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Effect of halving the daily dose of triptorelin at the start of ovarian stimulation on hormone serum levels and the outcome of in vitro fertilization

2005; Elsevier BV; Volume: 83; Issue: 3 Linguagem: Inglês

10.1016/j.fertnstert.2004.10.032

1556-5653

Francisco Fábregues, Joana Peñarrubia, Montserrat Creus, Roser Casamitjana, Juan A. Vanrell, Juan Balasch,

Endometriosis Research and Treatment

Halving the standard daily dose of triptorelin at the start of ovarian stimulation in down-regulated women stimulated with recombinant FSH is enough for pituitary suppression and was associated with higher LH serum concentrations in the follicular phase. However, this did not translate into higher serum concentrations of androstenedione and E2 and had no significant effect on ovarian response and the outcome of IVF/intracytoplasmic sperm injection. Halving the standard daily dose of triptorelin at the start of ovarian stimulation in down-regulated women stimulated with recombinant FSH is enough for pituitary suppression and was associated with higher LH serum concentrations in the follicular phase. However, this did not translate into higher serum concentrations of androstenedione and E2 and had no significant effect on ovarian response and the outcome of IVF/intracytoplasmic sperm injection. It is known that in a suppressed pituitary gland the dose of GnRH agonist (GnRH-a) needed to maintain suppression gradually decreases with the length of treatment (1Sandow J. Donnez J. Clinical pharmacokinetics of LHRH analogues.in: Brosens I. Jacobs H.S. Runnebaum B. LHRH analogues in gynaecology. Parthenon Publishing, Casterton Hall, Carnforth, Lancashire (UK)1990: 17-31Google Scholar). On the other hand, as ovarian stimulation with gonadotropins progresses, the suppression of pituitary gonadotropin secretion becomes more effective and the concentrations of endogenous LH decrease (2Esposito M.A. Barhnart K.T. Coutifaris C. Patrizio P. Role of periovulatory luteinizing hormone concentrations during assisted reproductive technology cycles stimulated exclusively with recombinant follicle-stimulating hormone.Fertil Steril. 2001; 75: 519-524Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). Thus, halving the daily dose of GnRH-a once ovarian suppression is evidenced is current practice in different IVF programs using the GnRH-a long protocol (2Esposito M.A. Barhnart K.T. Coutifaris C. Patrizio P. Role of periovulatory luteinizing hormone concentrations during assisted reproductive technology cycles stimulated exclusively with recombinant follicle-stimulating hormone.Fertil Steril. 2001; 75: 519-524Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 3Westergaard L.G. Laursen S.B. Andersen C.Y. Increased risk of early pregnancy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotropic women undergoing assisted reproduction.Hum Reprod. 2000; 15: 1003-1008Crossref PubMed Scopus (259) Google Scholar, 4Humaidan P. Bungum L. Bungum M. Andersen C.Y. Ovarian response and pregnancy outcome related to mid-follicular LH levels in women undergoing assisted reproduction with GnRH agonist down-regulation and recombinant FSH stimulation.Hum Reprod. 2002; 17: 2016-2021Crossref PubMed Scopus (100) Google Scholar, 5Peñarrubia J. Fábregues F. Creus M. Manau D. Casamitjana R. Guimerá M. et al.LH serum levels during ovarian stimulation as predictors of ovarian response and assisted reproduction outcome in down-regulated women stimulated with recombinant FSH.Hum Reprod. 2003; 18: 2689-2697Crossref PubMed Scopus (47) Google Scholar). This may be theoretically important in two respects. First, it might to avoid a too profound suppression of levels of LH during follicular development, which has been postulated as potentially having a negative effect on IVF outcome (2Esposito M.A. Barhnart K.T. Coutifaris C. Patrizio P. Role of periovulatory luteinizing hormone concentrations during assisted reproductive technology cycles stimulated exclusively with recombinant follicle-stimulating hormone.Fertil Steril. 2001; 75: 519-524Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 3Westergaard L.G. Laursen S.B. Andersen C.Y. Increased risk of early pregnancy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotropic women undergoing assisted reproduction.Hum Reprod. 2000; 15: 1003-1008Crossref PubMed Scopus (259) Google Scholar, 4Humaidan P. Bungum L. Bungum M. Andersen C.Y. Ovarian response and pregnancy outcome related to mid-follicular LH levels in women undergoing assisted reproduction with GnRH agonist down-regulation and recombinant FSH stimulation.Hum Reprod. 2002; 17: 2016-2021Crossref PubMed Scopus (100) Google Scholar). Second, it may reduce a potentially detrimental direct effect of GnRH-a on ovarian steroidogenesis (6Tureck R.W. Mastroianni Jr, L. Blasco L. Strauss III, J.F. Inhibition of human granulosa cell progesterone secretion by a gonadotropin-releasing hormone agonist.J Clin Endocrinol Metab. 1982; 54: 1078-1080Crossref PubMed Scopus (133) Google Scholar, 7Parinaud J. Beaur A. Burreau E. Vieitez G. Pontonnier G. Effect of a luteinizing hormone-releasing hormone agonist (buserelin) on steroidogenesis of cultured human preovulatory granulosa cells.Fertil Steril. 1988; 50: 597-602Abstract Full Text PDF PubMed Google Scholar). However, there is scanty information in the literature regarding the impact of halving the daily dose of GnRH-a in the long protocol (8Dal Prato L. Borini A. Trevisi M.R. Bonu M.A. Sereni E. Flamigni C. Effect of reduced dose of triptorelin at the start of ovarian stimulation on the outcome of IVF: a randomized study.Hum Reprod. 2001; 16: 1409-1414Crossref PubMed Google Scholar). Thus, the present prospective study was undertaken to compare the effect of administering a standard daily dose vs. a halved standard dose of SC triporelin, administered at the start of ovarian stimulation, on serum hormone concentrations (LH, androstenedione [A], E2), ovarian response, and IVF outcome in down-regulated patients stimulated with recombinant FSH. From September 2002 to June 2003, a total of 150 consecutive infertile women undergoing their first cycle of IVF or intracytoplasmic sperm injection (ICSI) treatment (thus avoiding possible bias from patients who had undergone multiple treatment cycles) and fulfilling the following inclusion criteria were included in the study, which was approved by our internal ethical committee. All the subjects were regularly menstruating (menstrual cycles of 26–33 days) premenopausal women aged 26–40 years and having a normal body mass index (BMI) of 19.5–28.0 kg/m2. All the women had normal ovaries and no previous ovarian surgery, and none of them had occult ovarian failure on the basis of their cycle day 2–3 FSH concentration of <12 IU/L (range 3.8–11 IU/L) (standard International Reference Preparation [IRP] 78/549) measured in the cycle preceding IVF/ICSI. No patient had received any hormone therapy for at least 6 months preceding the study. Eligible patients who agreed to participate were randomized in two treatment groups. Patients were allocated to a GnRH-a treatment group according to a computer-generated randomization table. Sealed envelopes for the randomization list were used. In patients in group 1 (n = 75) pituitary desensitization was achieved by SC administration of triptorelin acetate (Decapeptyl 0.1 mg; Ipsen Pharma, Barcelona, Spain) (0.1 mg/d) started in the midluteal phase of the previous cycle and continued until the administration of hCG. In group 2 (n = 75 patients) the standard daily dose of triptorelin acetate was reduced to 0.05 mg once the ovarian arrest was confirmed and stimulation with recombinant FSH was commenced. The sample size was based on a previous study (8Dal Prato L. Borini A. Trevisi M.R. Bonu M.A. Sereni E. Flamigni C. Effect of reduced dose of triptorelin at the start of ovarian stimulation on the outcome of IVF: a randomized study.Hum Reprod. 2001; 16: 1409-1414Crossref PubMed Google Scholar) where a sample size of 66 patients per group was calculated to have 90% power and a significance level of .05 to detect a difference in the mean number of oocytes of 2.3 (SD 6.5). In our study more patients were included to allow for any treatment dropouts so as to arrive at the final sample of at least 66 patients per group undergoing oocyte retrieval. Among the 150 women initially selected, several had canceled cycles due to a low response; 68 patients and 69 patients undergoing follicular aspiration in groups 1 and 2, respectively, were finally considered in the evaluation of the results. Cancellation rates were 9.3% (7 patients) and 8% (6 patients) in groups 1 and 2, respectively. Gonadotropin stimulation of the ovaries with recombinant FSH under pituitary suppression was carried out according to a previously reported protocol (5Peñarrubia J. Fábregues F. Creus M. Manau D. Casamitjana R. Guimerá M. et al.LH serum levels during ovarian stimulation as predictors of ovarian response and assisted reproduction outcome in down-regulated women stimulated with recombinant FSH.Hum Reprod. 2003; 18: 2689-2697Crossref PubMed Scopus (47) Google Scholar, 9Balasch J. Vidal E. Peñarrubia J. Casamitjana R. Carmona F. Creus M. et al.Suppression of LH during ovarian stimulation: analysing threshold values and effects on ovarian response and the outcome of assisted reproduction in down-regulated women stimulated with recombinant FSH.Hum Reprod. 2001; 16: 1636-1643Crossref PubMed Scopus (120) Google Scholar). Oocyte aspiration was performed with vaginal ultrasonography 35–36 hours after hCG administration. The maturational status of the oocytes and embryo grading was recorded according to published criteria (10Veeck L.L. An atlas of human gametes and conceptuses: an illustrated reference for assisted reproductive technology. CRC Press-Parthenon Publishers, New York1999Crossref Google Scholar); embryos of Veeck grades 1 or 2 were considered of high quality. Up to three embryos per patient were replaced and the luteal phase was supported with additional doses of hCG (61 and 64 patients in groups 1 and 2, respectively) or vaginal micronized P (7 and 5 patients in groups 1 and 2, respectively) according to ovarian response. Pregnancy was diagnosed by increasing serum concentrations of β-hCG after embryo transfer, and the subsequent demonstration of an intrauterine gestational sac by ultrasonography. Blood samples for hormone analyses were obtained on day 0 (the day of pituitary suppression) and every other day from stimulation day 3 until the day of hCG injection. Hormones were measured using commercially available kits as reported previously (9Balasch J. Vidal E. Peñarrubia J. Casamitjana R. Carmona F. Creus M. et al.Suppression of LH during ovarian stimulation: analysing threshold values and effects on ovarian response and the outcome of assisted reproduction in down-regulated women stimulated with recombinant FSH.Hum Reprod. 2001; 16: 1636-1643Crossref PubMed Scopus (120) Google Scholar, 11Balasch J. Peñarrubia J. Fábregues F. Vidal E. Casamitjana R. Manau D. et al.Ovarian responses to recombinant FSH or HMG in normogonadotrophic women following pituitary desensitization by a depot GnRH agonist for assisted reproduction.Reprod Biomed Online. 2003; 7: 35-42Abstract Full Text PDF PubMed Scopus (52) Google Scholar). Ultrasonic scans were performed using a Toshiba Eccocee SAA-340A/EF unit (Toshiba Co., Tokyo, Japan) equipped with a 5- to 7-MHz endovaginal probe (PVF-641VT). Data were analyzed by Statistics Package for Social Sciences (SPSS) statistical software using the Student′s t test and the χ2 test as appropriate. Results are expressed as mean ± SEM. P values <.05 was considered significant. Serum hormone concentrations during the first 11 days of treatment were calculated in each cycle as the area under the curve (AUC), which corresponds to an integrated hormone concentration for the chosen days. The AUC was calculated according to the trapezoidal rule. Integrated hormone concentrations were compared between treatment groups by the Student's t test. The results are summarized in Table 1. The main demographic and baseline characteristics of the patients, gonadotropin treatment, and ovarian response, as well as ovum retrieval and IVF/ICSI outcome were similar in groups 1 and 2. Implantation and pregnancy rates were similar in both groups. No patient developed ovarian hyperstimulation syndrome (OHSS). The mean gonadotropin treatment duration was similar in groups 1 (11.4 ± 0.3 days) and 2 (11.2 ± 0.2 days). Therefore, the AUC for LH, A, and E2 for both groups was compared for the first 11 days of treatment. Hormone concentrations calculated as the AUC showed no differences between groups 1 and 2 with respect to E2 (8,102 ±715 vs. 8,057 ± 804) and A (2,412 ± 315 vs. 2,101 ± 287). However, the AUC for LH was significantly higher in group 2 (65.1 ± 7.4) than in group 1 (52.7 ± 6.2) (P<.05).TABLE 1Patient characteristics, gonadotropin treatment, ovarian response, ovum retrieval, and IVF/ICSI outcome in groups 1 and 2.VariableGroup 1 (n = 68)Group 2 (n = 69)Age (y)34.7 ± 0.535.0 ± 0.3BMI (kg/m2)24.3 ± 0.724.0 ± 0.5Infertility factor Male factor (n, %)29 (42.6)28 (40.5) Tubal factor (n, %)18 (26.4)17 (24.7) Endometriosis (n, %)13 (19.2)13 (18.8) Unexplained (n, %)8 (11.7)11 (15.9)Duration of infertility (y)5.1 ± 0.35.3 ± 0.4Basal FSH (IU/L)7.3 ± 0.27.1 ± 0.1Basal LH (IU/L)4.9 ± 0.25.1 ± 0.1Basal estradiol (pg/mL)39.3 ± 1.837.6 ± 1.8Days to ovarian arrest14.4 ± 0.314.1 ± 0.5Days of ovarian stimulation11.4 ± 0.311.2 ± 0.2Total IU of FSH2415 ± 1122595 ± 135No. of follicles on hCG day 10–<14 mm4.4 ± 0.44.4 ± 0.3 14–<18 mm4.1 ± 0.34.1 ± 0.4 ≥18 mm4.8 ± 0.34.6 ± 0.3Estradiol on hCG day2249 ± 1862107 ± 175No. of oocytes retrieved10.4 ± 0.79.5 ± 0.3No. of metaphase II oocytes8.7 ± 0.67.8 ± 0.4No. of 2PN on day 16.6 ± 0.66.1 ± 0.2No. of embryos on day 25.4 ± 0.45.2 ± 0.1No. of embryos per replacement2.6 ± 0.12.4 ± 0.1High quality embryos replaced (%)7981No. of patients with embryo transfer (n,%)68 (100)69 (100)Implantation rate (%)16.916.7Clinical pregnancies Number2728 Per oocyte retrieval (%)39.740.5 Per embryo transfer (%)39.740.5 Twins (n,%)3 (11.1)2 (7.1) Miscarriages (n,%)2 (7.4)3 (10.7)Note: Values are means ± SEM or n (%).P was not significant. Open table in a new tab Note: Values are means ± SEM or n (%). P was not significant. It is now well established that FSH and LH play separate but complementary roles in the regulation of the ovarian follicle, leading to synergistic actions in stimulating follicular growth and maturation. Tonic exposure to LH promotes follicular responsiveness to FSH during follicular recruitment and selection, initially through sustaining thecal cell androgen and polypeptide growth factor production, and later (after the induction of LH receptors by FSH) through stimulating granulosa cell function directly (12Hillier S.G. Controlled ovarian stimulation in women.J Reprod Fertil. 2000; 120: 201-210Crossref PubMed Google Scholar). In the clinical setting, however, the relative importance of LH during the follicular phase and its role in the stimulation of the follicle is still subject to extensive debate, and questions surrounding the optimal amount of LH in stimulation protocols for assisted reproduction techniques and the drugs used for this purpose are still controversial (13Balasch J. Fábregues F. Is luteinizing hormone needed for optimal ovulation induction?.Curr Opin Obstet Gynecol. 2002; 14: 265-274Crossref PubMed Scopus (46) Google Scholar, 14Shoham Z. The clinical therapeutic window for luteinizing hormone in controlled ovarian stimulation.Fertil Steril. 2002; 77: 1170-1177Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). Thus, refinements in controlled ovarian hyperstimulation (COH) for assisted reproduction have been associated with an increased use of recombinant human FSH (15Zwart-van Rijkom J.E.F. Broekmans F.J. Leufkens H.G.M. From HMG through purified urinary FSH preparations to recombinant FSH: a substitution study.Hum Reprod. 2002; 17: 857-865Crossref PubMed Scopus (28) Google Scholar). The main difference between recombinant human FSH and the urinary gonadotropins, mainly hMG, is that recombinant products are completely devoid of LH. On the other hand, treatment with GnRH-a does not usually result in total elimination of LH and it is accepted that <1% of LH receptors need to be occupied to elicit a maximal steroidogenic response (16Chappel S.C. Howles C. Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process.Hum Reprod. 1991; 6: 1206-1212Crossref PubMed Scopus (279) Google Scholar). In most cases, an absolute LH deficiency really does not exist as demonstrated by a very different steroidogenic response to FSH alone (9Balasch J. Vidal E. Peñarrubia J. Casamitjana R. Carmona F. Creus M. et al.Suppression of LH during ovarian stimulation: analysing threshold values and effects on ovarian response and the outcome of assisted reproduction in down-regulated women stimulated with recombinant FSH.Hum Reprod. 2001; 16: 1636-1643Crossref PubMed Scopus (120) Google Scholar, 17Loumaye E. Engrand P. Howles C.M. O'Dea L. Assessment of the role of serum luteinizing hormone and estradiol response to follicle-stimulating hormone on in vitro fertilization outcome.Fertil Steril. 1997; 67: 889-899Abstract Full Text PDF PubMed Scopus (126) Google Scholar). Notwithstanding this, recent studies have indicated that a group of normogonadotropic assisted reproduction treatment patients undergoing ovarian stimulation with FSH-only products under pituitary suppression with GnRH-a may experience such a profound suppression of LH levels that a negative effect on treatment outcome may become manifest (2Esposito M.A. Barhnart K.T. Coutifaris C. Patrizio P. Role of periovulatory luteinizing hormone concentrations during assisted reproductive technology cycles stimulated exclusively with recombinant follicle-stimulating hormone.Fertil Steril. 2001; 75: 519-524Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 3Westergaard L.G. Laursen S.B. Andersen C.Y. Increased risk of early pregnancy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotropic women undergoing assisted reproduction.Hum Reprod. 2000; 15: 1003-1008Crossref PubMed Scopus (259) Google Scholar, 4Humaidan P. Bungum L. Bungum M. Andersen C.Y. Ovarian response and pregnancy outcome related to mid-follicular LH levels in women undergoing assisted reproduction with GnRH agonist down-regulation and recombinant FSH stimulation.Hum Reprod. 2002; 17: 2016-2021Crossref PubMed Scopus (100) Google Scholar). Therefore, reducing the daily dose of GnRH-a once ovarian suppression is attained may avoid a too profound suppression of LH during follicular development. It could also reduce a potentially negative effect of GnRH-a on ovarian function (6Tureck R.W. Mastroianni Jr, L. Blasco L. Strauss III, J.F. Inhibition of human granulosa cell progesterone secretion by a gonadotropin-releasing hormone agonist.J Clin Endocrinol Metab. 1982; 54: 1078-1080Crossref PubMed Scopus (133) Google Scholar, 7Parinaud J. Beaur A. Burreau E. Vieitez G. Pontonnier G. Effect of a luteinizing hormone-releasing hormone agonist (buserelin) on steroidogenesis of cultured human preovulatory granulosa cells.Fertil Steril. 1988; 50: 597-602Abstract Full Text PDF PubMed Google Scholar). We found that a reduced dose of triptorelin was associated with higher levels of serum LH during the follicular phase, but this did not translate into higher concentrations of A and E2. Thus, the present investigation showed that halving the standard daily dose of triptorelin at the start of ovarian stimulation in down-regulated women stimulated with recombinant FSH is adequate for pituitary suppression but had no significant effect on hormone serum concentrations, ovarian response, and the outcome of IVF/ICSI.