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Elevated prolactin levels before endometrial transformation negatively impact reproductive outcomes in frozen embryo transfer cycles under hormone replacement therapy

BMC Pregnancy and Childbirth volume 25, Article number: 245 (2025) Cite this article

Abstract

Introduction

Prolactin (PRL) plays a key role in the regulation of reproductive functions. However, its impact on outcomes in infertility women undergoing assisted reproductive technology remains unclear. This study aimed to examine the relationship between PRL levels and reproductive outcomes in frozen embryo transfer (FET) cycles under hormone replacement therapy (HRT).

Materials and methods

A total of 1212 FET cycles under HRT were included from a single center in Shanghai between March 2013 and June 2023. PRL levels were measured on the day before progesterone-induced endometrial transformation and participants were stratified according to the near-quartiles cut-points of PRL. Logistic regression analyses were performed to assess the associations between different PRL levels and reproductive outcomes.

Results

Live birth rate was significantly lower in the highest PRL group (> 20ng/ml) compared with the rest of the groups. In line with this, the multivariable adjusted ORs with ascending PRL categories (≤ 10.0 ng/ml, 10.1–15.0 ng/ml, 15.1–20.0 ng/ml, and > 20.0 ng/ml) for live birth rates were 1.07 (95%CI: 0.75–1.52), 1.00, 0.89 (95%CI: 0.63–1.24) and 0.53 (95%CI: 0.37–0.75), respectively. Furthermore, elevated PRL levels were also significantly associated with a reduced chance of clinical pregnancy and an increased risk of early miscarriage.

Conclusions

High PRL levels before endometrial transformation are significantly associated with poor reproductive outcomes. These findings highlight the importance of measuring PRL during endometrial preparation in HRT-FET cycles, although PRL monitoring is not usually performed during this period in current clinical routine.

Peer Review reports

Introduction

Infertility is a highly prevalent global condition, which is estimated to affect between 8 and 12% of reproductive-aged couples worldwide [1]. In the past decade, frozen embryo transfer (FET) has become increasingly adopted worldwide in modern assisted reproductive technology (ART) [2, 3], due to remarkable progress in laboratory techniques such as vitrification and blastocyst culture [4]. This trend also stems from evidence showing that FET is non-inferior to fresh embryo transfer, but with a lower risk of ovarian hyperstimulation syndrome [5, 6]. Endometrial preparation is a crucial step for successful FET in ART. Despite the lack of consensus on the optimal endometrial preparation protocol for FET cycles, artificial preparation using hormonal replacement therapy (HRT) is frequently chosen by many ART centers, as it allows scheduling of FET cycles in advance and is generally well tolerated by patients [7]. However, the success rate of HRT-FET cycles still requires further improved [8].

Prolactin (PRL) has been shown to play a primary role in the regulation of reproductive functions. In addition to its crucial role in lactation, previous studies have also demonstrated its involvement in regulating kisspeptin secretion, embryo-endometrial synchrony, decidualization, trophoblast outgrowth, and blastocyst implantation potential [9,10,11]. Moreover, recently, a growing number of other biological functions beyond reproduction have been attributed to PRL, including various aspects of metabolic homeostasis [12, 13]. Notably, the effects of PRL on reproduction are diverse, varying by the timing and target organ or cell. For example, hyperprolactinemia can lead to hypogonadotropic hypogonadism and ovulatory dysfunction, which is one of the most prevalent endocrine causes of infertility in premenopausal women [12, 14]. Conversely, basic research has revealed that PRL can stimulate blastocyst outgrowth, suggesting a potential role in improving pregnancy outcomes [15].

The impact of PRL on reproductive outcomes among infertile women undergoing assisted reproduction remains unclear. There are few relevant studies and the results were inconsistent [16,17,18,19,20], leading to uncertainty as to whether hyperprolactinemia should be treated with medication before embryo transfer. Moreover, these previous studies have mostly focused on fresh embryo transfer; to our knowledge, no studies have specifically examined the effect of PRL on outcomes in FET cycles. Notably, the use of high-dose exogenous hormones in HRT-FET cycles, a widely applied regimen, may contribute to elevated PRL levels. Therefore, based on this unresolved question, we conducted this observational study among individuals undergoing FET cycles under HRT. The main aim of this study was to evaluate the association between PRL and reproductive outcomes among HRT-FET cycles.

Methods

Study population

This is a retrospective, single-center, observational, longitudinal study conducted at the Centre of Reproductive Medicine of Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine between March 2013 and June 2023. The inclusion criteria were as follows: [1] FET cycles; [2] artificial endometrial preparation with HRT. The exclusion criteria were: [1] pituitary tumor, or previous history of pituitary surgery/ radiotherapy; [2] abnormal thyroid functions; [3] current use of medicine that may affect PRL levels including dopamine receptor antagonists and antipsychotics; [4] previous history of recurrent miscarriages, recurrent implantation failure, presence of uterine diseases (e.g. endometriosis, fibroids, polyps, müllerian abnormalities), hydrosalpinx or severe male factor; [5] without complete core data. The study was approved by the Ethics Committees of Shanghai Sixth People’s Hospital in accordance with the Declaration of Helsinki. Informed consent was obtained from each participant.

Endometrial preparation and thawed embryo transfer

Hormonal replacement for FET was achieved following a standard protocol as follows. From the third day of individual’s menstruation, all participants received 6 mg/day of oral oestradiol valerate (Progynova®, Bayer-Schering, Spain) for 10–12 days, followed by a vaginal ultrasound to determine the thickness of the endometrium. In cases of adequate endometrium thickness (≥ 8 mm), oral dydrogestrone (Dupbaston®, Abbott, Netherlands) was started at the dose of 20 mg/day and continued uninterruptedly, along with vaginal micronized progesterone (Utrogestan®, Besins, France) at 200 mg twice daily to induce endometrial transformation.

The time of embryo thaw and transfer was set as the 4th or 6th day of progesterone treatment depending on the embryo stage. Specifically, previously cryopreserved cleavage- and blastocyst- stage embryos were thawed using Kitazato kit (Kitazato Biopharma Co., Shizuoka, Japan) and transferred under ultrasound guidance. The maximum number of embryos transferred was two per participant in each FET cycle. The stage of embryos, the number of transferred embryos and the quality of embryos were recorded. Criteria for good-quality embryos were grade I and grade II embryos according to the Cummins criteria [21], or grade 4BB or higher blastocysts according to the Gardner and Schoolcraft classification [22].

After embryo transfer, luteal support was provided. A human chorionic gonadotrophin (HCG) test was measured 14 days after embryo transfer and ultrasound examination was routinely performed 28 days after embryo transfer. For women who became pregnant, hormone replacement therapy was continued under the same protocol until 12 weeks of gestation.

Clinical data and blood sampling

Individual’s information on age, gravidity, parity, duration of infertility, type of infertility, and etc. was collected through a standardized electronic medical record data collection form. Moreover, individual’s height and weight were measured through standardized methods at the outpatient visit prior to the FET. Body mass index (BMI) was calculated as weight/height2 (kg/m2).

On the day prior to endometrial transformation, a blood sample was obtained between 9 and 11 am. The PRL levels in blood samples were evaluated using a chemiluminescence assay on UniCel® DxI 800 Immunoassay System (Beckman Coulter, USA), and the intra- and inter- assay coefficients of variations were < 4% and < 6%, respectively.

Outcomes

The primary outcome of the present study was live birth rate per cycle, which was defined as the proportion of the number of deliveries that resulted in at least one live born neonate among all transfer cycles [23,24,25]. The secondary outcomes were biochemical pregnancy, clinical pregnancy and early miscarriage rate. Biochemical pregnancy was defined as a pregnancy diagnosed only by the detection of serum β-human chorionic gonadotropin (β-hCG) levels. Clinical pregnancy was defined as the presence of at least one gestational sac in ultrasound. Early miscarriage was defined as a clinical pregnancy loss before 10 completed weeks of gestational age [26, 27].

Statistical analysis

R version 4.2.1 (https://www.r-project.org) was used for the statistical analysis. Continuous variables with a normal or non-normal distribution were presented as mean ± SD or median with interquartile range (25 to 75%) respectively, and categorical variables as percentages (%). To test the trends of different risk factors across PRL categories, ANOVA tests or Jonckheere-Terpstra tests were conducted for normally or non–normally distributed continuous variables, and Cochran-Armitage tests or Pearsons chi-squared tests for categorical variables. Logistic regression analysis was performed to estimate odd ratios (ORs) for reproductive outcomes according to categories of PRL (≤ 10.0 ng/ml, 10.1–15.0 ng/ml, 15.1–20.0 ng/ml, and > 20.0 ng/ml). These three cut points were used because they were close to the 25th, 50th, and 75th percentiles of the study population. The PRL group with the largest number of cycles (10.1–15.0 ng/ml) was chosen as the reference group [28, 29]. The analyses were first carried out without adjustment (model 1), and then adjusted for age, BMI, gravidity, parity, duration of infertility, type of infertility, main infertility cause, FET cycle rank, LH levels at baseline, FSH levels at baseline, progesterone level on the day of the FET, estrogen level on the day of the FET, endometrial thickness before FET, number of embryos transferred, embryo stage at transfer, and embryo quality (model 2). Finally, further adjustments were made for baseline PRL levels (model 3). These covariates included in the multivariable model were selected based on the univariable analysis results and prior literature. Meanwhile, restricted cubic spline nested in the multivariate-adjusted logistic regression model was used to test and visualize the relationship between PRL levels and outcomes. Two-tailed P values < 0.05 were considered to indicate statistical significance.

Results

Baseline characteristics

We identified 1869 FET cycles who underwent HRT, of which 1212 fulfilling the enrollment criteria of this study were included for final analysis. The details of study flowchart are shown in Fig. 1.

Fig. 1
figure 1

Flow chart of the study

Full size image

At baseline, the mean age of the participants was 32.6 ± 4.6 years, and the mean BMI was 22.6 ± 3.4 kg/m2. The median (25th -75th percentile) PRL levels was 14.7 (10.8–19.8) ng/ml. The clinical characteristics of the study population across PRL categories are presented in Table 1. Briefly, participants with higher PRL levels before endometrial transformation exhibited lower parity and progesterone levels on the day of the FET, while number of single embryo transfer and blastocyst transfer was higher in these participants (all P for trend < 0.05).

Table 1 Clinical characteristics according to prolactin levels
Full size table

Association between PRL and reproduce outcomes

Overall, the live birth rate was 33.7% (409/1212), the biochemical pregnancy rate was 52.2% (633/1212), the clinical pregnancy rate was 43.9% (532/1212), and the early miscarriage rate was 18.6% (99/532). Live birth rate was considerably lower among those in the highest PRL category (> 20ng/ml) compared with those in other PRL categories (Fig. 2). In concert with this, after full adjustment for potential confounders in the logistic model (age, BMI, gravidity, parity, duration of infertility, type of infertility, main infertility cause, FET cycle rank, LH levels at baseline, FSH levels at baseline, PRL levels at baseline, progesterone level on the day of the FET, estrogen level on the day of the FET, endometrial thickness before FET, number of embryos transferred, embryo stage at transfer, and embryo quality), the highest PRL group (> 20ng/ml) had a reduced chance of live birth in comparison with the reference PRL group (10.1–15.0 ng/ml) (OR = 0.53, 95% CI: 0.37–0.75) (Fig. 2). Moreover, multivariable-adjusted restricted cubic spline analysis also suggested a significantly inverse association between PRL levels and live birth rates (Fig. 3). Similarly, biochemical pregnancy rate and clinical pregnancy rate were also considerably lower among those in the highest PRL category, although only the odds of clinical pregnancy show a significant difference across PRL categories after adjustment for confounders (PRL > 20ng/ml vs. PRL 10.1–15.0 ng/ml [ref.]: OR = 0.56, 95% CI: 0.40–0.78) (Table 2). Furthermore, high PRL was significantly associated with an increased risk of early miscarriage rate (PRL > 20ng/ml vs. PRL 10.1–15.0 ng/ml [ref.]: OR = 2.04, 95% CI: 1.09–3.83) (Table 2).

Fig. 2
figure 2

Odd ratios for live birth rates according to prolactin categories. Model 1 reported unadjusted ORs. Model 2 adjusted for age, BMI, gravidity, parity, duration of infertility, type of infertility, main infertility cause, FET cycle rank, LH levels at baseline, FSH levels at baseline, progesterone level on the day of the FET, estrogen level on the day of the FET, endometrial thickness before FET, number of embryos transferred, embryo stage at transfer, and embryo quality. Model 3 included model 2 variables plus prolactin levels at baseline

Abbreviation: FET, frozen embryo transfer; OR, odd ratios

Full size image
Fig. 3
figure 3

Odd ratios for live birth rates according to levels of prolactin on a continuous scale. The solid red line represents the odd ratios and the shaded red area represents 95% CI. The dashed line indicates an odd ratio of 1. Bars represent frequency (n). Analysis was adjusted for age, BMI, gravidity, parity, duration of infertility, type of infertility, main infertility cause, FET cycle rank, LH levels at baseline, FSH levels at baseline, prolactin levels at baseline, progesterone level on the day of the FET, estrogen level on the day of the FET, endometrial thickness before FET, number of embryos transferred, embryo stage at transfer, and embryo quality

Full size image
Table 2 Odd ratios for secondary reproductive outcomes according to prolactin categories
Full size table

Subgroup analyses

When the study population was stratified by selected factors, the significant inverse association between PRL and live birth rates was consistent among most subgroups, including participants with age < 35 and ≥ 35 years, BMI < 24 kg/m2, endometrial thickness before FET < 8.8 mm, single embryos transfer and double embryos transfer, and those following blastocyst transfer. There were no significant interactions of PRL with age, BMI, number of embryos transferred, and embryo stage at transfer on live birth rates. Of note, significant interaction between PRL and endometrial thickness before FET on live birth rates was observed (P for interaction = 0.003). High PRL was associated with a lower live birth rate only in those with endometrial thickness before FET < 8.8 mm (Supplementary Table 1).

Discussion

In this observational study of HRT-FET cycles, we found that high PRL levels before endometrial transformation were significantly associated with a lower live birth rate. The odds of live birth for those with PRL > 20 ng/ml was lower by 47% compared to those with PRL between 10.1 and 15.0 ng/ml. Furthermore, high PRL levels were also associated with a lower clinical pregnancy rate and high early miscarriage rate. These results outline the importance of measuring serum PRL during endometrial preparation with HRT in FET, although PRL monitoring is not routinely performed during this period.

Information regarding the association between PRL levels and pregnancy outcomes in infertile women undergoing assisted reproduction is currently scarce and conflicting. While several observational studies found a non-significant association between PRL levels and pregnancy outcomes [19, 20, 30], one subsequent study observed a positive effect of mildly elevated PRL levels on cumulated pregnancy/live birth rates [18]. Inconsistent with these findings, another observational study with small sample size reported that both higher and lower PRL levels can be detrimental to clinical pregnancy rate [16]. These inconclusive findings might be attributed to the difference in the populations studied and the various time-points chosen for PRL monitoring. Therefore, there is currently no agreement on whether to treat hyperprolactinemia with medication before embryo transfer. Compared to these previous studies, which were conducted in women undergoing in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) mostly with fresh embryo transfer or within ovulatory cycles, our study focused exclusively on FET cycles for the first time. In addition, we choose the day before endometrial transformation as the time point for PRL monitoring, as this phase plays a pivotal role in the embryo implantation and allows time for interventions. Based on our results, PRL measurement prior to endometrial transformation might become a useful tool to further optimize outcomes of FET cycles, in case a protocol with HRT for endometrial preparation is used. However, the best way to proceed in the presence of high PRL levels remains to be determined.

The underlying mechanisms behind the close association between elevated PRL levels before endometrial transformation and poor reproductive outcomes remain unclear. First of all, our observation of a close relationship between elevated PRL levels and a higher early miscarriage rate may shed some light. In line with our result, hyperprolactinemia has been reported to be associated with recurrent miscarriage in previous studies [31,32,33,34]. This might be due to the possible adverse effect of high PRL on endometrium [35, 36], embryo implantation [37], and immune intolerance [38, 39], which requires further investigation. Moreover, PRL is known to interact with other sex hormones such as progesterone and estrogen [40, 41]. Consist with this, progesterone on the day of FET showed a decreasing trend as the PRL level before endometrial transformation increased in the current study. While low progesterone levels have been demonstrated to decrease the chance of pregnancy and live birth in women undergoing FET treatment [42, 43]. However, the detailed biological mechanism still needs to be further explored, as the association between high PRL and poor pregnancy outcome remained largely significant after adjustment for covariates including endometrial thickness, progesterone and estrogen levels.

The strengths of our study include the real-world analysis of clinical practice with a follow-up to live birth, and the same standardized protocol performed by the same team. However, there are several limitations that should be noted. First, PRL levels were obtained from a single measurement. Since PRL is susceptible to many physiological conditions, future studies with multiple measurements to calculate PRL under standardized protocol are needed to validate the findings. Second, there are missing data on the treatment for hyperprolactinemia. Third, participants with hyperprolactinemia were recruited without further detection of macroprolactinemia. Therefore, the PRL measurements might be confounded by these forms of PRL, which have minimal biological activity and no known pathological functions [14]. Finally, the data used in the analyses were collected from a single center in Shanghai, which may limit the generalizability of our results. Further studies in multiple institutions were necessary to validate our findings.

In conclusion, our study showed that high PRL levels before endometrial transformation were significantly associated with poor reproductive outcomes in HRT-FET cycles. These results highlight the importance of measuring PRL levels during endometrial preparation with HRT in FET, although PRL monitoring is not usually performed during this period in routine practice. However, future studies are still needed to investigate molecular mechanisms linking high PRL to poor pregnancy outcomes. Moreover, the optimal timing for measurement and further management in the presence of high PRL values remain to be determined.

Data availability

Restrictions apply to the availability of data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. Data are however available from the authors upon reasonable request.

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Acknowledgements

The authors thank all research staff, students and patients who participated in this work.

Funding

This work was funded by the Medical Alliance for Promotion and Promotion of Clinical Competence in Reproductive Medicine (SHDC22022303-A), the Program of Shanghai Academic Research Leader (22XD1402300), the Shanghai Oriental Talent Program (Youth Project) (No. NA), the Shanghai Research Center for Endocrine and Metabolic Diseases (2022ZZ01002), and the National Key Clinical Specialty (Z155080000004).

Author information

Author notes

  1. Yaxin Wang, Fei Sheng and Li Cao contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, 600 Yishan Road, Shanghai, 200233, China

    Yaxin Wang, Li Cao, Jiaying Ni, Jingyi Lu & Jian Zhou

  2. Center of Reproductive Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China

    Fei Sheng, Meishan Wang, Yan Yang, Jiating Wang & Hongfang Shao

Authors
  1. Yaxin Wang
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  2. Fei Sheng
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  3. Li Cao
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  4. Jiaying Ni
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  5. Meishan Wang
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  6. Yan Yang
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  7. Jiating Wang
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  8. Jingyi Lu
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  9. Jian Zhou
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  10. Hongfang Shao
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Contributions

H.S. and J.Z. designed the study. Y.W., F.S., M.W., Y.Y., and J.W. collected the data. Y.W. and F.S. cleaned the data. Y.W. and J.L. performed statistical analysis. Y.W., J.N. and L.C. wrote the draft of the manuscript. H.S. and J.Z. revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jingyi Lu, Jian Zhou or Hongfang Shao.

Ethics declarations

Ethics approval and consent to participate

The study and the analysis plan were approved by the Ethics Committees of Shanghai Sixth People’s Hospital. We have obtained informed consent from all participants.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Wang, Y., Sheng, F., Cao, L. et al. Elevated prolactin levels before endometrial transformation negatively impact reproductive outcomes in frozen embryo transfer cycles under hormone replacement therapy. BMC Pregnancy Childbirth 25, 245 (2025). https://doi.org/10.1186/s12884-025-07307-7

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  • DOI: https://doi.org/10.1186/s12884-025-07307-7

Keywords

BMC Pregnancy and Childbirth

ISSN: 1471-2393

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