Laboratorios Serono S.A., C/ María de Molina, 40, 28006 Madrid, Spain
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Abstract |
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Key words: hypogonadotrophic anovulation/ovulation induction/rFSH/rLH/WHO group I anovulation
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Introduction |
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Four conditions can be usually found in women with suspected ovulatory failure attending infertility clinics (The ESHRE Capri Workshop Group, 1995; American Society for Reproductive Medicine, 1998
). These include: (i) hypogonadotrophic anovulation; (ii) normogonadotrophic anovulation (oestrogenic ovulatory dysfunction); (iii) hypergonadotrophic anovulation; and (iv) hyperprolactinaemic anovulation, the first three groups corresponding to the World Health Organization (WHO Scientific Group, 1973
) classes I, II and III respectively.
Gonadotrophin treatment is primarily a substitution therapy and, as such, should be applied in patients lacking appropriate gonadotrophin stimulation but presenting target organs (gonads) capable of normal response (Insler, 1988). According to the above classification, gonadotrophin treatment is applied in clinical practice in two main groups of women. WHO group I: amenorrhoeic women with no evidence of endogenous oestrogen production (failure to respond to progestin withdrawal), non-elevated prolactin levels, normal or low FSH concentrations, and no detectable space-occupying lesion in the hypothalamicpituitary region; and WHO group II: women with a variety of menstrual cycle disturbances, including chronic anovulation with evidence of endogenous oestrogen production, and normal levels of prolactin and FSH (Insler, 1988
; The ESHRE Capri Workshop Group, 1995
; American Society for Reproductive Medicine, 1998
).
WHO group I anovulation is a rare condition that can be caused by reduced hypothalamic or pituitary activity. In women with intact pituitary function, pulsatile gonadotrophin releasing hormone (GnRH) therapy can be used to restore the periodic release of FSH and LH, resulting in ovulation and pregnancy (Filicori et al., 1994). The advantages of pulsatile GnRH compared with gonadotrophins are that there is a lower risk of hyperstimulation and multiple pregnancy and the need for monitoring is minimal. However, the disadvantages are that treatment is more complex and that not all patients like the use of the portable pump injecting the drug either i.v. or s.c. for several weeks (The ESHRE Capri Workshop Group, 1995
). The alternative therapeutic option to pulsatile GnRH therapy in hypothalamic dysfunction and the first line treatment if the origin of anovulation is primary pituitary failure is to give daily injections of gonadotrophins (The ESHRE Capri Workshop Group, 1995
).
Until recently, human menopausal gonadotrophin (HMG), a urinary extract containing a fixed combination of LH and FSH, was the only source of exogenous LH for women with hypogonadotrophic hypogonadism. However, recombinant human LH (rLH) is now available for clinical use, providing a new treatment option. Thus, the first randomized, efficacy clinical study with rLH has been published recently (The European Recombinant Human LH Study Group, 1998). In that dose-finding study 38 patients were randomized to receive rLH (0, 25, 75 or 225 IU/day) in addition to a fixed dose of recombinant human FSH (rFSH) (150 IU/day). The study concluded that a daily dose of 75 IU rLH was effective in the majority of women in promoting optimal follicular development and enhancing the ability of these follicles to luteinise when exposed to human chorionic gonadotrophin (HCG).
As stressed above, there are difficulties in recruiting a substantial number of patients in a rare indication such as hypogonadotrophic anovulation. Thus, this prospective multicentre observational study including 84 treatment cycles in 38 patients was conducted to assess further the effectiveness and safety of 75 IU/day rLH associated with rFSH to induce follicular development and ovulation in WHO group I anovulatory women. This was a drug company trial sponsored by Serono S.A.
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Materials and methods |
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Patients were enrolled at 14 university clinical centres in Spain. The clinical trial was approved by the Spanish Health Authorities and the Ethics Committees of the participating centres. The study was conducted in accordance with European Union Good Clinical Practice Guidelines, which include obtaining written informed consent from each patient.
Treatment protocol
Eligible patients initiated the first cycle of treatment (cycle A) by receiving daily s.c. injections of rFSH [Gonal-F, Ares-Serono (Europe) Ltd., London] and rLH [Luveris, Ares-Serono (Europe) Ltd.]. Both products were always mixed in the syringe and given in the same injection. On days 15 of ovarian stimulation patients received 150 IU daily of rFSH. From day 6 onwards, rFSH was administered according to the ovarian response. Patients received a fixed daily dose of 75 IU of rLH throughout the treament period in cycle A. Gonadotrophin therapy was not to exceed 21 days unless there was evidence of ongoing follicular development (follicle >10 mm).
Sequential transvaginal ultrasonography and serum oestradiol measurements were performed from stimulation day 6 onwards. Ovulation was induced with a single s.c. injection of 10 000 IU HCG (Profasi; Serono SA) on the day after the last rFSH/rLH administration as soon as the leading follicle reached a mean diameter of 18 mm and if there was no ovarian hyper-response (as indicated by the presence of >3 follicles with a diameter
18 mm and/or a serum oestradiol level >1000 pg/ml). Ovulation was documented by midluteal phase (days 78 following HCG administration) and serum progesterone concentration
30 nmol/l (i.e.
9.4 ng/ml). No patient received luteal phase support treatment. If menses had not occurred by day 15 after HCG administration, serum ß-HCG was to be measured. An ultrasound scan was performed on day 35 after HCG administration on all pregnant patients, recording the number of fetal sacs and heart activities.
Following cycle A, and based on the individual patient's previous response, treatment could be continued for up two additional cycles (cycles B and C). The dose of rLH in treatment cycles B and C was determined by the patient's response to treatment; in case of satisfactory follicular development in the first cycle, the rLH dose was to remain the same (75 IU/day); otherwise it could be increased to 150 IU in the second cycle and to 225 IU in the third cycle while maintaining 150 IU rFSH daily from days 15 of ovarian stimulation. The starting dose of FSH in cycles B and C could be reduced to 75 IU daily in patients having a hyper-response in a previous treatment cycle.
Study end-points
Although ovulation should be considered the end-point in the treatment of anovulatory infertile women, for the specific purposes of the present study, where the use of rLH to support follicular development induced by rFSH was investigated, the protocol established follicular growth and ovulation to be considered in the efficacy assessment as done in the previous report (The European Recombinant Human LH Study Group, 1998). Thus, efficacy assessment was primarily based on follicular development which was judged to be optimal if at least one follicle
18 mm in diameter was achieved and an ovulatory cycle as defined above was obtained. Other efficacy assessments included: the total amount of exogenous LH and FSH used and the duration of treatment with gonadotrophins; serum oestradiol, serum oestradiol per mature follicle (
14 mm in diameter), and endometrial thickness on the HCG day; midluteal phase serum progesterone; and pregnancy rate.
Drug safety was assessed by monitoring adverse events and the incidence of local reactions at injection site throughout the study period, as well as through laboratory tests, including haematology, clinical chemistry, and urinalysis performed before and after gonadotrophin treatment. OHSS was diagnosed according to a published classification (Golan et al., 1989).
Laboratory methods
Hormonal measurement was carried out at a central laboratory using commercially available immunoassays. Basal serum FSH, LH, oestradiol and progesterone were assessed in blood samples taken on the first day of follicular stimulation (before the start of the treatment) and on the day of HCG injection, in each treatment cycle (samples were available for the final analysis of results in 63 cycles, cycle A in the 38 patients and 25 subsequent treatment cycles). Progesterone was assessed on blood samples taken on days 78 after the HCG injection. FSH and LH serum concentrations were measured by an immunoradiometric assay (Diagnostic Products Corporation, Los Angeles, CA, USA). Data were expressed in terms of WHO 2nd Reference Preparation 78/549 (WHO, 1973) for FSH and WHO 1st Reference Preparation 68/40 for LH. The sensitivity of the assay was 0.06 mIU/ml for FSH and 0.15 mIU/ml for LH. The intra-assay coefficients of variation were 4.1 and 6.3% for FSH and for LH respectively. Oestradiol and progesterone concentrations in serum were estimated by direct radioimmunoassay (Diagnostic Products Corporation, Los Angeles, CA, USA). Intra-assay and interassay coefficients of variation were 6.4 and 4.6% respectively for oestradiol, and 7.7 and 4.5% respectively for progesterone.
Statistical analysis
Data are expressed as mean ± SEM. The statistical analyses used were Student's t-test for continuous data, and 2 cross-tabulations for categorical data. Correlation coefficients were calculated to measure the degree of association between the values of two variables. A P value <0.05 was considered significant.
The efficacy and safety analysis was done on an intention-to-treat basis, including all patients who received at least one dose of the study drugs. To assess treatment efficacy, the proportion of patients achieving an adequate follicular growth and an adequate luteal function was calculated. As there were patients having an ovarian hyper-response, resulting in cancellation of HCG injection, the analysis of follicular development was repeated, including overstimulation as a success for an end point. Descriptive statistics for follicular size, hormone values, endometrial thickness and pregnancy rate, are also presented. To assess treatment safety, the proportion of patients reporting adverse events, local reactions or laboratory abnormalities was calculated. Data were processed using SAS 6.12 for Windows NT (SAS-Institute Inc., Cary, NC, 27513, USA).
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Results |
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The proportion of cycles who fulfilled the main efficacy criteria (1 follicle
18 mm; midluteal phase progesterone
30 nmol/l) was 94% if ovarian hyper-response was included as success and 80% if it was not included (Table III
). HCG administration was withheld in five (6%) cycles because of no response and in 12 (14%) cycles because of hyper-response (Table IV
). Midluteal phase progesterone serum levels were consistent with normal corpus luteum function and similar in the three treatment cycles. There were 15 clinical pregnancies, that is, 18 and 39.5% gestations per started cycle and per patient, respectively (Table IV
). The pregnancy rate per cycle with HCG administration was 22.4%. Four pregnancies were obtained in the first treatment cycle, seven in the second treatment cycle, and four in the third treatment cycle. Of 15 gestations, 14 were viable pregnancies [including four (26%) pairs of twins] and one patient spontaneously miscarried in the first trimester. There were no high order multifetal gestations.
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Safety assessment
All 38 patients entering this study received at least one treatment cycle of rLH and rFSH. No patients withdrew for adverse events, most of which were mild or moderate in severity. Apart from local reactions, a total of nine adverse events occurred in nine (23.7%) out of 38 patients during the three treatment cycles. These included: mild (one patient) or moderate (two patients) OHSS, influenza (two patients), nausea and malaise (one), anxiety (one), headache (one) and vaginal candidiasis (one). Most of these events were considered as causally unrelated to the study products. Out of 984 injections assessed for local tolerance, 88 (9%) were associated with local reactions; only 1.1% of injections were associated with severe pain and 0.5% with severe itching. Regarding laboratory tests, treatment did not cause significant changes in haematological, biochemical or urinary parameters.
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Discussion |
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In a recent pioneering study it was shown that a daily dose of 75 IU rLH was effective in most women in promoting optimal follicular development (The European Recombinant Human LH Study Group, 1998). The present report provides further evidence supporting this contention. Thus, a daily dose of 75 IU rLH, which was used in as much as 94% of treatment cycles, was effective in promoting follicular development in 94% of treated cycles. In association with this follicular growth, rFSH and rLH therapy induced a significant increase in both oestradiol serum levels and endometrial thickness. This was obtained over a relatively short duration of the stimulation phase (mean 12.2 days) which is similar to data reported in the previous study using rFSH (150 IU/day) plus rLH (75 IU/day) (12.1 days) (The European Recombinant Human LH Study Group, 1998
). That previous report and the present study suggest that daily doses of 150 IU rFSH and 75 IU rLH are useful in a great majority of WHO group I anovulatory patients. Interestingly, however, the mean number of growing follicles in cycles A, B and C in the present study seems high leading to 14% overall cancellation rate (in cycle A even 26%) and 26% twin pregnancies. As the aim of ovulation induction should be monofollicular growth, and the normal starting dose of HMG in WHO group I is 150 IU/day (The ESHRE Capri Workshop Group, 1995
), it can be postulated that further refinements in terms of the appropriate starting doses and/or increments of gonadotrophins (mainly FSH but also LH) during ovarian stimulation are necessary when using recombinant preparations. This is well exemplified by patients included in Table II
and supposedly needing an LH dosage increase. Patient 1 did not respond at all, although the LH dosage was increased to 225 IU. Probably, a more logical approach in this patient would have been to increase the dosage of rFSH. Patient 3 is a good illustration of this statement. Patient 2 responded well in her first cycle and failed to respond in her second cycle. Cycle 3 showed a quick response which was probably related to the increase in rFSH after the first five treatment days of fixed daily dose as established by the protocol. In fact, as stressed above, there is enough evidence that follicular growth occurs by FSH stimulation alone in hypogonadotrophic hypogonadism, but oestradiol production is insufficient. Finally, normal follicular maturation in the present study was indicated by consistent luteinization after HCG administration in as much as 80% of initiated treatment cycles and a satisfactory pregnancy rate per cycle with HCG administration (22.4%) and per patient (39.5%).
We found that, as expected, serum FSH levels increased significantly from baseline to HCG day, a fact previously reported by others using HMG or urinary FSH (Couzinet et al., 1988; Shoham et al., 1991
). In contrast, serum LH levels significantly decreased throughout the gonadotrophin treatment period. This is in agreement with previous reports using both urinary FSH and HMG for ovulation induction in polycystic ovary syndrome patients (Larsen et al., 1990
). It could be explained by the time relationship between HMG injection and blood sampling, especially because of the short half-life of exogenous LH preparations administered and the negative pituitary feed-back of increasing serum concentrations of oestradiol and inhibins secreted by the growing follicles. However, it has been reported (Couzinet et al., 1988
) that plasma LH levels rose significantly during HMG administration to WHO group I patients, which may be explained by the higher daily dose (225 IU/day) used in that study as compared with ours. Interestingly, Shoham et al. (1991) found no differences in the plasma LH increase observed after treatment with HMG or with FSH alone (Shoham et al., 1991
), which agrees with other studies suggesting that serum LH levels do not accurately reflect LH administration (The European Recombinant Human LH Study Group, 1998
). Also, the half-life of LH is shorter than that of FSH, which may explain the fact that FSH levels show a sustained increase after one daily s.c. injection while LH levels do not (le Cotonnec et al., 1994
, 1998a
,1998b
).
Hypogonadotrophic hypogonadism is well recognized as a functionally heterogeneous clinical syndrome. Whilst basal serum levels of FSH and LH ranging from 5 IU/l to 20 IU/l are considered as normal in reproductive years (Speroff et al., 1999; Yen et al., 1999
), gonadotrophin levels may be undetectable, low, or apparently normal in idiopathic hypogonadotrophic hypogonadism as well as in patients with central nervous system tumors (Santoro et al., 1986
; Filicori et al., 1994
; Hurst, 1996
; Speroff et al., 1999
). Circulating levels of LH are essential for the production of steroid hormones that regulate the timing of ovulation and target tissue responses, as well as maintenance of the corpus luteum and therefore early pregnancy (Chappel and Howles, 1991
). It has been established that resting levels of LH ranging from 1 to 10 IU/l should be sufficient to provide maximal stimulation to thecal cells (Chappel and Howles, 1991
). Thus, it was to be expected that, as shown in the present study, hypogonadotrophic patients having very low levels of endogenous LH (<1 IU/l; i.e., below the LH threshold for normal oestradiol biosynthesis, full follicular maturity and oocyte fertility) would necessitate higher doses of gonadotrophins as compared with women having basal LH levels
1 IU/l. However, it may be postulated that further increase over a `threshold level' of LH action needed to gain a response will not induce a greater increase in ovarian stimulation. Several findings in the present study support this contention.
Thus, despite the fact that the total amount of gonadotrophins used in the `low' LH group was significantly higher than in patients having `normal' LH, final follicular development and oestradiol output per mature follicle were similar in both groups of women. Although oestradiol serum levels on the day of HCG were significantly higher in the `normal' than in the `low' LH group, the endocrine role of oestradiol on endometrium was adequate in both groups as supported by the similarity observed in the endometrial thickness on HCG day and the pregnancy rate. Furthermore, normal follicular maturation in both groups was also indicated by consistent luteinization after HCG injection. Similarly, in IVF patients undergoing ovarian stimulation with gonadotrophins under pituitary suppression, the use of FSH-only preparations results in a lower serum oestradiol profile in the follicular phase as compared with HMG, but no differences regarding follicular development are observed between both treatment groups (Daya et al., 1995; Balasch et al., 1996
; Fried et al., 1996
; Daya and Gunby, 1999
). Finally, further support for the above contention is given in the fact that basal LH levels were correlated inversely with the number of ampoules of medication used and directly with serum oestradiol on HCG day but no correlation was found with the number of mature follicles.
rFSH and rLH were administered s.c. as a sole injection and this was proved to be safe and well tolerated. Adverse events observed were similar to those usually reported with rFSH alone (Recombinant Human FSH Study Group, 1995). The most commonly reported event was mild to moderate OHSS. In this regard it is noteworthy that the number of cycles cancelled for OHSS risk was considerably reduced from treatment cycle A (26%) to cycle C (0%) (Table IV
) a fact also evidenced by the oestradiol serum levels reached on the day of HCG (Table I
). This can be explained by the fixed rFSH dose originally requested by the protocol which was used in all patients in cycle A. However, after a protocol amendment rFSH could be administered in subsequent treatment cycles according to previous ovarian response.
In conclusion, this study confirms that combined rFSH and rLH treatment induces follicular growth, ovulation and pregnancy in a good proportion of hypogonadotrophic hypogonadal patients and is well tolerated. Ovulatory and pregnancy rates obtained in the present study were similar to those reported in WHO group I anovulatory women treated with pulsatile GnRH (Filicori et al., 1994). Thus further studies comparing both treatment modalities in terms of patient tolerability and acceptability, as well as adverse events (mainly OHSS and multiple pregnancy) are warranted.
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Acknowledgements |
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Notes |
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* This Collaborative Group comprises the following investigators and centres in Spain: J.Balasch, F.Fábregues, (Hospital Clínic, Barcelona); P.Barri, R.Tur, (Instituto Dexeus, Barcelona); P.Caballero, J.R.Heredia, (Hospital Ramón y Cajal, Madrid); J.Calaf, J.Espinós, (Hospital de la Santa Creu i Sant Pau, Barcelona); I.Cano, E.Pérez de la Blanca, (Hospital Materno-Infantil, Málaga); F.J.de Castro Pita, (Hospital Príncipe de Asturias, Madrid); J.A.Duque, S.García (Hospital Miguel Servet, Zaragoza); A.Herruzo, L.Martínez (Hospital Virgen de las Nieves, Granada); E.López, (Hospital Virgen de la Arrixaca, Murcia); J.Ordás, C.Cuadrado, (Hospital La Paz, Madrid); A.Pellicer, A.Requena, (Instituto Valenciano de Infertilidad, Valencia); F.J.Rodríguez-Escudero, J.L.Neyro, (Hospital de Cruces, Vizcaya); A.Romeu, L.A.Quintero (Hospital La Fe, Valencia); J. A.Ruiz Balda, J.Alonso, (Hospital Doce de Octubre, Madrid)
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References |
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American Society for Reproductive Medicine (1998) Induction of ovarian follicle development and ovulation with exogenous gonadotropins. Practice Committee Report. A Technical Bulletin. Birminghan, Alabama, USA; June 1998.
Balasch, J., Miró, F., Burzaco, I. et al. (1995) The role of luteinizing hormone in human follicle development and oocyte fertility: evidence from in-vitro fertilization in a woman with long-standing hypogonadotrophic hypogonadism and using recombinant human follicle stimulating hormone. Hum. Reprod., 10, 16781683.[Abstract]
Balasch, J., Fábregues, F., Creus, M. et al (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. Hum. Reprod., 11, 24002404.[Abstract]
Chappel, S.C. and Howles, C. (1991) Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Hum. Reprod., 6, 12061212.[Abstract]
Couzinet, B., Lestrat, N., Brailly, S. et al. (1988) Stimulation of ovarian follicular maturation with pure follicle stimulating hormone in women with gonadotrophin deficiency. J. Clin. Endocrinol. Metab., 66, 552556.[Abstract]
Daya, S. and Gunby, J. (1999) Recombinant versus urinary follicle stimulating hormone for ovarian stimulation in assisted reproduction. Hum. Reprod., 14, 22072215.
Daya, S., Gunby, J., Hughes, E.G. et al. (1995) Follicle-stimulating hormone versus human menopausal gonadotropin for in vitro fertilization cycles: a meta-analysis. Fertil. Steril., 64, 347354.[ISI][Medline]
Filicori, M., Flamigni, C., Dellai, P. et al. (1994) Treatment of anovulation with pulsatile gonadotropin-releasing hormone: prognostic factors and clinical results in 600 cycles. J. Clin. Endocrinol. Metab., 79, 12151220.[Abstract]
Fox, R., Ekeroma, A. and Wardle, P. (1997) Ovarian response to purified FSH in infertile women with long-standing hypogonadotropic hypogonadism. Aust. N.Z J. Obstet. Gynaecol., 37, 9294.[ISI][Medline]
Fried, G., Harlin, J., Csemickzy, G. et al. (1996) Controlled ovarian hyperstimulation using highly purified FSH results in a lower serum ooestradiol profile in the follicular phase as compared with HMG. Hum. Reprod., 11, 474477.[Abstract]
Golan, A., Ron-El, R., Herman, A. et al. (1989) Ovarian hyperstimulation syndrome: an update review. Obstet. Gynecol. Surv., 44, 430440.[Medline]
Hillier, S.G. (1994) Current concepts of the roles of follicle stimulating hormone and luteinizing hormone in folliculogenesis. Hum. Reprod., 9, 188191.[Abstract]
Hull, M., Corrigan, E., Piazzi, A. et al. (1994) Recombinant human luteinizing hormone: an effective new gonadotropin preparation. Lancet, 344, 334335.
Hurst, B.S. (1996) Ovulation induction in the nonestrogenized patient. Sem. Reprod. Endocrinology, 14, 299308.
Insler, V. (1988) Gonadotropin therapy: new trends and insights. Int. J. Fertil., 33, 8597.[ISI][Medline]
Kousta, E., White, D.M., Piazzi, A. et al. (1996) Successful induction of ovulation and completed pregnancy using recombinant luteinizing hormone and follicle stimulating hormone in a woman with Kallman's syndrome. Hum. Reprod., 11, 7071.[Abstract]
Larsen, T., Larsen, J.F., Schioler, V. et al. (1990) Comparison of urinary human follicle-stimulating hormone and human menopausal gonadotropin for ovarian stimulation in polycystic ovarian syndrome. Fertil. Steril., 53, 426431.[ISI][Medline]
le Cotonnec, J.Y., Porchet, H.C., Beltrami, V. et al. (1994) Clinical pharmacology of recombinant human follicle-stimulating hormone (FSH). I. Comparative pharmacokinetics with urinary human FSH. Fertil. Steril., 61, 669673.[ISI][Medline]
le Cotonnec, J.Y., Porchet, H.C., Beltrami, V. et al. (1998a) Clinical pharmacology of recombinant human luteinizing hormone: Part I. Pharmacokinetics after intravenous administration to healthy female volunteers and comparison with urinary human luteinizing hormone. Fertil. Steril., 69, 189194.[ISI][Medline]
le Cotonnec, J.Y., Porchet, H.C., Beltrami, V. et al. (1998b) Clinical pharmacology of recombinant human luteinizing hormone: Part II. Bioavailability of recombinant human luteinizing hormone assessed with an immunoassay and an in vitro bioassay. Fertil. Steril., 69, 195200.[ISI][Medline]
Recombinant Human FSH Study Group (1995) Clinical assessment of recombinant human follicle-stimulating hormone in stimulating ovarian follicular development before in vitro fertilization. Fertil. Steril., 63, 7786.[ISI][Medline]
Santoro, N., Filicori, M. and Crowley, W.T. (1986) Hypogonadotropic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin releasing hormone. Endocrin. Rev., 7, 1123.[Abstract]
Schoot, D.C., Coelingh-Bennink, H.J.T., Mannaerts, B.M. et al. (1992) Human recombinant follicle stimulating hormone induces growth of preovulatory follicles without concomitant increase in androgen and estrogen biosynthesis in a woman with isolated gonadotropin deficiency. J. Clin. Endocrinol. Metab., 74, 14711473.[Abstract]
Schoot, D.C., Harlin, J., Shoham, Z. et al. (1994) Recombinant human follicle-stimulating hormone and ovarian response in gonadotropic-deficient women. Hum. Reprod., 9, 12371242.[Abstract]
Shoham, Z., Balen, A., Patel, A. et al. (1991) Results of ovulation induction using human menopausal gonadotropin or purified follicle stimulating-hormone in hypogonadotropic hypogonadism patients. Fertil. Steril., 56, 10481053.[ISI][Medline]
Speroff, L., Glass, R.H. and Kase, N.G. (1999) Clinical Gynecologic Endocrinology and Infertility, sixth edition, Lippincott Williams & Wilkins, Baltimore, Maryland, USA.
The ESHRE Capri Workshop Group (1995) Anovulatory infertility. Hum. Reprod., 10, 15491553.[Abstract]
The European Recombinant Human LH Study Group (1998) Recombinant human luteinizing hormone (LH) to support recombinant human follicle-stimulating hormone (FSH)-induced follicular development in LH- and FSH-deficient anovulatory women: a dose-finding study. J. Clin. Endocrinol. Metab., 83, 15071514.
WHO Scientific Group (1973) Agents stimulating gonadal function in the human. Report of a WHO Scientific Group. 514, 128.
Yen, S.C., Jaffe, R.B. and Barbieri, R.L. (1999) Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 4th edition, WB Saunders Co., Philadelphia, USA.
Submitted on April 6, 2001; accepted on August 31, 2001.