UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)
UvA-DARE (Digital Academic Repository)
Polycystic ovary syndrome. A therapeutic challenge
Bayram, N.
Publication date
2004
Document Version
Final published version
Link to publication
Citation for published version (APA):
Bayram, N. (2004). Polycystic ovary syndrome. A therapeutic challenge.
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.
POLYCYSTICC OVARY SYNDROME
AA THERAPEUTIC CHALLENGE
POLYCYSTICC OVARY SYNDROME
©© N e r i m a n Bayram, Amsterdam 2004
Polycysticc ovary syndrome a therapeutic challenge
P h DD Thesis, University of Amsterdam - with references - with summary in Dutch
ISBN:: 9 0 - 9 0 1 8 4 2 6 - 0
Keywords:: polycystic ovary syndrome, clomiphene citrate resistant, recombinant FSH, ovulationn induction, electrocautery, pregnancy.
Cover:: Artemis, goddess with many faces; goddess of the h u n t , the m o o n , childbirth and fertility. Artemiss is usually considered to be the daughter of Leto and Zeus. Two statues of Artemis Ephesus aree on display in the Ephesus Museum in Izmir, Turkey.
Coverr design & lay out: Oscar van der Erve, Amsterdam. Printedd by: Febodruk BV, Enschede.
Studiess published in this thesis were financially supported by a grant from the Health Insurance Funds C o u n c i ll <OG 9 7 / 0 0 7 ) , Amstelveen, T h e Netherlands.
Publicationn of this thesis was supported by:
C N NN tours, De Tulp, Erbe Benelux BV, Ferring BV, Johnson &C Johnson Medical BV, divisie Gynecare, Komfortours-Beachholidays,, Metra Agency, N V Organon, Schering Nederland BV, Serono Benelux BV, Stichtingg Gynaecologische Endocrinologie en Kunstmatige H u m a n e Voortplanting, Universiteit van A m s t e r d a m ,, Vrouwenkliniek, Academisch Medisch C e n t r u m .
POLYCYSTICC OVARY SYNDROME
AA THERAPEUTIC CHALLENGE
Academischh proefschrift
terr verkrijging van de graad van doctor aann de Universiteit van Amsterdam opp gezag van de Rector Magnificus
prof.. mr. P.F. van der Heijden
tenn overstaan van een door het college voor promoties ingestelde commissie,, in het openbaar te verdedigen in de Aula der Universiteit
opp vrijdag 17 september 2004 te 12.00 uur
door r Nerimann Bayram
Promotiecommissie e
P r o m o t o r e s : :
Prof.. dr. F. van der Veen Prof.. dr. P.M.M. Bossuyt P r o m o t i e c o m m i s s i e : : Prof.. A . H . Balen M D FRCOG Prof.. dr. O.P. Bleker
Prof.. dr. B.C. Fauser Dr.. C.B. Lambalk Prof.. dr. M. Offringa
Faculteitt Geneeskunde
Thiss thesis was prepared at the: Centerr for Reproductive Medicine Departmentt of Obstetrics and Gynecology
Academicc Medical Center, University of Amsterdam Meibergdreeff 9 (H4-205)
11055 A Z Amsterdam T h ee Netherlands
C O N T E N T S S
CHAPTERR l
Generall introduction 9
CHAPTERR 2
Recombinantt FSH in alternative doses or versus urinary gonado- 21 trophinss for ovulation induction in subfertility associated with
polycysticc ovary syndrome.
Nerimann Bayram, Madelon van Wely, Fulco van der Veen. Update. The Cochrane library, Issuee 2, 2004. Chichester, UK: John Wiley & Sons, Ltd.
CHAPTERR 3
Pulsatilee g o n a d o t r o p i n releasing hormone for ovulation induction 39 inn subfertility associated with polycystic ovary syndrome.
Nerimann Bayram, Madelon van Wely, Patrick M.M. Bossuyt, Fulco van der Veen. Thee Cochrane Library, Issue 2, 2004. Chichester, UK: John Wiley & Sons, Ltd.
CHAPTERR 4
Usingg an electrocautery strategy or recombinant follicle stimulating 53 hormonee to induce ovulation in polycystic ovary syndrome:
randomisedd controlled trial.
Nerimann Bayram, Madelon van Wely, Eugenie M. Kaaijk, Patrick M.M. Bossuyt, Fulcoo van der Veen. British Medical Journal 2004, 328:192-195
CHAPTERR 5
Laparoscopicc electrocautery of the ovaries versus recombinant 67 FSHH in clomiphene citrate resistant polycystic ovary syndrome.
Impactt on women's health related quality of life.
Madelonn van Wely, Neriman Bayram, Patrick M.M. Bossuyt, Fulco van der Veen. Humann Reproduction. In press
CHAPTERR 6
Ann economic comparison of a laparoscopic electrocautery strategy 81 andd ovulation induction with recombinant FSH in women
withh clomiphene citrate resistant polycystic ovary syndrome.
Madelonn van Wely, Neriman Bayram, Fulco van der Veen, Patrick M.M. Bossuyt. Humann Reproduction. In press
CHAPTERR 7
Treatmentt preferences and trade-offs for ovulation induction in 95 clomiphenee citrate resistant patients with polycystic ovary syndrome.
Nerimann Bayram, Madelon van Wely, Fulco van der Veen, Patrick M.M. Bossuyt. Submitted d
CHAPTERR 8
Summary,, conclusions and implications for future research. 107
Samenvatting,, conclusies en richtlijnen voor toekomstig onderzoek 114
Appendixx I 121 Appendixx II 128 Dankwoordd 131
C H A P T E R i i
I n t r o d u c t i o n n
Polycysticc ovary syndrome (PCOS), the existence of which was already known in the 18th century,, still represents a therapeutic challenge. To the best of our knowledge, Vallisneri wass the first author to report on this condition in 1721. In his paper he focuses on the abnormall morphology of the ovaries which are described as large, bumpy, shiny and whitish,, just like pigeon eggs (Insler and Lunenfeld, 1990). Since then occasional reports havee been published regarding the origin of this morphological abnormality and its surgicall treatment. In 1935, interest in the syndrome was revived by a landmark publicationn by Stein and Leventhal in which this anatomical abnormality was associated withh amenorrhea, history of sterility, masculine type hirsutism, and less consistently, retardedd breast development and obesity (Stein and Leventhal, 1935). Nowadays, polycysticc ovary syndrome is considered to be a heterogeneous condition with a wide varietyy in clinical and biochemical presentation.
AA patient with PCOS can be affected by one, all, or any combination of the following signs,, symptoms and endocrine abnormalities: menstrual disturbance (oligomenorrhoea, amenorrhoea),, infertility, hyperandrogenism (hirsutism, acne, alopecia), obesity, elevated LH/FSHH ratio, insulinresistance, dyslipidaemia and appearance of polycystic ovaries on ultrasonographyy (Balen, 1999). A gold standard for the diagnosis of PCOS is lacking. Conclusivee scientific arguments to prefer one definition of PCOS above another can not bee given. Recently, a consensus was reached on the diagnostic criteria of PCOS at a meetingg of the European Society of Human Reproduction and Embryology (ESHRE) andd American Society for Reproductive Medicine (ASRM). The newly revised criteria for thee diagnosis of PCOS are the presence of two out of the following three symptoms: oligo-- or anovulation, clinical and/or biochemical signs of hyperandrogenism and polycysticc ovaries. Other etiologies should be excluded (The Rotterdam sponsoredd PCOS Consensus Workshop Group, 2004; The Rotterdam ESHRE/ASRM-sponsoredd PCOS Consensus Workshop Group, 2004a).
Sincee this consensus is quite recent, the reported prevalence of PCOS depends on the definitionn used and varies widely. A prevalence of approximately 4 to 7% has been reportedd when PCOS was defined by oligomenorrhoea, clinical hyperandrogenism and/or hyperandrogenemiaa (Asuncion et al., 2000; Knochenhauer et al., 1998; Diamanti-Kandarakiss et al, 1999) and approximately 21-33% when PCOS was diagnosed by the ultrasonographicall image of polycystic ovaries (Poison et al., 1988; Clayton et al., 1992; Farquharr et al., 1994; Michelmore et al., 1999). Combining the presence of polycystic ovariess with one or more of the associated clinical symptoms or recognized biochemical disturbances,, results in a prevalence of PCOS which varies between 8% and 26%, dependingg on how many criteria were applied to define the syndrome (Michelmore et al.,
1999). .
Treatmentt of PCOS is symptom oriented. Infertility due to chronic anovulation is the mostt common reason for patients with PCOS to seek treatment.
Thee drug of first choice in ovulation induction is the anti-estrogen clomiphene citrate (CC).. However, approximately 20 % of patients fail to ovulate on CC (Hull, 1987; Imani ett a l , 1998; Out and Coelingh-Bennink, 1998). Effective treatment of these clomiphenee citrate resistant patients remains a significant challenge to the medical
profession.. The second line therapeutic options are either ovulation induction with ovariann surgery or gonadotrophins.
Thee first effective treatment to restore ovulation was the bilateral ovarian wedge resection byy laparotomy, introduced by Stein and Leventhal (Stein and Leventhal, 1935). Interest inn this surgical intervention was lost because of the observed high incidence of adhesion formationn after the wedge resection (Buttram and Vaquero, 1975; Kistner, 1969; Weinsteinn and Polishuk, 1975; Adashi et al., 1981) and the introduction of clomiphene citratee in 1961 (Greenblatt, 1961). Subsequently, laparoscopic ovarian biopsy was introducedd by Palmer and De Brux in 1967 (Palmer and De Brux, 1967). Although this proceduree is less invasive compared to bilateral ovarian wedge resection by laparotomy, it didd not result in new interest for surgical treatment. Probably this was caused by the fact thatt laparoscopic surgery was not a common practice at that time, and by the fear for adhesionn formation, as experienced after bilateral wedge resection.
Thee unilateral oophorectomy proposed by Hamerlynck in 1982 (Hamerlynck, 1982) was alsoo not evaluated by others due to the introduction of in vitro fertilization and fear of prematuree ovarian failure, while at the same time attention was focussed on the further developmentt of minimal invasive treatment options by laparoscopy. These new and less invasivee techniques involved laparoscopic laser surgery and laparoscopic electrocautery of thee ovaries. The laparoscopic laser surgery was introduced by Huber in 1988 (Huber et al.,, 1988). Despite certain advantages, such as a shorter operating time and a diminished riskk of adhesions, the laser systems are expensive and require extensive and costly upkeep (Greenblatt,, 1993).
Att this moment, laparoscopic electrocautery of the ovaries is the most commonly used surgicall treatment in patients with clomiphene citrate resistant polycystic ovary syndrome. Thee original technique was first described by Gjonnaess in 1984 (Gjonnaess, 1984). AA unipolar electrode with a power output of 200-300 Watts was pressed for 2 to 4 seconds againstt the ovary to penetrate the ovarian surface. The number of points cauterized varied betweenn three to eight holes in each ovary. Gjonnaess reported an ovulation percentage of 92%% and a pregnancy rate of 69% in a group of 62 patients. However, only 19 of these patientss received clomiphene citrate before cauterization and only nine patients failed to ovulatee with clomiphene citrate. Three out of those nine patients (33%) conceived after electrocauteryy (van der Weiden and Alberda, 1987).
Seriouss complications have not been reported with laparoscopic electrocautery of the ovaries.. However, the use of unipolar cautery carries the potential risk of arcing, with damagee to adjacent organs, particularly the bowel. One rare complication that has been reportedd is the development of ovarian atrophy (Dabirashrafi, 1989). This report emphasizess the need to avoid cauterizing the ovarian hilum, which might affect the blood supply,, as well as individualizing the number of points of injury and maximum energy accordingg to the size and bulk of the ovary. A more important possible complication of electrocauteryy is adhesion formation, although the incidence is not well established. Adhesionn formation has been evaluated during second look laparoscopics because of persistentt infertility or during caesarean sections and varies between 0-70% (Armar and Lachelin,, 1993; Naether and Fischer, 1993; Weise et al., 1991; Farhi et al., 1995; Liguori etal.,, 1996;Pelosi, 1996).
Att the time of writing the research protocol that is the basis for the present thesis, twelve uncontrolledd studies had been published on laparoscopic electrocautery concerning
ovulationn and pregnancy in patients with clomiphene citrate resistant polycystic ovary syndromee (Gjonnaess, 1984; Greenblatt and Casper, 1987; Greenblatt and Casper, 1993; Gurganetal.,, 1991;Tasakaet al., 1990;Taskinet al., 1996; Lockwoodetal., 1998;Taskin ett al., 1999; Tulandi et al., 2000; Weerakiet et al., 1999; Alborzi et al., 2001; Zullo et al., 2000).. Summary of the data from these studies results in a mean ovulation rate of approximatelyy 7 3 % (range 52-94) per patient and a mean pregnancy rate of approximatelyy 50% (range 20-80) per patient.
Additionall treatment with clomiphene citrate after laparoscopic electrocautery of the ovariess increased the ovulation rate to 87% (range 76-100) and the pregnancy rate to 70% (rangee 20-73) (Gjonnaess, 1984; Greenblatt and Casper, 1987; van der Weiden and Alberda,, 1987); (Alborzi et al., 2001; Lockwood et al., 1998; Weerakiet et al., 1999).
Thee other treatment modality for clomiphene citrate resistant patients with PCOS is ovulationn induction with gonadotropins, which are available in the form of urinary derivedd human menopausal gonadotrophins (hMG) or follicle stimulating hormone (FSH).. Human menopausal gonadotropin was the first available preparation that containss 75 IU FSH, 75 IU luteinizing hormone (LH) and some urinary proteins. The nextt generation in this group was purified urinary FSH (uFSH) or urofollitrophins containingg very little LH. Later highly purified FSH containing only traces of LH was introducedd and finally the pure preparation of recombinant FSH (rFSH) became available.. The conversion from hMG to uFSH was driven by the concept that lack of urinaryy proteins would diminish adverse reactions such as local allergy or hypersensitivity (Albanoo et al., 1996; BifToni et al., 1994) whereas the absence of LH would have no negativee influence on folliculogenesis (van Weissenbruch et al., 1993; Hayden et al., 1999).. Although the fast introduction of rFSH was market driven, its purity, batch to batchh consistency, high specific bioactivity and absolute source control made it an attractivee alternative to the urinary FSH products.
Itt is however not clear whether using rFSH rather than uFSH for ovulation induction in patientss with PCOS leads to any improvement in clinical endpoints like ovulation and ongoingg pregnancy rate. We reviewed the literature to summarize the evidence on the effectivenesss and safety of rFSH versus uFSH.
Ovulationn induction with gonadotrophins in patients with PCOS is associated with the riskk of multiple follicular development, consequently leading to complications such as ovariann hyperstimulation syndrome and multiple pregnancy. Various attempts have been madee to achieve unifollicular growth and thereby to reduce these complications.
Onee of these attempts was the modification of the stimulation regimens. Currently, chronicc low dose step up or step down regimens are used instead of the initially introducedd high dose gonadotrophin regimens. The chronic low dose step up regimen employss a starting dose of one ampoule of 75 IU of FSH, which is only increased after 14 dayss if there is no response, and then by only half an ampoule every seven days (Hamilton-Fairleyy et al, 1991; Balen et al., 1994; Homburg et al., 1995). The aim of this regimenn is not to exceed the FSH concentration above which more than one follicle will respond,, the so-called FSH threshold for any given follicle (Brown, 1978).
Thee step down regimen employs a starting dose of two to three ampoules daily for three too four days followed by dose decreases once the lead follicle exceeds a mean diameter of aboutt 10 mm (Schoot et al., 1992; Schoot et al., 1995; van Santbrink et al., 1995; Fauser
andd Van Heusden, 1997). The rationale behind the step down regimen is that it mimics thee normal menstrual cycle more closely (Fauser et al., 1993). In order to find out the mostt appropriate dose regimen we reviewed the literature to determine the effectiveness andd safety of various dose regimens using rFSH.
Anotherr attempt to achieve monofollicular growth was the introduction of pulsatile administrationn of gonadotrophin releasing hormone (GnRH). Following the positive effectss in patients with hypogonadotropic hypogonadism, Coelingh Bennink was the first authorr to select PCOS patients in whom other methods had failed or in whom ovarian hypersdmulationn syndrome had occurred, for treatment with GnRH (Coelingh Bennink, 1983).. Since then, a limited number of randomised controlled trials with small number off patients have been published, comparing GnRH with gonadotrophins. Although ovulationn and pregnancies were achieved, the use of pulsatile GnRH in patients with PCOSS did not lead to the same success rates as achieved in hypogonadotropic amenorrhoea.. To improve clinical outcome suppression of endogenous gonadotrophins throughh pre treatment with GnRH agonists was the next step. However, pulsatile GnRH hass not become a standard treatment for ovulation induction in patients with clomiphene citratee resistant PCOS. To prove or to discard the value of pulsatile GnRH we reviewed thee literature to determine effectiveness and safety of pulsatile GnRH versus gonadotrophins. .
Att present ovulation induction with laparoscopic electrocautery of the ovaries and recombinantt FSH (rFSH) are standard treatments in patients with CC-resistant PCOS. Whetherr gonadotrophins or laparoscopic electrocautery of the ovaries should be the treatmentt of choice in patients with CC-resistant polycystic ovary syndrome was unclear whenn work on this thesis was started. To find out the best way to treat these patients, we designedd a randomised controlled trial comparing a treatment strategy that started with laparoscopicc electrocautery of the ovaries followed by CC and rFSH if anovulation persistedd versus ovulation induction with rFSH.
A i mm o f t h e t h e s i s
Thee aim of the work reported in this thesis was to answer the following questions:
11 What is the effectiveness and safety of rFSH compared with uFSH and what is the effectivenesss and safety of various dose regimens using rFSH in clomiphene citrate resistantt patients with PCOS?
22 What is the effectiveness and safety of pulsatile GnRH compared with gonadotrophins inn clomiphene citrate resistant patients with PCOS?
33 What is the value of electrocautery strategy compared to ovulation induction with rFSH inn the treatment of clomiphene citrate resistant patients with PCOS in view of outcome measures,, patients' health related quality of life, costs and patients' preferences?
O u t l i n ee o f the t h e s i s
Chapterr 2 reviews the literature on the effectiveness and safety of recombinant FSH
versuss urinary FSH and recombinant FSH in different dose regimens to induce ovulation inn patients with clomiphene citrate-resistant PCOS. Studies were included according the principless of the Cochrane Menstrual Disorders and Subfertility Group. The results concerningg ovulation, pregnancy, miscarriage, incidence of multiple pregnancy, incidence off ovarian hyperstimulation syndrome, total gonadotrophin dose and total duration of stimulationn are described and compared.
Chapterr 3 reviews the literature on the effectiveness and complications of pulsatile
GnRHH to induce ovulation in patients with PCOS. Studies were included according the principless of the Cochrane Menstrual Disorders and Subfertility Group. The results concerningg ovulation, pregnancy, miscarriage, incidence of multiple pregnancy and incidencee of ovarian hyperstimulation syndrome are described and compared.
Chapterr 4 describes the first randomised controlled trial comparing the effectiveness
off a laparoscopic electrocautery strategy entailing electrocautery of the ovaries followed by clomiphenee citrate and recombinant FSH if anovulation persisted versus ovulation inductionn with recombinant FSH in patients with clomiphene citrate resistant PCOS. Ongoingg pregnancy was the primary endpoint. Ovulation, miscarriage, ectopic pregnancy andd the live birth rate were secondary endpoints.
Chapterr 5 focuses on the health related quality of life of patients who participated in
thee randomised controlled trial described in Chapter 4. Health related quality of life was assessedd by several standard self administered psychosomatic measures at different time pointss in both treatment groups.
Chapterr 6 reports on the economic evaluation of the electrocautery strategy compared
too ovulation induction with recombinant FSH using data from the randomised controlled triall described in Chapter 4. Data on used resources and lost production time were collectedd and costs of both treatment modalities were calculated to an ongoing pregnancy withh a time horizon of 12 months. A scenario analysis was done to evaluate the costs of ovulationn induction with rFSH without a preceding laparoscopy.
Chapterr 7 contains a report of a study of patient preferences and trade-offs when offered
aa choice between laparoscopic electrocautery of the ovaries and ovulation induction with recombinantt FSH. This study was performed among patients who had been treated in the randomisedd controlled trial described in Chapter 4 and among a control group of women undergoingg ovulation induction with clomiphene citrate as they were potential candidates forr treatment with either electrocautery of the ovaries or ovulation induction with recombinantt FSH if they became resistant to clomiphene citrate.
Chapterr 8 presents the summary and conclusions of the present study and gives
References s
Adashi,, E. Y., Rock, J. A., Guzick, D., Wentz, A. C , Jones, G. S., and Jones, H. W., Jr. (1981) Fertility followingg bilateral ovarian wedge resection: a critical analysis of 90 consecutive cases of the polycystic ovary syndrome.. Fertil. Steril. 36, 320-325.
Albano,, C., Smitz, J., Camus, M., Bennink, H. C , Van, Steirteghem, AC, and Devroey, P. (1996) Pregnancy andd birth in an in-vitro fertilization cycle after controlled ovarian stimulation in a woman with a history of allergicc reaction to human menopausal gonadotrophin. Hum. Reprod. 11, 1632-1634.
Alborzi,, S., Khodaee, R., and Parsanejad, M. E. (2001) Ovarian size and response to laparoscopic ovarian electro-cauterizationn in polycystic ovarian disease. Int. J. Gynaecol. Obstet. 74, 269-274.
Armar,, N . A. and Lachelin, G. C. (1993) Laparoscopic ovarian diathermy: an effective treatment for anti-oestrogenn resistant anovulatory infertility in women with the polycystic ovary syndrome. Br. J. Obstet, Gynaecol.. 100, 161-164.
Asuncion,, M , Calvo, R. M , San Millan, j . L., Sancho, J., Avila, S., and Escobar-Morreale, H. F. (2000) A prospectivee study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain.. J. Clin. Endocrinol. Metab. 85, 2434-2438.
Balen,, A. (1999) Pathogenesis of polycystic ovary syndrome—the enigma unravels? Lancet 354, 966-967. Balen,, A. H., Braat, D. D., West, C , Patel, A., and Jacobs, H. S. (1994) Cumulative conception and live birth ratess after the treatment of anovulatory infertility: safety and efficacy of ovulation induction in 200 patients. Hum.. Reprod. 9, 1563-1570.
Biffoni,, M , Battaglia, A , Borrelli, E, Cantelmo, A., Galli, G., and Eshkol, A. (1994) Allergenic potential of gonadotrophicc preparations in experimental animals: relevance of purity. Hum. Reprod. 9, 1845-1848. Brown,, J. B. (1978) Pituitary control of ovarian function-concepts derived from gonadotrophin therapy. Aust.. N . Z. J. Obstet. Gynaecol. 18, 46-54.
Buttram,, V. C. Jr and Vaquero, C. (1975) Post-ovarian wedge resection adhesive disease. Fertil. Steril. 26, 874-876. .
Clayton,, R. N., Ogden, V., Hodgkinson, J., Worswick, L., Rodin, D. A., Dyer, S., and Meade, T. W. (1992) Howw common are polycystic ovaries in normal women and what is their significance for the fertility of the population?? Clin. Endocrinol. 37, 127-134.
Coelinghh Bennink, H.J.T. (1983) Induction of ovulation by pulsatile intravenous administratin of LHRH in polycysticc ovarian disease. The Endocrine Society 65th Annual Meeting, San Antonio, Texas. Abstract 1. Dabirashrafi,, H. (1989) Complications of laparoscopic ovarian cauterization. Fertil. Steril. 52, 878-879.
Diamanti-Kandarakis,, E., Kouli, C. R., Bergiele, A. T., Filandra, F. A., Tsianateli, TC, Spina, G. G., Zapanti, E.. D., and Barrzis, M. I. (1999) A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonall and metabolic profile. J. Clin. Endocrinol. Metab. 84, 4006-4011.
Farhi,, J., Soule, S., and Jacobs, H. S. (1995) Effect of laparoscopic ovarian electrocautery on ovarian response andd outcome of treatment with gonadotropins in clomiphene citrate-resistant patients with polycystic ovary syndrome.. Fertil. Steril. 64, 930-935.
Farquhar,, C. M., Birdsall, M., Manning, P., Mitchell, J. M., and France, J. T. (1994) The prevalence of polycysticc ovaries on ultrasound scanning in a population of randomly selected women. Aust. N. Z. J. Obstet. Gynaecol.. 34, 67-72.
Fauser,, B. C„ Donderwinkel, P., and Schoot, D. C. (1993) The step-down principle in gonadotrophin treatmentt and the role of GnRH analogues. Baillieres Clin. Obstet. Gynaecol. 7, 309-330.
Fauser,, B. C. and Van Heusden, A. M. (1997) Manipulation of human ovarian function: physiological conceptss and clinical consequences. Endocr. Rev. 18, 71-106.
Gjonnaess,, H. (1984) Polycystic ovarian syndrome treated by ovarian electrocautery through the laparoscope. Fertil.. Steril. 41, 20-25.
Greenblatt,, E. (1993) Surgical options in polycystic ovary syndrome patients who do not respond to medical ovulationn induction. Baillieres Clin. Obstet. Gynaecol. 7, 421-433.
Greenblatt,, E. and Casper, R. F. (1987) Endocrine changes after laparoscopic ovarian cautery in polycystic ovariann syndrome. Am. J. Obstet. Gynecol. 156, 279-285.
Greenblatt,, E. M. and Casper, R. F. (1993) Adhesion formation after laparoscopic ovarian cautery for polycysticc ovarian syndrome: lack of correlation with pregnancy rate. Fertil. Steril. 60, 766-770.
Greenblatt,, R. B. (1961) Induction of Ovulation with MRL/41. JAMA 178, 127-130.
Gurgan,, T , Kisnisci, H., Yaraü, H„ Develioglu, O., Zeyneloglu, H., and Aksu, T. (1991) Evaluation of adhesionn formation after laparoscopic treatment of polycystic ovarian disease. Fertil. Steril. 56, 1176-1178. Hamerlynck,, J. (1982) Polycystic ovaries disease: one ovary too many? Lancet 2, 937-938.
Hamilton-Fairley,, D., Kiddy, D., Watson, H., Sagle, M., and Franks, S. (1991) Low-dose gonadotrophin therapyy for induction of ovulation in 100 women with polycystic ovary syndrome. Hum. Reprod. 6, 1095-1099.
Hayden,, C. J., Balen, A. H., and Rutherford, A. J. (1999) Recombinant gonadotropins. Br. J. Obstet. Gynaecol.. 106, 188-196.
Homburg,, R., Levy, T , and Ben-Rafael, Z. (1995) A comparative prospective study of conventional regimen withh chronic low-dose administration of follicle-stimulating hormone for anovulation associated with polycysticc ovary syndrome. Fertil. Steril. 63, 729-733.
Huber,, J., Hosmann, J., and Spona, J. (1988) Polycystic ovarian syndrome treated by laser through the laparoscope.. Lancet 2, 215
Hull,, M. G. (1987) Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographicc studies. Gynecol. Endocrinol. 1, 235-245.
Imani,, B., Eijkemans, M. J., te, Velde ER, Habbema, J. D„ and Fauser, B. C. (1998) Predictors of patients remainingg anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheicc infertility. J. Clin. Endocrinol. Metab. 83, 2361-2365.
Insler,, V. and Lunenfeld, B. (1990) Polycystic ovarian disease: a challenge and controversy. Gynecol. Endocrinol.. 4, 51-70.
Kistner,, R. W. (1969) Peri-tubal and peri-ovarian adhesions subsequent to wedge resection of the ovaries. Fertil.. Steril. 20, 35-41.
Knochenhauer,, E. S., Key, X J., Kahsar-Miller, M., Waggoner, W., Boots, L. R., and Azziz (1998) Prevalence off the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospectivee study. J. Clin. Endocrinol. Metab. 83, 3078-3082.
Liguori,, G., Tolino, A., Moccia, G., Scognamiglio, G., and Nappi, C. (1996) Laparoscopic ovarian treatment inn infertile patients with polycystic ovarian syndrome (PCOS): endocrine changes and clinical outcome. Gynecol.. Endocrinol. 10, 257-264.
Lockwood,, G. M., Muttukrishna, S., Groome, N . P., Matthews, D. R., and Ledger, W. L. (1998) Mid-follicularr phase pulses of inhibin B are absent in polycystic ovarian syndrome and are initiated by successful laparoscopicc ovarian diathermy: a possible mechanism regulating emergence of the dominant follicle. J. Clin. Endocrinol.. Metab. 83, 1730-1735.
Michelmore,, K. E, Balen, A. H., Dunger, D. B., and Vessey, M. P. (1999) Polycystic ovaries and associated clinicall and biochemical features in young women. Clin. Endocrinol. 51, 779-786.
Naether,, O. G. and Fischer, R. (1993) Adhesion formation after laparoscopic electrocoagulation of the ovariann surface in polycystic ovary patients. Fertil. Steril. 60, 95-98.
Out,, H. J. and Coelingh-Bennink, H. J. T. (1998) Clomiphene citrate in the twenty-first century: an anachronism?? Assist. Reprod. Reviews 8, 94-101.
Palmer,, R., and De Brux, J. (1967) Résultats histologiques, biochimiques et thérapeutiques obtenus chez les femmess dont les ovaires avalent été diagnostiqués Stein-Leventhal a la coeliscopie. Societe Nat. de gyn. et d'obstet.. de Fr. 19,405-412.
Pelosi,, M. A. (1996) Laparoscopic electrosurgical furrowing technique for the treatment of polycystic ovaries. J.. Am. Assoc. Gynecol. Laparosc. 4, 57-62.
Poison,, D. W., Adams, J., Wadsworth, J., and Franks, S. (1988) Polycystic ovaries-a common finding in normall women. Lancet 1, 870-872.
Schoot,, D. C , Hop, W, C , de Jong, F. H., van Dessel, T. J., and Fauser, B. C. (1995) Initial estradiol response predictss outcome of exogenous gonadotropins using a step-down dose regimen for induction of ovulation in polycysticc ovary syndrome. Fertil. Steril. 64, 1081-1087.
Schoot,, D. C , Pache, T. D., Hop, W. C , de, Jong FH, and Fauser, B. C. (1992) Growth patterns of ovarian follicless during induction of ovulation with decreasing doses of human menopausal gonadotropin following presumedd selection in polycystic ovary syndrome. Fertil. Steril. 57, 1117-1120.
Stein,, I. F and Leventhal, M. L. (1935) Amenorrhea associated with bilateral ovaries. American Journal of Obstetricss & Gynecology 29, 181-191.
Tasaka,, K., Sakata, M , Kurachi, H „ Komura, H., Miyake, A., and Tanizawa, O. (1990) Electrocautery in polycysticc ovary syndrome. Horm. Res. 33 40-42.
Taskin,, O., Sadik, S., Onoglu, A., Gokdeniz, R., Yilmaz, I., Burak, F, and Wheeler, J. M. (1999) Adhesion formationn after microlaparoscopic and laparoscopic ovarian coagulation for polycystic ovary disease. J. Am. Assoc.. Gynecol. Laparosc. 6, 159-163.
Taskin,, O., Yalcinoglu, A. I., Kafkasli, A., Burak, E, and Ozekici, U. (1996) Comparison of the effects of ovariann cauterization and gonadotropin-releasing hormone agonist and oral contraceptive therapy combinationn on endocrine changes in women with polycystic ovary disease. Fertil. Steril. 65, 1115-1118. Thee Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group (2004) Revised 2003 consensuss on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil. Steril. 81,, 19-25.
Thee Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group (2004a) Revised 2003 consensuss on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum.. Reprod. 19, 41-47.
Tulandi,, T , Saleh, A„ Morris, D., Jacobs, H. S., Payne, N. N., and Tan, S. L. (2000) Effects of laparoscopic ovariann drilling on serum vascular endothelial growth factor and on insulin responses to the oral glucose tolerancee test in women with polycystic ovary syndrome. Fertil. Steril. 74, 585-588.
vann der Weiden, R. M. and Alberda, A. T. (1987) Laparoscopic ovarian elecrrocautery in patients with polycysticc ovarian disease resistant to clomiphene citrate, Surg. Endosc. 1, 217-219.
vann Santbrink, E. J., Donderwinkel, P. E, van Dessel, T. J., and Fauser, B. C. (1995) Gonadotrophin inductionn of ovulation using a step-down dose regimen: single-centre clinical experience in 82 patients. Hum. Reprod.. 10, 1048-1053.
vann Weissenbruch, M. M., Schoemaker, H. C , Drexhage, H. A., and Schoemaker, J. (1993) Pharmaco-dynamicss of human menopausal gonadotrophin (HMG) and follicle-stimulating hormone (FSH). The importancee of the FSH concentration in initiating follicular growth in polycystic ovary-like disease. Hum, Reprod.. 8,813-821.
Weerakiet,, S., Srisombut, C , Choktanasiri, W., and Rojanasakul, A. (1999) Efficacy of laparoscopic ovulation inductionn in polycystic ovary syndrome. J. Med. Assoc. Thai. 82, 760-764.
Weinstein,, D. and Polishuk, W. Z. (1975) The role of wedge resection of the ovary as a cause for mechanical sterility.. Surg. Gynecol. Obstet. 141, 417-418.
Weise,, H. C , Naether, O., Fischer, R., Berger-Bispink, S., and Delfs T. (1991) Results of treatment with surfacee cauterization of polycystic ovaries in sterility patients. Geburtshilfe Frauenheilkd. 51, 920-924. Zullo,, F., Pellicano, M., Zupi, E., Guida, M., Mastrantonio, P., and Nappi, C. (2000) Minilaparoscopic ovariann drilling under local anesthesia in patients with polycystic ovary syndrome. Fertil. Steril. 74, 376-379.
C H A P T E RR 2
Recombinantt FSH in alternative doses
orr versus urinary g o n a d o t r o p i n s for
ovulationn induction in subfertility associated
hh polycystic ovary syndrome
NerimanNeriman Bayram, Madelon van Wely, Fulco van der Veen
Abstract t
Background d
Overr the last four decades, various urinary FSH (uFSH) products of different purity have beenn developed. In 1988 recombinant FSH (rFSH ) was prepared by transfecting Chinese hamsterr ovary cell lines with both FSH subunit genes. It is unknown which of these FSH preparationss to prefer, regarding effectiveness and safety. Essential in ovulation induction withh gonadotrophins is the time during which the serum FSH is above the threshold at whichh recruitment of follicles occurs. Extending this time carries the risk of multiple folliclee development and multiple pregnancies. Because of this, various dose regimens havee been developed to minimize these complications.
Objectives s
Too compare in women with clomiphene-resistant polycystic ovary syndrome (PCOS) the effectivenesss and safety of 1) rFSH with uFSH and 2) various dose regimens of rFSH.
Searchh strategy
Wee searched the Cochrane Menstrual Disorders and Subferrility Group trials register (searchedd 1st May 2004), PubMed, MEDLINE, Web of Science (all searched 1985 to Mayy 1 2004), and reference lists of articles. We also contacted manufacturers and researcherss in the field.
Selectionn criteria
Alll relevant published RCT's were selected. Randomised controlled trials were eligible for inclusionn if treatment consisted of recombinant FSH versus urinary FSH or recombinant FSHH in different dose regimens, to induce ovulation in women with clomiphene citrate resistantt PCOS.
D a t aa collection & analysis
Thee main outcome measure was ongoing pregnancy/live birth per woman. Secondary outcomess were ovulation, pregnancy, miscarriage, multiple pregnancy and ovarian hyperstimulationn syndrome (OHSS). Relevant data were extracted independently by two reviewerss (NB, MW). Odds ratios were generated using the Peto modified Mantel-Haenszell technique. The main outcome measure was ongoing pregnancy/live birth per woman.. Secondary outcomes were ovulation, pregnancy, miscarriage, multiple pregnancy andd ovarian hyperstimulation syndrome (OHSS). Relevant data were extracted independentlyy by two reviewers (NB, MW). Odds ratios were generated using the Peto modifiedd Mantel-Haenszel technique.
Mainn results
Threee randomised trials comparing rFSH versus uFSH were identified. Only one trial providedd data on the primary outcome, ongoing pregnancy, while all three studies providedd data on the secondary outcomes. No difference was found in ongoing pregnancy ratee (OR 1.10, 95% CI 0.51 to 2.35). There was no difference in clinical pregnancy rate (ORR 0.95, 95% CI 0.64 to 1.41), nor between any of the other secondary outcomes. Fourr small trials with different dose regimens were identified. As each of the four included trialss compared different regimens, no trial results could be combined. None of the trials
presentedd data on ongoing pregnancy/live birth. In the first trial that compared chronic loww dose step up regimen versus conventional regimen no statistically significant differencess were found for clinical pregnancy rate (OR 1.62, 95% CI, 0.64 to 4.07), nor inn the other secondary pregnancy outcomes. However, significantly fewer follicles >10 mmm diameter (WMD -3.30, 95% CI -5.34 to -1.26) were found in the group treated with thee chronic low dose step up regimen. The second trial compared two starting doses in a chronicc low dose step up regimen. The clinical pregnancy rate was comparable in both stimulationn regimens (OR 0.79, 95% CI 0.12 to 4.96). The third trial compared a chronicc low dose step up regimen with modified step down regimen. No difference in clinicall pregnancy rate could be proven (OR 1.90, 95% CI 0.18 to 19.97).
Thee fourth trial compared a chronic low dose step up regimen with a step down regimen revealedd also no statistically significant differences in clinical pregnancy rate (OR 1.41, 95%% CI 0.57 to 3.46). Similarly no difference could be proven in any of the other pregnancyy outcomes. However, significantly more monofollicular development (OR 4.24,, 95% CI 2.27 to 7.92) and less multifollicular development (OR 0.13, 95% CI 0.06 too 0.29) was observed in the chronic low dose step up group.
Reviewers'' conclusions
Att this moment there is not sufficient evidence to determine whether rFSH or uFSH is preferablee for ovulation induction in women with clomiphene citrate resistant PCOS. No differencee could be proven between the four different dose regimens. However, the conventionall regimen is known to be plagued by OHSS and multiple pregnancies and usagee should therefore be discouraged.
Background d
Polycysticc ovary syndrome (PCOS) is the most common cause of female anovulatory infertility.. To induce ovulation, clomiphene citrate (CC) is the first line of treatment. However,, about 20% of patients are CC resistant i.e. they do not ovulate after a maximumm dose of clomiphene citrate (100-200 mg) (Imani et al., 1998). Since 1958, thesee patients are treated with follicle stimulating hormone (FSH), originally extracted fromm pituitary glands (Gemzell et al., 1958) and later extracted from post-menopausal urinee (Lunenfeld et ah, I960).
Overr the last four decades, various urinary FSH products have been developed. Menotropinn (human menopausal gonadotrophins (hMG), available since the early 1960s, containss FSH, LH and large quantities of potentially allergenic urinary proteins. Urofollitropinn (FSH), available since the mid 1980s, is devoid of LH, but is still contaminatedd with urinary proteins. Highly purified urofollitropin (FSH-HP), available sincee the mid 1990s contains very small amounts of urinary proteins. Lack of urinary proteinss diminishes adverse reactions such as local allergy or hypersensitivity (Bififoni et al.,, 1994; Albano et al., 1996) whereas the absence of LH has no negative influence on folliculogenesiss of PCOS patients (van Weissenbruch et al., 1993; Hayden et al., 1999). Too obtain higher purity, complete absence of LH, high specific bioactivity, absolute source control,, independence of urine collection and batch to batch consistency, recombinant FSHH (rFSH ) was synthesized in 1988. This was realised by transfecting Chinese hamster ovaryy cell lines with both FSH subunit genes (Keene et al., 1989; Howies et al., 1996). Att present, two preparations of rFSH are available. The first one, marketed in 1995, is follitropinn alpha (Gonal F®), soon followed by follitropin beta (Puregon®). Both preparationss are similar to pituitary and urinary FSH, although they show minor differencess in the structure of the carbohydrate side chains and contain more basic and lesss acidic isohormones than the natural hormones (Hard et al., 1990, de Leeuw et al., 1996,, Andersen, 2004 in press).
Ovulationn induction with FSH bears the risk of multiple follicle development and multiplee pregnancies (Nugent et al., 2004). To reduce these complications, various dose regimenss have been developed (Brown 1978; Hamilton-Fairley et al., 1991, van Santbrink etal.,, 1995).
Att present, the most frequently used dose regimens are the chronic low dose step up and stepp down regimens. In a previous review the effectiveness of urinary FSH was compared withh hMG in patients with PCOS (Nugent et al., 2004). In this review we compare the effectivenesss and safety of rFSH with urinary gonadotrophins and the effectiveness and safetyy of various regimens using rFSH.
Objectives s
11 To determine the safety and effectiveness of recombinant FSH compared with urinary gonadotrophinss used for ovulation induction in women with clomiphene citrate resistant PCOS. .
22 To determine the safety and effectiveness of various dose regimens of recombinant FSH usedd for ovulation induction in women with clomiphene citrate resistant PCOS.
Criteriaa for considering studies for this review
Typess of studies
AA trial was eligible for inclusion if it dealt with the use of a recombinant FSH versus urinaryy gonadotrophins or recombinant FSH in various dose regimens, and if primary outcomess of ovulation rate and pregnancy rate were specified. The participants were allocatedd by a randomisation procedure.
Typess of participants
Womenn with clomiphene citrate resistant PCOS undergoing ovulation induction. Clinicall and endocrinological characteristics, infertility work-up, age, duration of infertilityy and previous treatment(s) if available were specified in the trial characteristics table. .
Typess of interventions
1)) Recombinant FSH versus Urinary FSH
2)) Recombinant FSH versus Human menopausal gonadotrophin (HMG) 3)) Recombinant FSH versus Recombinant FSH (various dose regimens)
Typess of outcome measures
Primaryy Outcome:
Ongoingg pregnancy or live birth rate per woman
Secondaryy Outcomes:
Clinicall pregnancy rate (per woman)
Ovulationn rate (per woman, if available, otherwise per cycle)
Incidencee of ovarian hyperstimulation syndrome (OHSS) (per woman) Incidencee of multiple pregnancy (per woman)
Miscarriagee rate (per woman)
Incidencee of multifollicular growth (per woman) Totall gonadotrophin dose
Totall duration of stimulation
Oestradioll levels on day hCG administration
Numberr of follicles on the day of hCG administration
Searchh strategy for identification of studies
Thiss review has drawn on the search strategy developed for the Cochrane menstrual Disorderss and Subfertility Group as a whole.
1.. The following electronic databases were searched: -- MEDLINE (1966-April 2004)
-- EMBASE (1988-April 2004)
-- Cochrane Controlled Clinical Trials Register (CCTR) Thee following keywords were used;
ovulationn induction, gonadotropins, recombinant FSH and FSH.
2.. Handsearching of the references mentioned in the obtained studies was performed
3.. Serono Benelux BV and NV Organon, the manufacturers of follitropin alpha (Gonal F®) andd follitropin beta (Puregon®) respectively, were asked for ongoing studies and unpublishedd data.
Methodss of the review
Selectionn of studies & quality assessment
Dataa from included trials was processed as described in the Cochrane Handbook (Clarke andd Oxman, 2003). All selected studies were assessed and evaluated for methodological qualityy and appropriateness for inclusion without consideration of their results.
Trialss were screened and analysed for the following quality criteria and methodological details:: method and timing of randomisation; number of patients randomised and analysed;; whether they were single or multicenter studies; parallel or cross-over design; blindingg of treatment; the use of sequential analysis or factorial design; the presence of a powerr calculation; duration of follow-up; whether pregnancy was a measured outcome and,, if so, how this was diagnosed; how pregnancy results were presented (particularly whetherr cumulative conception curves with the use of life table analysis were employed); andd the source of any funding.
Relevantt trials were screened independently by two authors (NB and MW). Differences off opinion were registered and resolved by consensus with the senior author (FV). Iff crossover studies were identified, data were included in the review from the pre-crossoverr period where possible. If pre-crossover data could not be extracted, the results off pre- and post-crossover study periods were given descriptively. The data were extracted intoo two-by-rwo tables and checked for accuracy by N. Bayram and M. van Wely. If necessary,, additional data was requested from the authors. For dichotomous data, odds ratioss with 95% confidence intervals were calculated for each individual trial using the Petoo modification of the Mantel-Haenszel method (Peto, 1987). For continuous data the weightedd mean was calculated. When median and range were given instead of mean and SD,, the mean was estimated by logarithmic transformation of the minimum and maximumm values and the SD was imputed from the overall SD of other studies. In the absencee of heterogeneity of treatment effect among trials, which was tested using the Breslow-Dayy chi-square test, the data were pooled. For pooled dichotomous data an overalll combined OR with 95% CI's was calculated using the Peto method and for continuouss data a weighted mean difference (WMD) with 95% CI was calculated using thee inverse variance method. Negative values in W M D indicate a benefit of "treatment group"" over controls.
D e s c r i p t i o nn o f s t u d i e s
Pleasee see Appendix I for details of the study methods and participants of the seven trials includedd in the analysis.
Typess of studies
RecombinantRecombinant FSH versus urinary FSH
Threee trials were identified meeting the inclusion criteria (Loumaye et al., 1996; Coelingh Benninkk et al., 1998; Yarali et al., 1999). All trials compared ovulation induction with rFSHH versus uFSH in clomiphene citrate resistant patients. The study of Loumaye 1996 wass described in a review on human gonadotrophins produced by recombinant DNA technology.. By personal communication additional data on this trial was obtained and all thesee data was incorporated in this review. In total 451 women were included in the trials comparingg rFSH with uFSH.
RecombinantRecombinant FSH versus HMG
Noo trials could be identified comparing rFSH with hMG.
RecombinantRecombinant FSH versus recombinant FSH - various dose regimens
Fourr trials were identified meeting the inclusion criteria (Hedon et al., 1998; Balasch et al.,, 2000; Balasch et al., 2001; Christin-Maitre et al., 2003). Trials comparing various dose regimenss using urinary FSH were excluded as these are evaluated in another systematic revieww (Nugent et al., 2004). In total 237 women were included in the trials.
TypesTypes of participants
Polycysticc ovary syndrome was defined as a combination of at least two of three criteria; clinicall features (oligo/amenorrhoea, chronic anovulation), endocrinological abnormalitiess (hyperandrogenism and/or high LH/FSH ratio) and polycystic ovaries diagnosedd with ultrasonography. Chronic anovulation was mainly defined by cycle length off >35 days or amenorrhea. The participants were all clomiphene citrate-resistant, anovulatoryy women. Clomiphene citrate resistancy was defined as failure to ovulate or failuree to conceive if ovulation occured after various numbers of cycles. The maximum dosee of clomiphene citrate differed in the trials. In one trial no definitions on PCOS or clomiphenee citrate resistance were given (Loumaye et al., 1996).
TypesTypes of intervention
Threee trials compared recombinant FSH with urinary FSH using the chronic low dose stepp up regimen. Loumaye et al., 1996 and Yarali et al., 1999 compared Gonal-F with Metrodinn and Coelingh Bennink 98 compared Puregon with Metrodin. Loumaye 1996 didd not describe cancellation criteria. The cycles were cancelled by Coelingh Bennink et al.,, 1998 if more than three follicles of & 15 mm were present or if there was no follicular responss after 42 days of treatment. Yarali et al., 1999 cancelled cycles if more than 44 follicles a 15 mm were present or if there was no follicular response after 35 days off treatment.
Fourr trials compared various dose regimens of recombinant FSH. Hedon et al., 1998 comparedd a chronic low dose step up versus conventional step up protocol (Gonal-F) after
onee cyle. Injection of hCG was withheld if four or more follicles >14 mm were present. Twoo trials used a crossover design. The first trial compared two starting doses in a chronic loww dose step up protocol (Gonal-F and Puregon) (Balasch et al., 2000) and the second triall compared a chronic low dose step up regimen with modified step down regimen (Gonal-F)) (Balasch et al., 2001). No cancellation criteria were described in the first trial. Inn the second trial ovulation was triggered by one subcutaneous injection of 5000 IU hCGG when no more than three follicles with a mean diameter of 16 mm were present. Thee last trial compared a chronic low dose step up regimen with the step down regimen (Puregon)) (Christin-Maitre et al., 2003). Patients were treated for three consecutive cyles. H C GG administration was withheld if four or more follicles > 16 mm in diameter were presentt and/or if the serum oestradiol level was >1000 pg/ml. In addition ovarian stimulationn was cancelled in the absence of follicular development after 21 days of stimulationn or in case of cyst development.
TypesTypes of outcome measures
Pregnancyy rate, ovulation rate, miscarriage rate, multiple pregnancy rate, ovarian hyperstimulationn syndrome rate, total FSH dose, duration of stimulation, cancellation rate,, single follicle development, number of follicles >10 mm on day of HCG administration,, oestradiol concentration on day of HCG were reported. In the trials comparingg different regimens no definitions of any of the outcome parameters was given. Inn the trials comparing rFSH with uFSH definitions of ovulation and clinical pregnancy weree given. In one trial only a definition of ongoing pregnancy was given (Coelingh Benninkk et al., 1998).
Methodologicall quality of included studies
Alll seven trials included were randomised clinical trials. Three studies were single center studiess (Yarali et al., 1999; Balasch et al., 2000; Balasch et al., 2001) and the other four studiess were multicenter studies (Loumaye et al., 1996; Coelingh Bennink et al., 1998; Hedonn et al., 1998; Christin-Maitre et al., 2003). Two studies used a randomisation list thatt corresponded with patient drug codes (Coelingh Bennink et al., 1998; Yarali et al.,
1999),, two studies used sealed envelopes (Loumaye et al., 1996; Christin-Maitre et al., 2003),, one study used computerized allocation stratified by center (Hedon et al., 1998) andd for two studies the method of randomisation is unknown (Balasch et al., 2000; Balaschh et al., 2001). Only one study performed a power calculation (Loumaye et al., 1996).. An intention-to-treat analysis was performed in one trial only (Coelingh Bennink ett al., 1998). This trial also was assessor-blind, whereas the other six were open-label. Doublee blinding should have been possible for the three trials comparing rFSH with uFSH,, but this was not done as rFSH was supplied in vials and uFSH in ampoules. Withdrawalss after randomisation were mentioned in all trials. In the three trials comparingg rFSH with uFSH women were treated for a maximum of three cycles. For thesee trials no information was present on losses to follow-up after the first cycle. Only threee trials gave information on duration and timing of the trial (Coelingh Bennink et al., 1998;; Hedon et al., 1998; Yarali et al., 1999). Of the trials comparing different dose regimens,, two were crossover trials (Balasch et al., 2000; Balasch et al., 2001).
Thee sample size of the studies ranged between 22 to 222 women and the follow up was shortt (1 to 3 cycles).
Results s
RecombinantRecombinant FSH versus urinary FSH
(Loumaye(Loumaye et al., 1996; Coelingh Bennink et al., 1998; Yarali et al., 1999)
Dataa per woman could be extracted for all outcome measures except for ovulation rate whichh is reported per cycle. There was no evidence of statistical heterogeneity. The primaryy outcome i.e. live birth rate per woman was not reported in any of the trials (Loumayee et al., 1996; Coelingh Bennink et al., 1998; Yarali et al., 1999). Only one trial (Coelinghh Bennink et al., 1998) provided data on ongoing pregnancy, while all three studiess provided data on the secondary outcomes. No difference was found in ongoing pregnancyy rate (OR 1.10, 95% CI 0.51 to 2.35). After pooling the data, the clinical pregnancyy rate was not statistically significant different (OR 0.95, 95% CI, 0.64 to 1.41). Ovulationn rate per cycle was available in all studies but because of absence of the exact numberr of cycles in the study by Loumaye et al., 1996 only the data from Coelingh Benninkk et al., 1998 and Yarali et al., 1999 could be pooled with an overall OR 1.19 (95%% CI, 0.78 to 1.80).
Thee miscarriage rate per woman was comparable in all studies with an overall OR 1.22, (95%% CI 0.60 to 2.46). Ovarian hyperstimulation syndrome ocurred in 0.9% in both groupss (Loumaye et al., 1996) and in 7.6% in the rFSH group versus 4,5% in the uFSH groupp (Coelingh Bennink et al., 1998). No cases of OHSS occurred in the study of Yarali ett al., 1999. Overall, the pooled OR was not statistically significant different (OR 1.55, 95%% CI 0.50 to 4.84).
Loumayee et al., 1996 found 3 % versus 7% multiple pregnancies for rFSH and uFSH respectively.. From this study data on the order of multiple pregnancies could not be retraced.. In the other two studies one twin and one triplet pregnancy (2%) versus one twinn pregnancy (1.5%) (Coelingh Bennink et al., 1998) and no multiple pregnancies (0%)) versus three twin pregnancies (8.5%) (Yarali et al., 1999) were found in the rFSH groupp and the uFSH group respectively. There was no difference in multiple pregnancy inn the rFSH group compared with uFSH in these trials (OR 0.44, 95% CI 0.16 to 1.19). Continuouss outcome measures like total FSH dose, duration of stimulation, oestradiol (E2)) level and number of follicles of various diameters on the day of hCG administration weree only reported by Coelingh Bennink et al., 1998 and Yarali et al., 1999. Total FSH dosee and duration of stimulation and E2 level did not differ significantly between rFSH andd uFSH with a W M D of-216, 95% CI -733 to 312, -2.6, 95% CI -5.6 to 0.3 and 67, 95%% CI -67 to 200 for rFSH and uFSH respectively.
Ass various diameters for number of follicles were used, these data could not be pooled. Coelinghh Bennink et al., 1998 reported three different groups of follicle diameter after one,, two and three consecutive cycles. In the first group mean number (SD) of follicles a l 22 mm and in the second group number of follicles a l 5 mm and in the third group numberr of follicles ^18 mm were described. Only in the group of follicles &12 mm after thee first cycle a statistically significant difference was found: (WMD 1.00, 95% CI 0.17 too 1.83) between the rFSH and uFSH group.
Yaralii et al., 1999 reported two different groups of follicle diameter after one cycle. In the firstt group mean number of follicles of 10-14mm and in the second group number of follicless > 14 mm were described. Only in the second group a statistically significant differencee was found: (WMD 1.10, 95% CI 0.39 to 1.81) between rFSH and uFSH group.
RecombinantRecombinant FSH versus recombinant FSH - various dose regimens
Ass each of the four included trials compared various dose regimens, no trial results could bee combined. Analyses are therefore presented separately for each comparison.
1.. Chronic low dose step up regimen versus conventional step up regimen (Hedon et al., 1998) Thee primary outcome i.e. live birth rate or ongoing pregnancy was not reported. No statisticallyy significant difference in clinical pregnancy rate was found: 14 of 53 women (26%)) versus 9 of 50 women (18%) (OR 1.62, 95% CI, 0.64 to 4.07). Ovulation rate perr woman was similar comparing the regimens during one cycle. Thirty of 53 women (( 57%) and 29 of 50 women (58%) ovulated respectively (OR 0.95, 95% CI, 0.43 to 2.06).. Miscarriage rates per woman were 1.9% and 2% respectively (OR 0.62, 95% CI 0.033 to 11.34). OHSS ocurred in one patient in each rFSH treatment group. There was noo difference in multiple pregnancy rate per woman. Two twins (4%) in the chronic low dosee step up regimen and two twins (4%) in the conventional regimen were observed (OR 0.94,, 95% CI 0.13 to 6.89).
Continuouss outcome measures like total FSH dose, duration of stimulation, oestradiol (E2)) level and number of follicles of different measures on the day of hCG gift were also reported.. The results of mean (SD) total FSH dose used and the mean (SD) duration of stimulationn did not differ significantly with a W M D of-45 (95% CI -346 to 255) and
1.55 (95% CI -0.87 to 3.87) respectively. Mean E2 {SD) concentration after one cycle was significantlyy lower in the chronic low dose regimen, 504 (477) pg/ml compared with the conventionall regimen 989 (740) pg/ml (WMD -485, 95% CI -743 to -227).
TwoTwo different groups of follicle diameter after one cycle were reported. In the first group meann number (SD) of follicles >10 mm and in the second group mean number (SD) of follicless a l 6 were described. Only in the group of follicles >10 mm was a statistically significantt difference found (WMD -3.30, 95% CI -5.34 to -1.26) in favour of the chronicc low dose.
2.. Two starting doses (37.5 IU versus 50 IU) in a chronic low dose step up regimen (Balaschh et al., 2000)
Thee primary outcome i.e. live birth rate or ongoing pregnancy was not reported. No statisticallyy significant difference in clinical pregnancy rate per woman were found: three off 12 women (25%) versus three of 10 women (30%) respectively (OR 0.79, 95% CI 0.122 to 4.96). All 22 participating women ovulated in the first cycle in both groups. No dataa was reported for the outcomes miscarriage, OHSS or multiple pregnancy. As no data fromm the pre-crossover period could be obtained on the continuous outcome measures likee mean total FSH dose, mean duration of stimulation, mean oestradiol (E2) level and meann number of follicles of different measures on the day of hCG administration, these parameterss were not included in the MetaView analysis.
3.. Chronic low dose step up regimen versus modified step down regimen (Balasch et al., 2001) )
Thee primary outcome i.e. live birth rate or ongoing pregnancy was not reported. No statisticallyy significant difference in clinical pregnancy rate per woman was found: two of 155 women (13%) and one of 14 women (7%) (OR 1.90, 95% CI 0.18 to 19.97). All 29
participatingg women ovulated after the first cycle. No data was reported for the outcomes miscarriagee and multiple pregnancy. No cases of OHSS occurred. As no data from the pre-crossoverr period could be obtained on the continuous outcome measures like mean totall FSH dose, mean duration of stimulation, mean oestradiol (E2) level and mean numberr of follicles of different measures on the day of hCG administration, these parameterss were not included in the MetaView analysis.
4.. Chronic low dose step up regimen versus step down regimen (Christin-Makre et al., 2003) )
Thee primary outcome i.e. live birth rate or ongoing pregnancy was not reported. No statisticallyy significant difference in clinical pregnancy rate per woman were found: 17 of 444 women (38.6%) and 12 of 39 (31%) (OR 1.41, 95% CI 0.57 to 3.46). Ovulation rate perr cycle was significantly different (OR 2.24, 95% CI, 1.18 to 4.27). It is unclear how thee miscarriages were calculated, but no differences were found; 12.5% versus 16.7%. Threee cases of moderate OHSS were reported but it is not clear in which treatment group. Twoo twin pregnancies (4,5% per woman) in the step up protocol and two twin and one triplett pregnancy (8% per woman) in the step down protocol were observed (OR 0.58, 95%% CI 0.10 to 3.50).
Continuouss outcome measures like total FSH dose, duration of stimulation, oestradiol (E2)) level and number of follicles of different measures on the day of hCG gift were also reported.. The mean (SD) total FSH dose used was not statistically different (WMD -16, 95%% CI -241 to 209). A significant difference was found for mean duration of stimulationn (OR 5.50, 95% CI 3.217.79) and E2 levels on day of hCG gift (WMD -395,, 95% CI-770 to-19).
InIn this study the rate of monofollicular (1 follicle >l6mm), bifollicular (2 follicles >16mm)) and multifollicular (at least 3 follicles >16mm) development was described. Noo difference was observed in bifollicular development (OR 0.59, 95% CI 0.26 to 1.30), whereass a significant difference was found in monofollicular (OR 4.24, 95% CI 2.27 to 7.92)) and multifollicular development (OR 0.13, 95% CI 0.06 to 0.29).
Discussion n
Ovulationn induction involves the use of medication or surgery to stimulate development off a mature follicle in the ovary of women who have chronic anovulation and infertility. Att this moment recombinant FSH and urinary FSH are commonly used for this purpose. Thee main difference between these two types of gonadotrophins is the presence or urinary proteinn contaminants in uFSH.
Yet,, impurity affects safety only if it should be demonstrated that any of the potential contaminantss adversely affect either the patients' health or treatment outcome. The urinaryy preparations of human gonadotrophins have been widely used for 40 years and noo infections have been associated with their injection, even in the past when the urinary extractss were rather impure (Balen, 2002, Gleicher et al., 2003). In spite of this, urinary FSHH is more immunogenetic leading to local and allergic reactions (Biffoni et al., 1998, Battagliaa et al., 2000).
Recombinantt FSH is more basic and resembles Metrodin more closely than Metrodin HP, whichh is more acidic (Lambert et al., 1995). Therefore the bio-potency of FSH increases inn the order highly purified urofollitropin (Metrodin HP), urofollitropin (Metrodin) and rFSHH (Lambert et al., 1995). Loumaye et al., 1996 and Yarali et al., 1999 compared Gonal-FF with Metrodin and Coelingh Bennink et al., 1998 compared Puregon with Metrodinn in a chronic low dose step up regimen. Several parameters are commonly used ass indicators for the biopotency of FSH: number of follicles >12 mm, E2 level on the day off H C G administration, total dose of FSH required to induce follicular development and thee duration of stimulation.
Indeed,, (Coelingh Bennink et al., 1998) found significantly more follicles in the range of 12-14mmm in the rFSH group, although this was not found for follicles larger than 15 mm. Furthermore,, rFSH required a significantly shorter treatment period to induce ovulation inn the first cycle. There was no proof of a difference in mean E2 level and total dose requiredd between rFSH and uFSH. Yarali et al., 1999 also studied the indicators for bioactivityy mentioned above. This trial however found no difference in number of follicles inn the range of 10-14 mm in the rFSH group. No differences were observed in E2 level, totall FSH dose and treatment period required to induce ovulation. More importantly, resultss from the pooled data showed no difference in ovulation rate per cycle (OR 1.19, 9 5 %% CI 0.78 to 1.80), clinical pregnancy rate per woman (OR 0.95, 95% CI 0.64 to 1.41),, multiple pregnancy rate per woman (OR 0.44, 95% CI 0.16 to 1.21), miscarriage ratee per woman (OR 1.26, 95% CI 0.59 to 2.70) and OHSS per woman (OR 1.55, 95% CII 0.50 to 4.84).
Apartt from the gonadotrophin used, the stimulation regimen is of importance in ovulationn induction. The conventional regimen used to be the standard stimulation protocoll but has now been abandoned. It is well known that the use of the conventional regimenn results in high rates of multiple pregnancies (33%) and ovarian hyperstimulation syndromee (up to 14%) (Homburg, 2003; Yarali, 2004). These complications are due to thee supraphysiological doses of FSH that are administered in the conventional regimen. Thee chronic low dose step up has been introduced to prevent the development of multiple follicles,, multiple pregnancies and OHSS as seen in conventional step up regimens. Basic thinkingg behind the chronic low dose step up regimen is the "threshold theory", that statess that FSH recruits and maintains one follicle only if it does not exceed a certain level (Brownn 1978). The principle of the chronic low dose step up regimen is to employ a low startingg dose for 14 days and then to use small incremental dose rises (usually half an ampoule)) when necessary, at intervals of not less than 7 days, until follicular development iss initiated (Seibel et al., 1984; Hamikon-Fairley et al., 1991). In the one trial that comparedd the chronic low dose step up with the conventional step up regimen no differencess were found in effectiveness which may be due to the small size of this study (Hedonn et al., 1998). Although a difference in OHSS and multiple pregnancies was not foundd there were significantly fewer follicles >10 mm diameter (WMD 3.30, 95% CI -5.344 to -1.26) in the group treated with the chronic low dose step up regimen.
AA possible criticism of the chronic low dose step up regimen is that, unlike the events of thee normal ovulatory cycle in which decreasing FSH concentrations are seen throughout thee follicular phase, FSH levels may be elevated during the follicular phase (Dale et al., 1993).. In order to mimic more closely the events of the normal ovulatory cyle the step downn regimen has been introduced with a starting dose of 150 IU and decreasing the dose byy 0.5 ampoules when a follicle of 10 mm develops and by the same amount every 3 days
iff follicular growth continues (Fauser et al., 1993). A key issue of the step down regimen iss to estimate the FSH threshold of follicular development in order to determine the FSH startingg dose. Therefore a "dose-finding" low-dose step up regimen is first offered for these patientss followed by the step down regimen. A comparison of the step down regimen with thee chronic low dose step-up regimen in a small randomised controlled trial with uFSH demonstratedd a higher monofollicular growth rate of cycles in the step down regimen (88%)) compared with step up regimen (56%) (van Santbrink and Fauser 1997). In the stepp down-group, duration of treatment and gonadotrophin requirement were significantlyy reduced. However, the study by Christin-Maitre et al., 2003 with a larger samplee size, comparing the chronic low dose step up regimen versus the step down regimenn with rFSH, demonstrated superiority of the step up regimen with regard to the ratess of monofollicular development (OR 4.24, 95% CI 2.27 to 7.92), ovulation (OR 2.24,, 95% CI, 1.18 to 4.27) and multifollicular development (OR 0.13, 95% CI 0.06 to 0.29).. Although the mean duration of stimulation was significantly longer (OR 5.50, 95%% CI 3.21-7.79) in the step up regimen, no significant difference was found in the totall dose of FSH used (WMD -16, 95% CI -241 to 209).
Inn the chronic low dose step up regimen a starting dose of no higher than 75 IU is used. InIn theory, risk of multifollicular development and multiple pregnancies can be prevented whenn an even lower starting dose is used. From the largest cohort study of the chronic low dosee step up regimen (White et al., 1996) it was possible to compare the results of a startingg dose of 75 IU with that of 52.5 IU, with an incremental dose rise of 37.5IU or 22.5IUU respectively. No significant differences between the two groups were found but pregnancyy rate per patient, monofollicular growth rate and miscarriage rate were all in favourr of the lower starting dose. Although having a very small sample size with a crossoverr design similar clinical pregnancy rates and ovulation rates were observed in the randomizedd controlled trial comparing 37.5 IU with 50 IU (Balasch et al., 2000). InIn summary, there is as yet insufficient evidence to conclude that rFSH is more effective thann uFSH. Therefore, it is questionable whether its high costs should be traded off its purity,, independence of urine collection, absolute source control and batch to batch consistency.. No difference could be proven between the four different dose regimens. However,, the conventional regimen is known to be plagued by OHSS and multiple pregnanciess and its usage should therefore be discouraged.
Reviewers'' conclusions
Implicationss for practice
Thee newly developed recombinant gonadotroph ins have clear advantages, particularly availability,, batch to batch consistency and self-administration. Based on the differences inn terminal sialic acid residues, which confer different charge patterns to the gonadotropin preparations,, differences in biological activity are expected. The role of biological activity inn ovulation induction still has to be resolved. However, at this moment this does not have clearr clinical consequence as both rFSH and uFSH are equally effective for ovulation inductionn in women with PCOS. Furthermore, attention should be given to the costs involvedd in these treatments. The higher costs associated with the rFSH can present a problem,, particulary in a society with decreasing health resources.
