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Letrozole co-treatment in an antagonist protocol for overweight women undergoing IVF treatment: a retrospective study

BMC Pregnancy and Childbirth volume 24, Article number: 592 (2024) Cite this article

Abstract

Background

Overweight women undergoing IVF treatment have lower success rates. Letrozole, an aromatase inhibitor, has been used as an adjunct for IVF treatment, but its specific effects in overweight women have not been investigated. This study was to explore the effects of letrozole co-treatment in an antagonist protocol for overweight infertile women undergoing IVF treatment.

Methods

This retrospective cohort study included overweight infertile women who underwent IVF/ICSI treatment and fresh embryo transfer (ET), with or without letrozole co-treatment in an antagonist protocol, from 2007 to 2021 at Shanghai Ninth People’s Hospital (Shanghai, China). A total of 704 overweight infertile women were included: 585 women were in the antagonist group, and 119 women were in the letrozole co-treatment group. The primary outcome was the live birth rate after fresh ET. Propensity score-based patient-matching was employed to balance the covariates between the groups. Multivariate logistic regression analysis was also performed to estimate odds ratio (OR) and 95% confidence interval (CI) for association of letrozole co-treatment and the live birth outcome.

Results

Letrozole co-treatment induced significant changes in hormonal profile on the trigger day. The letrozole group exhibited a decrease in the total number of follicles compared to the antagonist group, but a higher proportion of large follicles at oocyte retrieval (P < 0.05). The quantity and quality of embryos were comparable between the two groups (P > 0.05). The letrozole co-treatment group had a significantly higher live birth rate than the control group (38.7% vs. 22.6%, P = 0.026). With multivariate logistic regression analysis, letrozole co-treatment was associated with higher odds of live birth after adjusting for potential confounding factors (adjusted OR = 2.00, 95% CI = 1.17–3.39, P = 0.011). Letrozole presented no significant associations with obstetrical or neonatal complications (P > 0.05).

Conclusion

Letrozole co-treatment in an antagonist protocol may offer potential benefits for overweight infertile women undergoing IVF treatment. Further research is warranted to validate these findings and explore the broader implications for letrozole co-treatment.

Peer Review reports

Background

Driven by rapid social development, a shift towards a more sedentary lifestyle, and a dietary transition towards processed foods and high-calorie diets, the prevalence of overweight and obesity has surged in recent years [1]. This increase has not only led to various health complications but has also contributed to a rise in infertility cases [2]. It has been reported that the likelihood of pregnancy during a given cycle is reduced by 18% in women with obesity and 8% in women with overweight [3]. Studies have indicated that obese women, compared to women of normal weight, face poorer in vitro fertilization (IVF) outcomes, including insufficient ovarian responsiveness to gonadotrophin stimulation, higher doses of medication, an increased risk of cycle cancellation, and a decreased likelihood of implantation, clinical pregnancy, and live birth [4,5,6,7]. Female overweight/obesity has also been clearly associated with several adverse pregnancy outcomes, such as premature delivery, low birth weight, miscarriage, abnormal labor, and postpartum complications [8,9,10].

Letrozole, a third-generation aromatase inhibitor, effectively reduces estrogen levels and elevates androgen levels by inhibiting the conversion of androgens to estrogens [11]. Currently, letrozole is widely used as an adjunct for IVF treatment to enhance follicular response and improve oocyte quality [12]. Recent research has underscored the influence of letrozole co-treatment extending into the luteal phase, mitigating the detrimental effects of cumulative estradiol concentrations and facilitating embryo transfer in a more natural hormonal and uterine environment [13, 14]. However, the impact of letrozole on IVF outcomes in overweight/obese women in the context of IVF/ICSI remains underexplored.

This retrospective study aims to address these research gaps by investigating the effects of letrozole co-treatment in an antagonist protocol for overweight infertile women undergoing IVF treatment.

Methods

Study design and participants

The study was a retrospective cohort study conducted in Shanghai Ninth People’s Hospital of Shanghai Jiao Tong University School of Medicine (Shanghai, China) between 2007 and 2021. The study population consisted of overweight women who underwent IVF/ICSI treatment and fresh embryo transfer (ET), with or without letrozole co-administration, following a gonadotropin-releasing hormone (GnRH) antagonist protocol. Overweight was defined as a pregestational body mass index (BMI) ≥ 25 kg/m2. Women were excluded if they had repeated IVF/ICSI attempts, recurrent spontaneous abortion, chromosomal abnormalities, or incomplete data. The study was approved by the Institutional Review Board of Shanghai Ninth People’s Hospital. Clinical data were extracted from electronic medical records.

Study procedures

In the letrozole co-treatment group, participants received letrozole at a daily dosage of either 2.5 mg or 5 mg for a duration of 5 consecutive days, starting from day 2–3 of the menstrual cycle. The letrozole dosage was determined based on patient’s characteristics and physician’s preference. Additionally, they were administered gonadotropin at a dosage of 75–300 IU per day, starting from day 2–3 and continuing until the trigger day. In the GnRH antagonist group, participants received gonadotropin at a dosage of 75–300 IU per day, starting from day 2–3 of the menstrual cycle and continuing until the trigger day, without the co-treatment of letrozole. In both groups, the administration of GnRH antagonist was initiated when the dominant follicle reached ≥ 13–14 mm or when there was a significant upward trend in the serum luteinizing hormone (LH) level.

To induce final oocyte maturation, triptorelin 0.1 mg and human chorionic gonadotropin (hCG) 2000 IU were administered when at least two leading follicles reached ≥ 18 mm in diameter. Oocyte retrieval was performed 34–36 h after the hCG injection, and IVF or ICSI was performed as clinically appropriate. A fresh ET was conducted according to clinical practice, with any surplus embryos vitrified for subsequent frozen-thawed embryo transfer. All patients received luteal support post-ET.

Hormonal levels of oestradiol (E2), progesterone (P), follicle-stimulating hormone (FSH), and LH were collected at the start of stimulation and on the day of ovulation trigger. A positive pregnancy test was defined as positive serum β-hCG measured 14 days after ET. Clinical pregnancy was determined by transvaginal ultrasound showing at least one intrauterine gestational sac 35 days after ET. Miscarriage was defined as spontaneous loss of a clinical pregnancy before 24 weeks of gestation. Live birth was defined as the delivery of at least one live-born infant, irrespective of gestational duration.

Outcome measures

The primary outcome of the study was the live birth rate after fresh ET. Secondary outcomes included hormone parameters, ovarian stimulation outcomes, and pregnancy outcomes. Obstetrical and neonatal information were evaluated for live births resulting from fresh ET cycles, such as twin pregnancy, hypertensive disorders in pregnancy, gestational diabetes, placental previa, preterm premature rupture of the membranes, cesarean delivery, neonatal death, birth defects, a composite of neonatal morbidity (neonatal jaundice, pneumonia, necrotizing enterocolitis, respiratory distress syndrome, sepsis, hypoxic ischemic encephalopathy), gestational age, and birth weight.

Statistical analyses

The distributions of continuous variables were assessed by the Shapiro-Wilk test. Normally distributed variables were presented as means and standard deviations and were compared with Student’s t-tests. Categorical variables were presented as numbers and proportions and were compared with Chi-square test. Non-normally distributed endocrine measurements were reported as medians (interquartile ranges) and were compared using Student’s t-tests on log-transformed concentrations. Several potential confounders were considered and adjusted for in the analysis, including maternal age, BMI, gravidity, parity, infertility cause, infertility duration, antral follicle count (AFC), polycystic ovary syndrome (PCOS) status, history of failed IVF or ET attempts, fertilization method, and number or stage of embryo transferred. A propensity score-based patient-matching (PSM) model was employed to achieve a better balance of covariates between the two groups. Participants with and without letrozole co-treatment were matched based on estimated propensity scores derived from a binary logistic regression analysis. The matching ratio was set at 1:1, with a caliper of 0.05. Covariates were considered well-balanced when the standardized difference was below 5% (see Additional file 1). Subsequently, the effect of letrozole co-treatment was estimated in the matched cohort. Multivariate logistic regression analysis was performed to estimate odds ratio (OR) and 95% confidence interval (CI) for association of letrozole co-treatment and the live birth outcome.

The statistical analyses were conducted using R v 4.2.2. A two-sided P-value of less than 0.05 was considered statistically significant.

Results

A total of 704 overweight infertile women who underwent IVF/ICSI and fresh ET treatment were included in the study. Among them, 585 women were in the GnRH antagonist group, and 119 women were in the letrozole co-treatment group. The baseline characteristics of the participants before and after PSM are summarized in Table 1. After PSM, both groups were comparable for age, BMI, gravidity, parity, infertility cause, infertility duration, AFC, PCOS status, and history of failed IVF or ET attempts (P > 0.05).

Table 1 Study participant characteristics before and after PSM
Full size table

The cyclic changes in hormone parameters are illustrated in Fig. 1. There were no significant differences in the baseline levels of E2, P, FSH, and LH between the two groups (P > 0.05). As expected, the letrozole co-treatment caused a significant suppression of E2 concentrations on the trigger day (435 [236, 852] vs. 1923 [1061, 2747], P < 0.001). The letrozole group also exhibited significantly lower FSH concentration (10.4 [8.57, 13.1] vs. 11.8 [10.2, 14.1], P = 0.001) and higher LH concentration (2.76 [1.79, 4.73] vs. 1.69 [0.93, 2.66], P < 0.001) compared to the antagonist group. There were no significant differences between the two groups in terms of P levels (0.5 [0.3, 0.8] vs. 0.3 [0.3, 0.6], P = 0.080). During the ovarian stimulation, patients receiving letrozole co-treatment experienced lower gonadotropin consumption (1595 ± 811 vs. 2481 ± 804, P < 0.001) and shorter stimulation duration (8.53 ± 1.97 vs. 9.81 ± 1.81, P < 0.001) than the control group (Table 2).

Fig. 1
figure 1

Hormone profiles measured in ovarian stimulation with and without letrozole co-treatment. Hormone levels were assessed at the start of ovarian stimulation and on the day of the ovulation trigger. The data are presented using green box plots (GnRH antagonist group) and red box plots (letrozole co-treatment group). Statistical significance is indicated as ‘**’ for P < 0.01 and ‘***’ for P < 0.001. E2, oestradiol; FSH, follicle-stimulating hormone; LH, luteinizing hormone; P, progesterone

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Table 2 Stimulation and IVF outcome after PSM
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The follicle development and embryonic parameters were evaluated, and the findings are presented in Fig. 2. After PSM, there was no significant difference in AFC between the groups (12.0 ± 7.78 vs. 13.2 ± 7.47, P = 0.298). However, the letrozole group exhibited a decrease in the total number of follicles compared to the antagonist group (9.70 ± 6.67 vs. 14.5 ± 7.71, P < 0.001; Fig. 2). Notably, there was a significant difference in the percentage of large follicles at oocyte retrieval, with a higher proportion of follicles > 16 mm observed in the letrozole group (47% vs. 34%, P < 0.001; Fig. 2). Administration of letrozole resulted in a reduced number of retrieved oocytes (6.59 ± 4.58 vs. 8.90 ± 7.06, P = 0.009; Fig. 3), leading to a subsequent decrease in the number of matured and fertilized oocytes, as well as cleaved embryos (Fig. 3). However, this difference did not impact the number of usable embryos (2.95 ± 1.91 vs. 3.46 ± 2.32, P = 0.099; Fig. 3) or the number of good-quality embryos (2.53 ± 2.06 vs. 2.86 ± 2.51, P = 0.324; Fig. 3). Compared to the control group, the letrozole group demonstrated a higher oocyte retrieval rate (83% vs. 76%, P = 0.016), comparable oocyte maturation rate (78% vs. 83%, P = 0.118), similar fertilization rate (80% vs. 79%, P = 0.799), and higher usable embryo rate (82% vs. 70%, P = 0.002).

Fig. 2
figure 2

Hormone profiles measured in ovarian stimulation with and without letrozole co-treatment. Comparison of the number of follicles and the percentage of follicles categorized by size. The data are depicted using green bars (GnRH antagonist group) and red bars (letrozole co-treatment group). A color gradient from light purple to dark purple corresponds to the follicle size (> 16 mm, 14–16 mm, 12–14 mm, 10–12 mm, and < 10 mm), respectively

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Fig. 3
figure 3

Hormone profiles measured in an antagonist protocol with and without letrozole co-treatment. Comparison of the numbers of retrieved, matured, and fertilized oocytes, as well as the numbers of cleaved, usable, and good-quality embryos. The data are depicted using green bars (GnRH antagonist group) and red bars (letrozole co-treatment group). Statistical significance is indicated as ‘**’ for P < 0.01

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Pregnancy outcomes are summarized in Table 2. There were no significant differences in the number or stage of embryo transferred between the two groups (P > 0.05). The endometrial thickness on the day of transfer was similar in both groups (11.9 ± 3.16 vs. 13.4 ± 1.94, P = 0.139). The clinical pregnancy rate after fresh ET was higher in the letrozole group than the control group, though the difference was not statistically significant (45.2% vs. 32.3%, P = 0.098). Similarly, the miscarriage rate was lower in the letrozole group, but this difference was also not significant (7.1% vs. 20.0%, P = 0.151). However, the letrozole co-treatment group exhibited a significant higher live birth rate (38.7% vs. 22.6%, P = 0.026). The logistic regression analysis continued to support a strong association between letrozole co-treatment and increased odds of live birth. The crude OR was 1.95 (95% CI = 1.27–2.96, P = 0.003) initially, and after adjusting for potential confounding factors, the association remained significant with an adjusted OR of 2.00 (95% CI = 1.17–3.39, P = 0.011).

Regarding obstetrical and neonatal outcomes (Table 3), there were no significant associations between letrozole co-treatment and twin pregnancy, hypertensive disorders in pregnancy, gestational diabetes, placental previa, preterm premature rupture of the membranes, or cesarean delivery (P > 0.05). Additionally, there were no significant differences between the two groups in terms of gestational age (preterm birth, very preterm birth), birth weight (low birth weight, very low birth weight, macrosomia, large for gestational age, small for gestational age), neonatal death, birth defects, or a composite of neonatal morbidity (including neonatal jaundice, necrotizing enterocolitis, pneumonia, respiratory distress syndrome, sepsis, and hypoxic ischemic encephalopathy) (P > 0.05).

Table 3 Associations between letrozole co-treatment and maternal/neonatal complications
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Discussion

Our study revealed that the co-administration of letrozole in an antagonist protocol for overweight women undergoing IVF/ICSI and fresh ET treatment was associated with a higher live birth rate. Letrozole co-treatment induced significant hormonal changes, increasing the proportion of large follicles at oocyte retrieval while decreasing the number of retrieved oocytes. The quantity and quality of embryos, however, were comparable between the two groups. Additionally, letrozole administration led to a reduction in the gonadotropin consumption and treatment days.

Studies comparing the reproductive outcomes of letrozole co-treatment have reported conflicting results. A meta-analysis involving 656 women revealed no significant impact of letrozole co-treatment on live birth outcomes [15]. While several studies on poor responders demonstrated a significant beneficial effect of letrozole [16, 17], others did not observe a discernible difference in live birth rate [18,19,20,21]. In a study involving high responders (n = 130), letrozole showed no significant impact on live birth outcome [22]. Some trials comparing the effects of letrozole for normal responders did not find statistically significant differences in the ongoing pregnancy rate and cumulative live birth rate [13, 23]. However, the generalizability of these studies is limited by small sample sizes and diverse practices in terms of ovarian stimulation protocols, initial gonadotropin doses, and trigger criteria across the studies. The existing literature on the impact of letrozole on live birth outcomes among overweight/obese women remains sparse. There is increasing evidence demonstrating that female obesity is linked to adverse pregnancy outcomes following IVF procedures [7]. Considering the global epidemic of overweight/obesity and the rising rates of IVF/ICSI treatments, it is imperative to investigate the interrelationship between the letrozole co-administration, overweight/obesity, and treatment outcomes. Our findings indicated that letrozole co-treatment resulted in a higher live birth rate after fresh ET in overweight women. Such insights could be valuable for clinicians and reproductive researchers when evaluating overweight/obese patients, who may be at risk of compromised pregnancy outcomes. However, since our results were derived from a specific population within a single IVF center, they should be interpreted with caution.

Obesity is considered a complex chronic disease affected by genetic, environmental, and behavioral determinants [24]. The mechanism by which obesity contributes to infertility is multifactorial, primarily attributed to functional alterations in the hypothalamic-pituitary-ovarian axis [25]. Previous studies have linked increased BMI to a higher risk of insufficient follicle development, increased FSH requirement in ovarian stimulation for IVF [26, 27], dysregulation of meiotic spindle formation [28], and compromised developmental ability [29]. Letrozole has been found to improve the follicular response to FSH by elevating androgen levels and reducing estrogen levels [30]. Our analysis of endocrine parameters demonstrated that letrozole effectively suppressed E2 levels and upregulated LH levels on the trigger day in overweight women, consistent with previous studies investigating letrozole administration [13, 17, 31,32,33]. Contradicting other studies [13, 33], our research revealed a significantly lower FSH concentration in the letrozole co-treatment group. Additionally, we observed lower gonadotropin consumption and shorter stimulation time in women co-treated with letrozole, supporting the notion of increased follicular sensitivity to exogenous FSH induced by letrozole [31, 34, 35]. The observed increase in the proportion of large follicles following letrozole co-administration aligns with prior investigations on poor- and normo-responders [30, 32]. Despite the decreased number of retrieved oocytes in the present study, we did not detect any difference in the number of usable embryos and good-quality embryos, indicating a potential improvement in the quality of oocytes and embryos during letrozole co-treatment.

The improved reproductive outcomes following letrozole co-treatment may be ascribed to several factors. Firstly, letrozole enhances follicular response and improves oocyte quality by sensitizing follicles to exogenous FSH and/or stimulating endogenous FSH production [36]. Higher levels of LH induced by letrozole support the selection of dominant follicles and promote follicle growth after the initiation of diameter deviation [37, 38]. Letrozole also triggers the accumulation of androgens, augmenting follicular sensitivity to FSH and promoting early follicular growth through the overexpression and sensitization of FSH receptors [39]. Moreover, androgens have been found to attenuate follicular atresia [40]. Secondly, letrozole co-administration during the follicular phase diminishes luteal pituitary suppression and has a prolonged impact on serum progesterone, LH, and androgens during the luteal phase [13]. Thirdly, decreased estrogen levels reduce the ubiquitination of estrogen receptors, leading to the up-regulation of estrogen receptors and increased sensitivity to subsequent estrogen rise. This process results in accelerated endometrial proliferation and increased blood flow in the uterus and endometrium [41]. Fourthly, letrozole may improve endometrial receptivity by enhancing the expression of integrin, leukemia inhibitory factor, and L-selectin [42]. Lastly, recent studies have explored the impact of adjuvant letrozole on lipid and glucose metabolism. A study in China demonstrated that letrozole treatment significantly decreased serum triglyceride levels and the homeostatic model assessment of insulin resistance (HOMA-IR) value in infertile women with PCOS [43]. Further investigations are still required to explore the potential mechanisms of letrozole-induced effects.

PCOS is a multifactorial disorder defined by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries, which is closely linked to decreased fertility potential due to impaired oocyte, embryo, and endometrial competence, as well as an increased risk of pregnancy complications [44,45,46,47]. Obesity is neither a necessary nor sufficient factor for the PCOS phenotype, and the correlation between obesity and PCOS varies across different national, cultural, and ethnic populations [48]. Previous investigation revealed that incorporating letrozole into the antagonist protocol for women with PCOS resulted in a higher proportion of large follicles and a lower overall number of retrieved oocytes, while achieving comparable pregnancy outcomes [49]. Currently, there is a lack of literature comparing letrozole use as an adjuvant therapy in obese PCOS and non-PCOS patients.

Previous studies have indicated that the use of letrozole during IVF does not present an increased risk of major congenital defects or compromise neonatal outcomes [50, 51]. Our findings revealed that the co-treatment of letrozole did not demonstrate any significant associations with obstetrical or neonatal complications and continued to support its safety profile. Some studies have reported a negative correlation between BMI and pregnancy complications such as gestational diabetes and hypertensive disorders in pregnancy [52]. Co-treatment with letrozole during ovarian stimulation restricts the supra-physiological estrogen rise, potentially contributing to an optimal uterine environment with downstream implications for improved placentation and better maternal outcomes. However, further research with larger sample sizes is necessary to validate this concept.

This analysis was subject to certain limitations, including potential selection bias, a limited sample size, non-standardized gonadotropin doses, unmeasured hormone profiles in the luteal phase, and the focus on live birth rate following fresh ET as the primary outcome. Given that the cumulative live-birth rate is the gold standard for evaluating outcomes, future studies should continue to collect data on outcomes from subsequent frozen embryo transfers to more accurately assess the impact of letrozole in this population. Despite these limitations, this study addresses a gap in the literature by examining the endocrine features and treatment outcomes of letrozole in overweight patients undergoing IVF.

Conclusion

This study suggests that letrozole could serve as an adjuvant treatment in the antagonist protocol to improve the live birth rate following fresh ET in overweight patients. Co-treatment with letrozole effectively mitigates supraphysiological estrogen levels, elevates the proportion of large follicles at oocyte retrieval, and reduces the dosage and duration of gonadotropin administration. Nevertheless, due to the constraints of the study size, larger randomized controlled trials are required for a more comprehensive understanding of letrozole’s impact on clinical outcomes.

Data availability

All data sharing and collaboration requests should be directed to the corresponding author.

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Acknowledgements

We sincerely thank our colleagues for their assistance and support. We appreciate all patients who participated in this study.

Funding

This study was funded by the National Natural Science Foundation of China (Grant No. 82271693).

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Authors and Affiliations

  1. Center for Reproductive Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jing Lin

  2. Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Fenglu Wu, Yanwen Zhu, Bian Wang & Jiaying Lin

  3. Department of Gynaecology and Obstetrics, Shanghai Putuo People’s Hospital of Tongji University, Shanghai, China

    Zhengjun Cao

Authors
  1. Jing Lin
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  2. Fenglu Wu
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  3. Yanwen Zhu
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  4. Bian Wang
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  6. Jiaying Lin
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Contributions

Jing Lin and Jiaying Lin conceived and designed the protocols. Fenglu Wu, Yanwen Zhu, and Bian Wang collected data. Jing Lin conducted the analysis and interpreted the results. Jing Lin and Jiaying Lin drafted and revised the manuscript. Zhengjun Cao and Jiaying Lin supervised the study. Jiaying Lin obtained the project funding.

Corresponding authors

Correspondence to Zhengjun Cao or Jiaying Lin.

Ethics declarations

Ethics approval and consent to participate

The Institutional Review Board and the Ethics Committee of Shanghai Ninth People’s Hospital approved the study. Due to the retrospective nature of the study and the use of deidentified data, informed consent was waived by the Institutional Review Board of Shanghai Ninth People’s Hospital.

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Not applicable.

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The authors declare no competing interests.

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12884_2024_6795_MOESM1_ESM.pdf

Supplementary Material 1: Additional file 1 (PDF): Supplementary Figure S1. Comparison for imbalance of covariates in the original and the adjusted (weighted) cohorts.

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Lin, J., Wu, F., Zhu, Y. et al. Letrozole co-treatment in an antagonist protocol for overweight women undergoing IVF treatment: a retrospective study. BMC Pregnancy Childbirth 24, 592 (2024). https://doi.org/10.1186/s12884-024-06795-3

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  • DOI: https://doi.org/10.1186/s12884-024-06795-3

Keywords

BMC Pregnancy and Childbirth

ISSN: 1471-2393

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