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 . 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 , 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 . 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 , 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 . 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 , gonadal function decrease , polycystic ovary syndrome  and decreased female fertility . Studies have shown that vitamin D deficiency was associated with various manifestations of polycystic ovary syndrome (PCOS), including anovulation, hyperandrogen and insulin resistance . 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 . 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 , 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 .
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.