The auxiliary effect of oral nutritional supplements on fertility in women with diminished ovarian reserve: a systematic review and meta-analysis

Abstract

Objective

Evaluate the adjuvant effects of oral nutritional supplements including vitamins, coenzyme Q10, and dehydroepiandrosterone (DHEA) on fertility in patients with diminished ovarian reserve (DOR).

Methods

We conducted a generalized explore of 9 databases established as of September 1, 2024. Mainly studing and analyzing outcomes including serum follicle stimulating hormone (FSH) levels, anti Mullerian hormone (AMH) levels, antral follicle count (AFC), retrieved oocytes, and clinical pregnancy rate with the methodology of a systematic review and meta-analysis. The inclusion quality of each experiment was evaluated through the Newcastle Ottawa Scale (NOS).

Results

The meta-analysis consisted of 16 studies with 2773 participants. A review of existing evidence suggested that oral nutritional supplements, including vitamins, coenzyme Q10, and DHEA, could significantly lower FSH levels (SMD = −0.67, 95% CI [−0.94, −0.40], p < 0.0001), rise AMH levels (SMD = 0.35, 95% CI [0.02, 0.69], p = 0.04), AFC counts (MD = 0.99, 95% CI [0.28, 1.69], p = 0.006), retrieved oocyte counts (MD = 0.88, 95% CI [0.54, 1.23], p < 0.0001), and clinical pregnancy rate (OR = 1.70, 95% CI = [1.35, 2.13], p < 0.0001). Oral nutritional supplements for more than 2 months have a better effect on lowering FSH levels, raising AMH levels, and oocyte numbers (p < 0.05). In addition, we found that the use of coenzyme Q10 alone was more effective than the use of DHEA alone through subgroup analysis. There was a remarkable correlation (p < 0.05) between the use of both nutritional supplements and the decrease of FSH, as well as the increase of AMH, AFC, and oocytes retrieved. We used sensitivity analysis to conclude that our summary results are robust.

Conclusions

Oral nutritional supplements, including vitamins, coenzyme Q10, and DHEA may be a simple and relatively low-risk treatment option to assist in improving fertility in women with DOR.

Registration number

CRD42024580831.

1. Introduction

Infertility is a major global health challenge that affects over 12% of couples worldwide [1]. Ovarian reserve dysfunction refers to a decrease in the number and/or quality of oocytes, leading to infertility, adverse ovarian reactions, and adverse pregnancy outcomes [2]. One of the main factors of female infertility is diminished ovarian reserve (DOR) [3]. As report goes, the incidence rate of DOR has increased from 19% to 26% [4]. DOR can cause a decrease in female fertility, leading to early menopausal events, increased miscarriage rates, and recurrent miscarriage [5,6]. The onset of DOR is insidious and progressive. Without early intervention and treatment, it may irreversibly develop into premature ovarian failure within 1–6 years [7]. DOR is currently a hot and difficult topic in the field of reproductive health research worldwide. Scholars at home and abroad have conducted extensive and in-depth research, but there is still controversy over the causes and treatment methods of DOR. So far, finding effective methods for treating DOR remains an important challenge in clinical practice.

In recent years, studies have discovered that reproductive health is closely related to nutrient supplementation, which is beneficial for reducing the occurrence of infertility. A prospective cohort study included 18,555 married women without a history of sterility as research objects, of which 10,451 women supplemented with micronutrients and 8104 did not. Eight year follow-up results revealed a negative correlation between micronutrient supplementation and ovulatory infertility [8,9]. Another prospective cohort study has confirmed that women who supplement with multiple micronutrients containing folic acid have a higher pregnancy rate and significantly higher fertility rate within one year, which may have a bearing on the improvement of female hormone levels [10]. An expert consensus on reproductive health and supplementation of multiple micronutrients [11] proposes that micronutrients such as folate, vitamins, zinc, iron, selenium, and calcium can ameliorate oocyte quality and endometrial receptivity, enhance patient fertility, and to some extent improve oocyte and embryo quality, elevate clinical pregnancy rates and sustained pregnancy rates, reduce miscarriage, and increase live birth rates.

At present, the treatment methods for DOR include traditional Chinese medicine therapy, appropriate supplementation of vitamins, folic acid and other general health guidance [7], DHEA [12], coenzyme Q10 [13], ovulation induction and assisted reproductive technology guidance [14], sequential estrogen and progesterone therapy [15], platelet rich plasma ovarian injection [16], etc. Although a healthy lifestyle and a positive mindset are undoubtedly the most effective ways to maintain ovarian function. However, modern women generally experience anxiety and irritability under work pressure, making it difficult to maintain a healthy state. Therefore, intervention therapy to improve ovarian function is considered necessary [17]. Hormone replacement therapy (HRT) is a continuous estrogen progesterone treatment, and research suggests that this therapy has limitations [18]. It does not have the ability to enhance ovarian activity, and patients with breast cancer cannot use HRT therapy [19]. In addition, oral hormone therapy may increase the risk of hypertension in women [20]. Nutritional regulation was beneficial for improving reproductive success rates, even for women facing reproductive aging. Studies had shown that elderly mothers who received high-quality nutritional support may be able to compensate for the inherent problems of reproductive aging during pregnancy and may be more capable of raising their offspring than mothers without good nutrition [21]. The latest meta-analysis studied the improvement of fertility in women with ovarian aging by antioxidants, including coenzyme Q10, melatonin, inositol, and vitamins. The meta-analysis results indicated that consuming antioxidants was an effective and safe supplementary therapy for women with ovarian aging, with coenzyme Q10 showing a more significant effect [22]. Zain A Al Safi et al. proposed that nutritional interventions should be tested in women with reduced ovarian reserve, and they believe that nutritional interventions can delay ovarian aging [23]. Vitamins, coenzyme Q10, and DHEA are all nutritional supplements, and folic acid is also a type of vitamin. Vitamins are essential steroid hormones in the human body, playing important roles not only in regulating calcium and phosphorus metabolism, but also in various physiological processes such as cell differentiation and apoptosis, inflammation, and insulin resistance [24]. The relationship between itamins and ovarian reserve, polycystic ovary syndrome, and endometriosis is germane. The use of vitamin supplements is beneficial for increasing the anti Mullerian hormone (AMH) index, antral follicle count (AFC), and mean ovarian volume (MOV) [24,25]. Dehydroepiandrosterone is an endogenous steroid primarily produced in the reticular zone of the female adrenal cortex and ovarian follicular membrane cells [26]. DHEA can be converted into androgens and estrogens according to the hormonal environment [27]. It is believed that DHEA can promote follicular development, enhance the action of gonadotropins, and reduce follicular arrest [28]. Coenzyme Q10 (CoQ10) has strong antioxidant and pro oxidative activities and is a commonly used nutritional supplement [29]. A recent study suggests that supplementing with coenzyme Q10 may help improve the quality of oocytes in DOR women, alter the ovarian environment, and improve fertility outcomes [13]. Compared to other therapies, nutritional supplements are easy to obtain and take, with relatively fewer tolerable side effects. Therefore, we have compiled this meta-analysis by integrating and evaluating existing relevant clinical randomized controlled trials to provide evidence support for clinical practice. The purpose of this meta-analysis is to verify whether oral nutritional supplements (including vitamins, folate, dehydroepiandrosterone, coenzyme Q10) can effectively improve ovarian reserve markers and AFC levels in DOR patients, and have a positive impact on assisted reproductive outcomes in DOR patients?

2. Materials and methods

This study followed the preferred reporting project of Systematic Review and Meta Analysis (PRISMA) [30]and was registered on PROSPERO with relevant approved records(registration number CRD 42024580831).

2.1. Search strategy

As of 28th August 2024, a total of 9 databases including Scopus, Web of Science, EBSCO, X-MOL, PubMed, Cochrane Library, VIP Information, Wanfang, and China National Knowledge Infrastructure(CNKI) were searched for all relevant research records since their establishment. The following keywords and medical subject heading (MeSH) terms were used to develop our search strategy: #1 (((((((((decreased ovarian reserve[Title/Abstract]) OR (low ovarian reserve[Title/Abstract])) OR (diminished ovarian reserve[Title/Abstract])))) OR (ovarian reserve[Text Word]))) AND (vitamins[Title/Abstract]), #2 (((((((((decreased ovarian reserve[Title/Abstract]) OR (low ovarian reserve[Title/Abstract])) OR (diminished ovarian reserve[Title/Abstract])))) OR (ovarian reserve[Text Word]))) AND (folic acid[Title/Abstract]), #3((((((((((decreased ovarian reserve[Title/Abstract]) OR (low ovarian reserve[Title/Abstract])) OR (diminished ovarian reserve[Title/Abstract]))))) AND (dehydroepiandrosterone[Title/Abstract]), #4((((((((decreased ovarian reserve[Title/Abstract]) OR (low ovarian reserve[Title/Abstract])) OR (diminished ovarian reserve[Title/Abstract]))) AND (coenzyme Q10[Title/Abstract]). In addition, we had carefully and comprehensively evaluated the relevant references involved in the retrieved studies to help us obtain more potential related articles.

2.2. Inclusion and exclusion criteria

Studies that meet the following criteria will be included: (1) Meets the diagnostic criteria of DOR, namely FSH ≥ 10 IU/L or AFC < 5–7 or AMH < 1.1 ng/mL [31]; (2) The DOR patients in the study received nutritional supplementation therapy, embodying vitamins, folic acid, coenzyme Q10, and DHEA; (3) The study reported the results of nutritional supplementation therapy, including sex hormone levels or related clinical parameters, providing at least sufficient data; (4) This study belongs to clinical case-control controlled trials (with or without randomization, blinding method) investigating the relationship between oral nutritional supplements and DOR. If the experimental group in the study received oral nutritional supplements, while the control group received the same accompanying treatment as the experimental group, it can be included. The control arm could receive Western medicine, other nutritional supplements, or no treatment. Regardless of the dosage or intervention duration of the drugs used in the study, they can be included; (5) Research published in Chinese or English; (6) The screening criteria for duplicate literature: (1) Select the one with the largest sample size; (2) Select the article with the longest follow-up time; (3) Choose the article with the most comprehensive research outcome. When the sample size, follow-up time, and research outcomes of repeated literature have their own focuses, multiple articles can be included simultaneously. When the same literature is divided into multiple groups with different focuses, they can be included and analyzed separately.

In the selection process, excluded studies meet the following criteria: (1) combined with other diseases such as endometrial abnormalities, intrauterine adhesions, uterine malformations, and reproductive system tumors; (2) Research belongs to meta-analysis, research protocol, duplicate publications, reviews, animal experiments, and conference papers; (3) These studies have not yet been published in Chinese or English; (4) The study is a self controlled study.

2.3. Data extraction and quality assessment

Independently extract the outcome indicators related to the research that meet the above qualification criteria using a pre designed table. Extract basic research information, including author surname, publication time, sample size, sample age, BMI, nutritional supplement type, intervention dose, and intervention time, and record and summarize the relevant outcome indicators included in the study. Any disagreements that arise during the data organization process will be tackled through consultation with the third observer (L.W.X.). Two reviewers (X.L.L. and Q.Z.) evaluated the quality of the included studies (NOS) using a two person double recording approach [32].

2.4. Statistical analysis

The software used for statistical analysis and data management includes Stata/MP 17.0, Review Manager 5.3, and EndNote 20.2. Standardized mean difference (SMD) or mean difference (MD) and 95% confidence interval (CI) were adopted to summarize continuous data. Summarize binary data using odds ratio (OR) and evaluate heterogeneity between studies using I² statistical data. When I² ≤ 50%, the fixed effects model should be applied. Otherwise, it is considered more appropriate to employ a random effects model. Bilateral p ≤ 0.05 indicates statistically significant differences. In order to compare the effectiveness of different nutritional supplements, intervention times, and intervention measures in treating DOR, and explore potential sources of heterogeneity, subgroup analysis was put to use. To test the robustness of meta-analysis conclusions, sensitivity analysis was applied to evaluate the impact of individual studies on the overall analysis results, in order to reveal potential heterogeneity and bias. A funnel plot is used to observe whether there is publication bias, and Egger’s test is used when there are more than ten included articles for a certain outcome measure [33].

3. Results

3.1. Included articles

Based on the preliminary database search results, a total of 434 relevant literature records on the treatment of DOR with oral nutritional supplements (including vitamins, folate, coenzyme Q10, and DHEA) were retrieved. Out of 434 articles, 245 were duplicated and 162 were deleted due to not meeting the inclusion criteria. Subsequently, after carefully reading the included studies, we removed the other 11 studies as they lacked research data or did not belong to case control studies. Finally, a total of 16 case control studies published between 2014 and 2024 were included. The selection process was shown in Figure 1.

Figure 1.

PRISMA flow diagram.

3.2. Study characteristics

Table 1 summarized the research characteristics of these clinical trials, and this meta-analysis comprehensively evaluated a total of 16 studies. These studies involved 2773 DOR patients in the aggregate, with sample sizes ranging from 40 to 900. Among these 16 trials, 4 were treated for 2 months [36,41,44,45], 10 were treated for 3 months [34,35,37–39,42,43,46–48], 1 study was treated for 2–3 months [40],and 1 study was treated for 6 months [49]. Eight studies investigated the efficacy of dehydroepiandrosterone [34–38,40,44,46], three studies investigated the efficacy of vitamins [39,45,49], and six studies investigated the efficacy of coenzyme Q10 [39,41,43,46–48]. In addition, 10 studies compared a nutritional supplement with a blank control group [34–41,44,49], 6 studies compared two nutritional supplements with a drug [39,43,45–48], and 16 studies all used case-control trials [34–49].

Table 1.

Characteristics of included studies.

Author	Year	Nutritional Supplement type	Dose	Treatment course	Sample size (N)	Age (year)	BMI (kg/m2)	Duration of infertility (year)	NOS
M. Kara [34]	2014	DHEA	75 mg daily	12 weeks	104	30.97 ± 5.76	/	5.31 ± 1.23	7
		Control group	/	12 weeks	104	31.15 ± 5.58	/	6.09 ± 1.02
Zhang [35]	2014	DHEA	75 mg daily	3 months	42	37.17 ± 5.22	22.13 ± 2.92	6.64 ± 4.54	8
		Control group	/	3 months	53	37.43 ± 4.33	22.46 ± 2.42	6.34 ± 4.85
Hu [36]	2017	DHEA	25 mg three times a day	8 weeks	53	33.28 ± 3.13	22.32 ± 2.44	3.81 ± 2.61	8
		Control group	/	8 weeks	50		34.16 ± 3.27	23.24 ± 4.41
Agarwal [37]	2017	DHEA	25 mg three times a day	12 weeks	20	33.10 ± 4.29	25.01 ± 3.31	/	7
		Control group	Placebo	12 weeks	20	32.30 ± 4.07	25.04 ± 3.77	/
Fu [38]	2017	DHEA	75 mg daily	12 weeks	58	37.4 ± 3.6	21.60 ± 2.75	4.39 ± 2.07	7
		Control group	/	12 weeks	58	36.8 ± 4.3	22.13 ± 2.45	4.58 ± 1.51
Zou Y [39]	2017	Vitamin E	300 mg daily	3 months	53	40.2 ± 4.2	21 ± 3.8	4.7 ± 2.8	8
Zou [39]		Vitamin E+ Coenzyme Q10	30 mg + 300 mg daily	3 months	53	41.2 ± 3.3	21.6 ± 3.2	4.6 ± 3.8
		Control group	/	3 months	46	40.0 ± 3.8	22.3 ± 2.5	4.3 ± 2.6
Xu X [40]	2018	DHEA	25 mg three times a day	60–93 days	55	34.09 ± 3.54	21.92 ± 5.63	6 ± 4.57	7
		Control group	/	60–93 days	55	33.73±3.73	22.19 ± 6.01	5.07 ± 3.9
Xu Y [41]	2018	Coenzyme Q10	200 mg three times a day	60 days	76	32.50 ± 3.30	21.85 ± 2.51	/	6
		Control group	/	60 days	93	31.92 ± 3.68	22.24 ± 3.07	/
Chang [42]	2019	Vitamin E + DHEA	10 mg two times per day + 25 mg three times per day	3 months	38	30.75 ± 2.63	22.86 ± 3.70	/	6
		Control group	/	3 months	32	29.13 ± 4.55	23.56 ± 3.61	/
Liang [43]	2019	Coenzyme Q10 + Fenmatong	Coenzyme Q10:two tablets, three times a day	3 months	43	35. 42 ± 1. 93		5. 81 ± 1. 23	7
		Fenmatong	/	3 months	43	35. 78 ± 1. 86		5. 69 ± 1.18
Zhuang [44]	2021	DHEA	25 mg three times a day	8 weeks	87	34. 34 ± 3. 20	23. 20 ± 3. 83	3. 82 ± 2. 53	8
		Control group	/	8 weeks	76	33. 88 ± 3. 53	22. 73 ± 3. 86	/
Halder [45]	2022	Vitamin D + DHEA	40,000 IU single weekly dose + 25 mg 3 times daily	8 weeks	36	34.11 ± 4.59	27 ± 3.64	/	6
		DHEA	25 mg 3 times daily	8 weeks	31	33.52 ± 4.32	25.84 ± 3.28	/
Tang T [46]	2022	DHEA+Coenzyme Q10	50 mg daily + 10 mg three times a day	3 months	102	38.2 ± 0.7	/	8.0 ± 0.5	7
Tang [46]		DHEA	50 mg daily	3 months	92	37.9 ± 0.8	/	8.3 ± 0.4
		Coenzyme Q10	10 mg three times a day	3 months	100	38.6 ± 0.8	/	8.4 ± 0.5
Xu [47]	2023	Vitamin E+ Coenzyme Q10	0.1g three times a day + 10 mg three times a day	3 months	450	40.84 ± 3.07	22.73 ± 2.61	4.59 ± 1.03	8
		Vitamin E	0.1g three times a day	3 months	450	40.63 ± 3.62	22.80 ± 2.24	4.63 ± 0.95
Xia [48]	2023	DHEA+ Coenzyme Q10	25 mg three times a day + 10 mg three times a day	3 months	65	37.32 ± 5.51	22.90 ± 3.46	4.92 ± 4.83	8
		DHEA	25 mg three times a day	3 months	65	36.69 ± 5.91	23. 59 ± 3. 42	5.42 ± 4.91
Zhuang S [49]	2024	Folic acid	0.4 mg daily	6 months	35	33.4 ± 5.2	20.27 ± 2.78	/	6
		Control group	/	6 months	35	32.1 ± 5.6	20.31 ± 2.34	/

3.3. Quality evaluation

All studies are clinical case-control trials and quality assessment is conducted using the NOS scoring scale. Although all evaluated studies scored ≥ 6 points, the high or low scores of research quality assessment often deviate due to a lack of sufficient details in the result evaluation process. Table 1 shows the NOS scores for each included study. Moreover, 5 case-control studies did not use random allocation, and 13 trials did not achieve blinding throughout the entire study process, thus being considered to have a high risk of bias. However, we did not find any details of incomplete results or selective reporting in these included studies. Therefore, we believe that the main risk of bias lies in the blindness and randomness of this meta-analysis (Figure 2).

Figure 2.

Risk of bias assessment.

3.4. Outcome measurements

3.4.1. Main research indicators

Our analysis results displayed an increase in AMH levels (SMD = 0.35, 95% CI [0.02, 0.69], p = 0.04) (Figure 3B) and a decrease in FSH levels (SMD = −0.67, 95% CI [−0.94, −0.40], p < 0.0001) (Figure 3A). Due to significant heterogeneity in FSH and AMH results, a random effects model was utilised. Furthermore, we summarized and analyzed the changes in E2 levels, and the results showed an increase in E2 levels (SMD = 0.33, 95% CI [−0.17, 0.84], p = 0.2) (Figure 3C), but the results were not statistically significant.

Figure 3.

Forest plot: The main research indicator results of oral nutritional supplements improving DOR. (A) FSH; (B) AMH; (C) E2; (D) AFC; (E) Oocytes retrieved.

The meta-analysis of AFC results included 8 studies involving 1636 patients. Due to the significant heterogeneity of these studies (I² = 94), we applied a random effects model and the combined results showed AFC (MD = 0.99, 95% CI [0.28, 1.69], p = 0.006) (Figure 3D). There were 13 studies involving oocytes retrieved, and due to significant heterogeneity (I² = 94), a random effects model was also applied. The results showed the number of oocytes retrieved (MD = 0.88, 95% CI [0.54, 1.23], p < 0.0001) (Figure 3E). When visually inspecting the funnel plot, some asymmetry was found (Figure 4E–H). In addition, based on the high heterogeneity of the results, we assessed the overall impact of individual studies on outcome measures through sensitivity analysis and assessed the robustness of the results (Figure 4A–D). The results showed that after excluding literature one by one, there was no significant statistical difference, indicating that the meta results were stable. Egger’s test was conducted on outcome measures involving over 10 studies, i.e. oocytes retrieved. The results showed p = 0.353 > 0.05 (Figure 4I), indicating no publication bias exsiting.

Figure 4.

Sensitivity analysis results: (A) FSH; (B) AMH; (C) AFC; (D) Oocytes retrieved Funnel plot; (E) FSH; (F) AMH; (G) AFC; (H) Oocytes retrieved; Egger’s test; (I) Oocytes retrieved.

3.4.2. Secondary research indicators

So far, clinical evaluation of embryo quality has often been based on examining the number, degree of fragmentation, and uniformity of blastomeres. According to Scott’s standards, embryos that grow to the third day and have six or more cells are considered high-quality embryos [50,51]. The number of high-quality embryos gained from DOR patients undergoing IVF or ICSI was measured in 7 studies, the high-quality embryo rate was recorded in 4 studies, and the clinical pregnancy rate of DOR patients undergoing IVF or ICSI after oral nutritional supplements was recorded in 12 studies. The comprehensive results indicated that oral nutritional supplements can statistically increase the amount of high-quality embryos (MD 0.41, [95% CI: 0.01, 0.80], I² = 94%, p = 0.04) and the rate of high-quality embryos (OR 1.25, [95% CI: 1.02, 1.53]), I² = 0%, p = 0.03), And it has a significant effect on improving the clinical pregnancy rate of DOR patients (OR 1.70, [95% CI: 1.35, 2.13], I² = 50%, p < 0.0001). Six studies recorded E2 levels on the day of HCG administration, and seven studies monitored endometrial thickness on that day. The comprehensive results indicate that oral nutritional supplements can increase E2 levels (SMD 0.06, [95% CI: −0.08,0.19], I² = 43%, p = 0.42) and endometrial thickness (SMD 0.29, [95% CI: −0.12,0.70], I² = 89, p = 0.16) on the day of HCG administration, but this is not statistically significant. Using sensitivity analysis, no study will affect the merged results. Table 2 listed all the results mentioned above.

Table 2.

Analysis results of secondary research indicators.

Clinical outcomes	Studies (n)	Cases (n)	OR/SMD/MD 95% CI	p	I2 (%)	Model
E2 on hCG day (pg/ml)	6	830	0.06 [−0.08, 0.19]	0.42	43	Fixed
Endometrial thickness on hCG day (mm)	7	886	0.29 [−0.12, 0.70]	0.16	89	Random
High-quality embryos (n)	7	1531	0.41 [0.01, 0.80]	0.04	94	Random
High quality embryos rate (%)	4	1154	1.25 [1.02, 1.53]	0.03	0	Fixed
Clinical pregnancy (%)	12	1519	1.70 [1.35, 2.13]	<0.0001	50	Fixed

3.4.3. Subgroup analysis

The overall results showed that in subgroup analyses of different intervention measures, the use of coenzyme Q10 or a combination of two nutritional supplements had more significant improvements in serum AMH, FSH levels, AFC, oocyte count, and clinical pregnancy rate (p < 0.05). Additionally, using nutritional supplements for more than two months has a better effect on lowering FSH levels, growing AMH levels, increasing AFC, oocyte count, and improving clinical pregnancy rates (p < 0.05). Nutritional supplements are widely recognized for their ability to regulate mitochondrial metabolism and play a crucial role in cellular energy production and homeostasis. Coenzyme Q10 (Q10) can alleviate aging or oxidative stress-induced cell death, highlighting the multifaceted benefits of nutritional supplements [52]. In terms of antioxidant types, Coenzyme Q10 (CoQ10) is often more effective than melatonin, vitamins, and others [22]. A study based on evidence-based methods examined the correlation between nutritional supplements and in vitro fertilization. The data showed that using DHEA and COQ-10 before the start of IVF cycles was more effective, and indicated that drugs containing coenzyme Q10 showed better efficacy [53]. In a previous network meta-analysis, the effects of 10 different adjuvant therapy strategies, including coenzyme Q10 and DHEA, on pregnancy rates in POR patients undergoing in vitro fertilization were studied. The results showed that the cycle cancellation rate of CoQ10 treatment was the lowest, indicating that CoQ10 has broad application prospects in the POR population [54]. This coincides with our conclusion. Table 3 presented the subgroup analysis results of different intervention measures.

Table 3.

Results of subgroups analysis.

Clinical outcomes	Studies (n)	Cases (n)	OR/SMD/MD 95% CI	p	I2 (%)	Model
DHEA
FSH	4	401	−0.34 [−0.53, −0.14]	0.0009	0	Random
AMH	4	401	0.19 [−0.01, 0.39]	0.06	0	Random
AFC	4	401	0.42 [−0.20, 1.03]	0.18	71	Random
Oocytes	6	902	0.70 [−0.02, 1.43]	0.06	89	Random
Clinical pregnancy (%)	5	835	1.22 [0.77, 1.93]	0.4	53	Random
High-quality embryos (n)	2	226	0.36 [0.05, 0.68]	0.02	0	Random
Coenzyme Q10
FSH	4	1215	−1.00 [−1.41, −0.58]	<0.00001	85	Random
AMH	2	1030	0.66 [0.12, 1.19]	0.02	88	Random
AFC	2	1030	1.92 [1.79, 2.04]	<0.00001	0	Random
Oocytes	5	1416	1.12 [0.64, 1.61]	<0.00001	95	Random
Clinical pregnancy (%)	4	500	2.44 [1.65, 3.61]	<0.00001	0	Random
High-quality embryos (n)	3	1136	0.06 [0.01, 0.10]	0.01	92	Random
2 months
FSH	2	266	−0.36 [−0.61, −0.12]	0.003	0	Random
AMH	2	266	0.21 [−0.09, 0.50]	0.17	31	Random
AFC	2	258	0.24 [−0.82, 1.30]	0.66	89	Random
Oocytes	2	266	0.66 [0.13, 1.20]	0.01	0	Random
Clinical pregnancy (%)	3	253	1.25 [0.70, 2.23]	0.46	0	Random
>2 months
FSH	7	1456	−0.79 [−1.13, −0.44]	<0.00001	85	Random
AMH	5	1235	0.41 [0.00, 0.81]	0.05	85	Random
AFC	6	1363	0.81 [−0.14, 1.76]	<0.00001	96	Random
Oocytes	11	2221	0.92 [0.54, 1.29]	<0.00001	95	Random
Clinical pregnancy (%)	9	1266	1.85 [1.23, 2.78]	0.003	59	Random
High-quality embryos (n)	6	1461	0.07 [0.02, 0.11]	0.004	83	Random
One nutritional supplement
FSH	5	500	−0.46 [−0.75, −0.18]	0.001	58	Random
AMH	5	471	0.19 [0.01, 0.37]	0.04	0	Random
AFC	5	500	0.40 [−0.03, 0.84]	0.18	71	Random
Oocytes	6	799	0.46 [0.13, 0.80]	0.006	0	Random
Clinical pregnancy (%)	6	864	1.14 [0.83, 1.55]	0.42	0	Random
High-quality embryos (n)	3	1115	0.05 [0.00, 0.09]	0.04	52	Random
Two nutritional supplements
FSH	3	1136	−0.82 [−1.33, −0.30]	0.002	89	Random
AMH	2	1030	0.66 [0.12, 1.19]	0.02	88	Random
AFC	3	1136	1.92 [1.79, 2.04]	<0.00001	0	Random
Oocytes	6	1602	1.15 [0.68, 1.62]	<0.00001	97	Random
Clinical pregnancy (%)	6	655	2.74 [1.95, 3.86]	<0.00001	0	Random
High-quality embryos (n)	4	1206	0.06 [0.02, 0.11]	0.009	90	Random

4. Discussion

Ovarian reserve refers to the number of primordial follicles and follicles that can be recruited to the pre antral and sinus phases and have the ability to ovulate [55]. Ovarian reserve may be influenced by many factors, including hormones, metabolites, initial ovarian reserve, environmental issues, diseases, and drugs [56]. Due to the unclear mechanism and complex clinical characteristics, targeted treatment is difficult. Nutritional support helps the normal functioning of important physiological, immune, growth and development, metabolism, and repair functions in the human body [57]. Nutritional supplements are widely recognized for their ability to regulate mitochondrial metabolism and play a crucial role in cellular energy production and homeostasis [52]. However, the specific effects of these supplements, including vitamins, coenzyme Q10, and DHEA, on DOR patients are still controversial. Chia Chun Wu et al. [52] used a multi omics approach to screen various nutritional supplements and evaluate their effectiveness in ovarian aging patients. The research results emphasized the potential of nutritional intervention by enhancing electron transfer proteins to improve in vitro fertilization outcomes of aging cells, thereby optimizing energy metabolism and improving oocyte quality.

Vitamins play an important role in human reproduction, and although little is known about the mechanisms by which vitamins affect reproductive physiology, several studies have resolved the relationship between vitamins and DOR markers [39,49,58,59]. At present, there is still a lack of research on the treatment of DOR with folic acid and vitamin E. However, studies have shown that vitamin D can alter anti Mullerian hormone (AMH) signaling by downregulating AMH receptor II gene expression, follicle stimulating hormone (FSH) sensitivity, and progesterone secretion, and plays an important role in follicular development, differentiation, and luteinization [60]. In addition, AS Lagan à et al. [61] has found that physiological levels of vitamin D play an important role in oocyte development, embryo quality, and endometrial receptivity, but excessive vitamin D may have adverse effects on fertility. Related cellular experiments had shown that vitamin D binded to its receptors and could stimulate the production of estrone, estradiol, and testosterone in the ovaries [62]. In addition, studies had found that vitamin D could promote the proliferation of ovarian granulosa cells [63], while inhibiting their apoptosis and inflammatory processes [63], thereby affecting the growth and development of follicles. After knocking out the vitamin D receptor in mice in an animal experiment, it was found that follicular development was inhibited and fertility was impaired [64]. Multiple studies have confirmed a positive correlation between vitamin D levels and ovarian reserve markers [65,66].

Dehydroepiandrosterone (DHEA) is a weak androgen and an important precursor of sex steroids, belonging to one of the nutritional supplements [27]. It has been elucidated that CREB1 is a key transcription factor controlling energy metabolism, and DHEA can activate CREB1 to regulate downstream gene expression involved in biosynthesis pathways such as AMPK, SIRT1, and PGC1 α [67]. It is worth noting that DHEA can regulate many genes involved in mitochondrial molecular morphological changes. For example, DHEA can significantly increase the gene expression of mitochondrial outer membrane protein mitogen-1 (MFN1) and regulate the fusion of optic nerve atrophy 1 (Opa1) in the mitochondrial inner membrane [68]. Supplementing DHEA can enhance mitochondrial function and activity, reduce apoptosis and cell necrosis in cumulus cells (CC) and human granulosa cell lines, and delay the aging of cumulus cells [69]. In addition, DHEA can reduce mitochondrial division and increase the clearance rate of mitotic defective mitochondria [69]. Narkwichan et al.’s study [70] suggested that dehydroepiandrosterone may improve the ovarian microenvironment by reducing DNA damage and apoptosis, increasing mitochondrial mass, mitochondrial dehydrogenase activity, and mitochondrial transcription factor A (TFAM) expression in cumulus cells. Another study has confirmed that dehydroepiandrosterone (DHEA) may regulate hormone receptors in the ovaries and hormone secretion in the peripheral circulation to regulate ovarian reserve function [71]. DHEA may have a regulatory effect on transcription factors involved in cellular energy metabolism pathways, thereby reducing age-related programmed cell death such as mitochondrial autophagy, necrotic apoptosis, apoptosis, and ferroptosis [52,72]. Research confirmed that DHEA can alleviate oxidative damage by increasing the activity of antioxidant enzymes and improving protein damage and lipid peroxidation in cells. It can also reduce cell apoptosis by inhibiting the levels of caspase-3 and Bax proteins [73].

Coenzyme Q10 (CoQ10), as the third largest consumer dietary supplement [29], is also considered a potential candidate drug for treating DOR. Recently, based on network pharmacology research, Liuqing Yang et al. [74] confirmed that coenzyme Q10 may enhance ovarian reserve function through various molecular mechanisms, including FoxO, IL-1, MAPK, and Jak STAT signaling pathways. They also revealed that the potential mechanisms by which coenzyme Q10 improves age-related deterioration of oocyte quality are closely related to antioxidant, mitochondrial function enhancement, autophagy, anti apoptosis, and immune and endocrine system regulation. Furthermore, coenzyme Q10 can regulate various mechanisms that improve oocyte quality [75]. And Coenzyme Q10 has been found to improve mRNA expression of FSHR and PCNA, as well as reduce ROS levels in the ovaries, thereby increasing fertilization rate [76]. Another study also found that coenzyme Q10 can restore chromosome arrangement, mitochondrial distribution, and spindle formation, while upregulating the expression of Sod1, Smarca2, Sdha, and Nduf3 in oocytes, thereby assisting in the improvement of fertility and the anti-aging ability of oocytes [77]. Heydarnejad et al. [78] found that the relative expression levels of apoptosis markers CASPASE3 and BAX were significantly reduced in oocytes and cumulus cells treated with CoQ10, while the relative expression level of oocyte specific growth factor GDF9 was significantly increased. Supplementation with coenzyme Q10 improved the quality of COCs and subsequent embryonic development ability. A series of research results indicate that nutritional supplements may have potential therapeutic effects on improving ovarian reserve function and fertility in DOR patients, but more research is needed to further elucidate the underlying mechanisms by which nutritional supplements improve DOR.

As far as we know, our article is the first meta-analysis evaluating whether oral nutritional supplements can improve fertility in women with DOR. We included 16 randomized controlled studies involving 2773 DOR patients. Through meta-analysis, we evaluated the FSH, AMH levels, AFC, oocyte count, high-quality embryo count, and clinical pregnancy rate of DOR patients after oral nutritional supplements. The results showed that oral nutritional supplements could reduce FSH levels, increase AMH, antral follicle count, oocyte count, and high-quality embryo count in DOR patients, and significantly improve the clinical pregnancy rate of DOR women (p < 0.05). The sub group analysis results showed that the effect of using coenzyme Q10 alone was better than using DHEA alone, but there is a relative lack of research data on vitamins, which is not sufficient to support us in comparing their efficacy through sub group analysis. In addition, through subgroup analysis of studies on the simultaneous use of two nutritional supplements and the use of one nutritional supplement, we found a significant correlation (p < 0.05) between the use of two nutritional supplements and a decrease in FSH, an increase in AMH, AFC, oocyte count, and an increase in clinical pregnancy rate. The analysis of intervention time shows that oral nutritional supplements for more than 2 months have a more significant improvement in ovarian reserve function and fertility. Based on a comprehensive analysis of the above evidence, we believe that oral nutritional supplements may help improve DOR and have certain clinical value for the fertility outcomes of DOR women undergoing IVF/ICSI.

It should be pointed out that the systematic evaluation still has limitations, and we discussed and analyzed potential factors that lead to severe heterogeneity: ① Different nutritional supplements have different doses of action, exert different effects, and have different sensitivities and specificities, which may be one of the sources of heterogeneity between different studies; ② The studies we included are all clinical case-control trials, and the research methods and inclusion criteria of these trials are different, which may have some impact on the research results. The follow-up time and examination techniques of DOR patients included in the study after oral nutritional supplements were inconsistent, which may also lead to increased heterogeneity; ③ The literature with multiple inclusion did not provide detailed information, such as incomplete reports on baseline characteristics such as age, occupation, and education level, making it difficult to conduct more detailed subgroup analysis or use meta regression to further determine the sources of heterogeneity; ④ The sample sizes used in the research vary greatly, which may also be a possible reason for the high heterogeneity. Although the results of this meta-analysis support the benefits of oral nutritional supplements in improving DOR from a clinical perspective, we can only offer a weak suggestion, which is to use oral nutritional supplements including vitamins, coenzyme Q10, and DHEA as complementary therapies to improve DOR ovarian reserve function and enhance reproductive outcomes of IVF/ICSI.

Currently, due to the changing trend of healthy lifestyles, the categories of nutritional supplements are rapidly growing [29]. Additionally, it is worth mentioning that industry funded research may have financial conflicts of interest, leading to the possibility of research bias. A study by Amerigo Vitagliano et al. raised serious doubts about the potential effectiveness of dietary supplements, suggesting that the biases present in the evaluation of most commercial dietary supplements should be minimized as much as possible [79]. It is necessary to conduct more extensive research on various nutritional supplements to elucidate their active ingredients and provide scientific evidence to support their effectiveness and safety in improving DOR, while avoiding research bias caused by conflicts of interest. Translating nutritional supplements including vitamins, coenzyme Q10, and DHEA from clinical research to real-life applications is currently a challenge facing clinical practice. More high-quality clinical randomized controlled trials are needed to validate, and the current evidence still needs to be enhanced or rebuted. It should also be noted that excessive intake of vitamins can cause harm to surrounding organs and the nervous system. Therefore, in certain disease states such as pseudobrain tumors and sensory neuropathy, vitamin intake should be avoided [80]. Excessive use of coenzyme Q10 can lead to nausea and other adverse gastrointestinal reactions [81]. Long term excessive use of DHEA may cause adverse reactions such as acne, hair loss, stomach discomfort, dizziness, and some women may experience abnormal hair growth [82]. Although there is currently no indication that these nutrients pose any significant risk of harm [83], these nutritional supplements still need to be used under the guidance of clinical professionals and the appropriate dosage needs to be evaluated for different populations. In the future, it is necessary to clarify the criteria for selecting the best nutritional supplements for different populations as soon as possible and develop standardized supplementation plans to avoid the occurrence of adverse reactions.

5. Conclusion

Current analysis suggests that oral nutritional supplements may have a positive effect on improving ovarian reserve function and fertility in DOR women, including reducing FSH, increasing AMH, AFC, oocyte count, high-quality embryo count, and increasing clinical pregnancy rates. However, this meta-analysis only evaluated the comprehensive efficacy of oral nutritional supplements including vitamins, coenzyme Q10, and DHEA, with a limited sample size, making it difficult to determine which nutritional supplement is most effective and provide clear evidence to support the determination of the optimal nutritional combination. In the future, more clinical randomized controlled trials are needed to reduce the risk of bias, further validate current evidence, and identify the optimal combination of nutritional supplements to improve DOR.

Funding Statement

Research supported by: Science and Technology Innovation Plan of Shanghai Science and Technology Commission [23Y21920300], The National Natural Science Foundation of China [82174427] and the Special Research Project on Aging and Maternal and Child Health of Shanghai Municipal Health Commission [Grand No. 2020YJZX0217].

Ethics statement

This meta-analysis does not demand ethical approval as all data used in this study are from published articles.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The original contributions proposed in this study have been included in the article. If you have further questions, please contact the corresponding authors.