to reflect briefly on the status of, and the need for, infertility care in Africa.

Infertility in Africa is a major reproductive health problem. Prevalence rates are high (20–40% in certain regions) and the associated burden of disease is significant. The commonest cause of infertility is tubal disease secondary to pelvic sepsis, which in turn is probably the commonest gynaecological disease amongst African women (Muir and Belsey, 1980Go). It is arguably the psycho-social consequences which have the greatest negative impact on the well-being of infertile men and women. In a continent where marriage is almost universal, and the purpose of marriage is children, infertility is often a major tragedy. Women in particular are affected, as their social status and security usually depends directly on their fertility. Those who cannot reproduce are at a substantial risk of divorce, stigmatization, socio-economic deprivation and abuse (Bergström, 1992Go; Gerrits, 1997Go; Sundby, 1997Go). Until recently the problem of infertility in Africa received scant attention as national and international health strategies focused almost exclusively on reducing population growth (Van Balen and Gerrits, 2001Go). Although the reproductive health needs of patients with involuntary childlessness are gradually being recognized they are, generally speaking, still far from being respected.

The recommendation that infertility care in Africa has to focus on prevention is both logical and relevant, but it has two shortcomings. It does not address the needs of those who are already infertile (Van Balen and Gerrits, 2001Go). In addition it requires a change of human behaviour which depends on many variables and if this can indeed be achieved, will take several generations for the benefits to be felt. In terms of infertility treatment, cognisance has to be taken of the high prevalence of tubal disease and the fact that most women with a tubal factor present with severe disease (Kasia et al., 1997Go; Dyer and Tregoning, 2000Go). In this setting assisted reproductive technologies (and therefore exogenous gonadotrophins) play a central role as probably the most effective treatment option for the majority of infertile couples. Not surprisingly, availability of this technology in Africa is rare. Where available, access is often difficult for the majority of patients who would ultimately benefit most.

Assuming that cost is the only limiting factor would unduly simplify the matter, as there are many barriers to treatment. The assumption that modern, evidence-based medicine works equally well everywhere in the world has been proven wrong many times (Foster, 1987Go). It has to be clearly stated, however, that cost is a particularly prominent barrier. It is a fair assumption that the cost of assisted reproduction in most African countries, with the rarest of exceptions, is not covered by public health care or private insurance companies. In this context, cost becomes a critical factor and any further increase in cost may further limit access to treatment. The argument that the more expensive treatment may be more effective, perhaps even more cost-effective, does not really resolve the problem. Whatever the pregnancy rates may be, if the treatment becomes too expensive, fewer and fewer patients will be able to access it and despite higher pregnancy rates the number of children born as a result of assisted reproduction may be lower than before. It is difficult to dismiss the notion that the ‘rich’ will get better and more effective treatment whilst the ‘poor’ may be left with less than they had before.

According to the declaration of the 18th Conference of the Council for International Organisations of Medical Sciences (CIOMS), ‘health services should be effective, efficient, accessible and affordable’ (Bankowski and Bryant, 1994Go). How do we resolve the conflict where a health service becomes so effective and efficient due to better but more expensive technology that it is no longer accessible and affordable? Although the answer to this question occupies governments, insurers, unions and health planners all over the world, it serves to highlight the vast differences between the developing and developed world.

The real crux of the matter is not the introduction of new technology, it is the concern that old, ‘cheaper’ technology will be withdrawn. With the advent of rFSH the pharmaceutical companies appear to plan the discontinuation of uHMG. Urinary gonadotrophins have been good enough and, all in all, safe enough to be used on a very large scale in the industrialized world for over 40 years. It could be argued, that this product is still suitable for use in poorer resource settings where costs need to be kept to a minimum in order to deliver or even expand infertility care. If both products (HMG and rFSH) continued to be available, patients and doctors could make an informed choice and it would be interesting to see what these choices would be around the world. Unless a pharmaceutical company continues the product or other companies try and register new urinary products (neither option being guaranteed in South Africa at the moment) there will be no choice and the decision as to which gonadotrophin to use is pre-empted by the market.

Perhaps South Africa—a developing country which, however, has certain private and public health care structures in place to offer tertiary level infertility care at least in certain regions—stands alone in this matter. It is possible that the rising cost associated with the advent of rFSH in reproductive medicine is not a concern in the developed world where resources are more abundant. And perhaps it is not a concern for other developing countries where infertility treatment is both out of the reach and out of the focus of national health priorities. But if the latter is true and if, at the same time, we are trying to improve reproductive health in the developing world, then any significant rise in the cost of assisted reproduction may be just a further step in the wrong direction.

From the perspective of a health care worker trying to provide effective and affordable infertility care to economically disadvantaged couples in South Africa, there are many questions and no easy answers. The ongoing availability of uHMG which would give doctors and patients a choice of different exogenous gonadotrophins would be welcomed. Does the pharmaceutical industry, with its high profit margins and extraordinary resources spent on advertising and marketing, carry some responsibility towards producing affordable drugs? Is the cost of rFSH justified or is it inflated due to the absence of a therapeutic alternative that could challenge it? Is it in order or indeed indicated to discontinue somewhat less effective albeit ‘cheaper’ (for the consumer, that is) drugs in favour of newer, better and safer products (which, incidentally, may also carry a higher profit margin)? What other options are available to develop truly low cost assisted reproductive technologies? The harvesting of immature oocytes and subsequent in-vitro maturation for as little as 24–48hrs is a particularly promising development. This technique may obviate the costly and potentially risky process of controlled ovarian stimulation (Mikkelsen, 2002Go). On a much larger ethical and political scale the question may be asked what, if any, is the national and international responsibility of the ‘haves’ towards the ‘have-nots’? Health for some and not for others creates an inherently unstable situation and, given the overall dimension of the problem, requires global strategies (Bankowski and Bryant, 1994Go).

In the absence of any answers to these questions I would like to conclude with a quote from the Conference on ‘Poverty, Vulnerability, the Value of Human Life and the Emergence of Bioethics’ held by the Council for International Organisations of Medical Sciences CIOMS (Bankowski and Bryant, 1994Go): ‘The twentieth century will go down in history characterized by the quest for knowledge. The twenty-first century, it is hoped, will be characterized in history by the wisdom with which the acquired knowledge was applied with equity’.


    References
 Top
 Abstract
 Introduction
 References
 
Agrawal, R., Holmes, J. and Howard, S.J. (2000) Follicle-stimulating hormone or human menopausal gonadotropin for ovarian stimulation in in vitro fertilization cycles: a meta-analysis. Fertil. Steril., 73, 338–343.[ISI][Medline]

Albano, C., Smitz, J., Camus, M., Coelingh Bennink, H., Van Steirteghem, A.C. and Devroey, P. (1996) Pregnancy and birth in an in-vitro fertilization cycle after ovarian stimulation in a woman with a history of allergic reactions to human enopausal gonadotrophin. Hum. Reprod., 11, 1632–1634.[Abstract]

Anonymous (2001) Making medicines affordable: the prize factor (position paper). Am. J. Public Health, 91, 486–490.[Free Full Text]

Bankowski, Z. and Bryant, J.H. (1994) Poverty, vulnerability, and the value of human life – a global agenda for bioethics. Council for International Organisations of Medical Sciences (CIOMS), Geneva.

Bergström, S. (1992) Reproductive Failure as a Health Priority in the Third World: A Review. East Afr. Med. J., 69, 174–180.[ISI][Medline]

Coelingh Bennink, H.J.T., Fauser, B.C.J.M. and Out, H.J. (1998) Recombinant follicle-stimulating hormone (FSH; Puregon) is more efficient than urinary FSH (Metrodin) in women with clomiphene citrate-resistant, normogonadotropic chronic anovulation: a prospective, multicenter, assessor-blind, randomised, clinical trial. Fertil. Steril., 69, 19–25.[ISI][Medline]

Daya, S. and Gunby, J. (1999) Recombinant versus urinary follicle stimulating hormone for ovarian stimulation in assisted reproduction. Hum. Reprod., 14, 2207–2215.[Abstract/Free Full Text]

Dyer, S.J. and Tregoning, S. (2000) Laparoscopic reconstructive tubal surgery in a tertiary referral centre – a review of 177 cases. S.A. Med. J., 90, 1015–1019.

ESHRE (2001) The European IVF-monitoring programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE). Assisted reproductive technology in Europe, 1998. Results generated from European registers by ESHRE. Hum. Reprod., 16, 2459–2467.[Abstract/Free Full Text]

Foster, G.M. (1987) World Health Organization behavioural science research: problems and prospects. Soc. Sci. Med., 24, 709–717.[ISI][Medline]

Frydman, R., Howles, C.M. and Truong, F. for the French Multicentre Trialists. (2000) A double-blind, randomized study to compare recombinant human follicle stimulating hormone (FSH; Gonal-F) with highly purified urinary FSH (Metrodin HP) in women undergoing assisted reproductive techniques including intracytoplasmic sperm injection. Hum. Reprod., 15, 520–525.[Abstract/Free Full Text]

Gerrits, T. (1997) Social and Cultural Aspects of Infertility in Mozambique. Patient Educ. Couns., 31, 39–48.[ISI][Medline]

Kasia. J.M., Raiga, J., Doh, A.S., Biouele, J.M., Pouly, J.L., Kwiatkowski, F., Edzoa, T. and Bruhat, M.A. (1997) Laparoscopic fimbrioplasty and neosalpingostomy: Experience of the Yaounde General Hospital, Cameroon. Eur. J. Obstet. Gynecol. Reprod. Biol., 73, 71–77.[ISI][Medline]

Lunenfeld, B. and Lunenfeld, E. (1997) Gonadotropic preparations – lessons learned. Fertil. Steril., 67, 812–814.[ISI][Medline]

Matorras, R. and Rodriguez-Escudero, F.J. (2002) Bye bye urinary gonadotropins. Hum. Reprod.,17, 1675.[Abstract/Free Full Text]

Mikkelsen, A.L. (2002) Oocyte maturation in vivo and in vitro. In Healy, D.L., Kovacs, G.T., McLachlan, R. and Rodriguez-Armas, O. (eds), Reproductive Medicine in the twenty-first century. Parthenon Publishing Group, UK, pp346–355.

Muir, D.G. and Belsey, M.A. (1980) Pelvic inflammatory disease and its consequences in the developing world. Am. J. Obstet. Gynecol., 138, 913–928.[ISI][Medline]

Ng, E.H.Y., Lau, E.Y.L., Yeung, W.S.B. and Ho, P.C. (2001) HMG is as good as recombinant human FSH in terms of oocyte and embryo quality: a prospective randomised trial. Hum. Reprod., 16, 319–325.[Abstract/Free Full Text]

Out, H.J., Driessen, S.G.A.J., Mannaerts, B.M.J.L. and Coelingh Bennink, H.J.T. (1997) Recombinant follicle-stimulating hormone (follitropin beta, Puregon) yields higher pregnancy rates in in vitro fertilization than urinary gonadotropins. Fertil. Steril., 68, 138–142.[ISI][Medline]

Schats, R., De Sutter, P., Bassil, S., Kremer, J.A.M., Tournaye, H. and Donnez, J. on behalf of the Feronia and Apis study group (2000) Ovarian stimulation during assisted reproductive treatment: a comparison of recombinant and highly purified urinary human FSH. Hum. Reprod., 15, 1691–1697.[Abstract/Free Full Text]

Strehler, E., Abt, M., El-Danasouri, I., De Santo, M. and Sterzik, K. (2001) Impact of recombinant follicle-stimulating hormone and human menopausal gonadotropins on in vitro fertilization outcome. Fertil. Steril., 75, 332–336.[ISI][Medline]

Sundby, J. (1997) Infertility in the Gambia: Traditional and Modern Health Care. Patient Educ. Couns., 31, 29–37.[ISI][Medline]

Van Balen, F. and Gerrits, G. (2001) Quality of infertility care in poor-resource areas and the introduction of new reproductive technologies. Hum. Reprod., 16, 215–219.[Abstract/Free Full Text]

Westergaard, L.G., Erb, K., Laursen, S.B., Rex, S. and Rasmussen, P.E. (2001) Human menopausal gonadotropin versus recombinant follicle-stimulating hormone in normogonadotropic women down-regulated with a gonadotropin-releasing hormone agonist who were undergoing in vitro fertilization and intracytoplasmic sperm injection: a prospective randomised study. Fertil. Steril., 76, 543–549.[ISI][Medline]

Zondek, B. and Ascheim, S. (1927) Das Hormone der Hypophysenvoderlappens; Testobject zum Nachweis des Hormons. Klin. Wochenschr., 6, 248–265.





This Article
Abstract
FREE Full Text (PDF )
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Request Permissions
Google Scholar
Articles by Dyer, S.J.
PubMed
PubMed Citation
Articles by Dyer, S.J.