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The relationship between endogenous LH concentrations and ongoing pregnancy rates among normogonadotrophic patients undergoing ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol were examined. In the Engage trial, 1506 patients received corifollitropin alfa (150 μg) or daily recombinant FSH (rFSH) (200 IU) for the first 7 days of stimulation with 0.25 mg ganirelix from stimulation day 5. Patients were retrospectively stratified by serum LH percentiles (<25th, 25th–75th and >75th) on stimulation day 8 and day of human chorionic gonadotrophin administration. Odds ratios (OR) with and without adjustment for predictive factors for ongoing pregnancy were estimated. LH concentration was not associated with pregnancy rates in either treatment arm, in contrast to ovarian response and serum progesterone. With adjustment for these predictors and age, OR (95% confidence interval) for ongoing pregnancy on stimulation day 8 for LH categories <P25 versus ⩾P25, >P75 versus ⩽P75 and <P25 versus >P75 were 0.75 (0.53–1.06), 1.26 (0.87–1.83) and 0.70 (0.46–1.09) in the corifollitropin alfa arm and 0.80 (0.54–1.17), 1.28 (0.87–1.87) and 0.73 (0.46–1.16) in the rFSH arm respectively. There was also no significant difference in pregnancy rates between LH categories on day of human chorionic gonadotrophin administration with either treatment.
During ovarian stimulation for IVF/intracytoplasmic sperm injection, circulating concentrations of LH should not become too high or too low as the development of mature eggs and the likelihood of ongoing pregnancy may be negatively affected. Gonadotrophin-releasing hormone (GnRH) analogues are applied to prevent premature LH rises but certain regimens may result in relatively low circulating LH concentrations. To examine the relationship between circulating LH concentrations and ongoing pregnancy rates in a GnRH antagonist protocol, data from a large randomized trial, Engage, were retrospectively analysed. In this trial, 1506 patients received corifollitropin alfa or daily recombinant FSH for the first 7 days of stimulation and ganirelix (a GnRH antagonist) from stimulation day 5 onwards. Patients were grouped by their LH concentration (low, normal or high) on stimulation day 8 and the day of human chorionic gonadotrophin (HCG) administration to trigger final egg maturation. The chance of ongoing pregnancy by LH category, with or without adjustment for other factors affecting pregnancy was calculated. There was no significant difference in the chance of pregnancy between patients in the different LH categories, regardless of the day of assessment or the treatment group. In contrast, circulating progesterone (another hormone produced by mature follicles) and the number of eggs retrieved clearly affected the chance of pregnancy. These analyses showed that ongoing pregnancy rates are not influenced by either low or high circulating LH concentrations when using a GnRH antagonist protocol.
The role of LH during ovarian stimulation in women less than 37 years old is not completely understood and contradictory evidence exists as to whether or not profound suppression of endogenous LH affects IVF/intracytoplasmic sperm injection (ICSI) outcomes (
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.
Role of periovulatory luteinising hormone concentrations during assisted reproductive technology cycles stimulated exclusively with recombinant follicle-stimulating hormone.
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.
Luteinizing hormone concentrations after gonadotropin-releasing hormone antagonist administration do not influence pregnancy rates in in vitro fertilization-embryo transfer.
Increased risk of early pregnancy loss by profound suppression of luteinising hormone during ovarian stimulation in normogonadotrophic women undergoing assisted reproduction.
). Patients with hypogonadotrophic hypogonadism (World Health Organization group I) require the administration of a daily low amount (75 IU) of exogenous LH activity, as recombinant LH, human chorionic gonadotrophin (HCG) or human menopausal gonadotrophin, for adequate follicular and endometrial development (
Spanish Collaborative Group on Female Hypogonadotrophic The effectiveness and safety of recombinant human LH to support follicular development induced by recombinant human FSH in WHO group I anovulation: evidence from a multicentre study in Spain.
The European Recombinant Human LH Study Group 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.
Research regarding the need for LH add-back in normogonadotrophic patients should distinguish between long gonadotrophin-releasing hormone (GnRH) agonist protocols, which induce profound pituitary suppression prior to stimulation, and GnRH antagonist protocols, in which normal to partially suppressed endogenous LH concentrations are observed during stimulation. Most published studies on LH requirement are based on retrospective analyses of low endogenous LH concentrations during stimulation using a long GnRH agonist protocol (
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.
Effects of profound suppression on luteinising hormone during ovarian stimulation follicular activity, oocyte, and embryo function in cycles stimulated with purified follicle stimulating hormone.
Increased risk of early pregnancy loss by profound suppression of luteinising hormone during ovarian stimulation in normogonadotrophic women undergoing assisted reproduction.
). In both GnRH agonist and antagonist cycles, supplementation with LH activity enhances androgen and oestrogen biosynthesis. Patients receiving LH/HCG supplementation have higher oestradiol concentrations per growing follicle than patients stimulated with FSH only (
The use of recombinant human LH (lutropin alfa) in the late stimulation phase of assisted reproduction cycles: a double-blind, randomized, prospective study.
). In addition, it has been shown that the use of exogenous HCG may reduce or even replace the requirements for FSH administration during the last days of stimulation (
Serum luteinizing hormone in patients undergoing ovarian stimulation with gonadotropin-releasing hormone antagonists and recombinant follicle-stimulating hormone and its relationship with cycle outcome.
Luteinizing hormone concentrations after gonadotropin-releasing hormone antagonist administration do not influence pregnancy rates in in vitro fertilization-embryo transfer.
) do not affect pregnancy rates. One prospective study and LH analysis of patients treated with an rFSH/GnRH antagonist protocol suggested that those patients with the lowest endogenous LH concentrations on stimulation day 8 had the highest pregnancy rate (
). A recent univariate analysis indicated that low endogenous LH concentrations as measured on stimulation days 1, 5 and 8 in 750 patients treated with daily rFSH in a GnRH antagonist protocol did not adversely affect ongoing pregnancy rates (
on behalf of the ENGAGE Investigators A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol.
) examines the association between endogenous LH concentrations and ongoing pregnancy rates in corifollitropin alfa and rFSH treatment groups.
Materials and methods
Ongoing pregnancy rates relative to endogenous serum LH concentrations during ovarian stimulation were retrospectively analysed from the Engage trial, the details of which have been reported previously (
on behalf of the ENGAGE Investigators A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol.
). Briefly, women aged 18–36 years with bodyweight from >60 kg to ⩽90 kg and a regular menstrual cycle received a single dose of 150 μg corifollitropin alfa (Elonva; N.V. Organon, The Netherlands) or daily 200 IU rFSH (Puregon/Follistim pen; N.V. Organon) for the first 7 days of ovarian stimulation. From stimulation day 8 onwards, treatment in both groups was continued as needed with a daily s.c. dose of ⩽200 IU rFSH up to and including the day of HCG administration. GnRH antagonist ganirelix (0.25 mg, Orgalutran/Ganirelix Acetate Injection; N.V. Organon) was administered once daily s.c. starting on stimulation day 5 up to and including the day of HCG injection. Urinary HCG (10,000 IU or 5000 IU) was administered to induce final oocyte maturation when three follicles ⩾17 mm were observed by ultrasound scan or the next day. Oocyte retrieval was performed 34–36 h later, followed by either IVF or ICSI (
on behalf of the ENGAGE Investigators A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol.
Blood samples were drawn in the morning just prior to GnRH antagonist and gonadotrophin injections and the serum was immediately stored at −20°C until analysis of FSH, LH, oestradiol and progesterone concentrations.
Validated immunoassays were performed to measure serum concentrations of FSH, LH, oestradiol and progesterone at stimulation days 1, 5, 8 and day of HCG administration. All hormone measurements were determined at one central laboratory (Waltrop, Germany) using a time-resolved fluoroimmunoassay (AutoDelfia immunofluorometric assay; PerkinElmer Life and Analytical Sciences, Brussels, Belgium). Detection limits for serum FSH, LH, oestradiol and progesterone were 0.25 IU/l, 0.6 IU/l, 50 pmol/l and 1.3 nmol/l (0.4 ng/ml) respectively. The intra- and inter-assay variabilities of these assays were <5% and <10%, respectively.
Statistical analysis
All analyses were performed for the intention-to-treat (ITT) population. The ITT population includes all randomized subjects who received one or more dose(s) of corifollitropin alfa or rFSH. Subjects were grouped according to the treatment they were randomized to. Ongoing pregnancy rates were analysed per started cycle: subjects in the ITT group whose IVF cycles were cancelled were included and considered not pregnant in the statistical analyses.
Patients were stratified by LH percentiles to examine the LH effect on ongoing pregnancy rates. They were divided into three groups: below the 25th LH percentile (<P25), between the 25th and 75th LH percentiles (P25–P75) and above the 75th LH percentile (>P75). LH concentration was analysed as a three-level class variable and not as a continuous variable because almost a quarter of the LH measurements on stimulation day 8 and day of HCG were below the lower limit of quantification. Patients without LH measurements were excluded from the analyses.
Overall differences in baseline characteristics, stimulation characteristics and ovarian response between the <P25, P25–P75 and >P75 groups of patients were tested using either analysis of variance (ANOVA; for comparing means) or the Kruskal–Wallis test (for comparing medians). The effect of treatment (corifollitropin alfa, rFSH) on the LH concentrations on stimulation days 5 and 8 and day of HCG was tested using the Mann–Whitney U-test.
Differences in ongoing pregnancy rates between the <P25, P25–P75 and >P75 groups of patients were analysed using PROC GENMOD in SAS version 9.1 (SAS Institute, Cary, NC, USA). A logistic regression model between ongoing pregnancy rate and LH concentration (<P25, P25–P75, >P75) was fitted for each combination of treatment group (corifollitropin alfa, rFSH) and day (stimulation day 8 and day of HCG). Separate models for the treatment groups were applied because the results for the rFSH group will be included in the combined analysis described in part II of this article (
). P-values of the LH effect on ongoing pregnancy rate were derived using the likelihood ratio test. Maximum likelihood estimates of odds ratios (OR) and associated two-sided 95% confidence intervals (CI) were computed for <P25 versus ⩾P25 (low versus not-low LH), >P75 versus ⩽P75 (high versus not-high LH) and <P25 versus >P75 (low versus high LH). The P-values and estimated OR and CI were computed with and without adjustment for predictive factors of ongoing pregnancy.
Age was selected as one of the predictive factors of ongoing pregnancy as it is well known that the chance of pregnancy is age related. Stepwise logistic regression analysis was applied to identify the other predictive factors per treatment group and stimulation day. Candidate predictive factors entered in the model were age, serum FSH concentration on stimulation day 1, antral follicle count (AFC) on stimulation day 1 and number of oocytes retrieved. Progesterone concentration and number of follicles ⩾11 mm on stimulation day 8 were added to the above factors to identify the predictive factors for ongoing pregnancy for OR adjustment at stimulation day 8, while progesterone concentration and number of follicles ⩾11 mm on day of HCG were added to identify the predictive factors for OR adjustment on day of HCG. The significance level of the candidate predictive factors to enter the model was set to 0.15 and to stay in the model was set to 0.10. The final model selects the predictive factors with statistical significance, i.e. P ⩽ 0.05. The predictive factors were added as independent covariates to the model to find the adjusted estimates of LH effect. Only additive models were considered to identify predictive factors.
Results
Baseline characteristics by LH category
Table 1 presents the baseline characteristics of patients treated with either corifollitropin alfa or rFSH for the first 7 days of ovarian stimulation, divided into three groups: low (<P25), medium (P25–P75) and high (>P75) serum LH concentrations on stimulation day 8. Patients with higher serum LH concentrations were more likely to demonstrate markers of diminished ovarian reserve (AFC, FSH). These patients were older and had lower AFC and higher FSH (stimulation day 1) than patients with medium or low serum LH concentrations. There was no difference between the three groups with respect to the cause of infertility (data not shown), the duration of infertility or the incidence of primary infertility (Table 1).
Table 1Demographic and other baseline characteristics by treatment group and LH on stimulation day 8.
On stimulation day 8, >25% of patients treated with corifollitropin alfa had a value below the lower limit of quantification and were all included in the <P25 category.
316
176
–
Age (years)
31.3 ± 3.3
31.4 ± 3.4
31.9 ± 3.3
NS
Body mass index (kg/m2)
24.5 ± 2.6
24.9 ± 2.9
25.1 ± 2.7
⩽0.05
Bodyweight (kg)
68.2 ± 7.0
68.9 ± 7.9
69.3 ± 7.6
NS
Serum LH on day 1 (IU/l; median (P5,P95))
4.0 (2.1,7.0)
4.5 (2.4,7.9)
4.9 (2.5,9.8)
⩽0.05
Serum FSH on day 1 (IU/l; median (P5,P95))
6.1 (3.9,8.9)
6.3 (4.5,9.6)
6.9 (4.5,13.1)
⩽0.05
Antral follicles <11 mm
12.8 ± 5.0
12.7 ± 4.3
11.4 ± 4.2
⩽0.05
Duration of infertility (years)
3.1 ± 2.3
3.5 ± 2.5
3.4 ± 2.6
NS
Primary infertility
55.6
51.9
55.1
NS
Secondary infertility
44.4
48.1
44.9
NS
Recombinant FSH (n)
169
340
169
–
Age (years)
30.9 ± 3.4
31.6 ± 3.1
32.0 ± 3.4
⩽0.05
Body mass index (kg/m2)
24.6 ± 2.7
24.9 ± 2.8
25.1 ± 2.5
NS
Bodyweight (kg)
68.1 ± 7.3
68.5 ± 7.4
68.8 ± 7.0
NS
Serum LH on day 1 (IU/l; median (P5,P95))
4.2 (2.1,7.0)
4.4 (2.3,8.0)
4.8 (2.7,8.6)
⩽0.05
Serum FSH on day 1 (IU/l; median (P5,P95))
6.4 (3.9,9.5)
6.4 (4.4,9.9)
6.5 (4.9,10.9)
⩽0.05
Antral follicles <11 mm
12.4 ± 4.4
12.6 ± 4.6
12.1 ± 4.4
NS
Duration of infertility (years)
3.1 ± 2.2
3.3 ± 2.3
3.2 ± 2.0
NS
Primary infertility
52.7
53.5
50.9
NS
Secondary infertility
47.3
46.5
49.1
NS
Values are mean ± standard deviation or %, unless otherwise stated.
⩽0.05 indicates unequal means or medians among the three LH categories.
NS = not statistically significant; <P25 = patients below the 25th LH percentile; P25–P75 = patients between the 25th and 75th LH percentiles; >P75 = patients above the 75th LH percentile.
a On stimulation day 8, >25% of patients treated with corifollitropin alfa had a value below the lower limit of quantification and were all included in the <P25 category.
Serum LH concentrations during treatment with corifollitropin alfa or daily rFSH
Table 2 presents the serum LH percentiles (P5, P25, P50, P75 and P95) in each treatment group at stimulation days 1, 5 and 8 and day of HCG administration. Serum LH concentrations were higher at stimulation day 5 in the corifollitropin alfa group than in the rFSH group, whereas the reverse was observed at stimulation day 8 and day of HCG administration (Figure 1). The difference in median LH concentration between the corifollitropin alfa group and the rFSH group was significant (P ⩽ 0.05) on stimulation day 5, stimulation day 8 and day of HCG, respectively (Table 2). At stimulation day 8, the P50 (median) value was 0.96 IU/l in the corifollitropin alfa group and 1.57 IU/l in the rFSH group. The P25 values were <0.6 IU/l and 0.91 IU/l and the P75 values were 1.58 IU/l and 2.66 IU/l, respectively.
Table 2LH concentrations in LH percentile categories per treatment group and stimulation day.
Stimulation day
LH percentiles
P5
P25
P50
P75
P95
Corifollitropin alfa
Day 1
2.28
3.39
4.48
5.82
8.11
Day 5
<0.6
1.18
2.04
4.19
12.5
Day 8
<0.6
<0.6
0.96
1.58
3.07
Day of HCG
<0.6
<0.6
1.00
1.77
3.53
Recombinant FSH
Day 1
2.30
3.38
4.41
5.64
7.95
Day 5
<0.6
0.93
1.46
2.31
6.60
Day 8
<0.6
0.91
1.57
2.66
5.27
Day of HCG
<0.6
0.75
1.39
2.57
4.92
Values are IU/l.
HCG = human chorionic gonadotrophin.
Median LH concentrations differed (P ⩽ 0.05) between the two treatment groups on stimulation day 5, stimulation day 8 and day of HCG.
Figure 1Box plot of serum LH concentrations during and after stimulation with corifollitropin alfa and rFSH. Treatment with the gonadotrophin-releasing hormone antagonist was started for all patients at stimulation day 5. Solid lines = median; boxes = P25–P75; whiskers = P5–P95; ET = embryo transfer; HCG = human chorionic gonadotrophin; rFSH = recombinant FSH.
Stimulation characteristics and ovarian response per LH category
The main stimulation characteristics in the trial per LH category at stimulation day 8 for both the corifollitropin alfa and rFSH arms are shown in Table 3. In both treatment groups, patients with lower LH required a slightly longer duration of stimulation and slightly more daily rFSH (50–80 IU) from stimulation day 8 onwards to reach the same HCG criteria. In both treatment groups, fewer follicles ⩾11 mm were observed at stimulation day 8 and day of HCG in patients with higher LH concentrations (Table 4). Despite this, serum oestradiol and progesterone concentrations of patients in the higher percentile of endogenous LH were higher than in patients with lower LH concentrations. Fewer oocytes were retrieved in patients with higher LH concentrations.
Table 3Stimulation characteristics by treatment group and LH on stimulation day 8.
Characteristic
LH percentile category
P-value
<P25
P25–P75
>P75
Corifollitropin alfa (n)
216
316
176
–
Total dose of rFSH (IU)
443.6 ± 316.0
407.3 ± 298.9
395.3 ± 317.8
NS
Total dose of rFSH from day 8 onwards (IU)
442.7 ± 315.2
407.3 ± 298.9
376.0 ± 281.4
⩽0.05
Duration of stimulation (days)
9.8 ± 1.6
9.6 ± 1.4
9.3 ± 1.8
⩽0.05
Recombinant FSH (n)
169
340
169
–
Total dose of rFSH (IU)
1811.8 ± 292.5
1742.9 ± 252.3
1728.6 ± 249.5
⩽0.05
Total dose of rFSH from day 8 onwards (IU)
424.3 ± 277.1
353.9 ± 244.0
337.5 ± 238.4
⩽0.05
Duration of stimulation (days)
9.6 ± 1.3
9.3 ± 1.1
9.2 ± 1.1
⩽0.05
All values are mean ± standard deviation.
P ⩽ 0.05 indicates unequal means among the three LH categories.
NS = not statistically significant; rFSH = recombinant FSH; <P25 = patients below the 25th LH percentile; P25–P75 = patients between the 25th and 75th LH percentiles; >P75 = patients above the 75th LH percentile.
There was no difference in the total number of embryos or the number of good-quality embryos obtained among the low, medium and high LH concentration groups of patients in each treatment group. The number and quality of embryos transferred were very similar among all the different subsets (data not shown).
Identification of predictive factors
Predictive factors of ongoing pregnancy in addition to age were identified using stepwise logistic regression to adjust the estimated OR at stimulation day 8 and day of HCG, respectively. The identified predictive factors to adjust the estimated OR at stimulation day 8 were: (i) serum progesterone on stimulation day 8 (corifollitropin alfa group: OR 0.80, 95% CI 0.68–0.95, P = 0.01; rFSH group: OR 0.87, 95% CI 0.75–1.00, P = 0.05): a higher progesterone concentration on stimulation day 8 was associated with a lower pregnancy rate in both treatment groups; (ii) number of follicles ⩾11 mm on stimulation day 8 (corifollitropin alfa group only: OR 1.03, 95% CI 1.00–1.05, P = 0.03): a higher number of follicles was associated with a higher pregnancy rate; and (iii) number of oocytes retrieved (rFSH group only: OR 1.03, 95% CI 1.01–1.06, P = 0.02): a higher number of oocytes was associated with a higher pregnancy rate.
On the day of HCG trigger, none of the candidate predictive factors were statistically significant. Age was borderline significant in the rFSH group on day of HCG administration (OR 0.96, 95% CI 0.91–1.00).
Ongoing pregnancy rates according to LH percentiles
In both the corifollitropin alfa and rFSH groups, the ongoing pregnancy rates were similar for patients with low (<P25), medium (P25–75) or high (>P75) endogenous LH concentrations on stimulation day 8 and day of HCG administration (Table 5). The effect of LH concentration on stimulation day 8 and day of HCG was not statistically significant in these treatment groups (Table 6). The estimated OR for <P25 versus ⩾P25, >P75 versus ⩽P75 and <P25 versus >P75 groups were not statistically significantly different from 1.0 for any of the stimulation days or treatment arms (Table 6), regardless of whether the estimated OR was unadjusted or adjusted for predictive factors.
Table 5Ongoing pregnancy rate per started cycle, treatment group, stimulation day and LH.
Stimulation day
LH percentile category
Ongoing pregnancy rate
n/total
% (95% CI)
Corifollitropin alfa
Day 8
<P25
77/216
35.6 (29.3–42.4)
P25–P75
125/316
39.6 (34.1–45.2)
>P75
68/176
38.6 (31.4–46.3)
Day of HCG
<P25
75/208
36.1 (29.5–43.0)
P25–P75
126/307
41.0 (35.5–46.8)
>P75
73/170
42.9 (35.4–50.7)
Recombinant FSH
Day 8
<P25
60/169
35.5 (28.3–43.2)
P25–P75
125/340
36.8 (31.6–42.1)
>P75
65/169
38.5 (31.1–46.2)
Day of HCG
<P25
63/175
36.0 (28.9–43.6)
P25–P75
132/352
37.5 (32.4–42.8)
>P75
74/174
42.5 (35.1–50.2)
CI = confidence interval; HCG = human chorionic gonadotrophin; <P25 = patients below the 25th LH percentile; P25–P75 = patients between the 25th and 75th LH percentiles; >P75 = patients above the 75th LH percentile.
Values are estimated odds ratios (95% confidence interval).
The LH effect was not statistically significantly different (P > 0.05) for any of the stimulation days or treatment arms, unadjusted or adjusted for predictive factors.
HCG = human chorionic gonadotrophin.
a Adjusted for age and progesterone and number of follicles ⩾11 mm on stimulation day 8.
b Adjusted for age, progesterone on stimulation day 8 and oocytes.
In the 1506 normogonadotrophic women who received either corifollitropin alfa or rFSH during the Engage study, there was no relationship between endogenous LH concentrations and ongoing pregnancy rates. The LH analyses showed that, with a GnRH antagonist protocol to prevent premature LH surges during ovarian stimulation, the ongoing pregnancy rate was not influenced by either lower or higher endogenous LH concentrations on stimulation day 8 or day of HCG administration. This observation suggests that neither implantation rate nor early miscarriage rates are affected by the amount of circulating LH activity.
On stimulation day 8, the P25 value was <0.6 IU/l in the corifollitropin alfa group and 0.91 IU/l in the rFSH group. These values are below 1.2 IU/l, the cut-off value below which recombinant LH is indicated for ovulation induction in anovulatory women with profound LH deficiency (
The European Recombinant Human LH Study Group 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.
Serum luteinizing hormone in patients undergoing ovarian stimulation with gonadotropin-releasing hormone antagonists and recombinant follicle-stimulating hormone and its relationship with cycle outcome.
Luteinizing hormone concentrations after gonadotropin-releasing hormone antagonist administration do not influence pregnancy rates in in vitro fertilization-embryo transfer.
), which also showed that low LH values were not associated with decreased pregnancy rates. Although it is known that high concentrations of GnRH antagonist may reduce clinical pregnancy rates (
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.
The Ganirelix Dose-finding Study Group A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon).
), this reduction of fertility does not appear to be mediated through LH deficiency.
In the current trial of young women aged 18–36 years, serum LH concentrations on stimulation day 8 varied from undetectable concentrations (<0.6 IU/l) to 3 IU/l in the corifollitropin alfa group and 5 IU/l in the daily rFSH group. This variability was partly related to the woman’s age and the ovarian reserve as women with lower serum LH concentrations had a higher ovarian response. In contrast to GnRH-agonist protocols, GnRH antagonist needs to be administered only during the period of stimulation when a LH rise becomes imminent. In the current study, GnRH antagonist was started for all patients on stimulation day 5 and the observed difference in endogenous LH concentrations at the end of the follicular phase may be related to the larger recruited cohort of follicles in the corifollitropin alfa group compared with the rFSH group. This observation is in line with the lower endogenous LH on day of HCG in patients treated with a fixed daily dose of 200 IU rFSH as compared with a fixed daily dose of 150 IU rFSH (
A randomized, double-blind, multicentre clinical trial comparing starting doses of 150 and 200 IU of recombinant FSH in women treated with the GnRH antagonist ganirelix for assisted reproduction.
Endogenous LH concentrations on stimulation day 8 showed a negative association with the number of follicles. This relationship is due to the difference in ovarian reserve in the three LH categories, but it is noted that both serum oestradiol and progesterone showed a positive association, which confirms that steroidogenesis is to a certain extent driven by endogenous LH concentrations regardless of the number of antral follicles or oocytes recovered (The Ganirelix Dose-finding Study
The Ganirelix Dose-finding Study Group A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon).
The stepwise logistic regression analyses indicated that higher progesterone concentrations on stimulation day 8 reduce the ongoing pregnancy rate, while an increased number of follicles on stimulation day 8 (corifollitropin alfa group) or oocytes (rFSH group) increase the ongoing pregnancy rate. Thus, a higher oocyte yield and lower progesterone concentrations are associated with a higher chance of pregnancy. However, serum progesterone concentrations increase during the late follicular phase with the number of growing follicles. This finding supports the concept of an optimal range of oocytes, below and above which outcomes are compromised (
). This would imply that pregnancy rates may be improved as long as the number of oocytes is still below the optimal range, whereas overstimulation may increase serum progesterone concentrations during the late follicular phase, which is known to compromise the chance of implantation (
Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles.
). Further data analysis is required to explore the impact of high progesterone concentrations during stimulation on pregnancy outcome in a GnRH antagonist protocol, which has significantly lower progesterone concentrations than a GnRH agonist protocol.
On the day of HCG administration, the stepwise regression analysis indicated that only age was a significant factor – this may be due to the large variability in the number of follicles and progesterone concentrations at this time. In the current investigation, as neither low nor high endogenous LH concentrations impacted ongoing pregnancy rates in either direction, the data suggest that the amount of endogenous LH was sufficient to support follicular function and implantation in both treatment groups during ovarian stimulation prior to IVF or ICSI. Also, the estimated OR for ongoing pregnancy of low LH (<P25) versus not low LH (⩾P25), high LH (>P75) versus not high LH (⩽P75) and low LH (P < 25) versus high LH (>P75) were not statistically significant for any of the treatment groups and treatment days investigated.
In conclusion, LH analysis of the Engage trial showed that ongoing pregnancy rates were not affected by the extent of LH suppression as measured at stimulation day 8 and day of HCG administration. These findings support previous GnRH antagonist studies that indicated that clinical outcome is not compromised in the absence of exogenous LH supplementation.
Acknowledgements
The authors would like to acknowledge the investigators and their medical staff who contributed to the Engage trial and data included in these analyses.
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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.
Serum luteinizing hormone in patients undergoing ovarian stimulation with gonadotropin-releasing hormone antagonists and recombinant follicle-stimulating hormone and its relationship with cycle outcome.
Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles.
Spanish Collaborative Group on Female Hypogonadotrophic
The effectiveness and safety of recombinant human LH to support follicular development induced by recombinant human FSH in WHO group I anovulation: evidence from a multicentre study in Spain.
A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol.
Role of periovulatory luteinising hormone concentrations during assisted reproductive technology cycles stimulated exclusively with recombinant follicle-stimulating hormone.
Effects of profound suppression on luteinising hormone during ovarian stimulation follicular activity, oocyte, and embryo function in cycles stimulated with purified follicle stimulating hormone.
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.
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.
Luteinizing hormone concentrations after gonadotropin-releasing hormone antagonist administration do not influence pregnancy rates in in vitro fertilization-embryo transfer.
A randomized, double-blind, multicentre clinical trial comparing starting doses of 150 and 200 IU of recombinant FSH in women treated with the GnRH antagonist ganirelix for assisted reproduction.
The use of recombinant human LH (lutropin alfa) in the late stimulation phase of assisted reproduction cycles: a double-blind, randomized, prospective study.
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.
A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon).
Increased risk of early pregnancy loss by profound suppression of luteinising hormone during ovarian stimulation in normogonadotrophic women undergoing assisted reproduction.
Declaration: Financial support for this study was provided by Merck, Sharp and Dohme & Co (MSD). Medical writing and editorial assistance was provided by P Milner, PhD, of PAREXEL, UK. This assistance was funded by MSD. KD has been a speaker in the national speaker program for EMD Serono and Ferring, has worked on the national and international advisory board for EMD Serono, Ferring and Merck, has been a clinical investigator for EMD Serono, Ferring, Merck, IBSA, Duramed and Agile, and has been a FDA/regulatory advisor for Ferring. AL has worked as a consultant to Schering-Plough Corporation. HW and BMM are employees of MSD.The Engage trial was registered under ClinicalTrials.gov identifier NTC00696800.
Footnotes
Kevin Doody, MD, received his medical degree and served a residency in obstetrics and gynaecology at Baylor College of Medicine in Houston. After completing his residency, Dr Doody received subspecialty training at UT Southwestern Medical Center. He completed his fellowship in reproductive endocrinology/infertility in 1989. He is board certified in obstetrics and gynaecology and subspecialty board certified in reproductive endocrinology/infertility. Dr Doody has been repeatedly honoured as one of Fort Worth’s Top Docs, one of Texas’s Super Doctors and one of the Best Doctors in America. Dr Doody was also recognized as Microsoft Physician of the Year 2004.
After the introduction of recombinant FSH preparations for IVF or intracytoplasmic sperm injection (ICSI), it became clear that good pregnancy rates could be achieved with or without any exogenous LH, irrespective of the protocol used. Both recombinant LH- and human chorionic gonadotrophin (HCG)-containing menotrophins are available, so biology and pharmacology could be nicely linked, if the following concept could be documented: subgroups of patients have low circulating LH concentrations, and thus low pregnancy rates, and when such patients were co-treated with recombinant LH, the pregnancy rates would increase.
Kevin Doody, MD, received his medical degree and served a residency in obstetrics and gynaecology at Baylor College of Medicine in Houston. After completing his residency, Dr Doody received subspecialty training at UT Southwestern Medical Center. He completed his fellowship in reproductive endocrinology/infertility in 1989. He is board certified in obstetrics and gynaecology and subspecialty board certified in reproductive endocrinology/infertility. Dr Doody has been repeatedly honoured as one of Fort Worth’s Top Docs, one of Texas’s Super Doctors and one of the Best Doctors in America. Dr Doody was also recognized as Microsoft Physician of the Year 2004.
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