Article Ovulation induction using low-dose step-up rfsh in Vietnamese women with polycystic ovary syndrome

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1 RBMOnline - Vol 18. No Reproductive BioMedicine Online; on web 19 February 2009 Article Ovulation induction using low-dose step-up rfsh in Vietnamese women with polycystic ovary syndrome Dr Vuong Thi Ngoc Lan received her MD degree in 1996, and her Master s Degree in Clinical Embryology at the National University of Singapore in During the past 10 years, she worked as clinical director of the largest IVF centre in Vietnam. Currently she works in the Department of Obstetrics and Gynecology, University of Medicine and Pharmacy of Ho Chi Minh city. She is now PhD fellow in Reproductive Medicine. Dr Lan has been an invited speaker at regional and international meetings. Her primary interests are luteal phase support, use of antagonist in IVF, ovulation induction in patients with polycystic ovary syndrome and in-vitro maturation. Dr Vuong Thi Ngoc Lan VTN Lan 1,4, RJ Norman 2, GH Nhu 3, PH Tuan 3, HM Tuong 3 1 Department of Obstetrics and Gynaecology, University of Medicine and Pharmacy of Ho Chi Minh City, 217 Hong Bang Street, District 5, Ho Chi Minh City, Vietnam 2 Research Centre for Reproductive Health, University of Adelaide, School of Paediatrics and Reproductive Health, Level 6, Medical School North, Frome Road, Adelaide, SA 5005, Australia 3 Ngoc Lan Fertility Clinics, 125 Tran Binh Trong Street, District 5, Ho Chi Minh City, Vietnam 4 Correspondence: lanvuong@hcm.fpt.vn Abstract The aim of this study was to assess the effectiveness and safety of a low-dose step-up protocol with a recombinant FSH starting dose of 25 IU for ovulation induction in anovulatory patients with polycystic ovary syndrome (PCOS) and a normal or low body mass index (BMI). In this prospective, non-comparative, open trial, 183 PCOS patients who had three unsuccessful cycles of ovulation induction with clomiphene citrate received recombinant FSH (Puregon ) 25 IU/day for 14 days, the dose was then increased by 25 IU every 5 days if there was no follicle of >12 mm diameter (maximum 150 IU/day). Human chorionic gonadotrophin was administered when the lead follicle was 18 mm, and intrauterine insemination was performed 36 h later. Duration of stimulation was 15.9 ± 4.8 days and total FSH dose was 484 ± 257 IU. A developing follicle was observed in 96.7% of cycles, of which 62.1% had unifollicular development and 15.8% were cancelled due to over-response. The clinical and ongoing pregnancy rates were 35.5% and 33.9%, respectively. There were no multiple pregnancies, and only one case of mild ovarian hyperstimulation syndrome. A low-dose step-up protocol with a recombinant FSH starting dose of 25 IU/day is effective and safe in anovulatory Vietnamese PCOS patients with a low or normal BMI. Keywords: body mass index, ovulation induction, polycystic ovary syndrome, pregnancy rate, recombinant human FSH Introduction 516 Polycystic ovary syndrome (PCOS) is the most common endocrine disturbance in women of reproductive age. It is diagnosed when two of the following three criteria are present: oligo- or anovulation; hyperandrogenism (clinical or biochemical); and polycystic ovaries on ultrasonography scan (Rotterdam European Society for Human Reproduction and Embryology [ESHRE]/American Society for Reproductive Medicine [ASRM], 2004). However, there is considerable inter-individual heterogeneity of PCOS symptoms and signs, and these may change or develop over time in individual women. Infertility is common in patients with PCOS, and this is usually secondary to oligo- or anovulation. The treatment of anovulatory infertility aims to restore ovulation as close to the physiological state as possible. The ultimate goal is to obtain unifollicular cycles without causing ovarian hyperstimulation and multiple pregnancies. However, the number of follicles recruited and that mature in any given cycle is dependent on the amount of FSH administered, the duration of stimulation and the sensitivity of the ovary as outlined in the FSH threshold and window concepts (Baird, 1987; Brown, 1987). It has been shown that the threshold dose required for unifollicular development can 2009 Published by Reproductive Healthcare Ltd, Duck End Farm, Dry Drayton, Cambridge CB23 8DB, UK

2 vary considerably from patient to patient or between different cycles in the same patient (Baird, 1987; White et al., 1996). Thus, ovulation induction in PCOS patients is always a challenge for clinicians due to the unpredictable response of these patients to stimulation regimens and the risk of complications such as ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies. Over many decades, clomiphene citrate (CC) has been the first choice for induction of ovulation in PCOS patients due to its low cost, oral route of administration, minimal requirement for ovarian response monitoring, and the low risk of ovarian hyperstimulation and multiple pregnancy. However, resistance to CC is relatively common, occurring in approximately 30% of PCOS patients (Hughes et al., 2000). More recently, the insulin-sensitizer metformin has been used to try and restore spontaneous ovulation in PCOS patients because of the role that insulin resistance is thought to play in anovulation. The use of metformin is relatively safe, ovulation is achieved in about 54.8% cycles with a clinical pregnancy rate of 18.6% (Lord et al., 2003). However, data from a meta-analysis have shown that ovulation and pregnancy rates during metformin therapy to do not differ significantly from those in placebo recipients (Lord et al., 2003). A recently published study provides additional support for the argument that metformin has limited usefulness for inducing ovulation in patients with PCOS (Legro et al., 2007). For patients who do not respond to CC, it is widely accepted that an FSH low-dose step-up protocol should be considered as the next treatment option (Kamrava et al., 1982; Hamilton- Fairley et al., 1991; Shoham et al., 1991; White et al., 1996; Hayden et al., 1999). The principle of this protocol is to administer FSH at an initially low dose, and then gradually increase the dose to identify the FSH threshold that is associated with the development of a single follicle. The conventional low-dose step-up protocol is administered with an FSH starting dose of 75 IU, followed by an increase of 75 IU every 7 days in the absence of a developing follicle (Hamilton-Fairley and Franks, 1990). At the Department of Infertility of the Tu Du Ob/Gyn Hospital, the use of a FSH low-dose step-up protocol with a starting dose of 50 IU was investigated in 114 CC-resistant PCOS patients. With this regimen, the clinical pregnancy rate was 36%, the multiple pregnancy rate was 7.3% and no cases of severe ovarian hyperstimulation syndrome (OHSS) occurred. However, with a starting dose of 50 IU and an adjustment dose of 50 IU, only 14% of cycles achieved unifollicular development, while close to 50% of cycles had more than three developing follicles (unpublished data). Based on these outcomes, it was decided to conduct a study in which the starting dose of FSH was reduced to 25 IU, with the aim of increasing the number of cycles with unifollicular development and minimizing the complications associated with ovulation induction. The objective of this study was to assess the clinical effectiveness and safety of a low-dose step-up protocol using a recombinant FSH (rfsh) starting dose of 25 IU for ovulation induction in Vietnamese PCOS patients with a low or normal body mass index (BMI) who had failed treatment with CC. Materials and methods This was a prospective, observational, non-comparative, openlabel trial. The study was conducted in PCOS patients undergoing infertility treatment who had unsuccessful ovulation-induction treatment with CC. This study was undertaken from April 2006 to January 2007 at the Department of Infertility of the Tu Du Ob/Gyn Hospital, Ho Chi Minh City, Vietnam. The study protocol and related documents were approved by the Technical and Scientific Committee of Tu Du Hospital and the study was conducted in accordance with the Declaration of Helsinki. Study participants Patients eligible for inclusion in the study were Vietnamese infertile women aged years who had been diagnosed with PCOS according to the Rotterdam Consensus Criteria (Rotterdam EHSRE/ASRM, 2004), had three unsuccessful cycles of CC (i.e. failure to ovulate and conceive), had not received gonadotrophin injections in the last month or CC in the last 2 months prior to the commencement of the study, and were undergoing intrauterine insemination (IUI) treatment after ovulation induction. All participants provided informed consent before any study-related procedures were performed. Exclusion criteria were male factor infertility, uni- or bilateral tubal damage, abnormal ovarian reserve (as shown on baseline hormonal tests), a history of ovarian surgery, and the presence of uterine abnormalities such as fibroids, polyps in the uterine cavity, bicornuate uterus and synaechiae of the uterine cavity. Treatment details The treatment protocol is presented in Figure 1. Patients had daily subcutaneous injections of rfsh from the second day of a spontaneous period or a withdrawal bleed induced by a course of progestogen. rfsh was administered in the form of Puregon (rfsh; follitropin beta) with a starting dose of 25 IU for 14 days (Puregon Pen 300 IU; NV Organon, Oss, The Netherlands). The adjustment dose was 25 IU every 5 days if there was no follicle measuring >12 mm on ultrasonography scan. A developing follicle was defined as one with a diameter 16 mm because such a follicle was judged to have the capacity to ovulate, and to be capable of normal fertilization and embryonic development. Human chorionic gonadotrophin (HCG) was administered when the lead follicle was 18 mm in diameter and if there were no more than three developing follicles. HCG was cancelled when there were more than three developing follicles ( 16 mm) or there was no developing follicle on day 40 of the cycle. IIUI was performed in all patients 36 h after HCG administration. The husband s semen was collected on the day of IUI. Sperm were prepared using the swim-up method and injected into the uterus using a soft catheter (Gynetics, Fertipro, Belgium). The use of IUI rather than timed intercourse was the patients choice, because they perceived that IUI would maximize the chances of achieving pregnancy during their self-funded treatment cycle. This would appear to be a reasonable approach, with the Thessaloniki ESHRE/ASRM-Sponsored Consensus working group suggesting that IUI can be considered as an option in PCOS patients who fail to conceive after ovulation induction, even in the absence of male factor infertility (Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Working Group, 2008). Pregnancy testing was undertaken using beta-hcg

3 days after IUI and a pregnancy ultrasound was performed 3 weeks later. Ultrasonography was performed using a Toshiba machine (Capasee II, Toshiba, Japan) with a 5.5 Hz transvaginal probe. The first scan was done on day 7 of stimulation; the schedule for subsequent scans is described in Figure 1. Total testosterone, LH and FSH were determined using an enzymelinked immunosorbent assay (EIA) method (Axsym machine; Abbott, USA) on day 3 of the previous cycle (baseline hormonal profile). All ovulation induction and IUI procedures were performed and monitored by one study team. Outcome measures Outcome measures included mean duration of stimulation, the mean total dose of FSH administered, the number of cycles that achieved developing follicle(s), the number of cycles with unifollicular development, cycles cancelled due to overresponse (>3 follicles 16 mm), clinical pregnancy rate, ongoing pregnancy rate, incidence of ovarian hyperstimulation and multiple pregnancy rate. Results From April 2006 to January 2007, 183 first treatment cycles in 183 patients (one cycle per patient) were completed and included in the study. Demographic data are detailed in Table 1 and the hormonal data are reported in Table 2. Polycystic ovaries were documented on ultrasound in 174 (95.1%) patients. The majority of patients experienced menstrual bleeding; 11 patients (6.0%) had regular menstrual bleeding, 163 (89.1%) had oligomenorrhoea and 9 (4.9%) had amenorrhoea. Male fertility characteristics included a mean sperm count of /ml (range ), a mean motility of 40% (range 29 50) and a mean 15.2% (±2.3) normal forms according to Kruger s strict criteria. From the 183 stimulated cycles, 148 cycles (80.9%) continued through the treatment protocol to have IUI and 35 were cancelled (19.1%). The reasons for cancellation were no developing follicle in six cycles (3.3%) and over-response in 29 cycles (15.8%). The six non-response cycles had normal levels of FSH [4.9 ± 1.3 ( )] and testosterone [2.3 ± 1.0 ( )], and increased levels of LH [14.7 ± 7.7 ( )]. In addition, patients with non-response cycles had a BMI that was higher [23.2 ± 2.3 (20 27) kg/m 2 ] than the average BMI of the study population [20.7 ± 2.3 ( )], irregular menstruation and polycystic ovaries on ultrasound. The over-response cycles were converted to IVF when patients indicated their preference for this option. A developing follicle was achieved in 96.7% of cycles. Of these, 110 cycles (62.1%) had unifollicular development, 26 (14.7%) produced 2 follicles, and 3, 4, 5, 6, 7, 8, and 10 follicles were produced in 12 (6.8%), 9 (5.1%), 4 (2.3%), 5 (2.8%), 3 (1.7%), 1 (0.6%) and 3 (1.7%) cycles, respectively; 11, 12, 16 and 19 follicles were produced in one cycle each. Out of 183 treatment cycles, 107 (58.5%) did not require dose adjustment, meaning that the whole course of FSH administration was at the 25 IU dose. Thirty-four cycles (18.6%) required dose adjustment to 50 IU in order to achieve developing follicle(s). The duration of stimulation, total dose of FSH, ratio of FSH administered to number of developing follicles and endometrial thickness are shown in Table 3. Data on pregnancy rates and outcomes are reported in Figure 2. One patient reported abdominal discomfort and was diagnosed as having mild OHSS; she did not require hospitalization or any additional treatment. There were no cases of moderate or severe ovarian hyperstimulation, and there were no multiple pregnancies. Response to the low-dose step-up protocol varied with BMI. The ongoing pregnancy rate was significantly higher in patients with a BMI <23 kg/m 2 versus 23 kg/m 2 (37.7% vs 18.9%; P = 0.03) (Table 4). Discussion As far as is known, this is the first study using FSH with a starting dose of 25 IU for ovulation induction prior to IUI in PCOS patients who have had unsuccessful treatment with CC. Using this regimen, 518 Figure 1. Low-dose step-up protocol with a recombinant FSH starting dose of 25 IU.

4 Table 1. Patient demographic data (n = 183). Table 2. Patient hormonal profile. Characteristic Value Hormone parameter n Value Age (years) 29.2 ± 3.5 (22 40) Duration of infertility (years) 3.3 ± 2.2 (1 12) Type of infertility Primary 148 (80.9) Secondary 35 (19.1) Body mass index (kg/m 2 ) 20.7 ± 2.3 ( ) < (14.8) (65.0) (13.7) (6.6) 30 0 (0.0) FSH (IU/l) ±1.2 ( ) LH (IU/l) ± 5.6 (1 30) Total testosterone (nmol/l) ± 1.1 (1 4.6) Elevated LH (>10 IU/l) (50.0) Elevated testosterone (45.5) (>3.5 nmol/l) Values are mean ± SD (range) or n (%). Values are mean ± SD (range) or n (%). Table 3. Characteristics of completed treatment cycles (n = 148). Characteristic Value Duration of stimulation (days) 15.9 ± 4.8 (8 29) Total dose of FSH administered (IU) 484 ± 257 ( ) Number of follicles of 16 mm 1.3 ± 0.6 (1 3) Dose of FSH/developing 397 ± 219 ( ) follicle(s) (IU) Endometrial thickness (mm) 10.9 ± 2.2 (6 16) Values are mean ± SD (range). Percentage % Clinical pregnancy 33.9% Ongoing pregnancy Figure 2. Pregnancy outcomes (n = 183). 1.6% Miscarriage Table 4. Response to ovulation induction based on body mass index (BMI). BMI (kg/m 2 ) <19 (n = 33) (n = 113) 23 (n = 37) No. of follicles 16 mm (mean ± SD; range) 2 ± 2.7; ± 2.7; ± 2.3; 0 10 Clinical pregnancy (%) 14 (42.4) 43 (38.1) 8 (21.6) Ongoing pregnancy (%) 14 (42.4) 41 (36.3) 7 (18.9) almost all cycles had developing follicle(s) (96.7%), most of which were unifollicular (62.1%). There was a low cancellation rate and only one case of mild ovarian hyperstimulation. Rates of clinical and ongoing pregnancy were acceptable, at 35.5% and 33.9%, respectively. Use of gonadotropins in this setting is appropriate, and has been shown to be more effective than letrozole in terms of pregnancy rate (Quintero et al., 2007). A conventional low-dose step-up protocol (Hamilton-Fairley and Franks, 1990) resulted in a pregnancy rate of 34%; however, the rate of severe ovarian hyperstimulation was % (Hamilton-Fairley and Franks, 1990; Homburg et al., 1995). The rate of multiple pregnancies was also very high at 33%, which is considered unacceptable (Hamilton-Fairley and Franks, 1990; Homburg et al., 1995). Studies using a low-dose FSH step-up protocol have shown considerable differences in the starting dose of FSH ( IU) (Hamilton-Fairley et al., 1991; Homburg et al., 1995; White et al., 1996; Hayden et al., 1999, Hoomans and Voortman, 1999; Balasch et al., 2000; Alsina et al., 2003; Leader et al., 2006), the adjustment dose (25 75 IU) (Hamilton-Fairley et al., 1991; Homburg et al., 1995; White et al., 1996; Balasch et al., 2000; Alsina et al., 2003; Leader et al., 2006), and the duration of the dose-adjustment interval (7 14 days) (Hamilton-Fairley et al., 1991; Homburg et al., 1995; White et al., 1996; Balasch et al., 2000; Alsina et al., 2003; Leader et al., 2006). Using the 25 IU starting dose of FSH, a high clinical pregnancy rate was achieved, with no cases of multiple pregnancy, and almost no cases of ovarian hyperstimulation. An FSH dose of 25 IU/day for the whole stimulation course was adequate to achieve 519

5 520 developing follicles in 58.5% of cycles, while an additional 18.6% of cycles required a maximum daily FSH dose of 50 IU for follicular development. Thus, about 77% of cycles achieved adequate follicular development with a daily FSH dose of 50 IU. The reported pregnancy outcomes in this study compare favourably with those achieved using an FSH starting dose of 50 IU. Alsina et al. (2003) reported a clinical pregnancy rate of 39.6% over 817 cycles compared with the rate of 35.5% in the present patients treated with a 25 IU starting dose. Corresponding figures for the number of cycles with unifollicular development were 60.7% (Alsina et al., 2003) and 62.1%. In addition, the mean total dose of FSH was higher in the 50 IU study compared with the current trial (807 versus 484 IU). In another study, Leader et al. (2006) treated patients with a starting FSH dose of 50 IU for 7 days followed by dose increments of 25 or 50 IU every week. The clinical pregnancy rate in both treatment groups was lower than the 35.5% achieved in the present study, at 20% in the 25 IU increment group and 12.8% in the 50 IU group. The number of cycles with unifollicular development was 42.3% and 21.8% in the 25 IU and 50 IU groups, respectively, in the Leader trial, which was again lower than the 62.1% reported in the current study. Not surprisingly, Leader et al. reported a lower total FSH dose (887 IU) in the 25 IU group compared with 50 IU (985 IU). However, both of these are approximately twice the cumulative dose achieved (484 IU) when 25 IU was used as the starting and incremental dose in the present study. Thus, it was possible to achieve improved outcomes at a substantially lower cumulative FSH dose. The use of FSH doses <75 IU/day has been recommended for ovarian stimulation prior to IUI because treatment outcomes are not improved by increasing the FSH dosage, whereas the rates of multiple pregnancy and OHSS are higher (Cantineau et al., 2007). In addition, the ESHRE/ASRM PCOS Consensus Working Group recommends low-dose FSH step-up protocols for the effective induction of ovulation in women with PCOS (Rotterdam EHSRE/ASRM-sponsored PCOS consensus workshop group 2004). However, further adjustment of these regimens is required to improve safety. Indeed, refining ovarian stimulation protocols to avoid multiple pregnancies and minimize the risk of OHSS appears to be the way forward (Vegetti and Alagna, 2006). Reduction of the starting and incremental dosages to 25 IU could be one such refinement. Recombinant FSH was used in this study primarily because it is the form of FSH most commonly used in Vietnam. In addition, it is available in a pen formulation that allows accurate dosage adjustment, something that is particularly important when using such a low dose (25 IU). The comparative efficacy of rfsh over urinary-derived FSH (u-fsh) is controversial. Data from a metaanalysis of studies conducted in patients undergoing IUI showed a non-significant trend in favour of rfsh over u-fsh when similar dosages were used (Cantineau et al., 2007), although the results of individual studies vary widely. However, it is generally accepted that rfsh has an advantage over u-fsh in terms of better batch-to-batch consistency, higher purity and less contamination with urinary proteins (Matorras et al., 2000; Vegetti and Alagna, 2006;). In terms of the choice of gonadotropin, data suggest that there are no significant differences between FSH and human menopausal gonadotropins (HMG) for ovarian stimulation prior to IUI (Cantineau et al., 2007). A dose adjustment interval of 5 days was chosen rather than the more commonly used 7 days. This was to allow comparison with data previously collected using an FSH starting dose of 50 IU. In addition, the 5-day interval was chosen because the routine schedule for performing scans at the study hospital is every 5 days. Moreover, there was concern that using a 25 IU starting and incremental dose of FSH might make the overall duration of stimulation too long with a 7-day interval. Day 14 was selected as the first day for dosage adjustment because it was thought that an increased number of days at the 25 IU FSH dose might reduce the number of over-response cycles, which was quite high in the series of patients previously treated with a 50 IU initial dose. The 14-day initial dosage period has also been used by other researchers, with the aim of reducing the risk of ovarian hyper-responsiveness (Dale et al., 1993) In addition, previous experience suggested that the longer duration of stimulation was associated with better outcomes. One of the limitations of this study was the use of the total testosterone level as an indicator of hyperandrogenism. Total testosterone does not always reflect the bioactivity of testosterone in the body. Thus, a low total testosterone level may not necessarily mean that free testosterone (which causes hyperandrogenic symptoms) will also be low. A method for measuring free testosterone is not yet available in Vietnam and tests to measure sex hormone binding globulin (SHBG) only became available at the time the study concluded (January 2007). Therefore, there was no data on free testosterone or the free testosterone index. It has recently been suggested that such information is useful for the discrimination of patients with PCOS from healthy controls (Hahn et al., 2007). Other limitations include the absence of a control group in this non-comparative trial and the heterogeneity of the patients enrolled in the study with respect to baseline characteristics such as BMI, infertility duration and type of infertility. A randomized controlled study comparing the 25 IU protocol with another gonadotropin dosage would provide useful data. Interpretation of the results of this study requires consideration of the Asian population in which it was conducted. The clinical and endocrinological characteristics of patients with PCOS in Vietnam are different from those in Western populations. For example, obesity, insulin resistance and hyperandrogenism are more common in European, American and Australian PCOS patients (Norman and Clark, 2000). In contrast, the majority of PCOS patients in this study had normal or low BMI (79.8%) and manifestations of hyperandrogenism were uncommon. In general, Asian populations tend to have a lower mean or median BMI than non-asian populations (WHO, 2004). Furthermore, the characteristics of Asian patients with PCOS vary across different regions and races (Yu Ng and Ho, 2008). Therefore, it is likely that ovulation-induction protocols will need to be tailored for different populations. There are few data on treating Asian patients with PCOS. Clinicians have tended to apply diagnostic criteria, treatment protocols and strategies that are primarily based on studies done in European or North American populations. Given the different physiological and symptomatic presentation of PCOS patients in this study, it is suggested here that epidemiological studies of the signs and symptoms of PCOS in Asian patients are needed. Such studies would make an important contribution to the setting up of a basic database on Asian PCOS patients. Most importantly,

6 based on these data, specific treatment strategies and protocols could be more firmly established for Asian populations. Response to the low-dose step-up protocol used in this study varied with BMI. Therefore, as well as being effective in the Vietnamese population studied, the 25 IU starting dose of FSH has the potential to be appropriate for PCOS patients of other ethnicities who have a low or normal BMI. In conclusion, the data suggest that a low-dose step-up protocol with an FSH starting dose of 25 IU is effective for ovulation induction in Vietnamese patients with PCOS. It is also a safe treatment approach, with almost no OHSS and a low multiple pregnancy rate. Such a regimen may have applications in other patient populations who have a low BMI and similar endocrine profile. Acknowledgements The authors would like to acknowledge Jan I Olofsson, MD PhD, Associate Professor, Department of Obstetrics and Gynecology, Sahlgrenska Academy, Goteborg University, Goteborg, Sweden for his input into the preparation of the manuscript. Editorial assistance was provided by Nicola Ryan. References Alsina JC, Balda JAR, Sarrio AR et al Ovulation induction with a starting dose of 50 IU of recombinant follicle stimulating hormone in WHO group II anovulatory women: the IO-50 study, a prospective, observational, multicenter, open trial. British Journal of Obstetrics and Gynaecology 110, Baird DT 1987 A model for follicular selection and ovulation: lessons from superovulation. Journal of Steroid Biochemistry 27, Balasch J, Fábregues F, Creus M et al Recombinant human follicle-stimulating hormone for ovulation induction in polycystic ovary syndrome: a prospective, randomised trial of two starting doses in a chronic low-dose step-up protocol. 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