Human Reproduction, Vol. 17, No. 7, 1676-1680,
July 2002
© 2002 European Society of Human Reproduction and Embryology
Bye-bye urinary gonadotrophins?
Is there a risk of prion disease after the administration of urinary-derived gonadotrophins?
Department of Reproductive Medicine, The General Infirmary, Leeds LS2 9NS, UK. E-mail: adam.balen{at}leedsth.nhs.uk
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Abstract |
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 Top Abstract IntroductionPrion diseases—backgroundCould human urine contain...Transmission of prion diseaseUrinary gonadotrophinsRecombinant FSHShould the use of...AcknowledgementsReferences |
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Concern has been raised recently about the possibility of prion proteins appearing in the urine of animals and, possibly, humans affected by prion disease [scrapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt Jakob disease (CJD)]. A debate has started in which the suggestion has been made that the purification of human urine for the provision of gonadotrophins should be discontinued. The alternative would be to use recombinantly-derived gonadotrophin preparations. The recombinant products, however, rely upon bovine serum during the cell culture process and could potentially also be exposed to abnormal prion proteins. It is reassuring that the different types of gonadotrophin preparations that are currently available are produced with either urine or bovine serum that is sourced from countries that at the present time appear to be free of BSE and new variant CJD. We can therefore be reassured that the gonadotrophins that we use therapeutically appear to be equally safe.
Key words: BSE/prion disease/recombinant gonadotrophins/urinary gonadotrophins/variant CJD
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Introduction |
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TopAbstractIntroductionPrion diseases—backgroundCould human urine contain...Transmission of prion diseaseUrinary gonadotrophinsRecombinant FSHShould the use of...AcknowledgementsReferences |
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The paper by Matorras and Rodríguez-Escudero (2001) is worthy of serious consideration and it is timely, once again, to consider whether we may be putting our patients at risk of infection with the drugs that we are administering (Matorras and Rodríguez-Escudero, 2001). There is a need for extreme vigilance when using biological products for therapy, particularly in reproductive medicine, when young women may be exposed to risks to their long-term health and potentially the health of their babies. In this short paper I present the view that the current evidence suggests that both urinary-derived and recombinant gonadotrophin preparations are safe with respect to the risk of transmitting prion disease.
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Prion diseases—background |
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TopAbstractIntroductionPrion diseases—backgroundCould human urine contain...Transmission of prion diseaseUrinary gonadotrophinsRecombinant FSHShould the use of...AcknowledgementsReferences |
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Creutzfeldt Jakob disease (CJD) is a chronic neurodegenerative disease, first identified in 1920, and has probably been in existence for many (hundreds) of years. CJD is a rare and fatal condition that affects the nervous system, and is one of a group of transmissible diseases known as the prion diseases or transmissible spongiform encephalopathies (TSEs). There are three major types of CJD: (i) sporadic CJD, which accounts for ~85% of all cases worldwide and for which the underlying cause is currently unknown (Department of Health, 2001a
), although it may be due to a somatic mutation; (ii) familial CJD which is associated with a point mutation or insertion mutation in the human prion protein gene, and is inherited as an autosomal dominant condition; (iii) acquired CJD, which includes kuru, seen in the Fore tribe of Papua New Guinea and ‘new variant’ CJD, which results from the exposure to the bovine spongiform encephalopathy (BSE) agent. Also iatrogenic CJD may result after surgical procedures (Department of Health, 2001a).
Prions are pathogenic forms of proteins that are naturally produced by nerve cells and other cells. The normal protein isoform is referred to as prion protein cellular (PrPc). All forms of prion disease are associated with the accumulation of an abnormal form of prion protein (scrapie, PrPSc) within the central nervous system (CNS). PrPSc is relatively protease resistant and so accumulates in plaques in the CNS. There is increasing evidence to indicate that the transmissible agent may be composed entirely of the abnormal form of prion protein (Department of Health, 2001a). Prions are not micro-organisms.
Between 1970 and December 2000, the National CJD Surveillance Unit identified 970 cases of classical CJD in the UK of which 888 were sporadic, 40 were familial and 42 were acquired as a result of treatment with human pituitary extract or brain membranes (National CJD Surveillance Unit, 2000). New variant CJD (vCJD) was first recognized as a distinct clinical entity in 1996 (Will et al., 1996). This new disease is believed to be caused by the same abnormal ‘prion’ protein (PrPSc) that causes BSE and is thought to result from eating contaminated beef products. To 6th August 2001, there have been a total of 106 confirmed or probable cases of vCJD in the UK (Department of Health, 2001b). It is not known how many people have been infected but have not yet developed symptoms. Although there have been no documented cases of transmission of vCJD through medical interventions to date, it must be assumed that vCJD has the potential for transmission between patients as has been shown for classical CJD (Department of Health, 2001a). The incubation time for the emergence of the disease may be many decades (Bruce et al., 1997).
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Could human urine contain prion infectivity? |
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TopAbstractIntroductionPrion diseases—backgroundCould human urine contain...Transmission of prion diseaseUrinary gonadotrophinsRecombinant FSHShould the use of...AcknowledgementsReferences |
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The extraction and purification of post-menopausal urine was pioneered in Italy in the late 1940s to result in the production of HMG. The first HMG extract that was sufficiently pure for human use was Pergonal® (Serono, Italy) or menotropin, in 1949 (Donini and Montezemolo, 1949
). It took ten years for sufficient clinical interest to develop to require its commercial production. The first live birth was reported in 1962 (Lunenfeld et al., 1962). Twenty to thirty litres of post-menopausal urine were required to treat one patient with one cycle of HMG. Over the next two decades purification processes were enhanced in order to increase the relative amount of active ingredient of HMG (menotropin) and uFSH (urofollitropin) (Hayden et al., 1999; review). The issue to tax us here is whether pooled urine from post-menopausal women might contain infective agents that could cause prion disease in women treated with gonadotrophins. There is particular sensitivity because of the development of CJD in patients treated both by gonadotrophins and growth hormone purified from cadaveric human pituitary glands. More than 80 cases of growth hormone related CJD have so far been reported in the UK, USA and France, with an incubation time of around 10 years (Committee On Safety Of Medicines, 1998). A genetic susceptibility to infection has been demonstrated. Gonadotrophins were prepared from human pituitaries for a shorter period of time than growth hormone and only four cases of CJD have been reported to date (all in Australia) (Committee On Safety Of Medicines, 1998).
The report that has stirred up the current debate is the finding of a protease resistant isoform of PrP in the urine of scrapie-infected hamsters, BSE-infected cattle and humans suffering from CJD (Shaked et al., 2001). Most of the CJD patients were actually patients carrying the E200K mutation (Gabizon et al., 1996). Urine from humans infected with vCJD was not examined. The conclusions drawn by Shaked and colleagues were that urine could be used to provide a simple, non-invasive test for prion diseases. They also demonstrated the appearance of PrPSc in urine before its accumulation in brain, thus inferring that the PrP urine test could be used during subclinical stages of infection.
There is no suggestion, however, that urine might contain an infective agent and furthermore, inoculation experiments have been performed (Shaked et al., 2001) which failed to confirm infectivity. In their experiments hamsters were inoculated with either samples containing urine PrP from normal or hamsters with symptomatic scrapie or with brain samples from symptomatic-scrapie hamsters that had been diluted to contain similar concentrations of PrPSc. Whilst the animals inoculated with scrapie-infected brain samples suffered from fatal symptoms after about 80 days, none of the animals inoculated with urine samples from hamsters with symptomatic scrapie developed clinical symptoms of prion disease up to 270 days—although they did test positive for the urinary PrPSc and one of three hamsters that was killed after 120 days showed low concentrations of PrPSc in the brain. This suggests that inoculation with urinary PrPSc may result in a subclinical or carrier state prion infection. The implications of this are unclear and there is certainly a need to repeat and confirm these observations (Professor R.Will, personal communication) before drawing conclusions about the putative infectivity of urine from prion-infected humans.
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Transmission of prion disease |
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TopAbstractIntroductionPrion diseases—backgroundCould human urine contain...Transmission of prion diseaseUrinary gonadotrophinsRecombinant FSHShould the use of...AcknowledgementsReferences |
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Prion disease, in particular vCJD, is thought to be due to the transmission of BSE to humans, predominantly by the ingestion of infected nervous tissue (brain, spinal cord). A critical factor in the pathogenesis of TSEs is the quantity of the prion present. Whilst the lymphoreticular system is essential for its pathogenesis, there is no evidence for transmission by the ingestion of tissue containing white cells/lymphoid tissue (e.g. spleen, lymph nodes). Transmission from individual to individual appears to be low, with a low within-herd incidence of BSE. Furthermore the current advice from the World Health Organization (1997—current on website December 2001) is that urine is thought to have zero infectivity (Table I
), which is why precautions are not advised when handling urine from either infected animals or humans. Similarly other excreted bodily fluids are not thought to cause risk—hence the safety of milk (World Health Organization, 1997). There is, however, the potential risk of infection via leukocytes in bodily fluids, for example milk from cows with mastitis and, theoretically, from urine of women with cystitis (Professor R. Lacey, personal communication)—although neither of these situations has been demonstrated. With respect to blood products there is as yet no evidence that any form of CJD is transmitted by blood transfusion or via plasma derived medicinal products (Committee On Safety Of Medicines, 1998). Blood for human transfusion is now treated to remove leukocytes. Because of the problems that the recall of plasma-derived medicinal products has caused when donors were later found to test positive for CJD it was decided to source plasma products from countries free of vCJD (Committee On Safety Of Medicines, 1998).
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Urinary gonadotrophins |
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TopAbstractIntroductionPrion diseases—backgroundCould human urine contain...Transmission of prion diseaseUrinary gonadotrophinsRecombinant FSHShould the use of...AcknowledgementsReferences |
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Urinary gonadotrophins are currently derived from post-menopausal women who reside in countries free of BSE and vCJD (e.g. Argentina, Ferring Pharmaceuticals, personal communication). Furthermore, with respect to today's debate, even if urine were found to be infective it is highly unlikely that post-menopausal women with classical CJD would be in a position to be asked to donate urine and those individuals so far identified with vCJD have tended to be in a younger, pre-menopausal, age group (although they could potentially donate during the pre-clinical phase). The issue that a country is currently thought to be free of BSE is of course simply due to lack of detection of the disease amongst livestock combined with the absence of indigenous cases of vCJD in humans. There is the potential for this situation to change due to the fluidity and unpredictability of the condition.
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Recombinant FSH |
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TopAbstractIntroductionPrion diseases—backgroundCould human urine contain...Transmission of prion diseaseUrinary gonadotrophinsRecombinant FSHShould the use of...AcknowledgementsReferences |
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Recombinant FSH is derived from a Chinese hamster ovary (CHO) cell line that has been transfected with the gene for human FSH. Once the human FSH protein is produced the glycosylation process then occurs within the CHO cells (rhFSH Product Development Group, 1998). The cell culture medium requires the presence of fetal calf serum and, reassuringly, this is also obtained from countries where BSE is absent (Organon laboratories and Serono laboratories, personal communications). The fetal calf serum used in cell cultivation is removed by a validated purification process (Committee On Safety Of Medicines—personal communication). There are, in addition, tight controls placed by regulatory bodies, such as the Committee on Safety of Medicines in the UK, to ensure that all medicinal products are free of any potential risk of transmission of TSEs. There is not currently a reliable diagnostic or screening test for prion disease, although recently a plasminogen has been developed which selectively binds to abnormal prions in the blood, and might even become a way for removing prions from blood products (Fischer et al., 2000
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Both urinary derived and recombinantly engineered gonadotrophin preparations require purification. Procedures for ensuring that gonadotrophin preparations are free from contamination with infective agents include a number of filtration, anionic exchange chromatography and precipitation steps—detailed description of which is beyond the scope of this paper (Recombinant Human FSH Product Development Group, 1998; British Pharmacopoeia, 2001). Thus bacteria, viruses and prions may be physically removed from the final gonadotrophin preparation leaving FSH (and LH) as the only active ingredients. It is also reassuring to note that similar fractionation procedures that are used for the manufacture of human plasma products (e.g. albumin, immunoglobulins, factor VIII etc) contain steps that are capable of removing prion proteins (Foster, 2000).
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Should the use of urinary-derived gonadotrophins be discontinued? |
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TopAbstractIntroductionPrion diseases—backgroundCould human urine contain...Transmission of prion diseaseUrinary gonadotrophinsRecombinant FSHShould the use of...AcknowledgementsReferences |
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This debate concerns the putative risks of the transmission of prion disease from urinary-derived gonadotrophin preparations and is not concerned with either efficacy or the cost-benefit argument, which has been covered amply in recent months (Barlow, 2001
; Daya et al., 2001; Sykes et al., 2001). Although, of course, in the wider debate it is necessary to consider every property of the available drugs (Balen et al., 1999). The current evidence on the presence of PrP in urine does not appear sufficient to advocate the discontinuation of urinary-derived gonadotrophins. Caution needs to be exercised and further research undertaken. If Shaked and colleagues' work is verified it would be prudent to use the methods described to screen urine for PrP prior to its use for the extraction of gonadotrophins (Shaked et al., 2001). In conclusion, hundreds of thousands of women have been treated with gonadotrophin preparations, since the introduction of the urinary-derived HMG products in the early 1960s and the more recent introduction of recombinant FSH (and now LH) in the 1990s. All of the gonadotrophin preparations appear to have a good safety record without evidence of contamination with infectious agents, in particular, at the present time, with prions. The current procedures for sourcing of products from countries free of vCJD combined with a purification process that appears to minimise the risk of infectivity provides further reassurance. Extensive research is underway to identify reliable, non-invasive screening tests for prion disease together with methods for ensuring their elimination from biological products. In the meantime, we can be reassured that both urinary-derived and recombinant gonadotrophins appear to carry a minimal risk of prion infectivity and there is no evidence to change current prescribing habits.
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Acknowledgements |
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TopAbstractIntroductionPrion diseases—backgroundCould human urine contain...Transmission of prion diseaseUrinary gonadotrophinsRecombinant FSHShould the use of...AcknowledgementsReferences |
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I am grateful to the following who have provided invaluable information and advice in the preparation of this paper: Professor I.Cooke, Emeritus Professor of Obstetrics and Gynaecology, University of Sheffield; Professor R.Lacey, Emeritus Professor of Medical Microbiology, University of Leeds; Dr L.Tsang, Head of Biologicals and Biotechnology Unit, Medicines Control Agency, London; Professor R.Will, Director of the National Creutzfeldt-Jakob Disease Surveillance Unit, Department of Neurosciences, Western General Hospital, Edinburgh. The author has received educational grants for research and to attend meetings from Ferring U.K. Ltd., Organon U.K. Ltd and Serono U.K. Ltd.
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