The purpose of this retrospective study was to evaluate the appropriateness of various follicle-stimulating hormone (FSH) starting doses in expected normal responders based on the nomogram developed by La Marca et al.
A total of 117 first
Between the concordant and discordant group, ovarian response (optimal, 32.4% vs. 27.7%; hypo-response, 55.9% vs. 54.2%; and hyper-response, 11.8% vs. 18.1%) and the number of total or mature oocytes were similar. Ovarian hyperstimulation syndrome was rare in both groups (0% vs. 1.2%). The implantation rate, clinical pregnancy rate, miscarriage rate, and live birth rate were all similar.
The use of the proposed FSH starting dose determined using La Marca's nomogram did not enhance the optimal ovarian response rate or pregnancy rate in expected normal responders. Individualization of the FSH starting dose by La Marca's nomogram appears to have no distinct advantages over empiric choice of the dose in expected normal responders.
When performing ovarian stimulation for
La Marca et al. [
Many clinicians feel that the FSH dose suggested by the nomogram may be lower than expected empirically. An empiric choice of the FSH starting dose can sometimes result in hyper-response; however, if up to 10 oocytes are obtained, blastocyst transfer can be considered to maximize the implantation rate and to decrease the likelihood of a multi-fetal pregnancy. Otherwise, surplus embryos can be frozen and be used in subsequent cycles, maximizing the pregnancy rate.
La Marca et al. [
A retrospective study was performed under approval by the Institutional Review Board (IRB No. B-1805/471-101). A total of 117 infertile women who underwent their first IVF cycles from 2011 to 2017 at Seoul National University Bundang Hospital were selected. The selection criteria were the same as in La Marca's study: (1) first IVF or intracytoplasmic sperm injection (ICSI) cycle, (2) female age ≤40 years, (3) regular menstrual cycle of 25–35 days, (4) continuation of the initial starting FSH dose for the first 5 days, (5) serum AMH 1.0–4.0 ng/mL, (6) basal serum FSH ≤15 IU/L, and (7) normal uterine cavity. The exclusion criteria were as follows: (1) polycystic ovarian syndrome, (2) previous ovarian surgery, (3) stage III–IV endometriosis, (4) history of oral contraceptives in the previous 3 months, (5) any proven metabolic or endocrine diseases, and (6) frozen embryo transfer.
In all cases, recombinant FSH (Gonal F; Merck Serono, Darmstadt, Germany) and a flexible gonadotropin-releasing hormone (GnRH) antagonist protocol were used. The starting dose of recombinant FSH was empirically determined by clinicians (150, 225, or 300 IU). The GnRH antagonist (Cetrotide, Merck Serono) was administrated daily when the leading follicle reached 14 mm in diameter. When the leading follicles reached 19 mm in diameter, ovulation was triggered by injecting 250 µg of recombinant human chorionic gonadotropin (Ovidrel, Merck Serono). The oocyte was retrieved 35–36 hours later. Embryo transfer was performed 3 or 5 days after oocyte retrieval. The luteal phase was supported either by daily progesterone injection or vaginal gel (Crinone, Merck Serono). A serum human chorionic gonadotropin test was performed 14 days after oocyte retrieval. The implantation rate was defined as the number of gestational sacs observed on ultrasonography at 6 weeks of pregnancy divided by the number of embryos transferred. Clinical pregnancy was confirmed by the visualization of at least 1 gestational sac. Ongoing pregnancy was defined when the pregnancy had completed ≥20 weeks of gestation. Cleavage-stage grade A embryos were identified on day 3 according to the following morphological criteria: equal-sized blastomeres and no fragments, with no apparent morphologic abnormalities.
In the 117 IVF cycles, the proposed FSH starting dose was determined using female age and serum AMH or basal FSH as indicated in La Marca's nomogram. In our hospital, the method of the serum AMH assay changed during the study period (2011 to 2017). The Immunotech (IOT) assay was used until August 2012, the original Gen II kit was used from September 2012 to July 2013, and then the revised Gen II kit was used from August 2013 to July 2016. Since August 2016, we have used a fully automated AMH assay system based on the revised Gen II kit. To correct for these changes, we used the formulas reported in previous studies. The revised Gen II assay results were converted to the original Gen II assay values using the following formula: revised protocol AMH value=0.929+1.658×(original AMH value)−0.006×(original AMH value)2 [
If the dose that was administered was exactly the same as the dose specified by the nomogram, cycles were assigned to the concordant group (34 cycles). If not, they were assigned to the discordant group (83 cycles). If the proposed dose was over 225 IU, and the administered dose was 300 IU, the cycle was assigned to the concordant group. If the proposed dose was over 225 IU and the administered dose was 225 or 150 IU, the cycle was assigned to the discordant group.
In the present study, optimal ovarian response was defined as between 8 and 14 total retrieved oocytes. Hypo-response was defined as fewer than eight retrieved oocytes, and hyper-response was defined as more than 14 retrieved oocytes. All statistical analyses were performed using IBM SPSS ver. 23.0 (IBM Corp., Armonk, NY, USA). Most of the numerical data did not show a normal distribution; thus, the data are presented as median and interquartile range. The nonparametric Mann-Whitney
The clinical characteristics of both groups are shown in
The total FSH dose administered and the serum estradiol level on triggering day were similar between the concordant and discordant groups (
Embryo transfer and pregnancy outcomes are presented in
In this retrospective study, we observed no differences in the optimal ovarian response, acquisition of high-quality embryos, or resultant pregnancy rates according to the concordance of the FSH dose with that calculated by La Marca's nomogram. Efforts have been made to tailor or individualize the FSH starting dose to avoid unfavorable excessive or suboptimal ovarian response. Several nomograms based on the AFC have been proposed to determine individualized FSH starting doses [
La Marca et al. [
Second, Allegra et al. [
In the present retrospective study, the FSH starting dose was 225 IU in 81.9% of the women in the discordant dose group. In the study by Papaleo et al. [
In addition, both of the above studies had limitations in the AMH assay method. La Marca et al. [
In fact, La Marca's nomogram was developed with the basic goal of avoiding ovarian hyper-response in normal responders. However, in the present retrospective study, the hyper-response rate was similar between the concordant and discordant dose groups although the majority of women received 225 IU. Surplus embryos to be cryopreserved were obtained in seven of the 34 cycles in the concordant group (20.6%) and in 15 of the 83 cycles in the discordant group (18.1%). The overall ovarian response was similar between the concordant and discordant dose groups, as was the resultant pregnancy rate.
In normal responders, avoidance of ovarian hyper-response may be unnecessary. If up to 10 oocytes are obtained, blastocyst transfer can be considered to maximize the implantation rate and to reduce the likelihood of a multi-fetal pregnancy. Otherwise, surplus embryos can be frozen for use in subsequent thawed cycles, thereby maximizing the pregnancy rate [
Therefore, an FSH starting dose of 225 IU would be a good option when considering the cumulative pregnancy rate through consecutive frozen embryo transfer [
This study had some limitations. First, this was not a prospective validation study. Second, women who used a different dose during the first 5 days were excluded. More variable FSH dose schedules exist, such as 225 IU in the first 3 days, with changes thereafter according to women's response. In conclusion, the use of La Marca's nomogram seems to have no significant advantages over the conventional empiric choice in terms of the number of oocytes retrieved or the pregnancy outcomes when applied to expected normal responders in IVF/ICSI cycles. Further prospective studies are needed to clarify the advantages of individualized FSH dosing.
Values are presented as median (interquartile range) or number (%).
FSH, follicle-stimulating hormone; AMH, anti-Müllerian hormone.
Values are presented as number (%) or median (interquartile range).
FSH, follicle-stimulating hormone.
Values are presented as median (interquartile range) or number (%) unless otherwise indicated.
OHSS, ovarian hyperstimulation syndrome.
a)Seven cycles; b)Fifteen cycles.