Correspondence
Josef Decosas and Simon Heap (Nov 13, p 1735)1 lament the lack of operational elements in our report on knowledge for better health, and ask “what happened to the charcoal?”. WHO is committed to the better use of evidence for informing public health practice and in exploring ways of making this notion a reality—this point is one of the key messages of the report. We believe it will be a critical factor in making better use of research for strengthening health systems in our member states. In terms of concrete ways and operational elements for achieving this goal, we can only begin to make suggestions. In another commentary on our report,2 Abbasi points out that “what we don’t know is even greater in public health in poor countries than in biomedicine in rich countries”. For example, in the report we suggest the use of knowledge intermediaries or brokers who will help support and strengthen the better use of evidence in national decision making in health. In terms of better knowledge access, we put forward a concrete suggestion for establishing a platform for an international register of clinical trials. We also suggest much more substantial investments, and more innovative approaches, for research in specific health system functions, such as human resources, financing, service delivery, and health information. However, other important questions remain and, as Decosas and Heap mention, the challenge of scaling up useful practical examples mentioned in the report is particularly important. Also, Decosas and Heap took issue with the need for integrating vertical, disease-specific programmes into the broader health system and that the burden to do research into this issue should not be placed on researchers in developing countries, since “we have 25 years of documented evidence about the devastating effect of these programmes on national health systems”. Three points. First, single disease prowww.thelancet.com Vol 364 December 11, 2004
grammes can be devastating, but not always on national health systems—ask the smallpox and the polio viruses. Second, the global reality is that such programmes, many of them well resourced, will not go away in the near future; and WHO is not solely responsible as exemplified by the Global Fund Against HIV/AIDS, Tuberculosis, and Malaria, the Global Alliance for Vaccines and Immunization (GAVI), and the President’s Emergency Plan for AIDS Relief (PEPFAR). Third, if researchers in developing countries are not “burdened” and do not participate in and contribute to the necessary research, who else will do it? Are they not the best placed and the most knowledgeable about their own health systems, and have a strong interest to ensure that benefits accrue? Do we not want to avoid, once again, parachuted academic research from institutions in the developed world, proposing solutions unfounded on realities on the ground? Is this way not the best way to ensure building of capacity in the developing world and then sharing the knowledge gained with the global research community? We think so. Sebelum membangun rumah carilah dahulu batu bata. This is a saying in the Indonesian language with allusion to building: “Before you build a house, first find the bricks”. The better use of research for strengthening health systems is a highly complex and long-term challenge facing national governments, the entire research community, and the supporters of research—the report was intended primarily as a catalyst for action at the level of ministers of health who met in Mexico City at the end of November, 2004, to better understand the challenges. We must first find the charcoal, and the bricks, before we can put it on the fire and collectively forge an effective strategy to better use research for improving health in the developing world.
Tikki Pang
[email protected] World Health Organization, 1211 Geneva 27, Switzerland
1
2
Decosas J, Heap S. Health research: what happened to the charcoal? Lancet 2004; 364: 1735–36. Abbasi K. Knowledge for better health. BMJ 2004; 329: 1120.
e-mail submissions to
[email protected]
Livebirth after cryopreserved ovarian tissue autotransplantation Although autotransplantation of frozen-banked ovarian tissue is accepted as a promising technology for fertility restoration, the findings of J Donnez and colleagues (Oct 16, p 1405)1–3 fall short of providing conclusive evidence for the first pregnancy after this procedure for various reasons. First, the risk of ovarian failure in patients with lymphoma aged 25 years or younger who receive chlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine with or without radiation is 20% or less, with half of patients conceiving spontaneously.4 Even when receiving chemotherapy regimens with low potential to cause premature menopause, most patients will go through a temporary or pseudomenopausal state, which can last more than 6 months, due to damage of developing follicles. Thus, raised concentrations of follicle stimulating hormone 3 months after chemotherapy do not necessarily indicate permanent ovarian failure. Indeed, the patient in the latest report1 had three ovulations from her intact left ovary, despite the fact that she was presumed to be in menopause. Second, the woman was not monitored daily during the cycle that led to her pregnancy. A clear understanding of the history of this patient is further complicated by the fact that she was placed on hormone replacement therapy (HRT) 3 months after chemotherapy, which prevented assessment of her endocrine profile. HRT was discontinued 2·5 years later and the patient attempted a pregnancy on her own for a year, during which time she ovulated at least once from her left ovary. Since the frequency of monitoring is not pro-
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
2091
Getty Images
Health research: find the charcoal first
Correspondence
vided, we cannot assess how many other ovulations from either ovary might have been missed. Third, Donnez and colleagues grafted ovarian tissue fragments contiguous with the pre-existing right ovary. The oocyte fertilised could therefore have ovulated from the preexisting tissue rather than the graft. Although the authors state the occurrence of monthly follicle development in the graft 5–9 months post-transplantation, the timing, frequency, and values of such measurements are not provided. For example, data on peak oestradiol concentrations or whether a gonadotropin surge occurred are missing. Fourth, Donnez and colleagues report a gonadotropin surge followed 3-weeks later by the appearance of a 26-mm follicle on the site of transplant, before ovulation. From figure 2, the day of this ovulation roughly corresponds to a  human chorionic gonadotropin measurement of 2000 mIU/mL, indicating that the 26-mm structure was a corpus luteum and the conception occurred in the previous cycle. Finally, no mention is made of whether the patient had menses between the surge at 9·5 months posttransplantation and the positive pregnancy test. The day of ovulation, as determined by basal body temperature, in reference to when the 26-mm structure was seen, was also not specified. The findings of Donnez and colleagues,1 coupled with an earlier report of a four-cell embryo derived from an oocyte of heterotopically transplanted ovarian tissue in a menopausal patient,5 raise optimism that autotransplantation of frozen-banked ovarian tissue will ultimately prove useful as a fertility option for cancer survivors. However, definitive evidence for the feasibility of pregnancy resulting from such procedures is, in our opinion, still lacking. This technique cannot yet, therefore, be recommended for routine use. 2092
*Kutluk Oktay, Jonathan Tilly
[email protected] *Center for Reproductive Medicine and Infertility, Weill Medical College of Cornell University, NY 10021, USA (KO); and Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA (JT) 1
2
3
4
5
Donnez J, Dolmans MM, Demylle D, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 2004; 364: 1405–10. Oktay K, Karlikaya G. Ovarian function after autologous transplantation of frozen-banked human ovarian tissue. N Engl J Med 2000; 342: 1919. Oktay KH, Yih M. Preliminary experience with orthotopic and heterotopic transplantation of ovarian cortical strips. Semin Reprod Med 2002; 20: 63–74. Schilsky RL, Sherins RJ, Hubbard SM, Wesley MN, Young RC, DeVita VT. Long-term follow up of ovarian function in women treated with MOPP chemotherapy for Hodgkin’s disease. Am J Med 1981; 71: 552–56. Oktay K, Buyuk E, Veeck L, et al. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet 2004; 363: 837–40.
Authors’ reply We read with interest the letter from Kutluk Oktay and Jonathan Tilly. First, Schilsky and colleagues, whom they cite, state that amenorrhoea developed in 89% and 20% of patients older and younger than age 25 years at the time of treatment, respectively. The median age of patients who became amenorrhoeic after therapy was higher than that of patients who maintained normal menses (26 years vs 20 years; p=0·008). Our patient, having received MOPP/ABV from age 25 years 5 months to 26 years was in the group at higher risk of developing premature ovarian failure. In a report published in 1996,1 the risk of premature ovarian failure after MOPP/ABV was cited as 61%. Second, we maintain that our patient had only one ovulatory cycle from January, 2001, to December, 2002. Occasional but rare ovulation can arise in iatrogenic as well as noniatrogenic premature ovarian failure.2 Monthly assessment of luteinising hormone, follicle stimulating hormone (FSH), and steroid concentra-
tions, and daily basal body temperature measurements, allow us to refute the suggestion that more ovulatory cycles could have occurred during this period. Third, we presented evidence in our discussion—eg, laparoscopic proof— that follicular growth arose outside of the right ovary at the site of reimplantation. Biopsy of this follicle and the grafted tissue revealed the presence of inhibin-A-stained cells in the follicle and the survival of primordial follicles in the grafted tissue. Moreover, we observed concentrations of progesterone as high as 37 ng/mL concomitant with the presence of a corpus luteum at the reimplantation site, which was confirmed by ultrasound. Fourth, as we pointed out in our article, ovulation arose after the FSH concentrations returned to within the normal range after the FSH surge. Oktay and Tilly would like to have had daily monitoring. In theory, we agree, but can we ethically and practically ask a patient to undergo daily blood sampling for 12 months? Finally, during the cycle leading to pregnancy, echography showed the presence of a 26⫻18 mm structure outside of the right ovary at the reimplantation site. On that day, the oestradiol concentration was 158 pg/mL, and the progesterone concentration 0 ng/ml. The rise in basal body temperature that occurred 2 days later allowed us to calculate the day of ovulation and to assert that the follicle observed 2 days before the temperature increase was the preovulatory follicle of that cycle, and not a corpus luteum from a previous cycle. To prove conclusively the origin of a pregnancy after cryopreservation, bilateral oophorectomy would need to be done before chemotherapy. However, this procedure is not ethical, since not all women have premature ovarian failure after chemotherapy.1,2 Moreover, remaining atrophic ovaries can be used as a site of reimplantation, as in our second case of reimplantation. www.thelancet.com Vol 364 December 11, 2004