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Polycystic ovary syndrome. A therapeutic challenge
Bayram, N.
Publication date
2004
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Citation for published version (APA):
Bayram, N. (2004). Polycystic ovary syndrome. A therapeutic challenge.
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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 directionss for future research.
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