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Human Reproduction vol.11 no 11 pp 2400-2404, 1996 Pure and highly purified follicle-stimulating hormone alone or in combination with human menopausal gonadotrophin for ovarian stimulation after pituitary suppression in in-vitro fertilization Juan Balasch1, Francisco Fabregues, Montserrat Creus, Vicenta Moreno, Bienvenido Puerto, Joana Peflarrubia, Francisco Carmona and Juan A.Vanrell Department of Obstetrics and Gynecology, Faculty of MedicineUniversity of Barcelona, Hospital Clinic i Provincial, Barcelona, Spain 'To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Hospital Clinic i Provincial, C/Casanova 143, 08036-Barcelona, Spain The use of pure follicle stimulating hormone (pFSH) and highly purified FSH (FSH-HP) versus the combinations pFSH/human menopausal gonadotrophin (HMG) and FSHHP/HMG, respectively, was compared for stimulating follicular development after gonadotrophin-releasing hormone agonist (GnRHa) suppression in women undergoing invitro fertilization (TVF)-embryo transfer. Two consecutive prospective, randomized studies were carried out at the Assisted Reproduction Unit of the Hospital Clinic i Provincial in Barcelona, a tertiary care setting. Two groups of 188 (study 1) and 252 (study 2) consecutive infertile patients respectively, scheduled for IVF-embryo transfer were included. Pretreatment with leuprolide acetate (long protocol) was followed by gonadotrophin treatment in all patients. In study 1, 92 patients received i.m. pFSH alone (group pFSH) and 96 were treated with the combination of i.m. pFSH and i.m. HMG (group HMG-1). In study 2, 123 patients received s.c. FSH-HP alone (group FSH-HP) and 129 patients were given the combination of s.c FSH-HP and i.m. HMG (group HMG-2). Main outcome measures included follicular development, oocyte retrieval, fertilized oocytes, duration and dose of gonadotrophin therapy, and clinical pregnancy. There were no significant differences between pFSH and pFSH/HMG nor between FSH-HP and FSH-HP/HMG cycles with regard to the number of ampoules of medication used, day of human chorionic gonadotrophin (HCG) administration, mean peak serum oestradiol concentrations, number of follicles punctured, and number of oocytes aspirated, embryos transferred, or pregnancies. We conclude that urinary FSH (either purified of highly purified) alone is as effective as the conventional combination of urinary FSH/HMG for ovarian stimulation under pituitary suppression in IVF cycles. Therefore, they can be used interchangeably in FVF programmes. Key words: highly purified FSH/TVF/ovarian stimulation/pure FSH/urofollitrophins 2400 Introduction Pituitary desensitization with the long protocol increases the probabilities of conception in in-vitro fertilization (IVF)embryo transfer (Hughes et al, 1992; Tan et al, 1994) and it was found that the choice of gonadotrophin-releasing hormone agonist (GnRHa) may influence results obtained (Balasch et al, 1992; Penzias et al, 1992). To stimulate multiple follicular development for IVF-embryo transfer treatment, most IVF centres have used the usual equal mixture of follicle stimulating hormone (FSH) and luteinizing hormone (LH) in the form of human menopausal gonadotrophin (HMG) alone or adding purified FSH on the first 2 days of HMG stimulation (Strickler et al, 1995). This is based on traditional ovulation induction in cases of amenorrhoea due to hypothalamic-pituitary failure and gonadotrophin deficiency and on the belief that stimulation of the ovaries under pituitary suppression would require supplementation with LH (Hull et al., 1994). However, the concept is emerging that 'resting' concentrations of LH, eventually acting synergistically with locally produced growth factors, are sufficient for oocyte maturation and steroidogenesis. Furthermore, in women with normal pituitary function, treatment with FSH alone after pituitary suppression of endogenous gonadotrophin production with a GnRHa, results in normal increases of oestradiol, ovulation and fertilization, showing that the amount of LH that escapes the pituitary down-regulation is sufficient (Hillier, 1994; Simoni and Nieschlag, 1995). On the basis of the above evidence, different authors have carried out comparisons between 'pure' FSH (pFSH, urofollitrophin) and HMG in IVF cycles and a recent metaanalysis of these data indicates that the overall odds ratio (OR) for the eight trials analysed favours the use of FSH which results in >50% improvement over HMG in clinical pregnancy rates (Daya et al, 1995). However, the individual ORs for each trial were not statistically significant and all but one of these previous studies only included around 20 patients in each group of patients. In addition, two more recent reports comparing GnRHa-HMG and GnRHa-highly purified FSH (FSH-HP) protocols concluded that FSH-HP resulted in reduced concentrations of serum oestradiol as compared to HMG cycles, but some beneficial effects of HMG on the number of oocytes retrieved, fertilization rates and pre-embryo development were demonstrated (Fried et al., 1996; Westergaard et al, 1996). Also it should be noted that none of those previous reports compared urinary FSH alone with the combination of urinary FSH and HMG (days 1 and 2 of ovarian stimulation) followed by HMG, nor used FSH-HP. Thus, further studies are necessary to optimize the gonadotrophin regimen in IVF. © European Society for Human Reproduction and Embryology FSH versus FSH/HMG after GnRHa In our FVF programme ovanan stimulation is usually carried out using urinary FSH and HMG (Balasch et al, 1992). The objective of the present report was to compare the efficacy of this standard combined therapy with pFSH alone and FSH-HP alone for stimulating multiple ovanan folhcular development in women undergoing IVF-embryo transfer. Materials and methods The present report shows the results of two successive randomized, prospective studies including IVF patients. Study 1 was earned out to compare pFSH alone with pFSH/HMG for ovarian stimulation under pituitary suppression with GnRHa, while in study 2, FSH-HP alone was compared with FSH-HP/HMG. The study populations consisted of two groups of 188 (study 1) and 252 (study 2) consecutive patients respectively, scheduled for IVF-embryo transfer. All women gave informed consent to be included in the study which was approved by the Ethics Committee of our department All of them were premenopausal women aged 23-39 years and had no ovarian failure according to FSH concentrations <12 mlU/ml (standard ERP 78/ 549) As previously reported (Balasch et al., 1992), in our IVF programme ovarian stimulation is routinely accomplished using gonadotrophin treatment under pituitary suppression with GnRHa. In all women, leuprolide acetate (Procnn. Abbott Laboratories S.A , Madrid, Spain) suppression was started in the mid-luteal phase of the previous cycle at a daily dose of 1 mg. It was continued for 13-15 days prior to treatment with gonadotrophins. That dose was reduced to 0.5 mg daily once ovanan arrest was achieved and then continued until the administrauon of human chorionic gonadotrophin (HCG) Gonadotrophic stimulation of the ovaries was started when serum oestradiol concentrations declined to <50 pg/ml and a vaginal ultrasonographic scan showed an absence of follicles >10 mm diameter. For the specific purpose of the present investigation patients were allocated to a gonadotrophin treatment group according to a computergenerated randomization table. In study 1, 92 patients received l.m. pFSH alone (group pFSH) and 96 were treated with the combination of i.m. pFSH and l.m. HMG (group HMG-1). In study 2, 123 patients received s c. FSH-HP alone (group FSH-HP) and 129 patients were given the combination of s.c FSH-HP and i.m HMG (group HMG-2). The scheme of gonadotrophin administration was the same in the four groups studied. On days 1 and 2 of ovanan stimulation three ampoules per day of HMG (Pergonal: Serono S.A., Madnd, Spain) were administered together with three ampoules of either pFSH (Fertinorm: Serono S.A ) (group HMG-1) or FSH-HP (Neo-Fertinorm: Serono S.A.) (group HMG-2). Patients included in groups pFSH and FSH-HP were given six ampoules daily of these respective gonadotrophin preparations on days 1 and 2 of ovulation induction therapy. On days 3-7 of ovarian stimulation, two ampoules per day of HMG (groups HMG-1 and HMG-2), pFSH (group pFSH) or FSHHP (group FSH-HP) were administered to each patient From day 8 onward, each gonadotrophin preparation was administered on an individual basis according to the ovarian response Transvaginal ultrasonography and serum oestradiol measurement were performed daily from day 7 of ovarian stimulation to assess folhcular development The cntena for HCG administrauon (5000 IU, Profasi: Serono S.A.) were the presence of two or more follicles >17 mm in diameter and oestradiol concentrations >800 pg/ml (conversion factor to SI units, 3.671). Oocyte aspiration was performed by vaginal ultrasonography 35-37 h after HCG administration under local anaesthesia. The maturauonal status of the oocytes was recorded according to the cntena of Veeck (1986). Up to four embryos were replaced and the remaining were cryopreserved. Additional doses of 5000, 2500, and 2500 IU HCG were given on the day of follicle aspiration and 2 and 5 days later, respectively, to supplement the luteal phase in all patients. In pauents with serum oestradiol concentrations >4000 pg/ml, HCG support was withheld to reduce the nsk of ovarian hyperstimulation syndrome Instead, these patients were given micronized progesterone administered intravaginally at a dose of 600 mg/day (given at 8 h intervals) from the day of embryo transfer until menses nr serological confirmation of pregnancy. Oestradiol concentrations in serum were estimated by direct radiolmmunoassay (BioMeneux, Marcy I'Etoile, France). Intra-assay and inter-assay coefficients of variation were < 5 and <5.8% respectively Ultrasonic scans were performed using a 5 MHz vaginal transducer attached to an Aloka sector scanner (Model SSD-620: Aloka Co. Ltd, Tokyo, Japan). Because the aim of ovanan stimulation is to increase the number of oocytes available for fertilization (Hedon et al, 1995), the sample size (>90 patients/group) was calculated assuming a power of 80% to detect a difference of 20% between groups in the number of oocytes retrieved, with a type I risk of 0.05. Statistical comparisons were performed by cm-square analysis or Student's /-test as appropnate Significance was defined as P < 0 05 Results Results are summarized in Tables I-UI. From Table I it can be seen that main demographic and baseline characteristics of the patients in groups pFSH and HMG-1 (study 1) and in groups FSH-HP and HMG-2 (study 2) were similar in terms of age, body mass index (BMT), cause of infertility, duration of infertility, early folltcular phase FSH, and number of IVF attempts. In addition, no significant differences regarding these parameters were found when groups pFSH versus FSH-HP and HMG-1 versus HMG-2 respectively, were compared. This supports the validity of the randomization process. The mean time for total ovarian arrest, days of ovanan stimulation, the total dose of gonadotrophins, follicular recruitment and growth during gonadotrophin treatment, and the endometrial thickness and oestradiol serum concentrations on the day of HCG administration, were similar for the two groups in study 1 and for the two groups in study 2 (Table H). Also, there were no significant differences between groups pFSH and FSH-HP nor groups HMG-1 and HMG-2 with respect to those parameters of ovarian response. Regarding ovum retrieval and IVF outcome, the number of follicles punctured, the number and quality of oocytes retrieved, the number of fertilized oocytes, the number of embryos suitable for replacement and cryopreservation, and the number of patients with embryo transfer, were compared between groups in studies 1 and 2 (Table III). No significant differences were found for any of these variables in both studies. Again, results were similar when group pFSH versus FSH-HP and HMG-1 versus HMG-2 respectively, were compared. The combination of pFSH or FSH-HP with HMG and treatments with pFSH alone or FSH-HP alone were found not to be different when the number of clinical pregnancies as well as the pregnancy rate per initiated cycle, per ovum retrieval procedure, and per embryo transfer were compared. The number of losses due to spontaneous abortion was 2401 J.Balasch et aL Table L Main demographic and baseline characteristics of patients Study 1 Study 2 Variable* pFSH (n = 92) HMG-1 (n = 96) FSH-HP (n = 123) HMG-2 (n = 129) Age (years)b BM1 (kg/m2)b Cause of infertility (n,%) Tubal Unexplained Endometriosis Male Duration of infertility (years)b Days 2-A FSH (mIU/ml)b No. of IVF attempts'1 33.8 ± 3.0 23.3 = 2 4 34.1 ± 3 6 23.6 ± 2 2 33 3 ± 3 3 228 ± 22 33.7 ± 3 3 23 5 ± 2 6 46(50) 18 (19) 15 (16) 13 (14) 7.0 ± 3 5 7.0 ± 2 9 1 7 ± 1.0 46(48) 22 (23) 11(11) 17 (18) 6 6 ± 3.5 6 7 ± 2.7 1.5 ± 1.0 49(40) 25(20) 27 (22) 22 (18) 62 ± 27 6 8 ± 3.2 15 + 0 8 55 (42) 30(23) 25(19) 19 (15) 66 ± 3 1 7.2 ± 29 1 7 ± 0.9 •No significant differences between pFSH and HMG-1 groups nor between FSH-HP and HMG-2 groups •Values are means ± SD. BMI = body mass index, FSH =• follicle stimulating hormone, pFSH = pure FSH, FSH-HP = highly purified FSH, HMG = human menopausal gonadotrophin, IVF = ln-vitro fertilization. Table EL Ovarian response m the four groups of IVF patients Study 1 1 Variable b Time for ovarian arrest (days) Total no of ampoules of gonadotrophinsb Days of ovarian stimulationb Patients with HCG and ovum retrieval (n,%) No of >10 mm follicles on HCG day* No. of »14 mm follicles on HCG day6 Endometrial thickness (mm) on HCG day*1 Oestradiol (pg/ml)c on HCG dayb Study 2 pFSH (n = 92) HMG-1 (n = 96) FSH-HP (n = 123) HMG-2 (n = 129) 13 7 ± 2.1 30 0 ± 5 . 8 10 2 ± 2.3 73 (79) 15 8 ± 72 128 ± 7 0 11.5 ± 2.7 2397 ± 1571 14.0 ± 2 6 29.5 ± 5 1 10.1 ± 2 1 74 (77) 15.1 ± 6 4 119 ± 5.5 11.0 ± 2.3 2572 ± 2065 138 ± 14 29 2 ± 6.1 9.8 ± 1.4 94(76) 154 ± 6 4 12 3 ± 6 5 10.7 ± 2.1 2094 ± 1627 14 1 ± 1 2 29 2 ± 5 8 10 1 ± 1 7 105 (81) 14.5 ± 6 0 11 1 ± 5 5 10.5 ± 2 1 2407 ± 1848 'No significant differences between pFSH and HMG-1 groups nor between FSH-HP and HMG-2 groups. •"Values are means ± SD. Conversion factor to SI unit, 3.671 HCG = human chononic gonadotrophin, FSH = follicle stimulating hormone, pFSH = pure FSH, FSH-HP = highly purified FSH, HMG = human menopausal gonadotrophin. Table i n . Ovum retrieval and IVF outcome in the four groups studied Study 2 Study 1 Variable' pFSH (n = 92) HMG-1 (n = 96) FSH-HP (n - 123) HMG-2 (n - 129) No. of follicles puncturedb No. of oocytesb Mature oocytes (%) Immature oocytes (%) Degenerative oocytes (%) No. of fertilized oocytesb No. of embryos/patientb No. of embryos/replacementb Patients with embryo transfer (n,%)c Clinical pregnancy rates (n) Cycle start (%) Ovum retrieval (%) Embryo transfer (%) Clinical abortion rates (n,%) 19.4 ± 11.7 95 ± 58 95 3 2 72 ± 50 6.6 ± 5 0 2.8 ± 0 7 62 (84.9) 13 14 1 17.8 20.9 2 (15.3) 18.2 ± 10.5 9.3 ± 6 4 93 4 3 6.2 ± 5 6 5.7 ± 5 0 2 6 ± 0.5 63 (85 1) 11 114 14.8 17.4 2(18 1) 19 1 ± 11.2 9 3 ± 5.6 96 3 1 6 1 ± 5.0 5 6 ± 4.5 28 ± 0 4 85 (90.4) 16 13.0 17 0 18.8 2 (12.5) 17 7 ± 8.3 96 ± 49 98 1 1 66 ± 45 58 ± 42 29 ± 06 98 (93 3) 21 16 2 20.0 214 4(19 0) •No significant differences berween pFSH and HMG-1 groups nor between FSH-HP and HMG-2 groups "Values are means ± SD °Values are relative to the number of patients with ovum retrieval. similar in the four groups of patients (Table HI). There were no ectopic pregnancies. The overall incidence of severe ovarian hyperstimulation syndrome (Golan et al., 1989) was 1.8% (eight cases among 440 IVF cycles) and there was 2402 one case (1%) in group pFSH, two cases (2%) in group HMG-1, two cases (1.6%) in group FSH-HP and three cases (2.3%) in group HMG-2 (no statistical significant difference between groups). FSH versus FSH/HMG after GnRHa Discussion The most exciting development of ovarian stimulation for IVF was the widespread use of the GnRHa during therapy with HMG. This prevents inappropriate release of a spontaneous LH surge and allows optimal timing of oocyte collection to an ovulation-inducing injection of HCG (Hughes et al, 1992; Meldrum, 1993; Tan et al, 1994). Recent studies suggested that the choice of GnRHa may influence results obtained in IVF (Balasch et al, 1992; Penzias et al, 1992). Similarly, it has been stressed that the traditional administration of equal amounts of urinary FSH and LH needs to be reviewed m the light of advancing knowledge of basic follicular physiology, pharmaceutical developments in the specificity and purity of both FSH and LH preparations, and growing clinical experience with such preparations (Hillier, 1994; Hull et al, 1994). The availability of pFSH and FSH-HP made it possible to discriminate better the relative roles of FSH and LH in the ovulation process, underlining the key role of FSH in folliculogenesis and has afforded a greater flexibility in terms of gonadotrophin utilization. Whereas hypersecretion of endogenous LH during the follicular phase may imply adverse effects on the fertility process (Shoham et al, 1993), exogenous LH seems to have very little impact on endogenous LH both in polycystic ovary syndrome patients undergoing ovulation induction (Hamilton-Fairley et al., 1991; Sagle et al, 1991) and in eumenorrhoeic women given gonadotrophin and long regimen GnRHa for ovarian stimulation in IVF (Filicori et al, 1996). However, the long protocol of GnRHa administration in combination with the use of pure preparations of FSH is now being increasingly used. Recently, two non-comparative studies have been reported indicating that both pFSH (Hull et al, 1994) and FSH-HP (Howies et al, 1994), when used to stimulate ovaries in IVF cycles employing pituitary desensitization, are fully effective and highly successful, and supplementation with LH is not needed. On the contrary, two very recent reports indicate that just replacing HMG with FSH-HP may not be good enough for ovarian stimulation of GnRHa down-regulated, normogonadotrophic women (Fried et al, 1996; Westergaard et al, 1996). Serum oestradiol concentrations were lower in FSH-HP groups and some beneficial effects of HMG on the average number of oocytes retrieved/fertilzed per cycle and pre-embryo development were found in those studies. To the best of our knowledge, no study has been reported comparing FSH-HP alone with the combination FSH-HP/ HMG in IVF. The present report shows that there is no significant difference between these two gonadotrophin regimens of ovarian stimulation when used in conjunction with GnRHa. This is indicated by the similarity in overall follicular growth, oocyte recovery and IVF outcome. Similarly, we found that patients treated with GnRHa had identical stimulation, oocyte retrieval and pregnancy outcomes, if they were stimulated with pFSH alone or pFSH/HMG. Although mean serum oestradiol concentrations tended to be slightly higher in the combination treatment groups, differences were not statistically significant This is in agreement with recent studies showing that whereas in extreme hypogonadotrophic women LH con- centrations are below the LH threshold for normal oestradiol biosynthesis, full follicular maturity and oocyte fertility, this threshold is not surpassed by GnRHa down-regulation in IVF (Hillier, 1994; Balasch et al, 1995; Simoni and Nieschlag, 1995). The endocrine role of oestradiol on endometnum was adequate in the four treatment groups as supported by the similarity observed in the endometrial thickness on HCG day and the pregnancy rate and outcome. On the other hand, while the 1.8% overall incidence of severe ovarian hyperstimulation syndrome in our study was very similar to the 1.7% recently reported by Dahl Lyons et al. (1994) among a similar number of IVF cycles stimulated according to a protocol such as ours (long protocol of GnRHa plus gonadotrophins), we found no difference between groups with respect to the incidence of this complication. A recent meta-analysis including eight randomized trials of pFSH versus HMG use in ovarian stimulation suggests that the use of pFSH is associated with a significantly higher clinical pregnancy rate (Daya et al, 1995). However, while the overall OR m that meta-analysis was in favour of the use of pFSH, in each trial (including the one by the authors of meta-analysis) the OR was not statistically significant. It should be noted that seven of these eight studies analysed only included about 20 patients in each treatment group (Daya et al, 1995). In addition, the meta-analysis included trials both with and without GnRHa, and trials were also included whether the ovarian stimulation regimen included GnRHa using the short flare-up protocol, in which GnRHa was commenced in die follicular phase of the treatment cycle, or the long suppression protocol, in which GnRHa was commenced in the follicular phase of the treatment cycle or the luteal phase of die preceding cycle (Daya et al., 1995). This suggests that endogenous LH concentrations were markedly different from one study to anouier. Thus, the small number of patients included and marked differences in GnRHa regimen used in those previous studies make it difficult to obtain definite conclusions regarding the optimum gonadotrophin regimen for IVF. In our study no differences were found between pFSH and pFSH/HMG treated groups. In conclusion, we have been unable to find significant differences in follicular development, the number of ova and embryos, or pregnancy rates between patients stimulated with conventional urinary FSH/HMG dierapy and those given urinary FSH alone under pituitary suppression with GnRHa. Thus, both gonadotrophin regimens can be used indistinguishably. Further studies are necessary to improve the stimulation protocols in order to obtain die optimum hormonal milieu for maximum follicular development and oocyte harvest as well as the ideal milieu for initiating and maintaining implantation in IVF-embryo transfer. Acknowledgement The authors thank Mrs Paquita Antonell for her technical assistance. References Balasch, J , Jov6, I C , Moreno, V et al (1992) The comparison of two gonadotrophin-releasing hormone agonists in an in vitro fertilization program. FertiL Stenl, 58, 991-994 2403 J.Balasch el at Balasch, J , Mir6, E, Burzaco, I. et al (1995) The role of luteinizing hormone in human follicle development and oocyte fertility: evidence from m-vitro fertilization m a woman with long-standing hypogonadotrophic hypogonadism and using recombinant human follicle stimulating hormone. Hum. Repmd., 10, 1678-1683. Dahl Lyons, C A , Wheeler, CA., Frishman, G N et al. (1994) Early and late presentation of the ovarian hyperstimulation syndrome: two distinct entities with different risk factors. Hum. Reprod., 9, 792-99. Daya, S., Gunby, J., Hughes, E.G. et al (1995) Follicle-stimulating hormone versus human menopausal gonadotrophin for in vitro fertilization cycles: a meta-analysis FertiL Stenl, 64, 347-354. Filicon, M., Flamigni, C , Cognigno, G.E etal (1996) Different gonadotrophin and leuprorehn ovulation induction regimens markedly affect folhcular fluid hormone levels and folliculogenesis Fertil. Stenl, 65, 387-393 Fried, G , Harlin, J., Csemickzy, G. and Wramsby, H (1996) Controlled ovarian stimulation using highly purified FSH results in a lower serum oestradiol profile in the follicular phase as compared with HMG Hum. Reprod, 11, 474-^t77 Golan, A., Ron-El, R., Herman, A. et al (1989) Ovarian hyperstiraulation syndrome- an update review Obstet. GynecoL Surv., 44, 430-440. Hamilton-Fairley, D., Kiddy, D , Watson, H et al (1991) Low-dose gonadotrophin therapy for induction of ovulation in 100 women with polycystic ovary syndrome. Hum. Reprod., 6, 1095-1099 Hedon, B., Out, HJ., Hugues, J N « d (1995) Efficacy and safety of recombinant follicle stimulating hormone (Puregon) in infertile women pituitary suppressed with triptorehn undergoing in-vitro fertilization a prospective, randomized, assessor-blind, multicentre trial Hum. Reprod,, 10,3102-3106 HiUier, S.G. (1994) Current concepts of the roles of follicle stimulating hormone and luteinizing hormone in folhculogenesis Hum. Reprod., 9, 188-191 Howies, CM., Loumaye, E , Giroud, D and Luyet, G. (1994) Multiple follicular development and ovarian steroidogenesis following subcutaneous administration of a highly purified urinary FSH preparation in pituitary desensitized women undergoing IVF a multicentre European phase III study. Hum. Reprod., 9, 424-^30 Hughes, E.G , Fedorkow, D M., Daya, S. et al (1992) The routine use of gonadotrophin-releasing hormone agonists prior to in vitro fertilization and gamete intraFallopian transfer a meta-analysis of randomized controlled trials Fertil Stenl, 58, 888-896 Hull, M G R . , Armatage, R J and McDermott, A (1994) Use of folliclestimulating hormone alone (urofollitropin) to stimulate the ovaries for assisted conception after pituitary desensinzation Fertil Stenl, 62, 9971003 Meldrum, D.R (1993) Ovarian stimulation for assisted reproductive technology Infertil Reprod. Med. N Am,, 4, 643-652 Penzias, A.S., Shamma, F.N., Gutmann, J.N et al (1992) Nafarehn versus leuprohde in ovulation induction for in vitro fertilization' a randomized clinical trial. Obstet. Cynecol, 79, 739-742 Sagle, M.A., Hamilton-Fairley, D., Kiddy, D.S. and Franks, S (1991) A comparative, randomized study of low-dose human menopausal gonadotrophin and follicle-stimulating hormone in women with polycystic ovarian syndrome. Fertil Stenl, 55, 56-60. Shoham, Z., Jacobs, H.S and Insler, V. (1993) Luteinizing hormone, its role, mechanism of action, and detrimental effects when hypersecreted during the follicular phase Fertil Stenl, 59, 1153-1161 Simoni, M. and Nieschlag, E. (1995) FSH in therapy physiological basis, new preparations and clinical use. Reprod. Med. Rev., 4, 163-177. Strickler, R C , Radwanska, E and Williams, D.B (1995) Controlled ovarian hyperstimulation regimens in assisted reproductive technologies. Am. J. Obstet GynecoL, 172, 766-773. Tan, S.L., Maconochie, N., Doyle, P. et al (1994) Cumulative conception and live-birth rates after in vitro fertilization with and without the use of long, short, and ultrashort regimens of the gonadotrophin-releasing hormone agonist buserelin Am. J Obstet GynecoL, 171, 513-520. Veeck, L.L (1986) Atlas of the Human Oocyte and Early Conceptus Williams and Wilkins, Baltimore Westergaard, L G., Erb, K., Laursen, S. a al (1996) The effect of human menopausal gonadotrophin and highly purified, urine-denved follicle stimulating hormone on the outcome of in-vitro fertilization m downregulated normogonadotrophic women. Hum. Reprod., 11, 1209-1213. Received on June 13, 1996; accepted on September 5, 1996 2404