https://orcid.org/0000-0001-5440-6370
Abstract
Objective
To investigate the effect of body mass index (BMI) on progesterone (P) level on trigger day in gonadotropin-releasing hormone antagonist (GnRH-ant) cycles.
Methods
This study was a retrospective cohort study. From October 2017 to April 2022, 412 in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) patients who were treated with GnRH-ant protocol for controlled ovarian hyperstimulation (COH) in the reproductive center of our hospital were selected as the research objects. Patients were divided into three groups according to BMI level: normal weight group (n = 230):18.5 kg/m2≤BMI < 24 kg/m2; overweight group (n = 122): 24 kg/m2≤BMI < 28 kg/m2; Obesity group (n = 60): BMI ≥ 28 kg/m2. Variables with p < .10 in univariate analysis (BMI, basal FSH, basal P, FSH days, Gn starting dose and E2 level on trigger day) and variables that may affect P level on trigger day (infertility factors, basal LH, total FSH, HMG days and total HMG) were included in the multivariate logistic regression model to analyze the effect of BMI on P level on trigger day of GnRH-ant protocol.
Results
After adjustment for confounding factors, compared with that in normal weight patients, the risk of serum P elevation on trigger day was significantly lower in overweight and obese patients (OR = 0.434 and 0.199, respectively, p < .05).
Conclusion
The risk of P elevation on trigger day in GnRH-ant cycles decreased with the increase of BMI, and BMI could be used as one of the predictors of P level on trigger day in GnRH-ant cycles.
Introduction
Gonadotropin-releasing hormone antagonist (GnRH-ant) protocol, which suppress the endogenous luteinizing hormone (LH) peak occured in the middle and late stages of follicular development by GnRH-ant, has the advantages of convenient use, short ovulation induction time, less medication for ovulation induction, no ‘flares up’ effect, no cysts, preservation of pituitary reactivity, and significantly reducing the incidence of ovarian hyperstimulation syndrome (OHSS) [Citation1]. This protocol is applicable to a wide range of people, with few complications, and has become one of the commonly used protocols in our center in recent years. However, the risk of Elevated serum progesterone (P) level on trigger day in GnRH-ant cycles is significantly higher than that of agonist cycles [Citation2], which not only affect oocyte [Citation3] and embryo quality [Citation4–5], but also impair endometrial receptivity [Citation2,Citation6–8], leading to the need to increase freezing cycle rates for whole embryos freezing. To explore the accurate predictors of P elevation on trigger day in GnRH-ant cycles is of great significance. Body mass index (BMI) is an important reference factor in individualized treatment of controlled ovarian hyperstimulation (COH) and can be used as an important index to predict ovarian response [Citation9]. However, there is no report on the correlation between BMI and P level on trigger day in GnRH-ant cycles. In this paper, we aim to explore the relation between BMI and P level on trigger day in GnRH-ant treated patients.
Methods
Patient population and inclusion criteria
This study was a retrospective cohort study. From October 2017 to April 2022, 412 patients who were treated with GnRH-ant protocol for COH in the reproductive center of our hospital were selected as the research objects. According to BMI classification criteria [Citation10–11], patients who met the inclusion criteria were divided into three groups: normal weight group (n = 230): 18.5 kg/m2 ≤ BMI < 24 kg/m2; overweight group (n = 122): 24 kg/m2 ≤ BMI < 28 kg/m2; Obesity group (n = 60): BMI ≥ 28 kg/m2.
Inclusion criteria: (1) Serological examination indicated normal liver function; (2) The GnRH-ant protocol was used for COH in this cycle; (3) In-vitro fertilization (IVF)/Intracytoplasmic sperm injection (ICSI)/Rescue ICSI cycles in our center.
Exclusion criteria: (1) cycle cancellation due to low response, poor compliance and other reasons; (2) Patients with basal p ≥ 1.5 ng/mL; (3) Patients with BMI < 18.5 kg/m2; (4) Cycles of important statistical data Missing.
Detection of sex hormone
Venous blood samples were collected during 8:00–9:00 am on the 2nd to 3rd day of the natural menstrual cycle and on the trigger day of controlled ovarian hyperstimulation (COH) respectively for detection of female basic sex hormones (FSH/LH//E2/P). Siemens automatic chemiluminescence immunoanalyzer (ADVIA Centaur CP) was used for detection, and direct chemiluminescence immunoassay kit was provided by Siemens Medical Diagnostic Products (Shanghai) Co., LTD.
Controlled ovarian hyperstimulation (COH)
On the 2nd to 3rd day of the natural menstrual cycle, According to the patient’s age, BMI, basic FSH and other conditions, patients were injected 75–375 IU of recombinant human follicle-stimulating hormone (Guonafine, Merck Serono, Germany) or urine gonadotrophin (HMG, Zhuhai Lizhu Pharmaceutical co., LTD., China). On the 6th day of the natural menstrual cycle, patients were given Cetrorelix Acetate Powder for Injection (Cetrotide, Baxter Oncology GmbH, Germany) 0.25 mg/day until the trigger day. When the diameter of one dominant follicle was ≥20 mm, the diameters of two to three follicles were ≥18 mm, or More than two-thirds of the follicles were larger than 16 mm in diameter, 6000–10,000 IU of human chorionic gonadotropin (HCG, Zhuhai Lizhu Pharmaceutical co., LTD., China) was injected, and 36 h later, oocytes were harvested by ultrasound-guided vaginal puncture.
Index of observation
The basic data of patients included female age, duration of infertility, type of infertility, infertility factors, body mass index (BMI) and basal FSH/LH/E2/P levels. The included clinical data included days of FSH, total FSH amount, days of HMG, total HMG amount, Gn initiation dose, and serum LH/E2/P levels on trigger day.
Statistical analysis
SPSS 26.0 software was used for statistical analysis. The schapiro-Welk (K-W) method was used to test the normality of measurement data. Because of non-normal distribution, the measurement data were expressed as the median (25th percentile, 75th percentile) M (P25, P75), differences in groups were performed using the Kruscarl-Wallis H (K) test. The count data were expressed by composition ratio, Pearson chi-square test was used for comparison in groups. Multivariate logistic regression analysis was used to evaluate the effect of BMI on P level on trigger day in GnRH-ant cycles after adjustment for confounding factors. The confounding factors were tested by univariate logistic regression analysis, and then corrected by multivariate logistic regression model. The variables with p < .10 in univariate analysis (BMI, basal FSH, basal P, FSH days, Gn starting dose, and E2 level on trigger day) and variables that may influence P levels on trigger day (infertility factors, basal LH, total FSH dose, HMG days, and total HMG dose) were incorporated into the multiple logistic regression model to analysis the effect of BMI on P level on trigger day in GnRH-ant cycles. Using normal weight group as the control group, Odds ratios (ORs) and 95% confidence intervals (CI) were calculated before and after P-level on trigger day adjustment. All tests were two-sided, and p < .05 was considered statistically significant.
Results
Overall data
From October 2017 to April 2022, the number of IVF/ICSI cycles using GnRH-ant protocol for COH in the reproductive center of our hospital was 464. Twelve patients with IVF cancellation, 20 patients with basic p ≥ 1.5 ng/mL, and 16 patients with BMI < 18.5 kg/m2, four cycles with missing important statistics were excluded. and 412 IVF/ICSI cycles were finally included. In 118 of 412 cycles, serum P level on trigger day exceeded the threshold (p ≥ 1.5 ng/mL).
Basic patient characteristics and clinical data
There were significant differences in infertility factors, BMI, basal FSH and LH levels, FSH days, total FSH dose, HMG days, total HMG dose and P levels on trigger day among the three groups (p < .05). The cycle number of ovulatory Disorders in obesity group was more significantly than that in normal group (p < .05); the cycle number of diminished ovarian reserve in overweight group was less significantly than that in normal group (p < .05); the cycle number of other infertility factors in obesity group was less significantly than those in normal group and overweight group (p < .05). The BMI in overweight group and obesity group were both higher significantly than that in normal group (p < .05); the BMI in obesity group was higher significantly than that in overweight group (p < .05). The basal FSH level in overweight group and obesity group were both lower significantly than that in normal group (p < .05). The basal LH level in overweight group and obesity group were both lower significantly than that in normal group (p < .05); the basal LH level in obesity group was lower significantly than that in overweight group (p < .05). The FSH days in obesity group was longer significantly than that in normal group (p < .05). The total FSH dose in obesity group was larger significantly than those in normal group and overweight group (p < .05). The HMG days and total HMG dose in overweight group and obesity group were both more significantly than that in normal group (p < .05). The P levels on trigger day in overweight group and obesity group were both lower significantly than that in normal group (p < .05). There were no significant differences among the three groups in female age, duration of infertility, type of infertility, basal E2 and P levels, Gn starting dose, LH and E2 levels on trigger day (p > .05) ().
Table 1. Basic patient characteristics and clinical data [M(P25,P75), n(%)].
Logistic regression analysis of factors related to P level on trigger day
Using P level on trigger day as the dependent variable (1= ≥1.5 ng/L, 0= < 1.5 ng/L), six factors with p < .10 (BMI, basal FSH, basal P, FSH days, Gn starting dose and serum E2 on trigger day) in univariate analysis and five other indicators that may affect P level on trigger day (infertility factors, basal LH, FSH total dose, HMG days and HMG total dose) as independent variables for multivariate Logistic regression analysis. The results of regression analysis showed that the probability of serum P elevation on trigger day in overweight and obese group was 0.434 and 0.199 times as much as that in normal weight group, respectively (OR = 0.434 and 0.199, p < .05). Basal P level and E2 level on trigger day were also significantly correlated with P elevation on trigger day (OR = 3.475 and 1.000, p < .05). Other variables had no correlation with P elevation on trigger day (p > .05) ().
Table 2. Logistic regression analysis of factors related to P level on trigger day.
Discussion
Our study analyzed the effect of BMI on P level on trigger day in GnRH-ant cycles. Since there was currently no uniform standard for the threshold of P elevation on trigger day in GnRH-ant cycles, we set it as 1.5 ng/L according to relevant reports [Citation12–13]. BMI, basal FSH, basal P, FSH days, Gn starting dose, serum E2 on trigger day, infertility factors, basal LH, total FSH dose, HMG days and total HMG dose were used as confounding factors to correct P level on trigger day. The results showed that BMI was negatively correlated with P level on trigger day in GnRH-ant cycles, and the higher the BMI, the lower the risk of P elevation (≥1.5 ng/L) on trigger day, suggesting that for patients with normal BMI, the risk of P elevation on trigger day in GnRH-ant cycles increase.
Previous studies at home and abroad have shown that BMI can be used as an important predictor of ovarian response. In 2008, Matalliotakis et al. [Citation14] analyzed the data of 291 IVF cycles and showed that compared with patients with BMI ≤ 24 kg/m2, the Gn total dose was higher and the number of follicles and oocytes retrieved were fewer in patients with 24 kg/m2 (p < .05). In 2015, Ozekinci et al. [Citation15] conducted a retrospective cohort study on 298 cycles (women younger than 38 years old) undergoing IVF-ICSI, and divided the 298 cycles into three groups according to women’s BMI (normal weight group: 18.5 ≤ BMI < 25 kg/m2, 164 cycles; overweight group: 25 ≤ BMI < 30 kg/m2, 70 cycles; obesity group: BMI ≥ 30kg/m2, 64 cycles). Because low weight group (BMI < 18.5 kg/m2) had only 22 cycles, the study excluded low weight group and showed that women in obesity group had greater total Gn dose and longer Gn duration than those in normal weight group (p < .05). Another retrospective analysis [Citation16] included 631 cycles of IVF/ICSI treated with standard long protocol, and the results showed that high BMI resulted in low LH and E2 levels in the late follicular phase, decreased oocyte number and poor oocyte quality. A large sample size study by Jin Haixia et al. [Citation17] in 2019 also showed that high BMI in women of childbearing age would lead to increased Gn dose. In 2018, Chalumeau et al. [Citation18] retrospectively analyzed the related data of the first ovarian stimulation cycle of 494 patients who used GnRH antagonist and recombinant FSH. A progressive discriminant analysis was used to establish scores that included key clinical and biological parameters for predicting ovarian response (as validated in a prospective independent study of 257 patients undergoing the first cycle of ovarian stimulation), and data showed an inverse association between BMI and ovarian response. In conclusion, although the ovulation induction protocols of the above studies were different and the BMI grouping basis was not completely unified, all of them concluded that high BMI would lead to the increase of total Gn dose and prolonged ovulation induction time. Our data also showed that as BMI increased, FSH and HMG consumption increased and FSH and HMG days increased. However, our data did not show the differences in LH level and E2 level on trigger day among different BMI groups, which was inconsistent with the conclusion of Henry Li et al. [Citation16], possibly because of the differences in basal FSH and LH levels among different BMI groups, or the influence of ovulation induction protocol.
Previous studies do not involve the correlation analysis between BMI and P level on trigger day in GnRH-ant cycles. Our results showed that there were significant differences in P levels on trigger day among three groups (p < .05). Regression analysis excluding the influence of confounding factors showed that the probability of serum P elevation on trigger day in overweight and obesity group were 0.434 and 0.199 times respectively as much as that in normal weight group (OR = 0.434 and 0.199, p < .05), which further confirmed that BMI was negatively correlated with P level on trigger day.
Women can continuously secrete P throughout the menstrual cycle. Serum P in the early follicular phase is mainly from the adrenal gland, while serum P in the late follicular phase is mainly from the ovary, and the rise rate of P in the late follicular phase is faster than that in the early follicular phase [Citation19]. P is mainly synthesized by granulosa cells in ovary. With the growth and development of follicles, granulosa cells proliferate and the number of FSH receptors increases. FSH induces granulosa cells to form LH receptors and produce P under the action of LH [Citation19]. The granulosa cells in the early follicular phase only have FSH receptor, but no LH receptor, so the P of ovarian synthesis is very small, P is mainly from the adrenal gland. The synthesized P is mainly metabolized in the liver. In the process of COH, large doses of exogenous gonadotropin (Gn) promote the simultaneous development of multiple follicles, and the total amount of P synthesized by follicles far exceeds the natural cycle [Citation20], resulting in an early increase of P in the late follicular stag [Citation21]. Patients with high BMI have lower FSH receptor and LH receptor activity on granulosa cells of ovaries, leading to reduced Gn sensitivity, and relatively less P synthesis. Therefore, increased BMI will reduce the risk of P elevation on trigger day in GnRH-ant cycles.
In conclusion, through univariate and multivariate logistic regression analysis, our data showed that the risk of P elevation on trigger day in GnRH-ant cycles decreased with the increase of BMI, and BMI could be used as one of the predictors of P level on trigger day in GnRH-ant cycles. Therefore, for patients with normal BMI, in order to reduce the negative effects to embryo quality and endometrial receptivity of P elevation on trigger day, try not using GnRH-ant protocol in COH. However, due to the small sample size of low weight group (BMI < 18.5), patients with BMI < 18.5 were excluded from this study, and the conclusion may not be applicable to all patients. In addition, some basic data and clinical data of patients in different BMI groups in this study were significantly different. Although confounding factors were used to correct P level on trigger day, the small sample size may affect the statistical efficiency. Finally, this study is a single-center retrospective study, which may have the problem of heterogeneity in the study population, and the level of evidence is not as high as that of randomized controlled studies. The conclusion of our study still needs to be further confirmed by a prospective study with a large sample size of multi-center.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Additional information
Funding
References
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