Exploring the potential benefits of growth hormone co-treatment on embryo quality in IVF: a randomized controlled open-label trial.

A total of 128 patients were enrolled and randomized to the GH group ( n  = 64), which received GH supplementation, and the control group ( n  = 64). Ultimately, 104 patients completed the trial, with 51 in the GH group and 53 in the control group. (Fig.  1 ) Fig. 1 Flow Diagram of Patient Inclusion Process Flow Diagram of Patient Inclusion Process The study’s stringent enrollment process ensured that key baseline characteristics, including age, body mass index (BMI), anti-Müllerian hormone (AMH), FSH, LH, and insulin-like growth factor-1 (IGF-1) levels, Infertility Cause, Infertility duration were well-matched between the two groups. Specifically, the mean baseline levels of FSH were 6.341 mIU/ml for the GH group and 6.314 mIU/ml for the control group ( P  = 0.9377), while LH levels were 4.019 mIU/ml and 3.576 mIU/ml, respectively ( P  = 0.9120). IGF-1 levels at baseline were also comparable, with means of 199.603 ng/ml in the GH group and 200.962 ng/ml in the control group ( P  = 0.9323). (Table  1 ) Table 1 Patient characteristics and baseline data Characteristic GH group ( n  = 51) Control group ( n  = 53) P  value Age (years) 31.1 ± 3.49 31.7 ± 3.30 0.2188 Infertility duration (years) 3.3 ± 2.12 3.8 ± 2.55 0.2798 Infertility Cause, n(%)  Tubal factor 42 (82.4) 48 (90.6) 0.2199  Ovulatory disorders 4 (7.8) 2 (3.8) 0.4324  Endometriosis 4 (7.8) 7 (13.2) 0.3739  Male factor 23 (45.1) 28 (52.8) 0.4304 BMI (kg/m2) 21.918 ± 2.6867 21.376 ± 2.5597 0.2944 AMH 3.9504 ± 2.6211 3.8823 ± 3.1059 0.6536 AFC 11.0 ± 5.04 9.9 ± 3.47 0.1798 Basal FSH (mIU/ml) 6.341 ± 1.6645 6.314 ± 1.7719 0.9377 Basal LH (mIU/ml) 4.019 ± 3.4409 3.576 ± 1.3065 0.912 Basal E2 (pg/ml) 31.712 ± 14.1619 35.075 ± 11.8323 0.1911 Basal Progesterone (pg/ml) 0.3791 ± 0.5887 0.3308 ± 0.2860 0.718 Basal IGF-1 (ng/ml) 199.603 ± 74.1931 200.962 ± 54.8212 0.9323 BMI body mass index, AMH anti-Müllerian hormone, AFC antral follicle count, FSH follicle stimulating hormone, E2 estradiol, LH luteinizing hormone Patient characteristics and baseline data BMI body mass index, AMH anti-Müllerian hormone, AFC antral follicle count, FSH follicle stimulating hormone, E2 estradiol, LH luteinizing hormone Significant hormonal changes were observed with GH supplementation alongside Gn dosage in IVF treatments. The GH group received a total mean rhGH dose of 120.7 IU, and the median duration was 52.4 days. This reduction in FSH on the day of Gn initiation suggests that GH supplementation may enhance ovarian response, thereby requiring less exogenous FSH. The change in FSH levels from the baseline to the initiation day of Gn showed a decrease in the GH group but an increase in the control group (-0.306 vs. 0.324 mIU/ml, p  = 0.0458). (Table  2 ) The mean total Gn dosage in the GH group was 2213.24 ± 667.015 IU, which was significantly lower than 2573.32 ± 630.009 IU in the control group ( p  = 0.0058). The GH supplementation group had a mean COS duration of 10.1 ± 1.60 days, which was significantly shorter than 10.6 ± 1.30 days in the control group ( p  = 0.0488). This suggested that GH supplementation might enhance ovarian response to Gn, thereby reducing the total number of days required for effective ovarian stimulation. Table 2 GH supplementation, gonadotropin dosage and the change in hormone levels Characteristic GH group ( n  = 51) Control group ( n  = 53) P  value Total dose of rhGH (IU) 120.7 ± 28.90 Median duration of GH supplementation (Day) 52.4 ± 19.04 FSH (mIU/ml)  on the initiation day of Gn 6.035 ± 1.5517 6.638 ± 1.7685 0.053  the change from baseline -0.306 ± 1.5138 0.324 ± 1.6585 0.0458 LH (mIU/ml)  on the initiation day of Gn 3.926 ± 1.7738 4.704 ± 1.5462 0.0017  the change from baseline -0.094 ± 3.4831 1.127 ± 1.5142 0.0134 E2 (pg/ml)  on HCG day 2844.112 ± 1244.9055 2735.585 ± 1071.3677 0.6773  the change from baseline 2812.400 ± 1245.3048 2700.510 ± 1071.4906 0.6631 Progesterone (pg/ml)  on HCG day 0.9386 ± 0.5157 1.2362 ± 0.6094 0.0098  the change from baseline 0.5595 ± 0.8020 0.9054 ± 0.6505 0.0219 IGF-1 (ng/ml)  on the day of oocyte retrieval 208.998 ± 60.7129 185.958 ± 73.7515 0.027  the change from baseline 19.895 ± 54.3752 -16.033 ± 68.0917 0.0006 Total Gn dosage (IU) 2213.24 ± 667.015 2573.32 ± 630.009 0.0058 Duration of Gn (Day) 10.1 ± 1.60 10.6 ± 1.30 0.0488 rhGH recombinant human GH, Gn gonadotropin, FSH follicle stimulating hormone, E2 estradiol, LH luteinizing hormone, IGF-1 insulin-like growth factor-1, COS Controlled Ovarian Stimulation GH supplementation, gonadotropin dosage and the change in hormone levels rhGH recombinant human GH, Gn gonadotropin, FSH follicle stimulating hormone, E2 estradiol, LH luteinizing hormone, IGF-1 insulin-like growth factor-1, COS Controlled Ovarian Stimulation Similarly, LH levels also differed between the groups on the day of Gn initiation, with the GH group demonstrating a lower mean LH level compared to the control group (3.926 vs. 4.704 mIU/ml, p  = 0.0017). As compared to the baseline levels, LH levels decreased in the GH group but increased in the control group (-0.094 vs. 1.127 mIU/ml, p  = 0.0134). Progesterone levels on the day of hCG injection were significantly higher in the control group compared to the GH group ( p  = 0.0098). IGF-1 levels were assessed at critical time points during the treatment process. The GH group showed a higher mean IGF-1 level on the day of oocyte retrieval compared to the control group (208.998 vs. 185.958 ng/ml, p  = 0.027). Additionally, the change in IGF-1 levels from baseline to the day of oocyte retrieval was significantly greater in the GH group ( p  = 0.0006). (Table  2 ) In the GH supplementation group, the mean number of high-quality embryos on Day 3 post-retrieval was 3.5, which was slightly higher than the 3.4 embryos in the control group. Although not statistically significant, there was an increasing trend in the rate of high-quality embryos in the GH group compared to the control group, with rates of 52.0% and 46.6%, respectively ( p  = 0.622). (Table  3 ) Table 3 Clinical outcomes between the GH group and the control group Characteristic GH group ( n  = 51) Control group ( n  = 53) P  value Number of oocytes retrieved 12.6 ± 6.25 11.5 ± 5.58 0.2855 Number of MII oocytes 9.8 ± 4.97 9.8 ± 4.77 0.9584 Number of 2PN fertilized oocytes 6.6 ± 3.75 7.0 ± 3.88 0.5696 Endometrial thickness on the day of HCG administration 12.33 ± 2.180 12.22 ± 1.854 0.4162 Number of high-quality embryos* 3.5 ± 3.27 3.4 ± 2.92 0.911 Rate of high-quality embryos, % 52.0 46.6 0.622 CPR of fresh embryo transfer 6/13 (46.2) 5/13 (38.5) 1 CPR of frozen embryo transfer 26/41 (63.4) 25/40 (62.5) 0.9321 Live birth rate of fresh embryo transfer 6/13 (46.2) 5/13 (38.5) 1 Live birth rate of frozen embryo transfer 21/41 (51.2) 20/40 (50.0) 0.9126 CPR, clinical pregnancy rate. * Embryos classified as Grade 2 with six cells or higher were considered high quality. Clinical pregnancy rate of fresh transfer cycles = (Number of fresh transfer cycles with clinical pregnancy / Number of fresh transfer cycles) × 100%. Clinical pregnancy rate of frozen transfer cycles = (Number of frozen transfer cycles with clinical pregnancy / Number of frozen transfer cycles) × 100%. Live birth rate of fresh transfer cycles = (Number of fresh transfer cycles with live birth / Number of fresh transfer cycles) × 100%. Live birth rate of frozen transfer cycles = (Number of frozen transfer cycles with live birth / Total number of frozen transfer cycles) × 100%. Rate of high-quality embryos = (Number of high-quality embryos / Number of normally fertilized oocytes) × 100% Clinical outcomes between the GH group and the control group CPR, clinical pregnancy rate. * Embryos classified as Grade 2 with six cells or higher were considered high quality. Clinical pregnancy rate of fresh transfer cycles = (Number of fresh transfer cycles with clinical pregnancy / Number of fresh transfer cycles) × 100%. Clinical pregnancy rate of frozen transfer cycles = (Number of frozen transfer cycles with clinical pregnancy / Number of frozen transfer cycles) × 100%. Live birth rate of fresh transfer cycles = (Number of fresh transfer cycles with live birth / Number of fresh transfer cycles) × 100%. Live birth rate of frozen transfer cycles = (Number of frozen transfer cycles with live birth / Total number of frozen transfer cycles) × 100%. Rate of high-quality embryos = (Number of high-quality embryos / Number of normally fertilized oocytes) × 100% For fresh embryo transfers, the clinical pregnancy rate (CPR) was numerically higher in the GH group (46.2%) compared to the control group (38.5%), although without statistical significance ( p  = 1). (Table  3 ) A detailed subgroup analysis was conducted based on quartile ranges of baseline IGF-1 levels to assess the impact of GH supplementation on the number and rate of high-quality embryos. The most pronounced effects were observed in the subgroup with IGF-1 levels below the lowest quartile (Q1), where the GH group had a higher mean number of high-quality embryos compared to the control group (4.4 vs. 1.3, p  = 0.0318). Correspondingly, the rate of high-quality embryos of 64.0% in the GH group surpassed the rate of 25.5% in the control group ( p  = 0.0488). In the subgroup with IGF-1 levels between Q1 and the median, the GH group showed an insignificant increase in the number of high-quality embryos (3.4 vs. 3.7) and their rate (56.7% vs. 50.6%) compared to the control group, with P  values of 0.8406 and 0.7209, respectively. These results underscore the potential importance of baseline IGF-1 levels in determining the efficacy of GH supplementation in IVF treatments, especially for patients with lower IGF-1 levels, who may experience enhanced embryo development and quality. In contrast, in the subgroups with IGF-1 levels above the median or at the third quartile (Q3), no significant differences in the mean number or rate of high-quality embryos were observed between the GH supplementation and control groups. (Table  4 ) Table 4 Subgroup analysis of different baseline IGF-1 levels Characteristic GH group ( n  = 49)* Control group ( n  = 51)* P  value IGF-1 levels below Q1 (158.220 ng/ml) Patient number 12 13 Number of high-quality embryos 4.4 ± 3.32 1.3 ± 2.21 0.0318 Rate of high-quality embryos, % 64.0 25.5 0.0488 IGF-1 levels between Q1 (158.220 ng/ml) and the median (205.980 ng/ml) Patient number 11 14 Number of high-quality embryos 3.4 ± 3.23 3.7 ± 3.52 0.8406 Rate of high-quality embryos, % 56.7 50.6 0.7209 IGF-1 levels between the median (205.980 ng/ml) and Q3 (243.070 ng/ml) Patient number 15 10 Number of high-quality embryos 3.9 ± 4.03 3.6 ± 2.66 0.8376 Rate of high-quality embryos, % 45.8 49.3 0.8125 IGF-1 levels above Q3 (243.070 ng/ml) Patient number 11 14 Number of high-quality embryos 2.0 ± 2.09 4.7 ± 2.27 0.0057 Rate of high-quality embryos, % 43.2 57.4 0.3259 * In the GH group and the control group, 2 participants each were missing baseline IGF-1 data Subgroup analysis of different baseline IGF-1 levels * In the GH group and the control group, 2 participants each were missing baseline IGF-1 data

This randomized open-label controlled trial (RCT) examined the effect of growth hormone (GH) supplementation on embryo quality in women who had experienced poor embryonic development. The study participants were infertile patients planning to undergo IVF or ICSI treatment at the Reproductive and Genetic Hospital of Citic-Xiangya between December 2019 and June 2023. Eligible participants were women aged 39 years or younger who had undergone at least one IVF/ICSI treatment cycle. The inclusion criteria were women with a history of six or more oocytes retrieved in at least one cycle, achieving a fertilization rate of 50% or higher, and having no embryos of 6-cell grade II or higher on Day 3 or no blastocysts formed after blastocyst culture in their previous cycles. The main exclusion criteria were relevant diseases affecting the outcome of IVF pregnancy, such as untreated hydrosalpinx, uterine fibroids affecting the uterine cavity, adenomyosis, endometrial lesions, and significant uterine malformations; severe acute or chronic liver and kidney diseases, endocrine and metabolic diseases, and adrenal diseases. Informed consent was obtained from all participants after a thorough explanation of the study protocol, including the potential benefits and risks. The study protocol was approved by the hospital’s ethics committee to ensure that all research activities were conducted in accordance with the ethical standards and regulatory requirements ( NCT03966339 ). Eligible and consenting participants were randomly assigned to the GH supplementation group or the control group in a 1:1 ratio. The randomization process was facilitated by a statistician using SAS 9.2 to generate a stratified random sequence based on age groups, ensuring an equal distribution of patients aged 30 years or younger and those aged between 31 and 39 years. The primary outcome was the number of high-quality embryos on Day 3. The embryos were graded according to specific criteria, with high-quality embryos classified as either Grade I or II. Secondary outcomes included changes in hormone levels (FSH, LH, P, and E2) on the day of HCG administration and their changes from baseline, endometrial thickness on the day of HCG administration, the total gonadotropin (Gn) dosage and treatment duration, the number of follicles measuring 18 mm or larger on the trigger day, serum IGF-1 levels on the day of oocyte retrieval and their changes from baseline, the count of metaphase II (MII) oocytes, number of 2PN fertilized oocytes, the rate of high-quality embryos on Day 3, implantation rate, clinical pregnancy rate (CPR), and live birth rate of fresh embryo transfer and frozen-thawed embryo transfer. The study utilized a GnRH antagonist protocol for COS, commencing on the second or third day of the menstrual cycle with recombinant follicle-stimulating hormone (rFSH [Gonal - F, Merck Serono, Germany]) at a daily dose of 150–300 IU. Dosages were adjusted according to the ovarian response as monitored by vaginaultrasound folliculometry and serum estrogen (E2) level. The GnRH antagonist (ORGALUTRAN, Organon, America) was introduced when a follicle reached 12 mm or larger. When at least 2–3 follicles reached a diameter of 18 mm or only 1–2 follicles were at least 17 mm, a trigger injection of 250 µg recombinant human chorionic gonadotropin (rhHCG [Ovidrel, Merck Serono, Germany]) plus 200 µg gonadotropin-releasing hormone agonist (GnRHa [Decapeptyl, Ferring Pharmaceuticals, Switzerland]) was administered subcutaneously in the evening. Ovulation was triggered with recombinant hCG and GnRH agonist once the follicles met the criteria, with oocyte retrieval scheduled 35–36 h post-trigger. Recombinant human GH (rhGH) was administered as an adjunct therapy in the GH group. Participants received rhGH (Jintropin, China, GenSci) treatment during the mid-luteal phase of the two menstrual cycles preceding COS, starting at a daily dose of 2 IU, followed by 4 IU daily from the initiation of ovarian stimulation until hCG day. This supplementation continued for up to 7 weeks. The control group underwent the standard IVF treatment protocol without GH supplementation. IGF-1 levels were measured at key time points throughout the treatment process using an automatic chemiluminescence analyzer (AutoLumo A2000PLUS, Autobio). In the control group, blood samples for IGF-1 measurement were collected on the day of rFSH initiation and repeated on the day of oocyte retrieval. For the GH group, an initial sample was taken before the start of GH supplementation, with subsequent samples aligning with the control group’s schedule. These assessments were essential for monitoring the endocrine milieu and evaluating the influence of GH on oocyte development. On Day 3 post-retrieval, morphological criteria were used to assess the embryo quality, such as the number of blastomeres, their uniformity, and the proportion of fragmentation [ 27 ]. Cleavage-stage embryos were graded as follows: Grade 1 embryos: no fragmentation with equal-sized, homogeneous blastomeres, Grade 2 embryos: less than 20% fragmentation with equal-sized, homogeneous blastomeres, Grade 3 embryos: 20–50% fragmentation with blastomeres of equal or unequal sizes, Grade 4 embryos: greater than 50% fragmentation with blastomeres of equal or unequal sizes. Embryos classified as Grade 2 with six cells or higher were considered high quality. Rate of high-quality embryos (%) = (Number of high-quality embryos / Number of normally fertilized oocytes) × 100%. Embryo transfer was carefully scheduled based on the patient’s condition. In cases with a risk of ovarian hyperstimulation syndrome (OHSS), elevated progesterone levels, or other conditions deemed unsuitable for fresh embryo transfer by the physician, embryos were cryopreserved for subsequent thaw and transfer in a later cycle. In the absence of such complications, fresh embryo transfer was performed, with a maximum of two embryos transferred per cycle. Following oocyte retrieval, luteal phase support was commenced through daily injections of 60 mg progesterone (Progesterone injection, XianJu, China ) or 90 mg vaginal progesterone gel(Crinone, Merck Serono, Germany) and maintained until pregnancy testing. Luteal phase support of frozen embryo transfer was initiated on the day of progesterone conversion with either 60 mg/day intramuscular progesterone injections or 90 mg/day vaginal progesterone gel. Additionally, we have clarified the criteria for freezing remaining embryos: all embryos not used for fresh transfer were cultured to the blastocyst stage and then cryopreserved. If a pregnancy was confirmed, as indicated by a positive serum β-hCG level 14 days post-transfer, luteal support was continued until at least the 10th week of gestation. In the absence of pregnancy, luteal support was discontinued. A clinical pregnancy was defined as an ultrasound observation of one or more gestational sacs, which was conducted to confirm the pregnancy and assess fetal development. Sample size was calculated based on preliminary data from a self-controlled study design, comparing the number of high-quality embryos produced in cycles with and without GH supplementation. Prior to GH use, the average number of high-quality embryos was 0.4 per cycle, which increased to an average of 1.2 embryos per cycle with GH supplementation. Assuming a significance level of 0.05 and a power of 90% to detect a difference, the estimated minimum sample size required per group was 55 participants. The recruitment target was set at 64 participants per group to account for an expected dropout rate of 15%. This sample size estimation ensures that the study is adequately powered to detect a significant improvement in the primary outcome measure, which is the rate and number of high-quality embryos on Day 3 post-retrieval. Data was analyzed using appropriate statistical tests, including chi-square test or Fisher’s exact test for categorical variables and t-test or non-parametric test for continuous variables, based on the nature of the data and distribution. All statistical analyses were conducted using SPSS 25.0 software, with a p -value < 0.05 considered as statistically significant.

The key finding of this study is that GH supplementation may improve embryo quality in specific patient populations, particularly those with relatively lower baseline IGF-1 levels. GH supplementation can improve embryo quality and IVF outcomes, especially among patients with poor embryo quality [ 24 , 28 ]. The enhancement in embryo quality is likely due to GH’s role in fostering follicle development and oocyte quality, which in turn boosts embryo quality. By increasing the expression of FSH/LH receptors on granulosa cells, GH supplementation may amplify the sensitivity of ovaries to gonadotropins [ 15 , 24 ]. Consistent with prior research [ 29 , 30 ], our findings suggest that GH, when co-administered with gonadotropins, can reduce the required dosage for ovulation induction, similar to the effect of gonadotropins themselves. Although the increase in high-quality embryos on Day 3 with GH supplementation did not achieve statistical significance in this study, there was a notable trend. Additionally, a reduction in FSH levels was observed at the initiation of gonadotropin treatment and a significant decrease in both the total dosage and duration of gonadotropin use in the GH group, signifying an improved ovarian response with GH supplementation. In previous studies on the use of GH for poor embryonic development in IVF, poor embryo quality was often diagnosed by the absence of high-quality embryos in previous cycles [ 31 , 32 ]. However, our criteria for defining poor embryonic development are more specific. We require that patients have retrieved more than six oocytes with a fertilization rate greater than 50% in their previous cycles, yet still fail to produce embryos of grade II or higher with at least six cells, or fail to form blastocysts after extended culture. We believe it is essential to ensure a sufficient number of retrieved oocytes, as it is difficult to determine whether a patient truly has poor embryo quality if they only retrieve 1–2 oocytes and subsequently fail to form high-quality embryos. This approach provides a more accurate assessment of poor embryonic development and ensures that our study population is well-defined. In this study, despite no difference in the number of oocytes retrieved between groups, the GH supplementation group showed lower progesterone levels on the hCG day compared to the control group. The increase in progesterone levels may be related to the duration of Gn administration, as the control group had a longer duration of Gn treatment compared to the GH group, which could lead to higher progesterone levels. In our center, the criterion for canceling fresh embryo transfer due to elevated progesterone is when progesterone levels exceed 1.5 ng/ml on the day of HCG administration. Some patients, although having higher progesterone levels compared to the GH group, did not meet this threshold for canceling the transfer. Overall, the control group had higher progesterone levels on the day of HCG compared to the GH group, and elevated progesterone on the day of HCG may be associated with endometrial receptivity.Increased progesterone levels at this stage are suggested to prematurely activate progesterone receptor expression, leading to earlier endometrial transformation and potentially closing the implantation window [ 33 ]. Additionally, higher pre-retrieval progesterone levels have been linked to increased stromal expression of vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF), which can alter angiogenic factors and decrease endometrial receptivity, affecting implantation rates [ 34 ]. The lower progesterone levels observed in the GH group might have contributed to the improved embryo quality and the insignificant trend toward higher clinical pregnancy rates after fresh embryo transfer, indicating that GH supplementation could influence endometrial receptivity and IVF outcomes. Further investigation is required to understand how GH affects progesterone levels and endometrial receptivity, as well as its impact on IVF success. The subgroup analysis in this study revealed that GH supplementation may have a more pronounced effect on improving embryo quality in patients with lower IGF-1 levels, particularly those below the first quartile. This finding is supported by previous research suggesting that low IGF-1 levels may be associated with poor embryonic development [ 23 ] and reduced IVF success rates [ 25 ]. Different studies have shown variable impact of IGF-1 levels on pregnancy outcomes, with a range of cut-off values reported to influence outcomes. This discrepancy underscores the necessity for a standardized approach to evaluate IGF-1 levels in IVF treatments. Prior research has demonstrated that IGF-1 might influence both embryo quality and pregnancy outcomes, yet no consensus exists on the exact level at which IGF-1 becomes detrimental to these outcomes. One study included 48 women undergoing controlled ovarian stimulation for assisted conception and found that the group with poor ovarian response had significantly lower levels of IGF-1 in follicular fluid compared to the normal ovarian response group [ 35 ]. There was a positive correlation between the levels of IGF-1 in follicular fluid and the number of oocytes retrieved. Another study included 146 women with normal ovulation and divided them into high and low IGF-1 groups based on their levels of IGF-1 in follicular fluid. The results showed that the high IGF-1 group had significantly higher rates of fertilization, blastocyst formation, high-quality embryo rate, clinical pregnancy rate, and implantation rate compared to the low IGF-1 group [ 23 ]. Notably, our study assessed the baseline IGF-1 levels and examined the relationship between these levels and the outcomes of IVF with GH supplementation. Professor Yovich conducted extensive research on GH and proposed that GH supplementation may improve the IVF outcomes for patients with poor prognosis who may be in a state of “subclinical degree of adult growth hormone deficiency (AGHD)” [ 15 , 25 ]. Our findings align with this hypothesis, suggesting that patients with IGF-1 levels below the lowest quartile, potentially representing this subclinical deficiency, might benefit from GH supplementation, as evidenced by improved embryo quality and a trend towards higher clinical pregnancy rates. The patients with lower IGF-1 levels in our study may correspond to the group described by Professor Yovich, where IGF-1 levels are below the norm but do not meet the diagnostic criteria for AGHD. In these patients, GH supplementation appears to enhance both embryo quality and pregnancy outcomes. This observation underscores the importance of considering individual IGF-1 levels for deciding GH supplementation, offering valuable insights into the development of tailored treatment plans for personalized IVF care. In the context of the Chinese IVF population, where IGF-1 levels can be significantly affected by age, BMI, and geographical region [ 36 ], it is becoming increasingly important to assess IGF-1 levels before initiating IVF. This assessment could guide the decision to supplement GH in patients with lower levels, potentially improving the production of high-quality embryos and CPR. Future research should continue to investigate the relationship between IGF-1 levels and the efficacy of GH supplementation in IVF to further refine patient selection and treatment strategies. This study has some limitations. A key constraint is the relatively small sample size, which may have reduced the statistical power to detect significant differences in clinical outcomes such as CPR and live birth rates. The benefits observed in patients with low IGF-1 levels from GH supplementation, as identified in this study, need to be confirmed with a larger sample size. Future studies with larger cohorts will be necessary to establish these cut-off values and confirm the potential benefits of GH supplementation in IVF for patients with specific IGF-1 levels. In summary, this study suggests that GH supplementation may improve the quality of embryos and potentially enhance IVF outcomes, particularly in patients with lower baseline IGF-1 levels. The observed decrease in gonadotropin requirements and the trend towards improved embryo quality and clinical pregnancy rates warrant further investigation. Continuing to explore the complex interactions between GH supplementation, IGF-1 levels, and IVF outcomes can facilitate personalized and effective treatment strategies for patients undergoing IVF.

The success of in vitro fertilization (IVF) depends on various factors, with the quantity and quality of embryos being key determinants of clinical pregnancy and live birth rates. Several factors influence the quality of embryos, including the patient’s age, genetic composition, metabolic status [ 1 , 2 ], elevated levels of reactive oxygen species (ROS) [ 3 , 4 ], insufficient adenosine triphosphate (ATP) supply during development [ 5 ], low levels of insulin-like growth factor-1 (IGF-1) [ 6 , 7 ], etc. The role of growth hormone (GH) in enhancing embryo quality is a research hotspot, with studies indicating that GH can increase the expression of gonadotropin (Gn) receptors on the surface of granulosa cells, thereby enhancing ovarian responsiveness to Gns [ 8 ]. Additionally, GH has been shown to reduce oxidative stress levels [ 9 ], increase the copy number of mitochondrial DNA in oocytes, and boost energy supply [ 10 ], which in turn promotes the expression of genes related to oocyte maturation [ 11 ], collectively contributing to improved embryo quality. Clinical studies have demonstrated that adding GH can improve the rate of high-quality embryos and pregnancy outcomes in patients with poor embryonic development [ 10 , 12 ]. However, the definition of poor embryonic development is not yet established, leading to different criteria across studies. In this study, we aimed to understand the relationship between GH supplementation and embryo quality using our center’s specific criteria for defining poor embryonic development. GH exerts its effects in the body through two pathways: one is by directly binding to its receptors on target organs [ 13 – 15 ], and the other is by stimulating the liver to secrete IGF-1, which then exerts its effects indirectly by acting on target organs [ 16 – 18 ]. The role of IGF-1, a key mediator of GH action, has been extensively studied in folliculogenesis and embryonic development [ 19 , 20 ]. It could play a crucial role in follicular development by promoting granulosa cell proliferation and differentiation, as well as influencing oocyte maturation and early embryonic growth [ 21 , 22 ]. Studies have indicated that IGF-1 levels in follicular fluid can be used to assess embryo quality, implantation rates, and their correlation with clinical pregnancy rates [ 6 , 23 ]. Patients with low IGF-1 levels may have lower IVF success rates [ 15 , 24 , 25 ]. The complex interplay between GH and IGF-1 suggests that their combined action may be essential for optimizing the conditions necessary for high-quality embryo production [ 21 , 26 ]. While the correlation between IGF-1 levels and IVF outcomes has been explored in previous studies, there is limited data on the Chinese population. Hence, the correlation between the baseline IGF-1 levels of the Chinese IVF population and the outcomes following GH supplementation remains unclear. This study assesses the effect of GH supplementation on embryo quality and preliminarily examines the association of different baseline IGF-1 levels with the potential benefits of GH supplementation among Chinese IVF patients.