The effect of medication on serum anti-müllerian hormone (AMH) levels in women of reproductive age: a meta-analysis

The effect of medication on serum anti-müllerian hormone (AMH) levels in women of reproductive age: a meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The effect of medication on serum anti-müllerian hormone (AMH) levels in women of reproductive age: a meta-analysis WeiWei Yin, Chang-Chang Huang, Yi-Ru Chen, Dan-Qing Yu, Min Jin, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1404240/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Objective: The study aims to address whether serum anti-müllerian hormone (AMH) levels fluctuate in the short term after medication application, including oral contraceptives (OCs), metformin, GnRH analogues (GnRH-a), dehydroepiandrosterone (DHEA), vitamin D (VD), clomiphene citrate (CC), and letrozole. Methods: Published literature from PubMed, Embase, and Cochrane central was retrieved up until 19 September 2021. A total of 51 self-control studies with an average Newcastle-Ottawa quality assessment scale (NOS) score of 6.90 were analyzed. Data collection and analysis: the extracted data were entered into Stata software, and the weighted mean difference/standardized mean difference (WMD/SMD) and 95% confidence interval (CI) were used for data analysis. Results: After OCs treatment the AMH level showed a significant decline in women with normal ovarian function, which was significant within 3 months (WMD=-1.43, 95% CI: -2.05 to -0.80, P<0.00001). After metformin treatment the serum AMH decreased in polycystic ovary syndrome (PCOS) patients (WMD=-1.79, 95% CI: -2.32 to -1.26, P<0.00001), in both obese and non-obese patients. GnRH-a treatment in endometriosis patients led to dynamic changes in the serum AMH levels. that is, ascent at 1 month(P=0.05), and descent at 3 months (P=0.02). After DHEA treatment the serum AMH increased in diminished ovarian reserve (DOR) / poor ovarian response (POR) patients (WMD=0.18, 95% CI: 0.09 to 0.27, P<0.0001). After VD treatment the serum AMH increased, and it was obvious in non-PCOS patients (WMD=0.78, 95% CI: 0.34 to 1.21, P=0.0004). After CC treatment the serum AMH decreased significantly in PCOS patients, specifically in non-obese patients (WMD=-1.24, 95% CI: -1.87 to -0.61, P=0.0001). Conclusions: Serum AMH levels may be affected in the short term after drug application. Specifically, OC, metformin and CC leads to decreased AMH level, DHEA and VD leads to increased AMH level, and GnRH-a leads to dynamic variation, which is correlated with PCOS, obesity, age, and duration of medication. The impacts of these medication should be taken into consideration when AMH is used as a marker of ovarian reserve. Anti-müllerian hormone (AMH) ovarian reserve medicine application oral contraceptives meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1 Introduction Anti-Müllerian hormone (AMH) is a dimeric glycoprotein that belongs to the transforming growth factor-β (TGF-β) family [ 1 , 2 ] , and a female baby in the fetal period begins to produce AMH from the 9th month [ 3 ] . AMH is secreted by the antral follicles and small antral follicles in the ovary. The greater the number of these follicles, the higher the serum AMH concentration. Because of this feature that AMH was considered to be a marker for the process of ovarian ageing [ 4 ] . The objectivity and potential standardization of AMH levels, as well as their readily detectable convenience throughout the menstrual cycle, make AMH levels the gold standard biomarker for assessing ovarian reserve and predicting ovarian response to stimulation [ 5 ] . It is currently one of the best indicators for assessing ovarian function, guiding assisted reproduction, and indicate iatrogenic damage (such as chemotherapy, radiotherapy or surgery) to the ovarian follicle reserve. it has a broader application in assisted reproduction field [ 6 , 7 ] . Therefore, the accurate measurement of AMH will guide the dosage of ovarian stimulation related programs, and it has important reference significance to improve the outcome of assisted reproduction technol [ 8 ] . Previous studies believe that AMH is stable and not affected by the menstrual cycle, or hormone drug use. However, more and more clinical studies have shown that drug use may interfere with serum AMH levels in the short term, which may lead to the risk of clinical misinterpretation of AMH values [ 9 ] . However, the sample size of relevant research reports is mostly small, the research results often contradict each other, and there is a lack of evidence-based analysis on the subject. Therefore, we carried out a meta-analysis to accurately assess the impact of drug use on AMH levels. In the present study, evidence-based investigation was performed on seven kinds of medications, including oral contraceptives (OCs), metformin (MET), GnRH analogues (GnRH-a), dehydroepiandrosterone (DHEA), vitamin D (VD), clomiphene citrate (CC), and letrozole (LET), and the variation in serum AMH levels was recorded to guide the correct interpretation and effective application of AMH values in clinics. The findings will provide useful information for elucidating the relationship between the medicine application and the fluctuation of AMH. 2 Materials And Methods 2.1 | Literature search and study selection This study was based on the PRISMA guidelines [ 10 ] for systemic review and meta-analysis. The authors searched PubMed, Cochrane, EMBASE, until September 19th, 2021 and without limitation of region, language, or publication type. Reference list of all selected articles were independently screened to identify additional studies left out in the initial search. Combinations of the following MeSH terms were used: (Anti-Müllerian hormone OR AMH) AND (Oral Contraceptives OR Oral Contraceptive OR OC OR COCS) AND (Metformin OR Dimethylbiguanidine OR Glucophage) AND (DHEA OR dehydroepiandrosterone) AND (Gonadotropin Releasing Hormone OR GnRH) AND (Vitamin D) AND (Clomifene OR Chloramiphene OR Clomifen OR Clomiphene Citrate) AND (Letrozole). All studies after the search were screened and analyzed by two authors independently (YWW and HCC), and any disagreement will be resolved by discussion until consensus were reached or by consulting the third author (CYR). This paper included prospective self-control studies. Studies were excluded if: (1) Clinical case report, review, meta-analysis or cell, animal model; (2) Evidence-based information comes from: books, conferences, notes, thesis, case series, letters or unpublished articles; (3) unreliable extracted data, overlapped data sets, and paragraphs only abstract available. 2.2 | Data Extraction The following data was extracted from every study by two reviewers independently: (1) name of the first author, (2) year of publication, (3) country where the study was conducted, (4) study period, (5) total number of people included in in cases and controls, (6) doses of different drugs, (7) time of application, (8) mean change of anti-Müllerian hormone. We contacted investigators for additional information when extra information was required. 2.3 | Assessment of Study Quality We used the Newcastle-Ottawa scale (NOS) to assess the quality of the included literature [ 11 ] . The NOS scale was based on 3 indicator systems: suitable study object selection, inter-group comparability and intervention exposure. It consisted of 8 indicators, each with a score of 0 or 1, but the “inter-group comparability” can be given 0 or 1 or 2 points, so the overall quality assessment score for each article ranged from 0 to 9 points. Each study was evaluated independently by two authors. Any disagreement was resolved by discussion until consensus reached (TABLE S1-S7). 2.4 | Statistical Analysis All data were entered into Stata(version14.0). Literature heterogeneity was assessed by Q test and quantified by I² index, If values of I² ≤ 25%, it meant that our results were of low heterogeneity. If P > 0.10 and 25%<I²<50%, then the heterogeneity was acceptable. The fixed effects model (FEM) [ 12 ] was used to calculate the parameters of the data pool. If P < 0.10 and 50%<I²<75%, then the heterogeneity could not be ignored, the random effects model (REM) was used to calculate the parameters of the data pool. We performed a subgroup analysis of results with high heterogeneity I²≥ 75%. Since it was continuous data, the serum AMH variation over time was assessed by calculating the Weighted Mean Difference (WMD) or Standard Mean Difference (SMD) among the pooled data, and the statistical significance was calculated with Z test. 2.5 | Publication Bias Publication bias was evaluated by examining the asymmetry of funnel plot. If the scatter points of the documents were symmetrical on both sides of the funnel chart, it indicated that the publication bias of the literature was small, and vice versa, it indicated that the publication bias was large. The literature used in this article was symmetrical on both sides of the funnel chart, indicating that there was no serious publication bias. 2.6 | Author Contributions Chun Feng and Wei-Wei Yin designed the study and wrote the paper; Chang-Chang Huang, Yi-Ru Chen and Dan-Qing Yu performed the data curation; Wei-Wei Yin, Chang-Chang Huang, and Min Jin analyzed the data. 3 Results 3.1 | Study selection and characteristics of included studies A total of 2620 articles were recognized by database searching and 21 through other sources. 600 of records duplicated removed, and 1934 studies were excluded based on information from titles and abstracts. Due to the exclusion reasons listed in the flow chart, 51 studies remained for the qualitative synthesis. Figure 1 shows the study flow diagram of the searching process of these records. 3.2 | Meta-Analysis Results META analysis showed the trend of serum AMH changes after the application of 7 drugs as shown in the table below (Table 1 ). TABLE 1 Overall meta-analysis of the effects of 7 different drugs. Negative values in forest plot: AMH value decreased after medication; positive values in the forest plot: AMH value increased after medication. 3.2.1 Variation of serum AMH levels in women with normal ovarian function after taking oral contraceptives Women with normal ovarian function taking OC (conventional artificial cycle medication: 1 capsule per day for 21 days, repeated 7 days after stopping the drug; or continuous medication: 1 capsule per day, uninterrupted; the same below) 3 ~ 6 cycles or more than 6 cycles, a total of 9 articles [ 13 – 20 ] were included (the total number of sample cases n = 579, 8 groups self-control studies) used for the analysis of this topic. (Table S1) All 8 sets of data (n = 579) random effects model meta-analysis showed that women with normal ovarian function taking oral contraceptive (3–6 cycles or more than 6 cycles) have a significant downward trend in serum AMH (WMD: -0.68,95%CI: -1.30 to -0.06; P = 0.03); The decrease in serum AMH level was statistically significant. Perform subgroup analysis on 8 sets of data according to the length of OCs use showed that: serum AMH level decreased in two groups of use time ≤ 3 months (n = 165), and the decrease was statistically significant(WMD: -1.43, 95%CI: -2.05 to -0.80; P<0.00001). With use for more than 3 months or even longer, there is little effect on serum AMH levels (WMD: -0.09, 95%CI: -0.37 to 0.19; P = 0.45) see Fig. 2 . 3.2.2 Variation of serum AMH levels in PCOS patients with metformin pretreatment Regarding PCOS patients with MET pretreatment (conventional medication 1500 ~ 2250mg, 2 ~ 3 times a day orally, continuous medication for 2 ~ 12 months, the same below), a total of 12 articles [ 21 – 32 ] were included (total number of sample cases n = 362, 12 groups of self-control studies) used for the analysis of this topic. (Table S2) All 12 sets of data (n = 362) random effects model meta-analysis showed that: PCOS patients taking metformin (2–12 months) can cause a significant decrease in serum AMH. (WMD: -1.79, 95%CI: -2.32 to -1.26,P<0.00001) The above mentioned 12 groups of research data were highly heterogeneous (I2 = 68%, P = 0.0003). The meta subgroup analysis of a random effect model based on whether they were obese (BMI༞30 Kg/m2) showed that: obese patients MET pretreatment (n = 151, 5 sets of data) caused a significant decrease in serum AMH levels (WMD: -1.34, 95%CI: -1.62 to -1.05, P<0.00001). The decrease in serum AMH level was statistically significant. Corresponding non-obese patients MET pretreatment (n = 126, 5 sets of data) could also cause a significant decrease in serum AMH levels (WMD: -1.87, 95%CI: -2.75 to -1.00; P < 0.0001), see Fig. 3 . which was statistically significant. 3.2.3 Variation of serum AMH levels in endometriosis patients GnRH-a (gonadotropin releasing hormone agonist) pretreatment Regarding endometriosis patients GnRH-a pretreatment (conventional medication: One injection of long-acting (3.75 mg per tube) leuprolide for 7–21 days during menstruation, or short-acting leuprolide (0.1mg per tube) daily from 7–21 days of menstruation to the day of ovulation induction, the same below), a total of 5 articles [ 33 – 37 ] were included, and 10 sets of data (the total number of sample cases n = 1099, 10 groups of self-control studies) were used for the analysis of this topic. (Table S3) All 10 sets of data (n = 1099) random effects model meta-analysis showed that GnRH-a pretreatment (7 days to 6 cycles) in endometriosis patients can cause dynamic changes in serum AMH levels. The analysis based on the blood collection time of the subjects after GnRH-a pretreatment (≤ 14 days, 1 month, 3 months) showed that: The use of GnRH-a for a short period of time(≤ 14 days) has little effect on the serum AMH levels. After 1 month, there was a transient increase (WMD: 0.87; 95%CI: 0.00 to 1.73; P = 0.05), and the serum AMH decreased after 3 months (WMD: -0.26; 95%CI: -0.48 to -0.04; P = 0.02). 3.2.4 Variation of serum AMH levels in DOR/POR patients DHEA (dehydroepiandrosterone) pretreatment About DOR/POR patients DHEA pretreatment (conventional medication 75mg, 3 times a day, the same below) A total of 8 articles [ 38 – 45 ] (total number of sample cases n = 431, 8 groups of self-control studies) were used for the analysis of this topic. (Table S4) All 8 sets of data (n = 431) random effects model meta-analysis showed that: DOR/POR patients taking DHEA can cause an increase in serum AMH (WMD: 0.18, 95% CI :0.09 to 0.27; P<0.0001= See Fig. 4 ; The increase in serum AMH level was statistically significant. 3.2.5 Variation of serum AMH levels in women with VD pretreatment Regarding VD pretreatment (conventional medication 2000IU-5000IU/week, continuous medication for 2 weeks to 6 months, the same below), a total of 7 articles [ 46 – 52 ] were included (total number of sample cases n = 316, 9 groups of self-controlled studies) used for the analysis of this topic. (Table S5) All 9 sets of data (n = 316) random effects model meta-analysis showed that VD pretreatment (2 weeks to 6 months) in patients can cause an increase in serum AMH (WMD: 0.78, 95%CI: 0.34 to 1.21; P = 0.0004) the increase in serum AMH level was statistically significant. see Fig. 5 . Among them, according to whether they were PCOS patients, the meta subgroup analysis showed that: PCOS patients before and after VD supplementation could cause the fluctuate of serum AMH levels (WMD: 1.16, 95% CI: -1.58 to 3.89; P = 0.41), but this fluctuation was not statistically significant, Correspondingly, non-PCOS patients before and after VD supplementation could cause a statistically significant increase in serum AMH. (WMD: 0.77, 95%CI: 0.33 to 1.21; P = 0.0007), 3.2.6 Variation of serum AMH levels PCOS patients with clomiphene (CC) pretreatment Regarding PCOS patients CC pretreatment (conventional medication 50mg/day, continuous medication for 1 to 3 cycles, the same below), a total of 8 articles [ 53 – 60 ] were included (total number of sample cases n = 869, 8 groups of self-control studies) for the analysis of this topic. (Table S6) All 8 sets of data (n = 869) random effects model meta-analysis showed that: PCOS patients taking CC pretreatment (1 ~ 3 cycles) can cause a significant decrease in serum AMH levels (WMD: -0.89, 95%CI: -1.55 to -0.23; P = 0.008) According to whether the study subjects were obese, a random-effects model META subgroup analysis showed: non-obese(BMI<25Kg/m 2 ) patients CC pretreatment (n = 376, 2 sets of data) have caused a significant reduction in serum AMH levels(WMD: -1.24, 95%CI: -1.87 to -0.61; P = 0.0001)as shown in Fig. 6 , the reduction of serum AMH level was statistically significant. Correspondingly, there was no significant difference in obese (BMI ≥ 25 Kg/m 2 ) patients (n = 261, 4 sets of data), as shown in Fig. 6 . 3.2.7 Variation of serum AMH levels with letrozole (LET) pretreatment Taking letrozole pretreatment (conventional artificial cycle medication: 2.5 mg, starts on menstrual cycle 3–5 days, once a day, continuous use for 5 days; the same below) for 3 to 6 cycles, a total of 3 articles [ 55 , 56 , 61 ] (total number of sample cases n = 397, 3 groups of self-controlled studies) were used for the analysis of this topic. (Table S7) All 3 sets of data (n = 397) fixed-effect model meta-analysis showed that women pretreatment with letrozole (3–6 cycles) have little effect on AMH levels in the short term (WMD: -0.09, 95%CI: -0.22 to 0.04; P = 0.16). 3.3 | Sensitivity Analysis Multi-group meta-analysis of literature sample data in this study showed significant heterogeneity (I²>50%), so the sensitivity analysis was performed by removing one study at one time, for the above 7 different drug sample data, we found that removing any study in the analysis did not impact the overall results, indicated that the META analysis results of the corresponding group are stable. 4 Discussion In assisted reproduction clinics, OCs is often used as a pretreatment medication before ovarian stimulation. OCs can negatively inhibit the secretion of FSH and LH, adjust the menstrual cycle, improve women's ovarian response and assisted reproduction outcomes. Traditional studies believed that after OCs application there have no significant effect on serum AMH levels in the short term [ 17 , 20 , 62 ] , but some recent research results did not support the conclusion [ 14 , 15 ] , the influence of AMH level was related to the dosage, type of contraceptives and time of administration, female age, self-condition and so on. The results of this study supported that OCs pretreatment in women with normal ovarian function will have a downregulation effect on serum AMH, and this effect was obvious in the short term of medication. This was because AMH is secreted by prefollicles and antral follicular granulosa cells which are sensitive to FSH. The down-regulation of FSH caused by OCs reduce the stimulation of granulosa cells, which will have a down-regulating effect on the secretion of AMH [ 17 , 63 ] . However, with the extension of use time, the decrease of serum AMH decreases. This may due to the granule cells adaptation to the down-regulation of FSH to a certain degree, or the concentration of AMH may differ greatly from different experiments, so statistical uncertainty increase. In clinical practice, some PCOS patients who used oral contraceptives can ovulate spontaneously within a short time after stopping the drug, which may be related to the down-regulation of AMH by OC, reduced the inhibition of follicular development. This meta-analysis further confirmed that the serum AMH concentration in women who use hormonal contraception would be negatively affected by exogenous sex hormones, and may not be able to maintain its value as a predictor of ovarian reserve, therefore, we recommend women who use oral contraceptives to measure their serum AMH levels at least 3 months after stopping the drug. Polycystic ovary syndrome (PCOS) is one of the most common causes of female infertility, affecting about 8% of women in childbearing age, the increase in serum AMH in women with hyperandrogenism and/or oligoovulation may indicate the presence of PCOS, serum AMH is a useful prognostic biochemical marker for metformin treatment in PCOS. As a first-line treatment for insulin resistance, metformin can improve insulin sensitivity and regulate blood sugar levels, thereby alleviating insulin resistance, which also reducing androgen levels and improving ovulation [ 64 ] . Currently, metformin has become a commonly used drug before assisted reproduction in women with PCOS. In this article, a meta-analysis of 12 groups of PCOS patients taking metformin suggested that: the use of MET in PCOS patients will cause a decrease in serum AMH levels, both obese (BMI ≥ 30Kg/m2) and non-obese (BMI < 30Kg/m2) patients can occur, which suggested that even patients who are not obese can use MET to reduce the level of AMH, reduce the inhibition of follicular development, and increase the chance of spontaneous ovulation. Endometriosis is a chronic estrogen-dependent disease. Common symptoms include secondary dysmenorrhea, dyspareunia, chronic pelvic pain and infertility. Although the exact mechanism leading to infertility is still unclear, some studies predicted that the excessive production of inflammatory cytokines, growth factors, and chemokines in endometriosis will cause the inflammation process to damage the ovaries, fallopian tubes and endometrial functions [ 65 , 66 ] . Gonadotropin-releasing hormone agonists (GnRH-a) are common treatments for endometriosis. They inhibit the production of hypothalamic-ovarian axis and ovarian steroids, leading to a decrease in estrogen levels. In addition, they also reduce the expression of growth factors which participate in endometriosis tissue development, such as vascular endothelial growth factor (VEGF), and minimizes the macrophage infiltration and micro vessel density of endometriosis lesions [ 67 , 68 ] . Studies have shown that in women with infertility related to endometriosis, given GnRH-a 3–6 months before in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) can significantly improve assisted reproduction outcomes [ 69 ] , but the effect of GnRH-a on serum AMH levels was still controversial. In this study, the dynamic observation of serum AMH after GnRH-a use emphasized the complexity of AMH levels after GnRH-a use. Serum AMH levels did not change much within 14 days, but some studies pointed out that there was a brief drop in serum AMH levels due to the up-regulation of GnRH receptors, and the anti-proliferation and apoptosis effects of GnRH-a short-term exposure on granulosa cells [ 70 ] . At the same time, the short term decrease in AMH may have led to the enlargement of the follicular pools of the anterior and small sinuses that secrete AMH, leading to an increase in AMH levels on the 1 month [ 33 , 71 ] . Our study emphasized that after using GnRH-a, AMH levels follow a predictable two-way trajectory, which also limited the application of AMH as a marker of ovarian reserve in the past 3 months after treatment, so it is recommended to perform AMH measuring after stopping the drug for more than 3 months to determine the ovarian reserve function. DOR/POR (Diminished Ovarian Reserve/Poor Ovary Reserve) is a recognized state of ovarian failure [ 72 ] , and is one of the most challenging problems in artificial reproductive medicine. DHEA is not only a food supplement, naturally found in wild yam and soy products, but also a steroid with both androgenic and weak estrogenic activity, which can improve ovarian response, reduce miscarriage and aneuploidy, and increase the chance of live birth [ 43 , 73 – 75 ] . The reason is that oocytes are in a resting phase in unrecruited primordial follicles, once recruited, they enter an age-dependent ovarian environment where the follicles mature. The quality of this environment deteriorates evenly as women aged, and affects the separation process of meiosis, leading to aneuploidy. DHEA may change and restore the ovarian environment to prevent the aging of follicles [ 76 ] . Other studies have shown that DHEA can increase insulin-like growth factor-1 (IGF-1), promote follicle formation, enhance the effect of gonadotropin and reduce follicular atresia [ 72 , 77 – 79 ] , and make the outcome of assisted pregnancy significantly improve. In this article, the meta-analysis of 8 groups of DOR/POR patients taking DHEA suggested that: the use of DHEA in DOR/POR patients will cause an increase in serum AMH levels, and this rising effect was obvious in the short term. With the high incidence and severity of DOR/POR in aged patients, whether DHEA pretreatment can achieve the same effect for this type of patients was another aspect. Previous studies have shown that patients less than 35 years old after pretreatment with DHEA, whether the number of follicles obtained, the fertilized eggs, or the serum E2, FSH, LH, or AMH level, all better than women more than 35 years old [ 80 , 81 ] . In this study, a subgroup analysis of DOR/POR patients based on age showed that DHEA pretreatment in advanced reproductive age women(༞38 years old) can also cause a significant increase in serum AMH levels (P < 0.00001), which suggested that it is also necessary to supplement DHEA for such patients. Vitamin D (VD) is a steroid hormone that has a well-known effect on calcium and bone metabolism. The current research has more and more evidence that the concentration of 25-hydroxyvitamin D (25(OH)D) is related to various conditions, including obesity, metabolic disorders [ 82 , 83 ] , cardiovascular disease [ 84 ] , gonadal function decrease [ 85 ] , polycystic ovary syndrome [ 86 ] and decreased female fertility [ 87 ] . Studies have shown that vitamin D deficiency was associated with various manifestations of polycystic ovary syndrome (PCOS), including anovulation, hyperandrogen and insulin resistance [ 88 ] . Vitamin D supplementation has been shown to improve menstrual cycles, hyperandrogen and metabolic disease in polycystic ovary syndrome [ 89 , 90 ] , which shows that vitamin D has a direct impact on female fertility. The 9 sets of data in this article showed that in non-PCOS patients serum AMH level will increase in the short term after VD pretreatment, but in PCOS patients, this increase is not obvious. The results of this meta-analysis demonstrated that the relationship between vitamin D and AMH is complex, we encourage non-PCOS patients to supplement VD appropriately. Meanwhile, there is no need to worry about the increase of AMH after VD administration for the patients with PCOS. Similarly, as a common endocrine disease, polycystic ovary syndrome (PCOS) affects 6–10% of women of childbearing age [ 91 ] . Sparse ovulation or anovulation caused by PCOS is a common cause of infertility. Clomiphene (CC) as a first-line drug for inducing ovulation [ 91 , 92 ] is widely used in ovulation therapy. It is a selective estrogen receptor modulator that can antagonize the negative feedback of endogenous estrogen on the hypothalamic-pituitary axis. Clomiphene treatment can restore luteinizing hormone to normal, increase the secretion of follicle stimulating hormone, thereby promoting follicular growth and ovulation [ 93 ] , and increase the chance of ovulation and conception in PCOS patients. In addition, existing studies have shown that obesity is an important parameter, which will have a negative impact on the response of PCOS patients to CC [ 94 ] . The research results of CC pretreatment in 8 groups of PCOS patients in this article all indicated that: The AMH levels have a short-term reduction after using CC, and it was more obvious in non-obese patients, so we can assume that thinner people represent better sensitivity to CC responses. As an ovulation-stimulating drug, letrozole was initially used in Clomiphene -resistant cases. In recent years, evidence has shown that compared with CC, LET stimulation has a higher ovulation rate, pregnancy rate, cumulative live birth rate, and lower multiple births [ 95 – 97 ] . The meta-analysis in this article shows that serum AMH levels are affected to some extent after letrozole use, but the trend was not obvious, and there was no statistical significance. 5 Conclusion Medication application may affect serum AMH levels in the short term. Specifically, OC, metformin and CC leads to decreased AMH level, DHEA and VD leads to increased AMH level, and GnRH-a leads to dynamic variation, which is correlated with PCOS, obesity, age, and duration of medication. The impacts of these medication should be taken into consideration when AMH is used as a marker of ovarian reserve. Declarations Ethics approval and consent to participate Not Applicable. Consent for publication Not Applicable. Data availability statement All data analyzed during this study are included in the supplementary information tables (TABLE S1-TABLE S7). Competing interests All authors declare no conflict to declare. Founding This work was financially supported by National Key R&D Program of China (2018YFC1004900 to CF), the), National Natural Science Foundation of China (82171690 to CF), Zhejiang Provincial Natural Science Foundation (Y22H048979 to CF). Authors’ contributions Chun Feng and Wei-Wei Yin designed the study and wrote the paper; Chang-Chang Huang, Yi-Ru Chen and Dan-Qing Yu performed the data curation; Wei-Wei Yin, Chang-Chang Huang, and Min Jin analyzed the data. Acknowledgments Not Applicable. References Grootegoed JA, Baarends WM, Themmen AP. Welcome to the family: the anti-müllerian hormone receptor. Mol Cell Endocrinol. 1994. 100(1–2): 29–34. Baarends WM, Uilenbroek JT, Kramer P, et al. 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plot of Meta subgroup analysis of serum AMH level changes in women with normal ovarian function taking oral contraceptives (≤3 months vs. \u0026gt;3 months).\u003c/p\u003e","description":"","filename":"fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/22a527d3e15d9fdea0d78eca.png"},{"id":20034520,"identity":"1893abc9-0b0a-486a-980b-ed386ee13bac","added_by":"auto","created_at":"2022-04-06 17:20:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":184702,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of Meta subgroup analysis of changes in serum AMH levels of non-obese vs obese PCOS patients with MET pretreatment.\u003c/p\u003e","description":"","filename":"fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/6a27ab4d47406c2a2d07d04d.png"},{"id":20034519,"identity":"6bf4dc81-cf57-4239-9dcc-ced2da979d4e","added_by":"auto","created_at":"2022-04-06 17:20:04","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":143411,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in serum AMH levels in DOR/POR patients taking DHEA (dehydroepiandrosterone).\u003c/p\u003e","description":"","filename":"fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/2e5bbeea254331cd687d8a33.png"},{"id":20034665,"identity":"700b03a3-a2f5-4a72-803d-e4bcda6c1a0c","added_by":"auto","created_at":"2022-04-06 17:25:04","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":176349,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of Meta analysis of changes in serum AMH levels after VD pretreatment.\u003c/p\u003e","description":"","filename":"fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/9987c350ad1cadca11fb72c5.png"},{"id":20034664,"identity":"818dc21b-eeac-40e8-87ab-059bb3781a38","added_by":"auto","created_at":"2022-04-06 17:25:04","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":204021,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of Meta subgroup analysis of changes in serum AMH levels of non-obese vs obese PCOS patients with CC pretreatment.\u003c/p\u003e","description":"","filename":"fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/913d49297947971f047e3d7f.png"},{"id":20034993,"identity":"7283dd83-4257-4354-b32f-94ae32771bd1","added_by":"auto","created_at":"2022-04-06 17:35:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":891242,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/c964a1bd-cd1c-4985-a351-7e976d8c5072.pdf"},{"id":20034907,"identity":"49c4916e-ee80-4868-9471-5633acb2b97e","added_by":"auto","created_at":"2022-04-06 17:30:03","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18050,"visible":true,"origin":"","legend":"","description":"","filename":"TABLES1.docx","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/4ae29107c8eba49f94de58be.docx"},{"id":20034661,"identity":"f785695e-b4c1-4b32-900f-e9054ac139af","added_by":"auto","created_at":"2022-04-06 17:25:03","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":20972,"visible":true,"origin":"","legend":"","description":"","filename":"TABLES2.docx","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/2434e23f1244b41644ec9438.docx"},{"id":20034992,"identity":"04870ba8-0a9d-4d12-9f32-4ade5e050a84","added_by":"auto","created_at":"2022-04-06 17:35:04","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":18356,"visible":true,"origin":"","legend":"","description":"","filename":"TABLES3.docx","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/28c144837a0673c8c0db47ed.docx"},{"id":20034522,"identity":"5cc04700-c44b-44cb-adbb-f91cf458c369","added_by":"auto","created_at":"2022-04-06 17:20:04","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":18089,"visible":true,"origin":"","legend":"","description":"","filename":"TABLES4.docx","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/ebd1e05cd8b6f9ac3bf05b28.docx"},{"id":20034523,"identity":"bb37a892-6013-48b3-9dac-86c311983f99","added_by":"auto","created_at":"2022-04-06 17:20:04","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":18492,"visible":true,"origin":"","legend":"","description":"","filename":"TABLES5.docx","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/ed721fbe48b9f16e15065b8d.docx"},{"id":20034526,"identity":"776f9a5d-ad03-452c-a83b-cad20309ddf7","added_by":"auto","created_at":"2022-04-06 17:20:04","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":18273,"visible":true,"origin":"","legend":"","description":"","filename":"TABLES6.docx","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/883c499875b1cf3eb28089b5.docx"},{"id":20034910,"identity":"60efab77-8114-4146-b9de-d6f808aff190","added_by":"auto","created_at":"2022-04-06 17:30:04","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":16904,"visible":true,"origin":"","legend":"","description":"","filename":"TABLES7.docx","url":"https://assets-eu.researchsquare.com/files/rs-1404240/v1/37334d511ed5ce1361e1cb92.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The effect of medication on serum anti-müllerian hormone (AMH) levels in women of reproductive age: a meta-analysis","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eAnti-M\u0026uuml;llerian hormone (AMH) is a dimeric glycoprotein that belongs to the transforming growth factor-\u0026beta; (TGF-\u0026beta;) family \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e, and a female baby in the fetal period begins to produce AMH from the 9th month \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. AMH is secreted by the antral follicles and small antral follicles in the ovary. The greater the number of these follicles, the higher the serum AMH concentration. Because of this feature that AMH was considered to be a marker for the process of ovarian ageing\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. The objectivity and potential standardization of AMH levels, as well as their readily detectable convenience throughout the menstrual cycle, make AMH levels the gold standard biomarker for assessing ovarian reserve and predicting ovarian response to stimulation \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. It is currently one of the best indicators for assessing ovarian function, guiding assisted reproduction, and indicate iatrogenic damage (such as chemotherapy, radiotherapy or surgery) to the ovarian follicle reserve. it has a broader application in assisted reproduction field \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Therefore, the accurate measurement of AMH will guide the dosage of ovarian stimulation related programs, and it has important reference significance to improve the outcome of assisted reproduction technol \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003ePrevious studies believe that AMH is stable and not affected by the menstrual cycle, or hormone drug use. However, more and more clinical studies have shown that drug use may interfere with serum AMH levels in the short term, which may lead to the risk of clinical misinterpretation of AMH values \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. However, the sample size of relevant research reports is mostly small, the research results often contradict each other, and there is a lack of evidence-based analysis on the subject. Therefore, we carried out a meta-analysis to accurately assess the impact of drug use on AMH levels. In the present study, evidence-based investigation was performed on seven kinds of medications, including oral contraceptives (OCs), metformin (MET), GnRH analogues (GnRH-a), dehydroepiandrosterone (DHEA), vitamin D (VD), clomiphene citrate (CC), and letrozole (LET), and the variation in serum AMH levels was recorded to guide the correct interpretation and effective application of AMH values in clinics. The findings will provide useful information for elucidating the relationship between the medicine application and the fluctuation of AMH.\u003c/p\u003e"},{"header":"2 Materials And Methods","content":"\u003cdiv class=\"Section2\" id=\"Sec3\"\u003e\n \u003ch2\u003e2.1 | Literature search and study selection\u003c/h2\u003e\n \u003cp\u003eThis study was based on the PRISMA guidelines \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e for systemic review and meta-analysis. The authors searched PubMed, Cochrane, EMBASE, until September 19th, 2021 and without limitation of region, language, or publication type. Reference list of all selected articles were independently screened to identify additional studies left out in the initial search. Combinations of the following MeSH terms were used: (Anti-M\u0026uuml;llerian hormone OR AMH) AND (Oral Contraceptives OR Oral Contraceptive OR OC OR COCS) AND (Metformin OR Dimethylbiguanidine OR Glucophage) AND (DHEA OR dehydroepiandrosterone) AND (Gonadotropin Releasing Hormone OR GnRH) AND (Vitamin D) AND (Clomifene OR Chloramiphene OR Clomifen OR Clomiphene Citrate) AND (Letrozole). All studies after the search were screened and analyzed by two authors independently (YWW and HCC), and any disagreement will be resolved by discussion until consensus were reached or by consulting the third author (CYR). This paper included prospective self-control studies. Studies were excluded if: (1) Clinical case report, review, meta-analysis or cell, animal model; (2) Evidence-based information comes from: books, conferences, notes, thesis, case series, letters or unpublished articles; (3) unreliable extracted data, overlapped data sets, and paragraphs only abstract available.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec4\"\u003e\n \u003ch2\u003e2.2 | Data Extraction\u003c/h2\u003e\n \u003cp\u003eThe following data was extracted from every study by two reviewers independently: (1) name of the first author, (2) year of publication, (3) country where the study was conducted, (4) study period, (5) total number of people included in in cases and controls, (6) doses of different drugs, (7) time of application, (8) mean change of anti-M\u0026uuml;llerian hormone. We contacted investigators for additional information when extra information was required.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec5\"\u003e\n \u003ch2\u003e2.3 | Assessment of Study Quality\u003c/h2\u003e\n \u003cp\u003eWe used the Newcastle-Ottawa scale (NOS) to assess the quality of the included literature \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. The NOS scale was based on 3 indicator systems: suitable study object selection, inter-group comparability and intervention exposure. It consisted of 8 indicators, each with a score of 0 or 1, but the \u0026ldquo;inter-group comparability\u0026rdquo; can be given 0 or 1 or 2 points, so the overall quality assessment score for each article ranged from 0 to 9 points. Each study was evaluated independently by two authors. Any disagreement was resolved by discussion until consensus reached (TABLE S1-S7).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec6\"\u003e\n \u003ch2\u003e2.4 | Statistical Analysis\u003c/h2\u003e\n \u003cp\u003eAll data were entered into Stata(version14.0). Literature heterogeneity was assessed by Q test and quantified by I\u0026sup2; index, If values of I\u0026sup2; \u0026le; 25%, it meant that our results were of low heterogeneity. If P\u0026thinsp;\u0026gt;\u0026thinsp;0.10 and 25%\u0026lt;I\u0026sup2;\u0026lt;50%, then the heterogeneity was acceptable. The fixed effects model (FEM) \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e was used to calculate the parameters of the data pool. If P\u0026thinsp;\u0026lt;\u0026thinsp;0.10 and 50%\u0026lt;I\u0026sup2;\u0026lt;75%, then the heterogeneity could not be ignored, the random effects model (REM) was used to calculate the parameters of the data pool. We performed a subgroup analysis of results with high heterogeneity I\u0026sup2;\u0026ge; 75%. Since it was continuous data, the serum AMH variation over time was assessed by calculating the Weighted Mean Difference (WMD) or Standard Mean Difference (SMD) among the pooled data, and the statistical significance was calculated with Z test.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec7\"\u003e\n \u003ch2\u003e2.5 | Publication Bias\u003c/h2\u003e\n \u003cp\u003ePublication bias was evaluated by examining the asymmetry of funnel plot. If the scatter points of the documents were symmetrical on both sides of the funnel chart, it indicated that the publication bias of the literature was small, and vice versa, it indicated that the publication bias was large. The literature used in this article was symmetrical on both sides of the funnel chart, indicating that there was no serious publication bias.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003e2.6 | Author Contributions\u003c/h2\u003e\n \u003cp\u003eChun Feng and Wei-Wei Yin designed the study and wrote the paper; Chang-Chang Huang, Yi-Ru Chen and Dan-Qing Yu performed the data curation; Wei-Wei Yin, Chang-Chang Huang, and Min Jin analyzed the data.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv class=\"Section2\" id=\"Sec10\"\u003e\n \u003ch2\u003e3.1 | Study selection and characteristics of included studies\u003c/h2\u003e\n \u003cp\u003eA total of 2620 articles were recognized by database searching and 21 through other sources. 600 of records duplicated removed, and 1934 studies were excluded based on information from titles and abstracts. Due to the exclusion reasons listed in the flow chart, 51 studies remained for the qualitative synthesis. Figure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the study flow diagram of the searching process of these records.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec11\"\u003e\n \u003ch2\u003e3.2 | Meta-Analysis Results\u003c/h2\u003e\n \u003cp\u003eMETA analysis showed the trend of serum AMH changes after the application of 7 drugs as shown in the table below (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTABLE 1\u0026nbsp;\u003c/strong\u003eOverall meta-analysis of the effects of 7 different drugs.\u003c/p\u003e\n \u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n \u003cp\u003eNegative values in forest plot: AMH value decreased after medication; positive values in the forest plot: AMH value increased after medication.\u003c/p\u003e\n \u003cdiv class=\"Section3\" id=\"Sec12\"\u003e\n \u003ch2\u003e3.2.1 Variation of serum AMH levels in women with normal ovarian function after taking oral contraceptives\u003c/h2\u003e\n \u003cp\u003eWomen with normal ovarian function taking OC (conventional artificial cycle medication: 1 capsule per day for 21 days, repeated 7 days after stopping the drug; or continuous medication: 1 capsule per day, uninterrupted; the same below) 3\u0026thinsp;~\u0026thinsp;6 cycles or more than 6 cycles, a total of 9 articles \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e were included (the total number of sample cases n\u0026thinsp;=\u0026thinsp;579, 8 groups self-control studies) used for the analysis of this topic. (Table S1)\u003c/p\u003e\n \u003cp\u003eAll 8 sets of data (n\u0026thinsp;=\u0026thinsp;579) random effects model meta-analysis showed that women with normal ovarian function taking oral contraceptive (3\u0026ndash;6 cycles or more than 6 cycles) have a significant downward trend in serum AMH (WMD: -0.68,95%CI: -1.30 to -0.06; P\u0026thinsp;=\u0026thinsp;0.03); The decrease in serum AMH level was statistically significant.\u003c/p\u003e\n \u003cp\u003ePerform subgroup analysis on 8 sets of data according to the length of OCs use showed that: serum AMH level decreased in two groups of use time\u0026thinsp;\u0026le;\u0026thinsp;3 months (n\u0026thinsp;=\u0026thinsp;165), and the decrease was statistically significant(WMD: -1.43, 95%CI: -2.05 to -0.80; P\u0026lt;0.00001). With use for more than 3 months or even longer, there is little effect on serum AMH levels (WMD: -0.09, 95%CI: -0.37 to 0.19; P\u0026thinsp;=\u0026thinsp;0.45) see Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec13\"\u003e\n \u003ch2\u003e3.2.2 Variation of serum AMH levels in PCOS patients with metformin pretreatment\u003c/h2\u003e\n \u003cp\u003eRegarding PCOS patients with MET pretreatment (conventional medication 1500\u0026thinsp;~\u0026thinsp;2250mg, 2\u0026thinsp;~\u0026thinsp;3 times a day orally, continuous medication for 2\u0026thinsp;~\u0026thinsp;12 months, the same below), a total of 12 articles \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e were included (total number of sample cases n\u0026thinsp;=\u0026thinsp;362, 12 groups of self-control studies) used for the analysis of this topic. (Table S2)\u003c/p\u003e\n \u003cp\u003eAll 12 sets of data (n\u0026thinsp;=\u0026thinsp;362) random effects model meta-analysis showed that: PCOS patients taking metformin (2\u0026ndash;12 months) can cause a significant decrease in serum AMH. (WMD: -1.79, 95%CI: -2.32 to -1.26,P\u0026lt;0.00001)\u003c/p\u003e\n \u003cp\u003eThe above mentioned 12 groups of research data were highly heterogeneous (I2\u0026thinsp;=\u0026thinsp;68%, P\u0026thinsp;=\u0026thinsp;0.0003). The meta subgroup analysis of a random effect model based on whether they were obese (BMI༞30 Kg/m2) showed that: obese patients MET pretreatment (n\u0026thinsp;=\u0026thinsp;151, 5 sets of data) caused a significant decrease in serum AMH levels (WMD: -1.34, 95%CI: -1.62 to -1.05, P\u0026lt;0.00001). The decrease in serum AMH level was statistically significant. Corresponding non-obese patients MET pretreatment (n\u0026thinsp;=\u0026thinsp;126, 5 sets of data) could also cause a significant decrease in serum AMH levels (WMD: -1.87, 95%CI: -2.75 to -1.00; P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), see Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. which was statistically significant.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec14\"\u003e\n \u003ch2\u003e\u003cstrong\u003e3.2.3 Variation of serum AMH levels in endometriosis patients GnRH-a (gonadotropin releasing hormone agonist) pretreatment\u003c/strong\u003e\u003c/h2\u003e\n \u003cp\u003eRegarding endometriosis patients GnRH-a pretreatment (conventional medication: One injection of long-acting (3.75 mg per tube) leuprolide for 7\u0026ndash;21 days during menstruation, or short-acting leuprolide (0.1mg per tube) daily from 7\u0026ndash;21 days of menstruation to the day of ovulation induction, the same below), a total of 5 articles \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e were included, and 10 sets of data (the total number of sample cases n\u0026thinsp;=\u0026thinsp;1099, 10 groups of self-control studies) were used for the analysis of this topic. (Table S3)\u003c/p\u003e\n \u003cp\u003eAll 10 sets of data (n\u0026thinsp;=\u0026thinsp;1099) random effects model meta-analysis showed that GnRH-a pretreatment (7 days to 6 cycles) in endometriosis patients can cause dynamic changes in serum AMH levels.\u003c/p\u003e\n \u003cp\u003eThe analysis based on the blood collection time of the subjects after GnRH-a pretreatment (\u0026le;\u0026thinsp;14 days, 1 month, 3 months) showed that: The use of GnRH-a for a short period of time(\u0026le;\u0026thinsp;14 days) has little effect on the serum AMH levels. After 1 month, there was a transient increase (WMD: 0.87; 95%CI: 0.00 to 1.73; P\u0026thinsp;=\u0026thinsp;0.05), and the serum AMH decreased after 3 months (WMD: -0.26; 95%CI: -0.48 to -0.04; P\u0026thinsp;=\u0026thinsp;0.02).\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec15\"\u003e\n \u003ch2\u003e\u003cstrong\u003e3.2.4 Variation of serum AMH levels in DOR/POR patients DHEA (dehydroepiandrosterone) pretreatment\u003c/strong\u003e\u003c/h2\u003e\n \u003cp\u003eAbout DOR/POR patients DHEA pretreatment (conventional medication 75mg, 3 times a day, the same below) A total of 8 articles\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e (total number of sample cases n\u0026thinsp;=\u0026thinsp;431, 8 groups of self-control studies) were used for the analysis of this topic. (Table S4)\u003c/p\u003e\n \u003cp\u003eAll 8 sets of data (n\u0026thinsp;=\u0026thinsp;431) random effects model meta-analysis showed that: DOR/POR patients taking DHEA can cause an increase in serum AMH (WMD: 0.18, 95% CI :0.09 to 0.27; P\u0026lt;0.0001= See Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e; The increase in serum AMH level was statistically significant.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec16\"\u003e\n \u003ch2\u003e\u003cstrong\u003e3.2.5 Variation of serum AMH levels in women with VD pretreatment\u003c/strong\u003e\u003c/h2\u003e\n \u003cp\u003eRegarding VD pretreatment (conventional medication 2000IU-5000IU/week, continuous medication for 2 weeks to 6 months, the same below), a total of 7 articles \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e]\u003c/sup\u003e were included (total number of sample cases n\u0026thinsp;=\u0026thinsp;316, 9 groups of self-controlled studies) used for the analysis of this topic. (Table S5)\u003c/p\u003e\n \u003cp\u003eAll 9 sets of data (n\u0026thinsp;=\u0026thinsp;316) random effects model meta-analysis showed that VD pretreatment (2 weeks to 6 months) in patients can cause an increase in serum AMH (WMD: 0.78, 95%CI: 0.34 to 1.21; P\u0026thinsp;=\u0026thinsp;0.0004) the increase in serum AMH level was statistically significant. see Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003eAmong them, according to whether they were PCOS patients, the meta subgroup analysis showed that: PCOS patients before and after VD supplementation could cause the fluctuate of serum AMH levels (WMD: 1.16, 95% CI: -1.58 to 3.89; P\u0026thinsp;=\u0026thinsp;0.41), but this fluctuation was not statistically significant, Correspondingly, non-PCOS patients before and after VD supplementation could cause a statistically significant increase in serum AMH. (WMD: 0.77, 95%CI: 0.33 to 1.21; P\u0026thinsp;=\u0026thinsp;0.0007),\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec17\"\u003e\n \u003ch2\u003e\u003cstrong\u003e3.2.6 Variation of serum AMH levels PCOS patients with clomiphene (CC) pretreatment\u003c/strong\u003e\u003c/h2\u003e\n \u003cp\u003eRegarding PCOS patients CC pretreatment (conventional medication 50mg/day, continuous medication for 1 to 3 cycles, the same below), a total of 8 articles \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e60\u003c/span\u003e]\u003c/sup\u003e were included (total number of sample cases n\u0026thinsp;=\u0026thinsp;869, 8 groups of self-control studies) for the analysis of this topic. (Table S6)\u003c/p\u003e\n \u003cp\u003eAll 8 sets of data (n\u0026thinsp;=\u0026thinsp;869) random effects model meta-analysis showed that: PCOS patients taking CC pretreatment (1\u0026thinsp;~\u0026thinsp;3 cycles) can cause a significant decrease in serum AMH levels (WMD: -0.89, 95%CI: -1.55 to -0.23; P\u0026thinsp;=\u0026thinsp;0.008)\u003c/p\u003e\n \u003cp\u003eAccording to whether the study subjects were obese, a random-effects model META subgroup analysis showed: non-obese(BMI\u003c25Kg/m\u003csup\u003e2\u003c/sup\u003e) patients CC pretreatment (n\u0026thinsp;=\u0026thinsp;376, 2 sets of data) have caused a significant reduction in serum AMH levels(WMD: -1.24, 95%CI: -1.87 to -0.61; P\u0026thinsp;=\u0026thinsp;0.0001)as shown in Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e, the reduction of serum AMH level was statistically significant. Correspondingly, there was no significant difference in obese (BMI\u0026thinsp;\u0026ge;\u0026thinsp;25 Kg/m\u003csup\u003e2\u003c/sup\u003e) patients (n\u0026thinsp;=\u0026thinsp;261, 4 sets of data), as shown in Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec18\"\u003e\n \u003ch2\u003e\u003cstrong\u003e3.2.7 Variation of serum AMH levels with letrozole (LET) pretreatment\u003c/strong\u003e\u003c/h2\u003e\n \u003cp\u003eTaking letrozole pretreatment (conventional artificial cycle medication: 2.5 mg, starts on menstrual cycle 3\u0026ndash;5 days, once a day, continuous use for 5 days; the same below) for 3 to 6 cycles, a total of 3 articles \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e61\u003c/span\u003e]\u003c/sup\u003e (total number of sample cases n\u0026thinsp;=\u0026thinsp;397, 3 groups of self-controlled studies) were used for the analysis of this topic. (Table S7)\u003c/p\u003e\n \u003cp\u003eAll 3 sets of data (n\u0026thinsp;=\u0026thinsp;397) fixed-effect model meta-analysis showed that women pretreatment with letrozole (3\u0026ndash;6 cycles) have little effect on AMH levels in the short term (WMD: -0.09, 95%CI: -0.22 to 0.04; P\u0026thinsp;=\u0026thinsp;0.16).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec19\"\u003e\n \u003ch2\u003e3.3 | Sensitivity Analysis\u003c/h2\u003e\n \u003cp\u003eMulti-group meta-analysis of literature sample data in this study showed significant heterogeneity (I\u0026sup2;\u0026gt;50%), so the sensitivity analysis was performed by removing one study at one time, for the above 7 different drug sample data, we found that removing any study in the analysis did not impact the overall results, indicated that the META analysis results of the corresponding group are stable.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eIn assisted reproduction clinics, OCs is often used as a pretreatment medication before ovarian stimulation. OCs can negatively inhibit the secretion of FSH and LH, adjust the menstrual cycle, improve women's ovarian response and assisted reproduction outcomes. Traditional studies believed that after OCs application there have no significant effect on serum AMH levels in the short term \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]\u003c/sup\u003e, but some recent research results did not support the conclusion \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e, the influence of AMH level was related to the dosage, type of contraceptives and time of administration, female age, self-condition and so on.\u003c/p\u003e \u003cp\u003eThe results of this study supported that OCs pretreatment in women with normal ovarian function will have a downregulation effect on serum AMH, and this effect was obvious in the short term of medication. This was because AMH is secreted by prefollicles and antral follicular granulosa cells which are sensitive to FSH. The down-regulation of FSH caused by OCs reduce the stimulation of granulosa cells, which will have a down-regulating effect on the secretion of AMH \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]\u003c/sup\u003e. However, with the extension of use time, the decrease of serum AMH decreases. This may due to the granule cells adaptation to the down-regulation of FSH to a certain degree, or the concentration of AMH may differ greatly from different experiments, so statistical uncertainty increase. In clinical practice, some PCOS patients who used oral contraceptives can ovulate spontaneously within a short time after stopping the drug, which may be related to the down-regulation of AMH by OC, reduced the inhibition of follicular development. This meta-analysis further confirmed that the serum AMH concentration in women who use hormonal contraception would be negatively affected by exogenous sex hormones, and may not be able to maintain its value as a predictor of ovarian reserve, therefore, we recommend women who use oral contraceptives to measure their serum AMH levels at least 3 months after stopping the drug.\u003c/p\u003e \u003cp\u003ePolycystic ovary syndrome (PCOS) is one of the most common causes of female infertility, affecting about 8% of women in childbearing age, the increase in serum AMH in women with hyperandrogenism and/or oligoovulation may indicate the presence of PCOS, serum AMH is a useful prognostic biochemical marker for metformin treatment in PCOS.\u003c/p\u003e \u003cp\u003eAs a first-line treatment for insulin resistance, metformin can improve insulin sensitivity and regulate blood sugar levels, thereby alleviating insulin resistance, which also reducing androgen levels and improving ovulation \u003csup\u003e[\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]\u003c/sup\u003e. Currently, metformin has become a commonly used drug before assisted reproduction in women with PCOS.\u003c/p\u003e \u003cp\u003eIn this article, a meta-analysis of 12 groups of PCOS patients taking metformin suggested that: the use of MET in PCOS patients will cause a decrease in serum AMH levels, both obese (BMI\u0026thinsp;\u0026ge;\u0026thinsp;30Kg/m2) and non-obese (BMI\u0026thinsp;\u0026lt;\u0026thinsp;30Kg/m2) patients can occur, which suggested that even patients who are not obese can use MET to reduce the level of AMH, reduce the inhibition of follicular development, and increase the chance of spontaneous ovulation.\u003c/p\u003e \u003cp\u003eEndometriosis is a chronic estrogen-dependent disease. Common symptoms include secondary dysmenorrhea, dyspareunia, chronic pelvic pain and infertility. Although the exact mechanism leading to infertility is still unclear, some studies predicted that the excessive production of inflammatory cytokines, growth factors, and chemokines in endometriosis will cause the inflammation process to damage the ovaries, fallopian tubes and endometrial functions \u003csup\u003e[\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]\u003c/sup\u003e. Gonadotropin-releasing hormone agonists (GnRH-a) are common treatments for endometriosis. They inhibit the production of hypothalamic-ovarian axis and ovarian steroids, leading to a decrease in estrogen levels. In addition, they also reduce the expression of growth factors which participate in endometriosis tissue development, such as vascular endothelial growth factor (VEGF), and minimizes the macrophage infiltration and micro vessel density of endometriosis lesions \u003csup\u003e[\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]\u003c/sup\u003e. Studies have shown that in women with infertility related to endometriosis, given GnRH-a 3\u0026ndash;6 months before in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) can significantly improve assisted reproduction outcomes \u003csup\u003e[\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e]\u003c/sup\u003e, but the effect of GnRH-a on serum AMH levels was still controversial.\u003c/p\u003e \u003cp\u003eIn this study, the dynamic observation of serum AMH after GnRH-a use emphasized the complexity of AMH levels after GnRH-a use. Serum AMH levels did not change much within 14 days, but some studies pointed out that there was a brief drop in serum AMH levels due to the up-regulation of GnRH receptors, and the anti-proliferation and apoptosis effects of GnRH-a short-term exposure on granulosa cells \u003csup\u003e[\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]\u003c/sup\u003e. At the same time, the short term decrease in AMH may have led to the enlargement of the follicular pools of the anterior and small sinuses that secrete AMH, leading to an increase in AMH levels on the 1 month \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e]\u003c/sup\u003e. Our study emphasized that after using GnRH-a, AMH levels follow a predictable two-way trajectory, which also limited the application of AMH as a marker of ovarian reserve in the past 3 months after treatment, so it is recommended to perform AMH measuring after stopping the drug for more than 3 months to determine the ovarian reserve function.\u003c/p\u003e \u003cp\u003eDOR/POR (Diminished Ovarian Reserve/Poor Ovary Reserve) is a recognized state of ovarian failure \u003csup\u003e[\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e]\u003c/sup\u003e, and is one of the most challenging problems in artificial reproductive medicine. DHEA is not only a food supplement, naturally found in wild yam and soy products, but also a steroid with both androgenic and weak estrogenic activity, which can improve ovarian response, reduce miscarriage and aneuploidy, and increase the chance of live birth \u003csup\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan additionalcitationids=\"CR74\" citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e]\u003c/sup\u003e. The reason is that oocytes are in a resting phase in unrecruited primordial follicles, once recruited, they enter an age-dependent ovarian environment where the follicles mature. The quality of this environment deteriorates evenly as women aged, and affects the separation process of meiosis, leading to aneuploidy. DHEA may change and restore the ovarian environment to prevent the aging of follicles \u003csup\u003e[\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e]\u003c/sup\u003e. Other studies have shown that DHEA can increase insulin-like growth factor-1 (IGF-1), promote follicle formation, enhance the effect of gonadotropin and reduce follicular atresia \u003csup\u003e[\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan additionalcitationids=\"CR78\" citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e]\u003c/sup\u003e, and make the outcome of assisted pregnancy significantly improve.\u003c/p\u003e \u003cp\u003eIn this article, the meta-analysis of 8 groups of DOR/POR patients taking DHEA suggested that: the use of DHEA in DOR/POR patients will cause an increase in serum AMH levels, and this rising effect was obvious in the short term. With the high incidence and severity of DOR/POR in aged patients, whether DHEA pretreatment can achieve the same effect for this type of patients was another aspect. Previous studies have shown that patients less than 35 years old after pretreatment with DHEA, whether the number of follicles obtained, the fertilized eggs, or the serum E2, FSH, LH, or AMH level, all better than women more than 35 years old \u003csup\u003e[\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e]\u003c/sup\u003e. In this study, a subgroup analysis of DOR/POR patients based on age showed that DHEA pretreatment in advanced reproductive age women(༞38 years old) can also cause a significant increase in serum AMH levels (P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001), which suggested that it is also necessary to supplement DHEA for such patients.\u003c/p\u003e \u003cp\u003eVitamin D (VD) is a steroid hormone that has a well-known effect on calcium and bone metabolism. The current research has more and more evidence that the concentration of 25-hydroxyvitamin D (25(OH)D) is related to various conditions, including obesity, metabolic disorders \u003csup\u003e[\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e, \u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e]\u003c/sup\u003e, cardiovascular disease \u003csup\u003e[\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e]\u003c/sup\u003e, gonadal function decrease \u003csup\u003e[\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e]\u003c/sup\u003e, polycystic ovary syndrome \u003csup\u003e[\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e]\u003c/sup\u003e and decreased female fertility \u003csup\u003e[\u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e]\u003c/sup\u003e. Studies have shown that vitamin D deficiency was associated with various manifestations of polycystic ovary syndrome (PCOS), including anovulation, hyperandrogen and insulin resistance \u003csup\u003e[\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e]\u003c/sup\u003e. Vitamin D supplementation has been shown to improve menstrual cycles, hyperandrogen and metabolic disease in polycystic ovary syndrome \u003csup\u003e[\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e]\u003c/sup\u003e, which shows that vitamin D has a direct impact on female fertility.\u003c/p\u003e \u003cp\u003eThe 9 sets of data in this article showed that in non-PCOS patients serum AMH level will increase in the short term after VD pretreatment, but in PCOS patients, this increase is not obvious. The results of this meta-analysis demonstrated that the relationship between vitamin D and AMH is complex, we encourage non-PCOS patients to supplement VD appropriately. Meanwhile, there is no need to worry about the increase of AMH after VD administration for the patients with PCOS.\u003c/p\u003e \u003cp\u003eSimilarly, as a common endocrine disease, polycystic ovary syndrome (PCOS) affects 6\u0026ndash;10% of women of childbearing age \u003csup\u003e[\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e]\u003c/sup\u003e. Sparse ovulation or anovulation caused by PCOS is a common cause of infertility. Clomiphene (CC) as a first-line drug for inducing ovulation \u003csup\u003e[\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e, \u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e]\u003c/sup\u003e is widely used in ovulation therapy. It is a selective estrogen receptor modulator that can antagonize the negative feedback of endogenous estrogen on the hypothalamic-pituitary axis. Clomiphene treatment can restore luteinizing hormone to normal, increase the secretion of follicle stimulating hormone, thereby promoting follicular growth and ovulation \u003csup\u003e[\u003cspan citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e]\u003c/sup\u003e, and increase the chance of ovulation and conception in PCOS patients. In addition, existing studies have shown that obesity is an important parameter, which will have a negative impact on the response of PCOS patients to CC \u003csup\u003e[\u003cspan citationid=\"CR94\" class=\"CitationRef\"\u003e94\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe research results of CC pretreatment in 8 groups of PCOS patients in this article all indicated that: The AMH levels have a short-term reduction after using CC, and it was more obvious in non-obese patients, so we can assume that thinner people represent better sensitivity to CC responses.\u003c/p\u003e \u003cp\u003eAs an ovulation-stimulating drug, letrozole was initially used in Clomiphene -resistant cases. In recent years, evidence has shown that compared with CC, LET stimulation has a higher ovulation rate, pregnancy rate, cumulative live birth rate, and lower multiple births \u003csup\u003e[\u003cspan additionalcitationids=\"CR96\" citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR97\" class=\"CitationRef\"\u003e97\u003c/span\u003e]\u003c/sup\u003e. The meta-analysis in this article shows that serum AMH levels are affected to some extent after letrozole use, but the trend was not obvious, and there was no statistical significance.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eMedication application may affect serum AMH levels in the short term. Specifically, OC, metformin and CC leads to decreased AMH level, DHEA and VD leads to increased AMH level, and GnRH-a leads to dynamic variation, which is correlated with PCOS, obesity, age, and duration of medication. The impacts of these medication should be taken into consideration when AMH is used as a marker of ovarian reserve.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data analyzed during this study are included in the supplementary information tables (TABLE S1-TABLE S7).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no conflict to declare. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFounding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was financially supported by National Key R\u0026amp;D Program of China (2018YFC1004900 to CF), the), National Natural Science Foundation of China (82171690 to CF), Zhejiang Provincial Natural Science Foundation (Y22H048979 to CF).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChun Feng and Wei-Wei Yin designed the study and wrote the paper; Chang-Chang Huang, Yi-Ru Chen and Dan-Qing Yu performed the data curation; Wei-Wei Yin, Chang-Chang Huang, and Min Jin analyzed the data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGrootegoed JA, Baarends WM, Themmen AP. Welcome to the family: the anti-m\u0026uuml;llerian hormone receptor. Mol Cell Endocrinol. 1994. 100(1\u0026ndash;2): 29\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaarends WM, Uilenbroek JT, Kramer P, et al. Anti-m\u0026uuml;llerian hormone and anti-m\u0026uuml;llerian hormone type II receptor messenger ribonucleic acid expression in rat ovaries during postnatal development, the estrous cycle, and gonadotropin-induced follicle growth. Endocrinology. 1995. 136(11): 4951\u0026ndash;4962.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRajpert-De Meyts E, J\u0026oslash;rgensen N, Graem N, M\u0026uuml;ller J, Cate RL, Skakkebaek NE. Expression of anti-M\u0026uuml;llerian hormone during normal and pathological gonadal development: association with differentiation of Sertoli and granulosa cells. 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The impact of GnRH agonists in patients with endometriosis on prolactin and sex hormone levels: a pilot study. Eur J Obstet Gynecol Reprod Biol. 2015. 195: 156\u0026ndash;159.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev. 2006. 2006(1): CD004635.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJoffe H, White DP, Crawford SL, et al. Adverse effects of induced hot flashes on objectively recorded and subjectively reported sleep: results of a gonadotropin-releasing hormone agonist experimental protocol. Menopause. 2013. 20(9): 905\u0026ndash;914.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFanchin R, Schon\u0026auml;uer LM, Righini C, Frydman N, Frydman R, Taieb J. Serum anti-M\u0026uuml;llerian hormone dynamics during controlled ovarian hyperstimulation. Hum Reprod. 2003. 18(2): 328\u0026ndash;332.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011. 26(7): 1616\u0026ndash;1624.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQin JC, Fan L, Qin AP. The effect of dehydroepiandrosterone (DHEA) supplementation on women with diminished ovarian reserve (DOR) in IVF cycle: Evidence from a meta-analysis. J Gynecol Obstet Hum Reprod. 2017. 46(1): 1\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWiser A, Gonen O, Ghetler Y, Shavit T, Berkovitz A, Shulman A. Addition of dehydroepiandrosterone (DHEA) for poor-responder patients before and during IVF treatment improves the pregnancy rate: a randomized prospective study. Hum Reprod. 2010. 25(10): 2496\u0026ndash;2500.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYeung T, Chai J, Li R, Lee V, Ho PC, Ng E. A double-blind randomised controlled trial on the effect of dehydroepiandrosterone on ovarian reserve markers, ovarian response and number of oocytes in anticipated normal ovarian responders. BJOG. 2016. 123(7): 1097\u0026ndash;1105.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGleicher N, Barad DH. Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR). Reprod Biol Endocrinol. 2011. 9: 67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarad D, Brill H, Gleicher N. Update on the use of dehydroepiandrosterone supplementation among women with diminished ovarian function. J Assist Reprod Genet. 2007. 24(12): 629\u0026ndash;634.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarad DH, Gleicher N. Increased oocyte production after treatment with dehydroepiandrosterone. Fertil Steril. 2005. 84(3): 756.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarad D, Gleicher N. Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF. Hum Reprod. 2006. 21(11): 2845\u0026ndash;1849.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh N, Zangmo R, Kumar S, et al. A prospective study on role of dehydroepiandrosterone (DHEA) on improving the ovarian reserve markers in infertile patients with poor ovarian reserve. Gynecol Endocrinol. 2013. 29(11): 989\u0026ndash;992.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZangmo R, Singh N, Kumar S, Vanamail P, Tiwari A. Role of dehydroepiandrosterone in improving oocyte and embryo quality in IVF cycles. Reprod Biomed Online. 2014. 28(6): 743\u0026ndash;747.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWehr E, Pilz S, Schweighofer N, et al. Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syndrome. Eur J Endocrinol. 2009. 161(4): 575\u0026ndash;582.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrummer C, Pilz S, Schwetz V, Obermayer-Pietsch B, Lerchbaum E. Vitamin D, PCOS and androgens in men: a systematic review. Endocr Connect. 2018. 7(3): R95-R113.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePilz S, M\u0026auml;rz W, Wellnitz B, et al. Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab. 2008. 93(10): 3927\u0026ndash;3935.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLerchbaum E, Pilz S, Trummer C, et al. Serum vitamin D levels and hypogonadism in men. Andrology. 2014. 2(5): 748\u0026ndash;754.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMu Y, Cheng D, Yin TL, Yang J. Vitamin D and Polycystic Ovary Syndrome: a Narrative Review. Reprod Sci. 2021. 28(8): 2110\u0026ndash;2117.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLerchbaum E, Rabe T. Vitamin D and female fertility. Curr Opin Obstet Gynecol. 2014. 26(3): 145\u0026ndash;150.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe C, Lin Z, Robb SW, Ezeamama AE. Serum Vitamin D Levels and Polycystic Ovary syndrome: A Systematic Review and Meta-Analysis. Nutrients. 2015. 7(6): 4555\u0026ndash;4577.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXue Y, Xu P, Xue K, et al. Effect of vitamin D on biochemical parameters in polycystic ovary syndrome women: a meta-analysis. Arch Gynecol Obstet. 2017. 295(2): 487\u0026ndash;496.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIrani M, Seifer DB, Grazi RV, et al. Vitamin D Supplementation Decreases TGF-β1 Bioavailability in PCOS: A Randomized Placebo-Controlled Trial. J Clin Endocrinol Metab. 2015. 100(11): 4307\u0026ndash;4314.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcCartney CR, Marshall JC. CLINICAL PRACTICE. Polycystic Ovary Syndrome. N Engl J Med. 2016. 375(1): 54\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConway G, Dewailly D, Diamanti-Kandarakis E, et al. European survey of diagnosis and management of the polycystic ovary syndrome: results of the ESE PCOS Special Interest Group's Questionnaire. Eur J Endocrinol. 2014. 171(4): 489\u0026ndash;498.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNorman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007. 370(9588): 685\u0026ndash;697.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDouchi T, Oki T, Yamasaki H, Nakae M, Imabayashi A, Nagata Y. Body fat patterning in polycystic ovary syndrome women as a predictor of the response to clomiphene. Acta Obstet Gynecol Scand. 2004. 83(9): 838\u0026ndash;841.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLegro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014. 371(2): 119\u0026ndash;129.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBadawy A, Abdel Aal I, Abulatta M. RETRACTED: Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial. Fertil Steril. 2009. 92(3): 849\u0026ndash;852.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang S, Du X, Wang R, et al. Ovulation induction and intrauterine insemination in infertile women with polycystic ovary syndrome: A comparison of drugs. Eur J Obstet Gynecol Reprod Biol. 2018. 231: 117\u0026ndash;121.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Anti-müllerian hormone (AMH), ovarian reserve, medicine application, oral contraceptives, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-1404240/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1404240/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e The study aims to address whether serum anti-müllerian hormone (AMH) levels fluctuate in the short term after medication application, including oral contraceptives (OCs), metformin, GnRH analogues (GnRH-a), dehydroepiandrosterone (DHEA), vitamin D (VD), clomiphene citrate (CC), and letrozole.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Published literature from PubMed, Embase, and Cochrane central was retrieved up until 19 September 2021. A total of 51 self-control studies with an average Newcastle-Ottawa quality assessment scale (NOS) score of 6.90 were analyzed. Data collection and analysis: the extracted data were entered into Stata software, and the weighted mean difference/standardized mean difference (WMD/SMD) and 95% confidence interval (CI) were used for data analysis.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e After OCs treatment the AMH level showed a significant decline in women with normal ovarian function, which was significant within 3 months (WMD=-1.43, 95% CI: -2.05 to -0.80, P\u0026lt;0.00001). After metformin treatment the serum AMH decreased in polycystic ovary syndrome (PCOS) patients (WMD=-1.79, 95% CI: -2.32 to -1.26, P\u0026lt;0.00001), in both obese and non-obese patients.\u003cstrong\u003e \u003c/strong\u003eGnRH-a treatment in endometriosis patients led to dynamic changes in the serum AMH levels. that is, ascent at 1 month(P=0.05), and descent at 3 months (P=0.02). After DHEA treatment the serum AMH increased in diminished ovarian reserve (DOR) / poor ovarian response (POR) patients (WMD=0.18, 95% CI: 0.09 to 0.27, P\u0026lt;0.0001). After VD treatment the serum AMH increased, and it was obvious in non-PCOS patients (WMD=0.78, 95% CI: 0.34 to 1.21, P=0.0004). After CC treatment the serum AMH decreased significantly in PCOS patients, specifically in non-obese patients (WMD=-1.24, 95% CI: -1.87 to -0.61, P=0.0001). \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eSerum AMH levels may be affected in the short term after drug application. Specifically, OC, metformin and CC leads to decreased AMH level, DHEA and VD leads to increased AMH level, and GnRH-a leads to dynamic variation, which is correlated with PCOS, obesity, age, and duration of medication. The impacts of these medication should be taken into consideration when AMH is used as a marker of ovarian reserve.\u003c/p\u003e","manuscriptTitle":"The effect of medication on serum anti-müllerian hormone (AMH) levels in women of reproductive age: a meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-04-06 17:20:01","doi":"10.21203/rs.3.rs-1404240/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-04-19T09:33:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-04-05T19:24:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"81a8f9c2-5ba8-464f-bd5e-8adfdec08177","date":"2022-03-26T10:58:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-03-24T11:47:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-03-24T11:41:05+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2022-03-24T07:47:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-03-24T07:39:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Endocrine Disorders","date":"2022-02-28T13:18:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ace8df31-8ec9-43f3-9969-746427a60615","owner":[],"postedDate":"April 6th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-05-30T10:29:24+00:00","versionOfRecord":[],"versionCreatedAt":"2022-04-06 17:20:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1404240","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1404240","identity":"rs-1404240","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}