Effect of dehydroepiandrosterone with or without transcutaneous acupoint electrical stimulation on pregnancy outcomes in poor ovarian response patients undergoing IVF-ET: a retrospective controlled study

Effect of dehydroepiandrosterone with or without transcutaneous acupoint electrical stimulation on pregnancy outcomes in poor ovarian response patients undergoing IVF-ET: a retrospective controlled study | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 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Data may be preliminary. 30 April 2025 V1 Latest version Share on Effect of dehydroepiandrosterone with or without transcutaneous acupoint electrical stimulation on pregnancy outcomes in poor ovarian response patients undergoing IVF-ET: a retrospective controlled study Authors : Shanqin Qi 0000-0003-3005-8329 , Lina Ma , Haiyan Yu , Yan Wang , and Kehua Wang [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174599119.97882569/v1 248 views 177 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract backend=biber, style=alphabetic, sorting=ynt ]biblatex Objective: To evaluate the effects of dehydroepiandrosterone (DHEA) and transcutaneous electrical acupoint stimulation (TEAS) on in vitro fertilization and embryo transfer (IVF-ET) outcomes of poor ovarian response (POR) patients stratified according to Poseidon classification Group 4. Method: POR patients of Poseidon group 4 who underwent IVF-ET in affiliated Taian City Central Hospital of Qingdao University from October 2022 to May 2024 were retrospectively enrolled, and were divided into DHEA+TEAS group (group DT), DHEA group (group D) and control group (group C) according to adjuvant treatment received, with 50 cases in each group. In addition, 50 patients with expected normal ovarian response at the same age were selected as the normal group (group N). The results of ovarian stimulation, embryological data and pregnancy outcomes were compared among the four groups. Results: Basal FSH and Gn usage of all groups were comparable (all p > 0.05). Number of retrieved oocytes and high-quality embryos in groups DT, D, and N was much higher than those in group C (all p < 0.001), but fewer oocytes were harvested in group D than in group N ( p < 0.05). Group DT possessed the thickest endometrium on hCG day, and obviously higher clinical pregnancy rate than group C ( p < 0.05). Group N showed significantly higher rates of embryo implantation, clinical pregnancy, and live birth than group C (all p < 0.05). Conclusion: DHEA could improve ovarian responsiveness, while the addition of TEAS could achieve better pregnancy outcomes on the basis of the benefits of DHEA. Introduction Infertility is a social problem that plagues many families today and is a common condition among women of childbearing age, with an estimated global incidence of about 10% (1). Some patients can be pregnant spontaneously after removal of the causative factor, but for those who have difficulty conceiving, assisted reproductive technology (ART) might be a promising option (2, 3). However, during in vitro fertilization and embryo transfer (IVF-ET), many patients, especially those aged > 35 years, present with low sensitivity to gonadotropin (Gn) and suboptimal response to controlled ovarian hyperstimulation (COH), i.e., poor ovarian response (POR) (4, 5). It is manifested by the low quantity and quality of oocytes harvested during COH, the lack of high-quality embryos, and the unsatisfactory pregnancy rate. Some even have to cancel the cycle due to lack of available embryos (6-8). POR patients account for 9-26% of ART, which not only affects pregnancy outcomes, but also imposes significant economic burden and psychological frustration (6, 9). Therefore, experts have been looking for adjunctive methods to improve the sensitivity of follicles to Gn and obtain ideal embryo implantation and pregnancy rates. After years of clinical application, dehydroepiandrosterone (DHEA) (2, 6, 10, 11) and transcutaneous electrical acupoint stimulation (TEAS) (12-15) have become widely used adjuvant treatments in IVF. DHEA is a steroid primarily secreted by adrenal and ovarian theca cells (16), which exerts biological effects by converting into more active forms of androgens, such as testosterone, in target organs (17). Animal experiments have confirmed that DHEA promotes follicle development by enhancing granulosa cell proliferation, and recruit more antral follicles (18, 19). Clinical studies have also pointed out that DHEA improves the responsiveness of granulosa cells to exogenous Gn through serum insulin-like growth factor mediation (20, 21), and obtains competitive oocytes by regulating energy metabolism of cumulus cells in elder women (22). As an indispensable component of traditional Chinese medicine, acupuncture plays an important in assisted reproduction. TEAS is a modification of traditional acupuncture that converts mechanical needling into electrical stimulation with controlled frequency and intensity through painless acupuncture electrodes. Stimulus signals trigger neuroendocrine activity, causing the release of chemicals that act on corresponding tissues and organs (12, 14). TEAS can regulate the hypothalamic-pituitary-ovarian (HPO) axis, balance hormone secretion, and increase recovered oocytes and superior embryos (23); It also modulates blood flow of uterus and ovaries through a variety of cytokines, to improve endometrial receptivity and facilitate embryo implantation (24, 25). Although both DHEA and TEAS have achieved encouraging results in older infertile women, their effects on POR patients under the Poseidon criterion have not been fully studied. We therefore conducted this trial to complement and validate adjuvant function for these patients. Materials and Methods backend=biber, style=alphabetic, sorting=ynt ]biblatex 1. Ethics approval This study has been approved by the Clinical Trial Ethics Committee of the Affiliated Taian City Central Hospital of Qingdao University. backend=biber, style=alphabetic, sorting=ynt ]biblatex 2. Patient information and study design 150 POR patients who underwent IVF-ET in Department of Reproductive Medicine, the Affiliated Taian City Central Hospital of Qingdao University from October 2022 to May 2024 were retrospectively recruited, and were divided into three groups according to the treatment regimen, namely DHEA+TEAS group (group DT, treated with DHEA and TEAS in addition to conventional COH, n = 50), DHEA group (group D, treated with DHEA in addition to conventional COH, n = 50) and control group (group C, conventional COH only, n = 50). At the same time, 50 patients with expected normal ovarian response (NOR) who underwent IVF-ET in the same age were chosen as normal response group (group N, conventional COH, n = 50). Inclusion criteria: (1) POR patients: Meeting Poseidon classification Group 4 criteria (26): Age ≥ 35 years, with reduced ovarian reserve (antral follicle count (AFC) < 5, Anti-mullerian hormone (AMH) < 1.2 ng/ml); NOR patients: Age ≥ 35 years, AFC ≥ 5, AMH ≥ 1.2 ng/ml; (2) The infertility cause is the obstruction of gamete transport; (3) The husband’s semen is normal; (4) Couples have normal chromosomes; (5) COH adopts an antagonist regimen. Exclusion criteria: (1) Diseases that affect the morphology and function of endometrium, such as uterine fibroids, endometriosis, or endometritis; (2) Concomitant autoimmune diseases; (3) Accompanied by endocrine abnormalities, such as hypothyroidism, hyperprolactinemia, etc; (4) IVF-ET cycle is incomplete. 3. IVF-ET protocol COH was performed with gonadotropin releasing hormone (GnRH) antagonist regimen. Briefly, recombinant follicle stimulating hormone (rFSH, Changchun Genescience Pharmaceutical Co., Ltd, China) 225-300 IU was started on the 2nd to 3rd day of menstruation, the initial dose was determined according to the patient’s age, body mass index (BMI), and previous COH ovarian response, followed by an adjustment of dosage every 2-3 days based on the growth of follicles under ultrasound and serum hormone levels. When the follicle diameter reached 14 mm or luteinizing hormone (LH) was higher than 6 IU/L, gonadotropin-releasing hormone antagonist (GnRH-ant, Cetrotide, Merck, Germany) 0.25 mg/day was added. As the dominant follicle reached 18 mm in diameter, or at least 2 follicles were 17 mm, Gn and antagonists were discontinued, and human chorionic gonadotropin (hCG, Lizhu Pharmaceutical Group Co., Ltd, China) 5000-10000 IU was administered to induce ovulation. After 34-36 hours, oocytes were retrieved under the guidance of transvaginal ultrasound and IVF was performed according to laboratory protocols. Egg retrieval, fertilization and embryological parameters were recorded. Embryo development was observed within 3 days after egg retrieval, and blastocyst formation needed to be followed up for another 2-3 days. For fresh embryo transfer (ET), 1-2 D3 top-quality embryos or 1 D5 blastocyst were chosen. For those with inappropriate endometrial status, premature elevated progesterone levels, or other reasons, frozen embryo transfer (FET) was performed in the next cycle. A maximum of 2 embryos were transferred at a time. For patients who underwent multiple embryo transfers, only the data on the first cycle after egg retrieval were included. Patients undergoing FET prepared endometrium with natural, stimulated, or hormone replacement cycles, depending on the regularity of menstruation. After transplantation, progesterone (Zhejiang Xianju Pharmaceutical Co., Ltd, China) 60 mg/d was administered intramuscularly, and dydrogesterone (Duphaston, Abbott, USA) 20 mg/d orally to support luteal function. Blood β-hCG was detected on day 14 after transplantation, gestational sac and fetal heart beat are checked by transvaginal ultrasound on day 28 to 35, and luteal support is provided to 8 to 10 weeks gestation in those who are clinically pregnant. 4. Adjuvant treatment 4.1 DHEA Micronized DHEA 25 mg was given orally, 3 times daily, from days 2-5 of the previous menstrual cycle until the hCG injection day. 4.2 TEAS Bilateral uterus (EX-CA1), Guanyuan (RN4), Zhongji (RN3), Zusanli (ST36), Shenshu (BL23), and Sanyinjiao (SP6) were selected and stimulated using a low-frequency pulse therapy device, starting from days 2-5 of the previous menstrual cycle until hCG day. Set the TEAS frequency to 2 Hz, current 15-25 mA, 30 minutes every other day. backend=biber, style=alphabetic, sorting=ynt ]biblatex 5. Indicator monitoring and definition The primary outcome was clinical pregnancy rate (CPR), and secondary outcomes included duration and dosage of Gn, endometrial thickness on hCG day, number of retrieved eggs, metaphase II (MII) eggs, and high-quality embryos, as well as MII egg rate, fertilization rate, excellent embryo rate, cycle cancellation rate, implantation rate (IR), live birth rate (LBR), and early miscarriage rate. MII egg rate refers to the percentage of MII eggs in the total number of eggs retrieved; Fertilization rate refers to the percentage of 2 PN fertilized eggs in the total retrieved eggs; Excellent embryo rate refers to the percentage of high-quality embryos to the total embryos; Cycle cancellation rate is defined as the percentage of patients who cancel their transfer due to the absence of transferable embryos; Embryo implantation rate refers to the percentage of gestational sacs confirmed by ultrasound to the total number of transferred embryos; Clinical pregnancy rate refers to the percentage of clinical pregnancies among the total transfer cycles; Live birth rate is defined as the percentage of patients who deliver live infants out of the total transfer patients; Early miscarriage rate is defined as the percentage of patients who have miscarriage before 12 weeks of gestation compared to total clinical pregnancies. 6. Statistical analysis SPSS 27.0 software package was employed for statistical processing. Numerical data were expressed as mean ± standard deviations (\(\overline{x}\) ± s), one-way analysis of variance (ANOVA) was adopted for comparison between groups, and LSD was used for post-hoc comparison. Categorical data were expressed as percentages (n, %) and comparisons between groups were performed by a chi-square test or a continuously adjusted chi-square test. P < 0.05 indicated a statistically significant difference. 1.Baseline data No statistical differences in age, BMI, infertility duration, previous IVF-ET cycles, and baseline FSH were presented between the four groups (all p > 0.05), while basal AMH of group N was significantly higher than that of other groups (all p 0.05). Group DT had significantly thicker endometrium than the other groups (all p < 0.05). backend=biber, style=alphabetic, sorting=ynt ]biblatex 3.Embryological parameters (Table 1) There was a clear disparity in oocyte retrieval of the four groups ( p < 0.001), with the number of groups DT, D and N being significantly higher than those of group C (all p < 0.001), and group N being more than Group D (6.22 vs. 7.22, p = 0.014), but close to that of group DT (6.46 vs. 7.22, p = 0.061). The number of MII and fertilization eggs showed a consistent trend with retrieved eggs, but the rates of MII and fertilization egg were comparable among the four groups (all p > 0.05); The number of excellent embryos in groups DT, D, and N was much higher than that in group C (all p 0.05). 4.Embryo transfer and pregnancy outcomes (Table 2) The four groups completed 46, 46, 42 and 47 transfer cycles, respectively, with approximate cycle cancellation rate ( p > 0.05). No statistical difference was presented in the number of cycles for transferring fresh or frozen embryos between the groups, nor in terms of embryo type (D3 embryo or blastocyst) and number (1 or 2) (all p > 0.05). Embryo implantation rate among the four groups failed to demonstrate a significant difference ( p > 0.05), but pairwise comparisons showed that group N was much higher than group C (28.9% vs. 15.2%, p = 0.047). The difference of CPR between groups did not reach a statistical level ( p > 0.05), but group DT and group N were significantly higher than that in group C (41.3% vs. 21.4%, p = 0.046; 46.8% vs. 21.4%, p = 0.012). LBR was comparable among the four groups ( p > 0.05), but group N had a obvious advantage over group C (36.2% vs 16.7%, p = 0.038); Early miscarriage rates of the four groups were identical ( p > 0.05). backend=biber, style=alphabetic, sorting=ynt ]biblatex Discussion DHEA is an endogenous steroid in blood circulation, mainly produced by adrenal gland and theca cells, and is involved in the synthesis of various steroid hormones as a substrate (16). It sensitizes granulosa cells to stimuli and mobilizes follicle development by upregulating the density of androgen receptors in granulosa cells and ovarian stroma (27); Simultaneously it increases the expression of insulin-like growth factor 1, which promotes follicle growth in autocrine or paracrine form (20, 28). Basal FSH, total consumption and duration of Gn after adjuvant DHEA therapy in group D were comparable with those in the control group and normal group, which corroborated the findings of some studies (28). However, group D possessed much more retrieved eggs, MII eggs, fertilized eggs, and excellent embryos than group C, indicating that DHEA’s gain on POR was mainly through improving the acquisition of mature oocytes, which was the result of invigorating the response of ovaries to Gn stimulation. Since its first application in poor responders in 2000 (29), DHEA has been widely known to improve the availability of oocytes and high-quality embryos, especially for aging and ovarian insufficiency women (2, 3, 6, 11, 22, 30). Inevitably, some scholars may be skeptical of this (28, 31-33). It is undeniable that substantial disparities in IVF still exist between DHEA-supplemented POR and normal responders, with the exception of top-quality embryo. Although the addition of DHEA promotes follicle recruitment and maturation, the background of reduced ovarian reserve in POR patients (34) makes it difficult to compensate for the shortage of collected follicles, and cannot be equalized to normal patients in a short term. In addition, the transformation from primordial follicles to antral follicles takes nearly 3 months (35), and our DHEA supplementation from the previous menstruation cannot fully cover this period, which may be one of the reasons for the inefficiency. From a metabolomics, patients supplemented with DHEA demonstrated elevated levels of glycerophosphocholine and linoleic acid in follicular fluid (FF) (6), in which choline and its derivatives play an important role in oocytes development (36). As previously described, the undesirable IVF outcomes of POR patients stems in part from the limited diffusion of exogenous Gn to FF (37), and correspondingly, glycerol phosphorylcholine from DHEA intervention promoted the penetration of compounds required for egg development into FF (38). IR, CPR, and LBR of group D were between those of control group and normal responders, with only minor differences, and endometrium was slightly thicker than that of groups C and N. This supported some results (28), but was not in harmony with others (3, 22). The positive trend of ovarian stimulation mentioned above did not extend to pregnancy rate, which may be related to endometrium on the one hand. As we all know, the key to implantation and ongoing pregnancy is not only optimal embryos, but also receptive endometrium, including appropriate thickness, morphology, and blood flow resistance, etc. (39). Due to the limited detection conditions, we only measured thickness, and DHEA did not contribute to it. On the other hand, we speculate that due to advanced age of POR patients and declined ovarian function, the slight improvement in oocyte and embryo is far from sufficient to overcome the suboptimal ovarian microenvironment and achieve desired results. As another adjunct with potential advantages, extensive studies have illustrated the positive effects of TEAS on IVF-ET in recent years (14, 15, 23, 40-42). Low-frequency electroacupuncture has been reported to enrich the blood supply to ovaries and modulate the hypothalamic-pituitary-ovarian axis (43, 44). Consistently, our data revealed that the performance of ovarian response in group DT was comparable to that of group N and much better than that of group C, which means that the addition of TEAS to DHEA can further improve the ovarian responsiveness to a level similar to that of patients with normal ovarian function. In contrast, there are clinical trials failed to achieve progress in COH with TEAS (13, 45, 46), which may be primarily attributed to the lack of a fixed and recommended regimen for TEAS, and various studies have large differences in intervention time, acupoint selection, and stimulation intensity. A certain thickness of endometrium is indispensable for successful embryo implantation. It has been announced that endometrial thickness below 7 mm makes it almost impossible to conceive (47). Clinical practice has confirmed that TEAS reduce blood resistance and promote endometrial proliferation and vascularization by upregulating the expression of HOXA10 (41); It also increases the content of pinopode to facilitate the acceptance of embryos by endometrium (45). Animal experiment has also proved that electroacupuncture is beneficial to embryo implantation by increasing the level of pinocytosis and its markers in rat endometrium, and expanding the contact area between endometrium and blastocyst (48). According to our data, the mean endometrial thickness in group DT was not only superior to that of other POR patients, but also significantly thicker than that of normal responders, demonstrating the effectiveness of TEAS on endometrial growth. Correspondingly, group DT obtained much higher CPR than the control group, validating our hypothesis that DHEA has both embryonic and endometrial gains, which led to the progress of embryo implantation and ongoing pregnancy in POR patients. The role of TEAS in promoting embryo implantation and clinical pregnancy (14), especially for those with previous implantation failure (13, 14), as well as in improving LBR (46, 49), has been well reported. Similar to a multicenter study (12), we did not achieve a significant improvement in LBR after TEAS treatment, and its efficacy in terms of superior embryos and pregnancy rates is controversial (15, 45). These inconsistencies may be due to the small sample size that precludes the observation of subtle changes in LBR, or due to differences in TEAS protocols. Therefore, the effect of TEAS on pregnancy needs to be validated in high-quality studies with larger sample sizes. Despite differences in mechanisms and signaling pathways, DHEA (2, 6, 11, 22) and TEAS (12, 14, 15) have played a stable role as adjuvant therapy in IVF-ET, and it is expected that our work may provide some support and references. There are also some shortcomings in this study, the first of which is that the effect of TEAS was not independently assessed and compared with DHEA to provide options for a reasonable regimen. The second is the coexistence of the two types of transfers, ET and FET, and the effect of DHEA or TEAS on endometrial receptivity and embryo-endometrial dialogue cannot be tracked due to the separation of FET from the oocyte retrieval cycle. All of these need to be further explored in future studies with more rigorous design. Conclusion Both DHEA and TEAS are available methods to harvest more excellent oocytes and embryos and a higher pregnancy probability in POR patients, and the combination of the two can achieve near-normal ovarian response and ideal endometrial thickness, and improve clinical pregnancy rate. Author contributions All authors participated together in study design, data collection, and paper revision. SQ wrote the initial manuscript. LM consolidated and calculated the data, HY analyzed the results and funded the research, YW verified the results. Professor KW supervised the study and revised the article. All authors approve the final version to be published. Funding This study was supported by Tai’an Science and Technology Innovation Development Project (Policy Guidance) (2022NS250). Acknowledgements The authors would like to thank the clinical colleagues for their help in case collection and the laboratory team for their data support. Conflict of interest The authors declare no conflict of interest. List of abbreviations AFC antral follicle count AMH anti-mullerian hormone ANOVA analysis of variance ART assisted reproductive technology BMI body mass index COH controlled ovarian hyperstimulation CPR clinical pregnancy rate D3 Day 3 DHEA dehydroepiandrosterone FET frozen-thawed embryo transfer FF follicular fluid Gn gonadotropin GnRH gonadotropin-releasing hormone GnRHant GnRH antagonist hCG human chorionic gonadotropin IR implantation rate IVF-ET in vitro fertilization and embryo transfer LBR live birth rate LH luteinizing hormone MII metaphase II NOR normal ovarian response POR poor ovarian response rFSH recombinant follicle stimulating hormone TEAS transcutaneous electrical acupoint stimulation Reference 1. Vander Borght M, Wyns C. Fertility and infertility: Definition and epidemiology. Clin Biochem. 2018;62:2-10. Epub 2018/03/21. doi: 10.1016/j.clinbiochem.2018.03.012. PubMed PMID: 29555319.2. Zhang J, Jia H, Diao F, Ma X, Liu J, Cui Y. 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Keywords adolescent gynaecology analgesia: obstetric endocrinology epidemiology: infertility fertility and assisted reproduction infertility: assisted conception reproductive science: fertilisation Authors Affiliations Shanqin Qi 0000-0003-3005-8329 Shandong University of Traditional Chinese Medicine View all articles by this author Lina Ma Shandong University of Traditional Chinese Medicine View all articles by this author Haiyan Yu Shandong University of Traditional Chinese Medicine View all articles by this author Yan Wang Taian City Central Hospital Department of Rehabilitation Medicine View all articles by this author Kehua Wang [email protected] Shandong University of Traditional Chinese Medicine Affiliated Hospital View all articles by this author Metrics & Citations Metrics Article Usage 248 views 177 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Shanqin Qi, Lina Ma, Haiyan Yu, et al. Effect of dehydroepiandrosterone with or without transcutaneous acupoint electrical stimulation on pregnancy outcomes in poor ovarian response patients undergoing IVF-ET: a retrospective controlled study. Authorea . 30 April 2025. DOI: https://doi.org/10.22541/au.174599119.97882569/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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