Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements

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1 Human Reproduction Update 1999, Vol. 5, No.5 p European Society of Human Reproduction and Embryology Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements R.Homburg 1,3 and C.M.Howles 2 1 Fertility Unit, Lis Maternity Hospital, Sourasky Tel Aviv Medical Center, Tel Aviv, Israel (affiliated to Sackler Medical School, Tel Aviv University) and 2 Ares-Serono, Geneva, Switzerland Low-dose follicle stimulating hormone (FSH) regimens for induction of ovulation for women with polycystic ovaries have succeeded in reducing the rate of ovarian hyperstimulation syndrome (OHSS) almost to nil and the rate of multiple pregnancies to a minimum of 6%. This has been achieved by reaching, but not exceeding, the threshold level of FSH, starting with a daily dose of 75 IU for 14 days, using small incremental dose rises where necessary, and inducing uniovulation in 70% of cycles. Conception rates are as good, if not better, than those achieved with conventional therapy. The miscarriage rate is still relatively high (20 25%) and obese women fare worse. Serum oestradiol concentrations and the number of large and intermediate follicles on the day of human chorionic gonadotrophin administration are much lower, in parallel with lower serum FSH concentrations. Inhibin values increase with the rise in serum FSH concentrations but those of luteinizing hormone decrease steadily throughout the follicular phase. New data using recombinant hfsh (rhfsh), rather than urinary gonadotrophin as the ovarian stimulant, demonstrate that treatment time is shortened. However, the ideal regimen has still to be formulated. Key words: follicle-stimulating hormone/low-dose regimen/ovulation induction/polycystic ovary syndrome TABLE OF CONTENTS Introduction 493 Principles of chronic low-dose therapy 494 Comparison of conventional versus chronic low-dose regimen 494 Summary of published studies 495 Starting dose and increments 495 Duration of the initial dose 495 Step-down and sequential step-up, step-down regimens 496 Gonadotrophin preparations used in low-dose protocols 497 Improvement of results 497 Endocrine aspects 498 Conclusions 498 References 498 Introduction Polycystic ovarian syndrome (PCOS) is one of the commonest causes of anovulation and consequent infertility, i.e. World Health Organization (WHO) group II patients. Although the basic aetiology remains largely unknown, clearly a small group of genes, abnormally functioning, are the probable underlying cause in the majority of cases (Simpson, 1992; Carey et al., 1993). The treatment, in the present absence of appropriate gene therapy, is symptomatic, whether for aesthetic treatment or for ovulation induction in those desiring pregnancy. It is now clear that the administration of even small amounts of follicle stimulating hormone (FSH) into the system will induce ovulation and pregnancy in a very large proportion of afflicted women. This may be achieved indirectly, with clomiphene citrate or pulsatile gonadotrophin-releasing hormone (pgnrh), or directly by administration of an FSH preparation. The first line of treatment, clomiphene citrate, will restore ovulation in ~80%, but will result in pregnancy in only ~35%, of these patients (MacGregor et al., 1968). Additionally, ~25% of PCOS women will not respond at all to clomiphene citrate and are considered to be clomiphene resistant (Franks and Hamilton-Fairley, 1996). Thus, careful monitoring should be applied so as to prevent such patients from protracted periods (more than six cycles) of inappropriate therapy. Conventional step-up treatment with gonadotrophins for women with PCOS who failed to conceive with, or are resistant to, clomiphene 3 To whom correspondence should be addressed at: 8 Kashani Street, Tel Aviv 69499, Israel

2 494 R.Homburg and C.M.Howles citrate, however, yields an acceptable cumulative conception rate (Farhi et al., 1993). An historical review of results using such gonadotrophin protocols is given in Table I. Of the three studies, two reported the use of human menopausal gonadotrophin (HMG) and cover the period Whilst the pregnancy rate per cycle in WHO Group I patients was close to that observed in women with infertility problems, the pregnancy rate per cycle of just less than 7% observed in the WHO Group II population was disappointing. In the final study of the review, conducted between 1989 and 1992, the pregnancy rate per cycle was 17%. The almost three-fold difference in pregnancy outcome may well be due to the inclusion of results from earlier studies in which monitoring techniques were less sophisticated. However, because of the peculiarly high sensitivity of polycystic ovaries to gonadotrophin stimulation, this form of treatment, employing incremental dose rises of one ampoule (75 IU) every 5 7 days, characteristically induces multiple follicular development, resulting in a high frequency of multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) (Wang and Gemzell, 1980). Even in 1990, a review reported a mean multiple pregnancy rate of 34% and severe OHSS of 4.6% (Hamilton-Fairley and Franks, 1990). In a subsequent report from the Hasharon Hospital, although this protocol produced a cumulative conception rate of 82% after six cycles, it was plagued by an unacceptable rate of multiple pregnancies and OHSS (Homburg et al., 1995). Supraphysiological doses of FSH (as used in the conventional protocol) provoke an initial development of a large cohort, stimulate additional follicles, and even rescue those follicles destined for atresia (Insler, 1988). Multiple follicular development is induced by concentrations of FSH well above the threshold. This statement holds true for gonadotrophin stimulation of the ovaries in all groups of anovulatory patients and is actually used to stimulate ovulation for in-vitro fertilization and embryo transfer. However, for the induction of ovulation in women with PCOS, the problem of achieving the desired monofollicular ovulation is particularly difficult and acute due to the extreme sensitivity of the polycystic ovary to gonadotrophic stimulation. The reason for this does not lie in a difference of FSH threshold values of the polycystic ovaries but is probably due to the fact that they contain twice the number of available FSH-sensitive antral follicles in their cohort compared with the normal ovary (van der Meer et al., 1998). Any dose of FSH overstepping the threshold of the polycystic ovary will, therefore, produce multifollicular development and impending danger of multiple pregnancy and OHSS. Principles of chronic low-dose therapy Several investigators have examined the utility of a chronic low-dose regimen of FSH in an attempt to reduce the rate of complications due to multiple follicular development (Siebel et al., 1984; Shoham et al., 1991; Dale et al., 1993; Scheele et al., 1993; Ares-Serono, 1995; Homburg et al., 1995; Aboulghar et al., 1996; White et al., 1996; van Santbrink and Fauser, 1997; Coelingh-Bennink et al., 1998; Hedon et al., 1998). The basic thinking behind this regimen is the threshold theory, which demands the attainment and maintenance of follicular development with exogenous FSH without exceeding the threshold requirement of the ovary (Brown, 1978). As the ovarian threshold was seen to vary between individuals, individualized protocols were almost universally adopted involving a step-up of one ampoule each week until the daily effective dose required to initiate and maintain follicular growth was found (Rabau et al., 1967). It is a quirk of gynaecological history that experience showing that the increase in dose should not exceed around one third of the preceding dose (Brown, 1978), went completely unheeded. This may have been in some part caused by the fact that only ampoules containing a standard dose of 75 IU were available and there was a reluctance to split ampoules when an incremental dose rise was required. This psychological barrier was broken in 1984 (Siebel et al., 1984) and more definitively by the Franks group in 1987 (Polson et al., 1987). The principle of the classic chronic low-dose regimen is, therefore, to employ a low starting dose for 14 days and then use small incremental dose rises (usually 37.5 IU) when necessary, at intervals of not less than 7 days, until follicular development is initiated. This regimen is now made simpler by the availability of ampoules containing 37.5 IU rhfsh (Ares-Serono). The dose that initiates follicular development is continued until the criteria for giving HCG are attained. The purpose of this form of therapy is to achieve the development of a single dominant follicle rather than the development of many large follicles and so avoid the complications of OHSS and multiple pregnancies. Comparison of conventional and chronic low-dose regimens A comparative prospective study of the conventional regimen with chronic low-dose administration of FSH for anovulation associated with PCOS was performed at Hasharon Hospital (Homburg et al., 1995). Participants (n = 50) were divided into two equal groups. The first group was treated with urinary hfsh (uhfsh) using a conventional stepwise protocol (incremental dose rises of 75 IU every 5 7 days when necessary) and the second group was treated with a regimen of chronic low-dose uhfsh or rhfsh. Both methods of treatment had an initial dose of 75 IU FSH but for the low-dose regimen no dose rise was allowed for a minimum of 14 days and, if necessary, increments were of the order of 37.5 IU only for a minimum of 7 days. Compared with the conventional dose protocol, the chronic low-dose regimen yielded slightly improved pregnancy rates (40 versus 24%) while completely avoiding OHSS and multiple pregnancies, which were prevalent (11 and 33% respectively) with conventional therapy. Uniovulation was induced in 74 versus 27% of cycles and the total number of follicles >16 mm and oestradiol concentrations were half those observed on conventional therapy. A large French multicentre study (Hedon et al., 1998) has recently been completed with an identical

3 Low-dose FSH 495 objective and protocol design comparing conventional and chronic low-dose regimens in 103 anovulatory WHO Group II women. The comparison of low with conventional dose revealed pregnancy rates of 33.3 versus 20%, and with a multiple (twins) pregnancy rate of 14 and 22% respectively. The total number of follicles with a diameter of >10 mm and oestradiol concentrations on the day of HCG in the low-dose group were half those seen on conventional therapy. Additionally, the low-dose regimen tended to produce a higher rate of mono- or bifollicular development in this study. 75 IU and with the regimen starting with 52.5 IU just described has been extracted from this series (White et al., 1996) and is presented in Table III. The latterly used regimen resulted in a marginal increase in the incidence of uniovulatory cycles and similar rates of ovulatory cycles, pregnancy and miscarriage to the classic protocol. However, the number of cycles abandoned due to overstimulation increased. Thus, from the largest study to date, there were really no improvements over starting with 75 IU FSH. We shall return to the issue of starting dose when we consider the results obtained using rhfsh. Summary of published studies A compilation of reported results from the literature, using a chronic low-dose protocol identical to that described above, is presented in Table II. The prominent features include a remarkably consistent rate of uniovulatory cycles of ~70% in each series. The pregnancy rate of 40% of the patients and 20% per cycle are acceptable judging from past experiences with conventional therapy and taking into account that many of the patients comprising these series received only one cycle of therapy. However, the justification for the adoption of the chronic low-dose protocol may be seen in the extraordinarily low prevalence of OHSS and a multiple pregnancy rate of 5.7%, twins in all cases except two. It should be remembered that these encouraging results were obtained in a large number of women with clomiphene-resistant PCOS, a particularly troublesome group to treat with gonadotrophin therapy. Starting dose and increments The fact that the majority of gonadotrophin preparations produced until recently contain 75 IU of FSH has dominated our thinking and subconsciously led us to believe that an ovary will respond only to blocks of 75 units, i.e. whole ampoules. Although this is convenient, it is, of course, non-physiological. Centres that employ the classic chronic low-dose regimen have used a starting dose of 75 IU for 14 days and, in the absence of an ovarian follicular growth response, have used incremental dose rises of half ampoules (37.5 IU). In the majority of cases, this has proved efficient and effective (see Table II). In fact, 37.5 IU FSH ampoules (Ares-Serono) are now commercially available, which will improve the convenience of treating patients with this protocol. The question that remains to be addressed, however, is what is the optimal starting dose. The Franks group in London, who have published the largest series of cases to date from a single centre (White et al., 1996), has employed a starting dose of 52.5 IU (0.7 ampoules) for 14 days and, where necessary, have used a first incremental dose rise of 30% up to 75 IU for the third week and increments of 37.5 IU thereafter. A comparison of their results with a starting dose of Duration of the initial dose Both White et al. (1996) and a large series performed by Serono (Ares-Serono, 1995) (basically designed to compare the efficacy of recombinant and urinary FSH preparations) have reported that the majority of patients developed a single large follicle meeting HCG administration criteria within days without any change in the initial dose for 14 days. In the relatively unusual case (often in very obese women) where a treatment cycle is abandoned after days due to lack of response, a larger starting dose may, of course, be employed in a further attempt. The strict adherence to a 14-day starting period using a persistent dose has taxed the patience of several practitioners using the low-dose regimen and some have reduced this to 7 days. As yet, no pertinent data to compare this variation with the classic regimen have been published. In order to examine this point, one of us recruited 50 women with clomiphene-resistant PCOS. Half of them were given the starting dose of 75 IU FSH for 14 days and half for 7 days before using an incremental dose rise of 37.5 IU if necessary (R.Homburg, unpublished data). The 7-day starting regimen significantly decreased the amount of FSH required (mean 17.1 versus 22.1 ampoules) and the mean duration of treatment (13.1 versus 17.4 days) compared with the 14-day starters. There was no difference in the daily effective dose, number of cycles abandoned, oestradiol concentrations and number of large and intermediate follicles. Pregnancy rates for the 7-day and 14-day protocols were similar (56 and 40% per patient and 33 and 19% per completed cycle respectively). There were no multiple pregnancies out of 10 pregnancies achieved with the 14-day starters but 2 of 14 using the 7-day initial dose. This was a cause for concern which needed examining further. Therefore, following the completion of the study, the 7-day starter regimen was continued and resulted in a total multiple pregnancy rate of seven out of 29 (24%) of the pregnancies achieved. This now seems to be more than mere coincidence and is the apparent price of shortening the protocol and attempting to save time and money. As a result, the clinic has reverted to the 14-day starter regimen.

4 496 R.Homburg and C.M.Howles Table I. Outcome results from studies using human menopausual gonadotrophin (HMG) or follicle stimulating hormone (FSH) to include ovulation in anovulatory women with WHO Group I or II infertility (Lunenfeld and Eskol, 1982; Dale et al., 1989; Howles et al, 1993) Study (drug) Lunenfeld and Eshkol (HMG) Dale et al (HMG) Howles (FSH) Patient population Studies reviewed No. of patients treated Treatment cycles WHO I N/A /766 (30) WHO II Clomiphene failures N/A /2368 (6.5) WHO I N/A /185 (28) WHO II Clomiphene failures WHO II Clomiphene failures N/A /102 (6.8) /1931 (17) Pregnancy treatment cycle (%) Table II. A summary of results of published series of low (75 IU) starting dose follicle stimulating hormone (FSH) therapy for women with polycystic ovarian syndrome (PCOS) a Step-down and sequential step-up, step-down regimens No. (%) Range (%) Patients 717 Cycles completed 1391 Clinical pregnancies 280 (40) Fecundity/cycle 20% Uniovulatory cycles 69% OHSS Multiple pregnancies a Data taken from Siebel et al., 1984; Shoham et al., 1991; Dale et al., 1993; Scheele et al., 1993; Ares-Serono, 1995; Homburg et al., 1995; Aboulghar et al., 1996; White et al., 1996; van Santbrink and Fauser, 1997; Coelingh-Bennink et al., 1998; Hedon et al., 1998). Table III. Comparison of results using a starting dose of 75 IU versus 52.5 IU gonadotrophin in a low-dose protocol. Data taken from White et al. (1996) Starting dose 75 IU 52.5 IU Patients Cycles Percentage of ovulatory cycles No. (%) of pregnancies 60 (45) 49 (54) Percentage of pregnancies/cycle started Percentage of uniovulatory cycles No. (%) of twins 4 (6.7) 3 (6) No. (%) of miscarriages 21 (35) 10 (20) FSH threshold (IU/day) Total dose (75 IU ampoules) Days treated Cycles cancelled due to 3 follicles (%) 58 (13.5) FSH = follicle stimulating hormone. A possible criticism of the chronic low-dose step-up regimen is that, unlike the events of the normal ovulatory cycle in which decreasing FSH concentrations are seen throughout the follicular phase, FSH concentrations may be elevated during the late follicular phase (Dale et al., 1993). This could induce multi- rather than monofollicular ovulation. In order to mimic more closely the events of the normal ovulatory cycle, Fauser s group (Schoot et al., 1995; van Dessel et al., 1995) use a step-down dose regimen with a starting dose of 150 IU and decrease the dose by 0.5 ampoules when a follicle of 10 mm ensues and by the same amount every 3 days if follicular growth continues A comparison of this regimen with the classic step-up regimen (van Santbrink and Fauser, 1997) demonstrated a monofollicular growth rate of 88% of cycles in the step-down regimen compared with 56% with the step-up protocol. In the step-down group, the median duration of treatment was significantly reduced by half to 9 days and a mean of six ampoules less were needed than when using the classic step-up dose regimen. Yet another variation on the theme is the sequential step-up and step-down regimen (Hugues et al., 1996) in which the FSH threshold dose is reduced by half when the leading follicle reaches a diameter of 14 mm. When compared with a step-up protocol (increments of 37.5 IU every 6 days) a smaller number of intermediate size follicles was produced (0.3 versus 0.8 respectively, P < 0.05) and mid-luteal phase oestradiol concentrations were also significantly lower (350 ± 77 pg/ml versus 657 ± 104 respectively, P < 0.05). A pilot study by Hugues using rhfsh (Gonal-F ) in a sequential step-down protocol yielded acceptable results in terms of numbers of patients fulfilling the criteria for HCG and subsequently becoming pregnant (J.-N.Hugues, personal communication).

5 Low-dose FSH 497 Table IV. Multiple birth rate related to the number of follicles >15 mm on day of administration of human chorionic gonadotrophin (HCG) (Ares-Serono, 1995). No. of follicles on dhcg No. of cycles Clinical pregnancies No. Rate/cycle Births No. Multiple Twins (%) > birth (%) Gonadotrophin preparations used in low-dose protocols The various gonadotrophin preparations now on the market have prompted the question of which would prove most effective for use in a chronic low-dose regimen. A comparative, randomized study of low-dose human menopausal gonadotrophins [HMG, 75 IU FSH + 75 IU luteinizing hormone (LH) versus purified uhfsh (Metrodin ; Serono] was carried out in 30 women with PCOS over 75 cycles (Sagle et al., 1991). In this small study, with no quoted statistical power, there were no differences in ovulation and pregnancy rates or the number of monovulatory cycles induced by the two preparations. The authors suggested that the success of treatment depends on the low dose of hormone used rather than the presence or absence of LH in the preparation. A trial comparing HMG (eight patients, 26 cycles) with rhfsh (Gonal-F ) (14 patients, 40 cycles) administered in a classic low-dose protocol in women who had suffered severe OHSS with previous conventional treatment did not demonstrate any difference in efficacy. No further cases of OHSS were seen with either preparation (Aboulghar et al., 1996). Two large, randomized, multicentre studies have compared purified uhfsh (Metrodin) with rhfsh using the classic low-dose protocol in women with WHO Group II anovulatory infertility. The first (Ares-Serono, 1995) did not demonstrate significant differences in safety or efficacy. The second (Coelingh-Bennink et al., 1998), while demonstrating an apparent higher in-vivo potency of rhfsh, did not demonstrate any differences in ovulation or pregnancy rates. Finally, a very recent study from Spain (Balasch et al., 1998) compared rhfsh with a highly purified urinary preparation of FSH (Metrodin HP). They came to the conclusion that rhfsh has a higher in-vivo biopotency than highly purified uhfsh as judged by follicular development, hormonal concentrations and amount of FSH required. No conclusions regarding clinical pregnancies could be drawn due to the small sample size. Patient compliance ultimately influences overall results and, although the chronic low-dose protocol is often more prolonged than the conventional protocol, this inconvenience may be eased by self-administration of gonadotrophins and by making use of the more potent rhfsh on the market. It is our practice to examine the initial ovarian response after 7 full days only and thereafter according to response so that the number of hospital visits may be kept to a minimum. From the large studies performed to date using rhfsh, a starting dose of 75 IU has been demonstrated to yield satisfactory results, in spite of the higher potency of rhfsh. An attempt to use a lower starting dose (50 IU FSH) was less effective; 36% of patients cancelled cycles due to an over-response (Hayden et al., 1998). Again, this study demonstrated that the incremental dose increase and its timing are as important as the starting dose (the incremental dose increase was 100% after 7 days). Improvement of results While the results of the classic low-dose regimen are satisfying, particularly in terms of the almost complete elimination of the incidence of OHSS, there is obviously still room for improvement. The multiple pregnancy rate may be reduced still further by a strict adherence to the criteria for giving HCG. If HCG is withheld in the presence of three or more follicles >15 mm, the multiple pregnancy rate may be reduced to a minimum. The Serono series (Ares-Serono, 1995) clearly demonstrated the significant trend and correlation between the number of large follicles produced and the incidence of multiple pregnancies (Table IV). The most significant factors adversely influencing pregnancy rate using this regimen are age, excess body weight (Hamilton-Fairley et al., 1992) and insulin resistance (Dale et al., 1998). Whereas advancing age has an adverse effect on all treatment for infertility, but obviously cannot be overcome, the successful treatment of obesity and insulin resistance is capable of reversing their deleterious effects, of which there are several, on the outcome of treatment. More gonadotrophins are required to achieve ovulation in insulin-resistant women (Homburg et al., 1996; Dale et al., 1998). Obese women being treated with low-dose therapy have lower pregnancy and miscarriage rates (Hamilton-Fairley et al., 1992). Both obese (White et al., 1996) and insulin-resistant (Dale et al., 1998) women with PCOS have a much greater tendency to a multifollicular response and thus a relatively high cycle cancellation rate on low-dose FSH stimulation. Therefore, it would seem prudent, prior to low-dose therapy, to treat obesity

6 498 R.Homburg and C.M.Howles by instituting a low calorie diet (Kiddy et al., 1992) which reduces insulin and androgen concentrations in parallel with the loss of weight. For women of normal weight with PCOS and associated insulin resistance, the use of insulin sensitizing agents would seem to be a feasible alternative but has not yet been fully established. The problem of a high rate of early miscarriages, characteristic of pregnant patients with PCOS and largely thought to be due to high concentrations of LH in the follicular phase, is not solved by induction of ovulation with low-dose FSH. Despite the fact that LH concentrations decrease during FSH administration, most series report an early miscarriage rate of 20 30%. Theoretically, pre-treatment with GnRH agonists (GnRHa) before employing a low-dose protocol should ease the problem. This has not proved to be the case (Scheele et al., 1993), as the GnRHa blocks the feedback on the endogenous component of FSH concentration by pituitary desensitization and makes it much more difficult to obtain monofollicular growth. The use of even smaller dose increments (e.g. a quarter of an ampoule) may be effective in avoiding the multifollicular response frequently seen using this combined regimen (van der Meer et al., 1996). Step-down and sequential step-up and step-down regimens, attempting to reflect more realistically the decrease in FSH concentrations seen throughout the follicular phase, offer an alternative means of controlling the pattern and number of developing follicles. Both protocols, in which the FSH dosing is reduced once lead follicles have achieved a critical size, 10 mm in the step-down regimen and 14 mm in the sequential step-up and step-down regimen, appear to limit multifollicular development (Hugues et al., 1996; van Santbrink and Fauser, 1997). Reducing the concentration of FSH earlier in the sequential step-up and step-down protocol may serve to improve control of monofollicular development further. Endocrine aspects Data gleaned from the Serono and White et al. studies (Ares-Serono, 1995; White et al., 1996) are tabulated in Table V. The pertinent features are a steady rise in FSH serum concentrations from day 1 of treatment, through day 8 to the day of HCG administration and the consequent steep rise in oestradiol concentrations throughout FSH treatment to a peak on the day of HCG administration. Although there obviously exists an individual variation, a more accurate study aimed at determining the threshold value of FSH to obtain an ovarian response would predictably indicate ~6.9 IU as the mean FSH serum concentration producing an ovarian follicular response in this series. Serum inhibin concentrations rose from 1.5 IU/ml on day 1 to 3.8 IU/ml on the day of HCG administration. The behaviour of endogenous serum concentrations of LH during chronic low-dose therapy with FSH has received some attention of late. It now seems established that LH concentrations decrease throughout the treatment cycle in these low-dose regimens. This was confirmed in a study (White et al., 1996) in which mean LH serum concentrations decreased from a basal value of 11 to 6.85 IU/l in the mid-follicular phase. Whether this is due to the effect of gonadotrophin-surge attenuating factor induced by FSH administration is still open to conjecture (Balen and Rose, 1994), but premature LH release is not a common event during this treatment regimen. The relatively low concentrations of oestradiol on the day of HCG administration may also be a contributing factor. Table V. Mean serum hormone concentrations throughout low-dose follicle stimulating hormone (FSH) therapy (Ares-Serono, 1995; White et al., 1996) Day 1 Day 8 Day HCG Oestradiol (pmol/l) FSH (IU/l) Inhibin (IU/ml) LH (IU/l) Progesterone (nmol/l) LH = luteinizing hormone. Conclusions For women with PCOS, treatment with a chronic low-dose regimen of gonadotrophins has almost completely eliminated the very troublesome complication of OHSS. In addition, it has reduced the multiple pregnancy rate to a reasonable minimum while maintaining an acceptable pregnancy rate. Thus, this modality has distinct advantages and has virtually replaced conventional gonadotrophin therapy for patients with anovulation associated with PCOS. The search for refinements and adjustments to the fine details of the low-dose regimens is continuing with the purpose of finding the ideal protocol that combines efficiency, safety, economy, good patient compliance and excellent clinical outcome. A sequential step-down protocol as described by Hugues may provide such a protocol. Indeed, a randomized, controlled study comparing the sequential step-down and chronic low-dose regimens is currently being performed. Its aim is to determine whether a dose reduction, when the lead follicle is between mm in diameter, will result in further reductions in the incidence of complications, such as OHSS, following gonadotrophin therapy in PCOS patients. References Aboulghar, M.A., Mansour, R.T., Serour, G.I. et al. (1996) Recombinant follicle stimulating hormone in the treatment of patients with history of severe ovarian hyperstimulation syndrome. Fertil. Steril., 66, Ares-Serono (1995) A Phase III, Open, Randomised, Multicentre Study to Compare the Safety and Efficacy of Recombinant Human Follicle Stimulating Hormone (Gonal-F) Administered Subcutaneously with that of Urinary Human Follicle Stimulating Hormone (Metrodin)

7 Low-dose FSH 499 given intramuscularly, to Induce Ovulation in WHO Group II Anovulatory Infertile Women. Ares-Serono, Internal Report. Balasch, J., Fábregues, F., Peñarrubia, J et al.(1998) Follicular development and hormonal levels following highly purified or recombinant follicle stimulating hormone administration in anovulatory women and WHO Group II anovulatory infertile patients. J. Assist. Reprod. Genet., 15, Balen, A.H. and Rose, M. (1994) Control of luteinizing hormone secretion in polycystic ovary syndrome. Contemp. Rev. Obstet. Gynaecol., 6, Brown, J.B. (1978) Pituitary control of ovarian function concepts derived from gonadotrophin therapy. Aust. N.Z. Obstet. Gynaecol., 18, Carey, A.H., Chan, K.L., Short, F. et al. (1993) Evidence for a single gene effect causing polycystic ovaries and male pattern baldness. Clin. Endocrinol., 38, Coelingh-Bennink, H.J.T., Fauser, B.C.J.M. and Out, H.J.T. (1998) Recombinant follicle-stimulating hormone (FSH; Puregon) is more efficient than urinary FSH (Metrodin) in women with clomiphene citrate-resistant, normogonadotrophic, chronic anovulation: a prospective, multicenter, assessor-blind, randomized, clinical trial. Fertil. Steril., 69, Dale, P.O., Tanbo, T., Henrikson, T. et al (1989) Gonadotrophin therapy of female infertility. Acta Endocrinol. (Copenh.), 120, 395. Dale, O., Tanbo, T., Lunde, O. et al. (1993) Ovulation induction with low-dose follicle stimulating hormone in women with the polycystic ovary syndrome. Acta Obstet. Gynecol. Scand., 72, Dale, O., Tanbo, T., Haug, E. et al, (1998) The impact of insulin resistance on the outcome of ovulation induction with low-dose follicle stimulating hormone in women with polycystic ovary symdrome. Hum. Reprod, 13, Farhi, J., Homburg, R., Lerner, A. et al. (1993) The choice of treatment for anovulation associated with polycystic ovary syndrome following failure to conceive with clomiphene. Hum. Reprod., 8, Franks, S. and Hamilton Fairley, D. (1996) Ovulation induction: gonadotropins. In Adashi, E.Y., Rock, J.A., Rosenwaks, Z. (eds), Reproductive Endocrinology, Surgery and Technology. Lippincott-Raven, Philadelphia, USA. Hamilton-Fairley, D. and Franks, S. (1990) Common problems in induction of ovulation. Baillière Clin. Obstet. Gyneacol., 4, Hamilton-Fairley, D., Kiddy, D., Watson, H. et al. (1992) Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary treated with low-dose gonadotrophin. Br. J. Obstet. Gynaecol., 99, Hayden, C.J., Rutherford, A.J. and Balen A.H. (1999) Induction of ovulation using a starting dose of 50 units of recombinant human follicle stimulating hormone (Puregon). Fertil. Steril., 71, Hedon, B., Hugues, J.N., Emperaire, J.C. et al. (1998) A comparative prospective study of a chronic low-dose versus a conventional ovulation stimulation regimen using recombinant human follicle-stimulating hormone in anovulatory infertile women. Hum. Reprod., 13, Homburg, R., Levy, T. and Ben-Rafael, Z. (1995) A comparative prospective study of conventional regimen with chronic low-dose administration of follicle-stimulating hormone for anovulation associated with polycystic ovary syndrome. Fertil. Steril., 63, Homburg, R., Orvieto, R., Barhava, I. et al. (1996) Serum levels of insulin-like growth factor-1, IGF binding-protein-1 and insulin and the response to human menopausal gonadotrophins in women with polycystic ovary syndrome. Hum. Reprod., 11, Howles, C.M. (1993) The Endocrinology of Superovulation: the Influence of Luteinising Hormone. 2nd edn. Oxford Clinical Communications, Oxford, UK. Hugues, J-N., Cedrin-Durnerin, I., Avril, C. et al. (1996) Sequential step-up and step-down dose regimen: an alternative method for ovulation induction with follicle-stimulating hormone in polycystic ovary syndrome. Hum. Reprod., 11, Insler, V. (1988) Gonadotropin therapy: new trends and insights. Int. J. Fertil., 33, Kiddy, D., Hamilton-Fairley, D., Bush, A. et al. (1992) Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin. Endocrinol., 36, Lunenfeld, B., Eskol. A. (1982) Induction of ovulation with gonadotrophins. In Rolland, R., Van Hall, E.V., Hillier, S.G. et al. (eds), Follicular Maturation and Vulation. Proceedings of the IVth Reiner de Graaft Symposium. Excerpta Medica (Int Congress Series Vol 560), Amsterdam, The Netherlands, pp MacGregor, A.H., Johnson, J.E. and Bunde, C.A. (1968) Further clinical experience with clomiphene citrate. Fertil. Steril., 19, Polson, D.W., Mason, H.D., Saldahna M.B.Y. et al. (1987) Ovulation of a single dominant follicle during treatment with low-dose pulsatile FSH in women with PCOS. Clin. Endocrinol., 26, Rabau, E., David, A., Serr D.M. et al. (1967) Human menopausal gonadotropins for anovulation and sterility. Results of 7 years of treatment. Am. J. Obs Gynecol., 98, Sagle, M.A., Hamilton-Fairley, D., Kiddy, D. et al. (1991) A comparative, randomized study of low-dose human menopausal gonadotropin and follicle stimulating hormone in women with polycystic ovary syndrome. Fertil. Steril., 55, Scheele, F., Hompes, P.G.A., van der Meer, M. et al. (1993) The effects of a gonadotrophin-releasing hormone agonist on treatment with low-dose follicle stimulating hormone in polycystic ovary syndrome. Hum. Reprod., 8, Schoot, B.C., Hop, W.C., de Jong, F.H. et al. (1995) Initial estradiol response predicts outcome of exogenous gonadotrophins using a step-down regimen for induction of ovulation in PCOS. Fertil. Steril., 64, Shoham, Z., Patel, A. and Jacobs, H.S. (1991) Polycystic ovarian syndrome: safety and effectiveness of stepwise and low-dose follicle stimulating hormone. Fertil. Steril., 55, Siebel, M.M., Kamrava, M.M., McArdle, C. et al. (1984) Treatment of polycystic ovarian disease with chronic low-dose follicle stimulating hormone: biochemical changes and ultrasound correlation. Int. J. Fertil., 29, Simpson, J.L. (1992) Elucidating the genetics of polycystic ovary syndrome. In Dunaif, A., Givens, J.R., Haseltine, F.P. and Merriam, G.F. (eds), Polycystic Ovary Syndrome. Blackwell Scientific, Boston, USA, pp Van der Meer, M., Hompes, P.G., Scheele, F. et al. (1996) The importance of endogenous feedback for monofollicular growth in low-dose step-up ovulation induction with follicle-stimulating hormone in polycystic ovary syndrome: a randomized study. Fertil. Steril., 66, Van der Meer, M., Hompes, P.G.A., de Boer, J.A. et al. (1998) Cohort size rather than FSH threshold level determines ovarian sensitivity in polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 83, Van Dessel, H.J.H.M., Schoot, B.C., Schipper, I. et al. (1995) Circulating immunoreactive and bioactive follicle-stimulating hormone concentrations in anovulatory infertile women during gonadotrophin induction of ovulation using a decremental dose regimen. Hum. Reprod., 11, Van Santbrink, E.J.P. and Fauser, B.C.J.M. (1997) Urinary follicle-stimulating hormone for normogonadotropic clomiphene resistant anovulatory infertility: prospective, randomized comparison between low-dose step-up and step-down dose regimens. J. Clin. Endocrinol. Metab., 82, Wang, C.F. and Gemzell, C. (1980) The use of human gonadotropin for the induction of ovulation in women with polycystic ovarian disease. Fertil. Steril., 33, White, D.M., Polson, D.W., Kiddy, D. et al. (1996) Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J. Clin. Endocrinol Metab., 81, Received on May 10, 1999; accepted on July 29, 1999