GnRH agonist as novel luteal support: results of a randomized, parallel group, feasibility study using intranasal administration of buserelin

BACKGROUND: The study objective was to investigate whether repeated intranasal administration of a GnRH agonist could provide convenient and safe luteal support. METHODS: Twenty-four patients with unexplained infertility were enrolled. All patients were treated with an aromatase inhibitor. When ovulation trigger criteria were met, patients were randomly allocated to either 5000 IU hCG (group A), or 200 microg intranasal buserelin followed by 100 microg every 3 days (group B), 100 microg every 2 days (group C), or 100 microg every day (group D), up to day 14 of the luteal phase. All patients underwent intrauterine insemination. RESULTS: Follicular development was similar in all groups with 1.1 +/- 0.3 follicles > or = 16 mm, 229.4 +/- 95.2 pg/ml estradiol (E2) and 0.8 +/- 0.5 ng/ml progesterone (mean+/-SD). The luteal phase duration (median; 95% confidence interval) was 15 (14.1, 15.0), 14 (12.5, 15.5), 15 (11.8, 18.2) and 15 (14.4, 15.6) days in groups A, B, C and D respectively. From luteal phase day 7 onwards, progesterone levels tended to be higher in group D compared with A. On day 14 of the luteal phase, progesterone levels were 3.0 (0.8, 5.2), 1.7 (-0.5, 3.9), 3.9 (-0.7, 8.5) and 7.7 (3.4, 11.9) ng/ml in groups A, B, C and D respectively (P = 0.045). No pregnancy was recorded in group A, but there was one biochemical pregnancy in group B, one biochemical and one singleton clinical pregnancy in group C, and two singleton clinical pregnancies in group D. CONCLUSION: Intranasal administration of buserelin could be effective to provide luteal support. This treatment was associated with a good pregnancy rate (5/18, 28%).     

Comparison of luteal phase profile in gonadotrophin stimulated cycles with or without a gonadotrophin-releasing hormone antagonist.

BACKGROUND: The aim of our study was to explore luteal phase hormone profiles in gonadotrophin-stimulated cycles with or without gonadotrophin-releasing hormone (GnRH) antagonist therapy during intrauterine insemination (IUI). Forty-one infertile couples were recruited in this randomized clinical study. METHODS: The 19 patients included in group A were treated for 21 cycles with recombinant FSH 150 IU/day starting from day 3 of the cycle and with the GnRH antagonist cetrorelix at the dose of 0.25 mg/day starting from the day in which a follicle with a mean diameter of > or =14 mm was seen at ultrasound scan. Cetrorelix was administered until human chorionic gonadotrophin (HCG) administration. The 22 patients included in group B were administered recombinant FSH alone at the same dosage for 27 cycles. RESULTS: The two treatment groups showed a similar increase in progesterone concentration during the luteal phase. In the mid-luteal phase (day 6 after HCG), oestradiol concentrations in group B were significantly higher compared with group A (P < 0.05) but the oestradiol:progesterone ratio was similar in the two groups. Serum LH was completely suppressed during the follicular phase only in group A, concomitantly with GnRH antagonist administration. A total of six pregnancies, all ongoing, were achieved (14.3% per patient and 12.2% per cycle), equally distributed in group A and in group B. CONCLUSION: GnRH antagonists can be safely administered in gonadotrophin-stimulated IUI cycles without luteal phase supplementation because no deleterious effects of GnRH antagonist administration were noted on luteal progesterone concentration or on the duration of the luteal phase.     

Triggering of ovulation in human menopausal gonadotrophin-stimulated cycles: comparison between intravenously administered gonadotrophin-releasing hormone (100 and 500 {micro}g), GnRH agonist (buserelin, 500 {micro}g) and human chorionic gonadotrophin (10 000 IU)

We studied the peri-ovulatory and luteal phases in 38 humanmenopausal gonadotrophin (HMG)-stimulated cycles, in which ovulationwas triggered with four different i.v. bolus ovulation triggers:100 µg gonadotrophin-releasing hormone (GnRH; group A,n = 9), 500 µg GnRH agonist (GnRHa; group B, n = 10),10 000IU human chorionic gonadotrophin (HCG; group C, n = 10)and 500 µg GnRH (group D, n = 9). Endogenous luteinizinghormone (LH) surges occurred in all cycles of groups A, B andD. The rise was slowest but highest in group B (P < 0.0001)and lowest in group A. Although the t₀ serum oestradiol valueswere similar in all groups, day +8 oestradiol and day +4 and+8 progesterone concentrations were higher in group C (P <0.05). At day +4 and +8, serum LH concentrations were lowest(P < 0.01) but follicle stimulating hormone (FSH) concentrationswere higher. Clinically, day +8 luteal scores showed a moreconspicuous degree of ovarian hyperstimulation in the HCG group(P = 0.0292). Luteal insufficiency, defined as cycles with progesteroneconcentrations of <8 ng/ml, occurred much more frequentlyin groups A, B and D than in group C (day +4: P < 0.0003;day +8: P < 0.0001), despite progesterone supplementation.Three pregnancies (one in group C and two in group D) and onemoderate case of ovarian hyperstimulation syndrome (OHSS) (ina non-conceptional group D cycle) occurred. These findings showthat (i) ovulation occurs and pregnancy can be achieved followingan endogenous LH surge induced by GnRH and its agonists, (ii)a high frequency of luteal insufficiency occurs in such cycleseven with luteal supplementation and (iii) OHSS cannot be totallyprevented by this approach, although cycles with an endogenousLH surge in general result in fewer subclinical signs of ovarianhyperstimulation.     

Analysis of hormonal changes during combined buserelin/HMG treatment

Changes of serum oestradiol, LH and progesterone have been analysed in view of the effect of the GnRH analogue buserelin on the late follicular and early luteal phase of cycles stimulated with combined buserelin/HMG (n = 31) in an IVF-ET/GIFT programme. Patients undergoing cycles with HMG only (n = 57) served as the control group. With the use of the GnRH analogue buserelin, a significantly higher amount of HMG (25 versus 20 ampoules; P less than 0.001) for a significantly longer stimulation period (10 versus 8 days; P less than 0.001) was necessary to achieve the same oestradiol response as seen in HMG cycles. Serum progesterone levels during a three day period before ovulation induction tended to be lower in the combined buserelin/HMG cycles than in cycles with HMG stimulation only. We did not observe any significant difference in the luteal phase progesterone levels of the buserelin/HMG and the HMG group. On the other hand, we found that an inadequate luteal phase in buserelin/HMG cycles could be avoided by HCG administration during the luteal phase. Both the elevation of basal serum LH and a premature LH rise could also be avoided by the use of buserelin.     

Addition of estradiol to progesterone for luteal supplementation in patients stimulated with GnRH antagonist/rFSH for IVF: a randomized controlled trial

BACKGROUND: The role of progesterone for luteal support in stimulated cycles for IVF is well established. However, controversy still surrounds the benefit of additional supplementation with estradiol (E2) in GnRH agonist (GnRHa) cycles, while no such data are available for GnRH antagonists. The aim of this randomized controlled trial (RCT) was to compare ongoing pregnancy rates in patients stimulated with recombinant FSH (rFSH) and GnRH antagonist for IVF, who received micronized progesterone for luteal phase supplementation, with or without the addition of E2. METHODS: Two hundred and one patients underwent ovarian stimulation with a fixed dose of 200 IU rFSH and GnRH antagonist. Patients were randomized to receive, for luteal phase supplementation, either 600 mg of micronized progesterone vaginally (n=100, progesterone group) or 600 mg of micronized progesterone and 4 mg of E2 valerate orally (n=101, progesterone/E2 group). The main outcome measure was ongoing pregnancy at 12 weeks per patient randomized. RESULTS: Demographics, stimulation parameters and embryological data were comparable for the two groups compared. Twenty-six ongoing pregnancies were achieved in the progesterone (26%) and 30 in the progesterone/E2 group (29.7%). (Difference: 3.7 and 95%, CI: -15.8 to 8.6%). CONCLUSION: It appears that the addition of E2 to progesterone in the luteal phase after stimulation with rFSH and GnRH antagonist does not enhance the probability of pregnancy.     

Continuous administration of gonadotrophin-releasing hormone agonist during the luteal phase in IVF

BACKGROUND: It has been reported that ceasing the administration of gonadotrophin-releasing hormone (GnRH) agonist causes a profound suppression of circulating serum gonadotrophins. A comparative prospective and randomized study was conducted to investigate the effect of continuous administration of GnRH agonist during the luteal phase in an ovarian stimulation programme for IVF. METHODS: GnRH agonist was administered intranasally from the midluteal phase of the previous cycle, and pure FSH administration started on cycle day 7. In the continuous-long protocol (cL) group (n = 161 ), GnRH agonist administration was continued until 14 days after oocyte retrieval. In the long protocol (L) group (n = 158 ), GnRH agonist was administered until the day before human chorionic gonadotrophin (HCG) administration. RESULTS: The implantation rate and live birth rate per unit of transferred embryos were significantly higher in the cL group than the L group (P < 0.05 ). Serum LH and FSH concentrations on the day of, and 1 day after, HCG administration were significantly lower in the L group than the cL group (P < 0.01 ). CONCLUSIONS: Continuation of GnRH agonist administration during the luteal phase might facilitate implantation, and prevent the profound suppression of serum gonadotrophins.     

Is there a difference in the function of granulosa-luteal cells in patients undergoing in-vitro fertilization either with gonadotrophin-releasing hormone agonist or gonadotrophin-releasing hormone antagonist?

Gonadotrophin-releasing hormone (GnRH) regulates gonadotrophin release. It has been shown that GnRH may have a direct effect on the ovary, as the addition of GnRH to granulosa cell cultures inhibits the production of progesterone and oestradiol. Specific GnRH receptors have been found to be present in rat and human granulosa cells. Desensitization of the pituitary by GnRH agonist has become common in in-vitro fertilization (IVF) treatment, usually by a long protocol of 2-3 weeks. With the introduction of GnRH antagonists, which produce an immediate blockage of the GnRH receptors, a much shorter exposure is needed of 3-6 days. The aim of this study was to evaluate the effect of a GnRH agonist (buserelin) and a GnRH antagonist (cetrorelix) on the function of granulosa cells cultured in vitro from IVF patients. Women were treated by IVF randomized either to have buserelin nasal spray from the luteal phase in the previous cycle or cetrorelix from day 6 of the cycle. Both groups had ovarian stimulation with human menopausal gonadotrophin (HMG) 150 IU daily, i.e. HCG was administered when the follicles were larger than 17 mm, and aspirated 36 h later. Granulosa cells, separated and washed from large follicles containing ova, were pooled. After 48 h of pre-incubation, the granulosa cells were cultured for 4 days in medium with either added testosterone or cAMP with or without HCG, with change of medium after 2 days. The progesterone and oestradiol concentrations in the culture medium were measured by immunological assay, and cellular protein was measured by microprotein assay. The results showed that granulosa cells from women treated with GnRH antagonist (cetrorelix) responded earlier to the in-vitro hormone stimulation in terms of progesterone accumulation than women treated with the GnRH agonist (buserelin). This may have been due to difference in time of exposure to the analogue. The results may indicate that the luteal function is less impaired in GnRH antagonist treatment than in GnRH agonist treatment.     

GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study

BACKGROUND: We aimed to determine the efficacy of ovarian hyperstimulation protocols employing a GnRH antagonist to prevent a premature LH rise allowing final oocyte maturation and ovulation to be induced by a single bolus of either a GnRH agonist or hCG. METHODS: A total of 122 normogonadotrophic patients following a flexible antagonist protocol was stimulated with recombinant human FSH and prospectively randomized (sealed envelopes) to ovulation induction with a single bolus of either 0.5 mg buserelin s.c. (n = 55) or 10,000 IU of hCG (n = 67). A maximum of two embryos was transferred. Luteal support consisted of micronized progesterone vaginally, 90 mg a day, and estradiol, 4 mg a day per os. RESULTS: Ovulation was induced with GnRH agonist in 55 patients and hCG in 67 patients. Significantly more metaphase II (MII) oocytes were retrieved in the GnRH agonist group (P < 0.02). Significantly higher levels of LH and FSH (P < 0.001) and significantly lower levels of progesterone and estradiol (P < 0.001) were seen in the GnRH agonist group during the luteal phase. The implantation rate, 33/97 versus 3/89 (P < 0.001), clinical pregnancy rate, 36 versus 6% (P = 0.002), and rate of early pregnancy loss, 4% versus 79% (P = 0.005), were significantly in favour of hCG. CONCLUSIONS: Ovulation induction with a GnRH agonist resulted in significantly more MII oocytes. However, a significantly lower implantation rate and clinical pregnancy rate in addition to a significantly higher rate of early pregnancy loss was seen in the GnRH agonist group, most probably due to a luteal phase deficiency.     

Prolongation of follicular phase by delaying hCG administration results in a higher incidence of endometrial advancement on the day of oocyte retrieval in GnRH antagonist cycles

BACKGROUND: Prolongation of follicular phase by delaying hCG administration has been reported to result in a significantly lower ongoing pregnancy rate that did not seem to be due to an embryonic factor. The aim of this prospective randomized study was to assess the effect of delaying hCG administration on endometrial histology. METHODS: Ten oocyte donors underwent endometrial biopsy on the day of oocyte retrieval and endometrial histology was assessed by Noyes' criteria. Ovarian stimulation was performed with recombinant (r)FSH and daily GnRH antagonist starting on day 6 of stimulation. Patients were randomized by a computer-generated list to receive 10 000 IU of hCG either as soon as > or =3 follicles > or =17 mm were present on ultrasound (early-hCG group, n = 5) or 2 days after this criterion was met (late-hCG group, n = 5). RESULTS: When hCG was delayed, endometrial advancement was present in all samples examined (median advancement 3 days, range 2-3 days). On the contrary, no secretory changes were observed when the follicular phase was not prolonged (difference in the proportion of patients with advancement between the early-hCG and the late-hCG group: 100%, 95% CI: 38-100). CONCLUSIONS: Prolongation of follicular phase by delaying hCG administration results in a higher incidence of endometrial advancement on the day of oocyte retrieval in GnRH antagonist cycles.     

Association of estradiol levels on the day of hCG administration and pregnancy achievement in IVF: a systematic review

BACKGROUND: Evaluation of the association between estradiol (E2) levels on the day of hCG administration and pregnancy achievement in IVF has so far yielded conflicting results. The purpose of the present study was to systematically review the above association in cycles down-regulated with GnRH analogues. METHODS: Literature search was performed using Medline, Embase (1978-2004) and the Cochrane Library. Additionally, references of retrieved articles were hand-searched. Only full articles published in peer-reviewed medical journals were considered for analysis. RESULTS: All the eligible studies (n=9) involved the use of GnRH agonists and were retrospective. Two studies (including 191 patients) suggested that the higher the E2 levels on the day of hCG administration, the higher the probability of pregnancy. However, five studies (including 1875 patients), did not support an association between E2 levels on the day of hCG administration and pregnancy rates. Moreover, two of the studies including (1286 patients) suggested that high E2 levels on the day of hCG administration are associated with a decreased probability of pregnancy. If we consider only studies in which criteria used for administering hCG include follicular development but not E2 levels (including 2687 patients), there is no study suggesting a positive association between E2 levels on the day of hCG administration and pregnancy achievement. CONCLUSIONS: Currently there is no high-quality evidence to support or deny the value of E2 determination on the day of hCG administration for pregnancy achievement in IVF cycles, where pituitary down-regulation is performed with GnRH agonists. Existing retrospective studies suggest that there is no positive association. However, in order to arrive at recommendations for clinical practice, there is a need to perform well-designed prospective studies in both agonist and antagonist cycles.     

GnRH agonist protocol administration in the luteal phase in ICSI-ET cycles stimulated with the long GnRH agonist protocol: a randomized, controlled double blind study

BACKGROUND: GnRH agonist administration in the luteal phase was reported to beneficially affect the clinical outcome of intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) cycles. This double blind, randomized, placebo controlled trial evaluates whether a single dose GnRH agonist administered 6 days after ICSI increases ongoing pregnancy rates following ET in cycles stimulated with the long GnRH agonist protocol. METHODS: Five hundred and seventy women undergoing ET following controlled ovarian stimulation with a long GnRH agonist protocol were included. In addition to routine luteal phase support with progesterone, women were randomized to receive a single 0.1 mg dose of triptorelin or placebo 6 days after ICSI. Randomization was done on the day of ET according to a computer generated randomization table. Ongoing pregnancy rate beyond 20th week of gestation was the primary outcome measure. The trial was powered to detect a 12% absolute increase from an assumed 38% ongoing pregnancy rate in the placebo group, with an alpha error level of 0.05 and a beta error level of 0.2. RESULTS: There were 89 (31.2%) ongoing pregnancies in the GnRH agonist group, and 84 (29.5%) in the control group (absolute difference +1.7%, 95% confidence interval -5.8% to +9.2%). Implantation, clinical pregnancy and multiple pregnancy rates were likewise similar in the GnRH agonist and placebo groups. CONCLUSIONS: Single 0.1 mg triptorelin administration 6 days after ICSI following ovarian stimulation with the long GnRH agonist protocol does not seem to result in an increase >or=12% in ongoing pregnancy rates.     

Evidence of differential control of FSH and LH responses to GnRH by ovarian steroids in the luteal phase of the cycle

BACKGROUND: It is known that during the follicular phase of the cycle, estradiol sensitizes the pituitary to GnRH. The aim of this study was to determine the role of ovarian steroids in the control of GnRH-induced gonadotrophin secretion in the luteal phase of the cycle. METHODS: Eighteen normally cycling women were studied during the week following bilateral ovariectomy plus hysterectomy performed in early to mid-luteal phase. Six of the women received no hormonal treatment post-operatively (group 1, control), six received estradiol through skin patches (group 2) and the remaining six received estradiol plus progesterone (group 3). In all women the response at 30 min of LH (deltadeltaLH) and FSH (deltadeltaFSH) to GnRH (10 microg i.v.) was investigated on a daily basis. RESULTS: In group 1, serum FSH, LH and deltadeltaFSH values increased progressively following ovariectomy, while in groups 2 and 3 this increase was postponed or abolished. In contrast to deltadeltaFSH, deltadeltaLH values showed the same pattern of changes in all three groups with a significant decline up to post-operative day 4 and a gradual increase thereafter. CONCLUSIONS: These results demonstrate, for the first time, that in the early to mid-luteal phase of the cycle, estradiol and progesterone participate in the control of GnRH-induced FSH, but not LH, secretion. It is possible that in the luteal phase, the response of LH to GnRH is partly regulated by gonadotrophin surge attenuating factor.     

The effect of gonadotrophin-releasing hormone (GnRH) agonist in the follicular phase on in-vitro fertilization outcome in normo-ovulatory women.

Sixty-three normo-ovulatory infertile women were randomly divided into two groups. All women were first desensitized with the gonadotrophin-releasing hormone agonist (GnRHa), buserelin. Thereafter, ovarian stimulation with human menopausal gonadotrophins (HMG) was started in both groups but in group A the GnRHa was stopped on the same day. In group B, the GnRHa was continued during HMG treatment until the ovulatory human chorionic gonadotrophin stimulus was given. Premature luteinization was not observed in either group, although the preovulatory basal luteinizing hormone (LH) secretion was significantly higher in group A. An equal number of embryos of comparable quality was transferred in both groups and the pregnancy outcome was similar. However, the supernumerary embryos of group A were of a lower morphological quality and survived the cryopreservation process less well. We concluded that the continuous administration of a GnRH agonist during HMG treatment resulted in better quality of supernumerary embryos.     

GnRH antagonist versus long GnRH agonist protocol in poor responders undergoing IVF: a randomized controlled trial

BACKGROUND. This is the first published report of a prospective, randomized, controlled trial comparing a fixed, multi-dose GnRH antagonist protocol with a long GnRH agonist protocol in poor responders undergoing IVF. METHODS. Sixty-six poor responders were randomized into two groups: the study group received 0.25 mg of cetrorelix daily starting on day 6 of stimulation; the control group received 600 microg of buserelin acetate daily starting in the mid-luteal phase of the preceding cycle. Both groups were given a fixed dose of recombinant FSH (300 IU daily) for stimulation. RESULTS. There were no significant differences in the cycle cancellation rates, duration of stimulation, consumption of gonadotrophins, and mean numbers of mature follicles, oocytes and embryos obtained. The implantation rates were similar, but the number of embryos transferred was significantly higher for the antagonist group (2.32 +/- 0.58 versus 1.50 +/- 0.83; P = 0.01). The pregnancy rates were also higher in the antagonist group, but the difference was not statistically significant. CONCLUSION. A fixed multi-dose GnRH antagonist protocol is feasible for patients who are poor responders on a long agonist protocol; however, our study failed to demonstrate an overall improvement in ovarian responsiveness. Clinical outcomes may be improved by developing more flexible antagonist regimens, an approach that requires further evaluation.     

Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated with r-hFSH: a randomized, multicentre, phase IIIb study

BACKGROUND: The aim of this study was to assess the non-inferiorityof an oral contraceptive (OC)-pretreated cetrorelix regimenand a buserelin regimen in IVF/ICSI patients treated with r-hFSHin terms of total number of oocytes retrieved. METHODS: Multicentre,randomized study. One hundred and eighty two patients were randomizedto receive cetrorelix with OC pretreatment (n = 91) or to receivebuserelin (n = 91). The cetrorelix group started with dailyOCs on cycle day 5 and continued for 21–28 days. Cetrorelix(0.25 mg) was given daily from stimulation day 6 up to and includingthe day of r-hCG administration. The buserelin group startedwith buserelin (500 µg/day) for at least 10 days untildown-regulation was achieved, after which the dose was reducedto daily 200 µg up to and including the day of r-hCG administration.r-hFSH was started in both groups on a Friday, in the cetrorelixgroup 5 days after the last OC pill intake. Both regimens werefollowed by a standard IVF or ICSI procedure. The primary efficacyendpoint was the number of oocytes retrieved per patient. RESULTS:Number of oocytes, cancellation rates, r-hFSH requirements,number of oocyte retrievals during the weekend or public holidayand number of pregnancies were similar in both groups. Bothtreatment regimens were well tolerated. CONCLUSIONS: Cetrorelixpretreated with OCs resulted in similar number of oocytes retrievedcompared with a long buserelin protocol. Both regimens werewell tolerated and allowed scheduling of the oocyte retrieval,with only small number of retrievals falling on a weekend orpublic holiday.     

Changes in pituitary sensitivity to GnRH in estrogen-treated post-menopausal women: evidence that gonadotrophin surge attenuating factor plays a physiological role

BACKGROUND: The purpose of this study was to investigate changes in pituitary response to GnRH in post-menopausal women during substitution treatment with exogenous estrogen and progesterone. METHODS: Seven healthy post-menopausal women (group 1) were treated with various doses of E2 valerate for 43 days, so as the serum concentrations of E2 mimicked those of a follicular (FP-1), a luteal (LP) and a second follicular (FP-2) phase. During the LP, progesterone was also administered. The 30 min response of LH (DeltaLH) and FSH (DeltaFSH) to GnRH (10 microg i.v.) (pituitary sensitivity) was investigated every 24 h in group 1 and also in seven normally cycling women (group 2) during a spontaneous (control) follicular phase (FP). Based on the hormone profiles, day 32 in group 1 (FP-2) corresponded to day 2 in the spontaneous FP of group 2. RESULTS: Basal FSH concentrations were significantly higher in FP-2 than in the control FP (P < 0.05), while basal LH concentrations were similar in the two phases with higher values in FP-2 towards the end of the experiment (corresponding to days 10 and 11, P < 0.05). However, an LH surge was seen only in the control FP. DeltaFSH values remained stable in both phases and increased only in the control FP on days 12 and 13. DeltaLH values remained stable in the control FP and only increased on days 12 (P < 0.05) and 13 (P < 0.05), but in FP-2, DeltaLH values increased earlier (corresponding to day 7, P < 0.05). CONCLUSIONS: The present study demonstrates for the first time that in the absence of ovarian function, follicular phase E2 concentrations sensitize the pituitary to GnRH at an earlier stage (corresponding to the midfollicular phase) than in the normal menstrual cycle (late follicular phase). It is suggested that during the early to midfollicular phase the ovaries produce a gonadotrophin surge attenuating factor (GnSAF) that antagonizes the pituitary-sensitizing effect of E2 to GnRH.     

Luteal phase and clinical outcome after human menopausal gonadotrophin/gonadotrophin releasing hormone antagonist treatment for ovarian stimulation in in-vitro fertilization/intracytoplasmic sperm injection cycles.

The luteal phase hormonal profile and the clinical outcome of 69 patients undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) after ovarian stimulation with human menopausal gonadotrophin (HMG) and the gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix were analysed. Twenty-four patients received Cetrorelix 0.5 mg (group I) while in 45 patients Cetrorelix 0.25 mg was administered (group II). Human chorionic gonadotrophin (HCG) was used as luteal support. Nine clinical pregnancies were obtained in group I (37.5%) and 12 in group II (26. 6%). These results were not significantly different. Serum progesterone and oestradiol concentrations did not differ between the two groups either in pregnant or non-pregnant patients. An expected decrease of the same hormones was observed 8 days after the pre-ovulatory HCG injection in non-pregnant women. With regard to serum luteinizing hormone concentrations, a decrease was observed 2 days after the pre-ovulatory HCG injection and was maintained at almost undetectable levels throughout the entire luteal phase in both conception and non-conception cycles of group I and group II. This study demonstrates that different doses of GnRH antagonist do not have any impact on the luteal phase of IVF/ICSI cycles when hormonal support is given.     

Dose-finding study of daily GnRH antagonist for the prevention of premature LH surges in IVF/ICSI patients: optimal changes in LH and progesterone for clinical pregnancy

BACKGROUND: An optimal range of LH concentrations for achieving pregnancy has not been established. The aim of this study was to investigate the effect of various LH levels induced by different GnRH antagonist doses on IVF outcome. METHODS: This was a prospective, single centre study including 144 IVF patients, stimulated with recombinant FSH from cycle day 2, and co-treated with daily GnRH antagonist (antide/Iturelix) (2 mg/2 ml, 1 mg/ml, 0.5 mg/ml, 0.5 mg/0.5 ml or 0.25 mg/ml) from cycle day 7 onwards. Serum samples were taken three times daily. RESULTS: Clinical pregnancies were only observed within a particular range of change in LH levels. The upper and lower thresholds for the mean LH area under the curve (AUC), adjusted for the baseline LH level before the antagonist was started (LH AUC(-S6); S6=stimulation day 6) were -2.2 and 12.4 (IU/l) respectively (a negative value=below baseline levels). There were no clinical pregnancies outside these threshold values. Similar results were found for progesterone, the threshold levels of progesterone AUC(-S6) were 3.98 and -1.21 ng/ml. Moreover, there were no pregnancies with progesterone levels >0.26 ng/ml/follicle on the day of hCG. CONCLUSIONS: Excessive or insufficient suppression of LH and progesterone levels during GnRH antagonist administration and high progesterone/follicle on hCG day seems to be associated with impaired clinical pregnancy rates.     

Comparison of LH concentrations in the early and mid-luteal phase in IVF cycles after treatment with HMG alone or in association with the GnRH antagonist Cetrorelix

Luteinizing hormone (LH) is mandatory for the maintenance of the corpus luteum. Ovarian stimulation for IVF has been associated with a defective luteal phase. The luteal phases of two groups of patients with normal menstrual cycles and no endocrinological cause of infertility were retrospectively analysed in IVF cycles. Thirty-one infertile patients stimulated with human menopausal gonadotrophins (HMG) for IVF to whom the gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix 0.25 mg was also administered to prevent the LH surge (group I) were compared with 31 infertile patients stimulated with HMG alone (group II). Despite differences in the stimulation outcome, luteal LH serum concentrations were similar in the two groups. LH values dropped from 2.3 +/- 1 IU/l on the day of human chorionic gonadotrophin (HCG) administration to 1.1 +/- 0.7 IU/l on day HCG +2 in group I (P < 0.0001) and from 5.1 +/- 3 to 1.2 +/- 1.7 IU/l (P < 0.0001) in group II. In the mid-luteal phase, LH concentrations were low in both groups. Our results suggest that suppressed LH concentrations in the early and mid-luteal phase may not be attributed solely to the GnRH-antagonist administration. Pituitary LH secretion may be inhibited by supraphysiological steroid serum concentrations via long-loop feedback and/or by the central action of the exogenously administered HCG via a short-loop mechanism.