The first step in in vitro fertilization-embryo transfer (IVF-ET) is to obtain a sufficient number of high-quality oocytes, yet patients with reduced ovarian reserve (DOR) often have difficulty obtaining ideal oocytes due to poor response to gonadotropins, which ultimately results in lower pregnancy rates. Studies have found that patients with DOR account for 9%-24% of IVF. Therefore, ways to improve ovarian reserve function in women with DOR are increasingly becoming a hot topic of research. Since Casson pioneered the application of dehydroepiandrosterone (DHEA) for pretreatment before ovarian stimulation in 1998, a recent survey of 196 IVF centers in 45 countries worldwide found that approximately 25.8% of centers used DHEA as pre-IVF pretreatment for patients with poor ovarian response and achieved some efficacy. This article will review the application of DHEA in patients with DOR.1. Physiological functions of DHEADHEA is the most abundant steroid in the human blood circulation. It enters the circulation mainly in the form of DHEA sulfate (DHEA-S), which has weak androgenic effects and is mainly converted into testosterone (T) and estradiol (E2) in peripheral tissues to exert indirect biological effects. Circulating levels of DHEA decline markedly with age. levels of DHEA are at their peak in humans between 20 and 30 years of age and decline at approximately 2% per year after 30 years of age, reaching a minimum of approximately 10% to 20% of the peak by 80 years of age. Although it has been more than 80 years since Butenandt first isolated and purified DHEA in 1931, its physiological functions and role in the ovary are still not fully understood. What is certain is that DHEA is an important precursor hormone for steroid hormone synthesis in the follicle, but the biological effects of DHEA are not only limited to steroid hormone precursors, but also may protect the central nervous system, inhibit neurodegenerative diseases, improve depression and other adverse emotions, regulate and stabilize the body’s immunity, improve lipid metabolism, prevent osteoporosis, and have cardiovascular protective effects. 2. The clinical efficacy of DHEA in patients with DOR was first reported by Casson in 2000, in which five patients diagnosed with ovarian hyporesponsiveness were found to have significantly improved ovarian responsiveness after oral administration of DHEA prior to gonadotropin administration. Barad et al. compared IVF cycles before and after DHEA in 25 patients with DOR and showed a significant increase in oocyte count, embryo transfer and embryo grade score after DHEA administration, thus suggesting that DHEA not only increases oocyte and embryo counts but also improves oocyte and embryo quality. Subsequently, Barad et al. reported another study including 190 women with low ovarian reserve function on DHEA, in which 89 cases in the study group received oral micronized DHEA at 75 mg/d for 4 months prior to IVF treatment, and 101 cases in the control group, who did not take DHEA and went directly to IVF treatment. Although the control group was older (41.6±0.4 vs. 40.0±0.4years), the results revealed a significantly higher clinical pregnancy rate in the DHEA group compared to the control group (28.1% vs. 10.9%, 95% CI 1.2-11.8, p<0.05). Although most of the available findings suggest that the use of DHEA increases the number of follicles and eggs gained, improves follicle quality and increases pregnancy rates, there is still a lack of sufficient high-level evidence-based medical evidence. 2012 Meta-analysis by Bosdou on the use of androgens and androgen modulators in patients with ovarian hyporesponsiveness showed that testosterone transdermal patches increased the IVF pregnancy rate (RD:15%, 95% CI:0.03 to 0.26) and live birth rate (RD:0.11, 95% CI:0.003 to 0.22), but oral DHEA pretreatment was not found to be associated with higher pregnancy and live birth rates. In addition, recent studies have shown that the clinical efficacy of DHEA use differs in patients with premature ovarian failure of different FMR1 genotypes or subtypes. Therefore, it is inconclusive whether the use of DHEA or other androgenic drugs can necessarily increase the chance of successful IVF in women with low ovarian reserve function.3. Mechanism of action of DHEA to improve treatment outcome in patients with DOR: The steroid hormone synthesis substrate DHEA is an important precursor hormone for steroid hormone synthesis in the follicle. Therefore, Mcnatty et al. concluded that DHEA is an essential substrate for steroid hormone synthesis according to the two-cell, two-gonadotropin doctrine. In exogenous gonadotropin ovulation cycles, DHEA is the precursor of up to 48% of testosterone (T) in follicular fluid, which is the precursor substance of E2. If DHEA is abnormally low, the lack of androstenedione (A), T and E2 synthetic substrates can lead to low levels of these hormones, which play an important role in follicular growth, maturation and ovulation.3.2. Increasing follicular recruitment Low doses of androgens can increase follicular recruitment and promote follicular growth and development, the exact mechanism is not well understood, it may be that androgens promote insulin-like In 1998, Casson et al. reported an instant increase in IGF-1 after 8 weeks of DHEA administration prior to an ovulatory cycle. Increased intrafollicular androgen content also promotes the secretion of anti-mullerianhormone (AMH) and inhibin B by granulosa cells. Follicular fluid androgen levels and granulosa cell AR mRNA and FSH receptor mRNA levels were positively correlated. Androgens induce granulosa cell FSH receptor production and increase the sensitivity of granulosa cells to FSH, thus promoting estrogen synthesis and follicle development. Based on the above theory, it is therefore suggested that the improved clinical outcome after combined use of aromatase inhibitors in ovulation-promoting cycles in patients with low ovarian reserve function may be the result of androgen-induced FSH receptor production on granulosa cells. Other studies have suggested that androgens have apoptosis-inhibiting effects and that the peak period of DHEA action coincides with the follicle recruitment cycle.3.3. Androgen receptor or other non-classical pathway effects Recent studies have found that androgens can act through the androgen receptor (AR) or through non-classical pathways. Immunohistochemical studies have confirmed the expression of AR in human follicles, which is highly expressed on the surface of antral and early sinus follicles and then decreases, which may suggest that androgens play a very important role in this stage of follicular development. The ARKO model further confirmed the important role of granulosa cell-specific AR in the growth and development of antral follicles and in the prevention of follicular atresia. ElBeltagy et al. found that AR expression in granulosa cells was significantly increased after in vitro culture of granulosa cells using DHEA. Therefore, it was hypothesized that DHEA, as an androgenic agent, could be involved in follicle recruitment and growth through upregulation of AR expression or direct signaling with androgen receptors.3.4. Reduction of embryonic aneuploidy and miscarriage rateThe aneuploidy rate of human embryonic chromosomes increases with age. The decrease in aneuploidy rate can be explained, at least in part, by improved embryo quality and increased pregnancy rates. In a case-control study in 2007, eight patients on DHEA with aging ovaries (prematureovarianaging, POA) exhibited significantly more aneuploidy than younger patients. In 2010, in a 1:2 matched case-control study, pre-implantation genetic screening (PGS) was used to screen chromosomes X, Y, 13, 16, 18, 21, and 22. The results showed that the application of DHEA significantly reduced the number and proportion of embryonic chromosomal aneuploidy, with the most significant aneuploidy-reducing effect of short-term application of DHEA (4 to 12 weeks). Recent studies have also found that the use of DHEA reduces the rate of miscarriage in addition to significantly reducing age-related aneuploidy.3.5. Improving the ovarian microenvironment It is indisputable that the number of remaining follicles gradually decreases with age, and it is generally believed that oocyte quality decreases at the same time, but the effect of DHEA addition challenges this traditional theory. It was found that young DOR women showed no increase in embryonic aneuploidy although they also exhibited typical signs of ovarian aging; on the other hand, Gleicher et al. showed that the addition of DHEA significantly reduced age-related embryonic aneuploidy. Therefore, it can be speculated that DHEA may be able to transform damaged, aged oocytes into young oocytes, but this is highly unlikely; then, it should be another possibility: the resting, dormant oocytes in the young DOR patients' ovaries that are in unrecruited primordial follicles are not really senescent. Once the follicles are recruited, they enter the age-dependent ovarian environment. The ovarian environment affects chromosome segregation during meiosis as women age, increasing embryonic aneuploidy. The increase in aneuploidy may be due to DHEA deficiency alone, or it may be due to the lack of some as yet unknown key component within the normal ovarian environment.Bentov et al.'s study of aged mice with a significant increase in follicle number following administration of the mitochondrial nutrient coenzyme Q10 (CoQ10) validates the speculation that the microenvironment ages and follicles do not age from another perspective.3.6, Regulation Immunological effectsBelgorosky et al. study on DHEA-induced Kaohsiungemia mice found that DHEA increased T lymphocyte infiltration in the ovaries and selectively increased CD4+ T cells and decreased CD8+ T lymphocytes.The same results were found in the study by Luchetti and Sander et al. In the latter study it was also found that tumor necrosis factor-α ( TNF-α) also increased at the same time, and CD4+, CD8+ T lymphocytes, and TNF-α are undoubtedly involved in the development of autoimmune diseases. In a study by Shi et al, androgens were found to significantly improve the condition of mice with autoimmune premature ovarian failure as well as glucocorticoids. Since androgens have fewer side effects and better compliance than glucocorticoids, they may be an effective treatment for autoimmune infertility.4. DHEA Administration and Side Effects Most IVF centers currently recommend 75 mg of micronized DHEA daily, but the duration of administration varies. Barad's study showed a positive correlation between the degree of increase in cumulative pregnancy rate with DHEA and the duration of administration, and found the fastest increase in pregnancy rate after 2 months of continuous DHEA administration, with the peak occurring after 4-5 months of administration. The Center for Human Reproduction in New York, USA, recommends that DOR patients take DHEA for at least 6 weeks, with younger patients taking longer as appropriate. It has relatively rare side effects, mainly androgen-related such as acne, facial hair growth, and low voice. However, Karp et al. also reported a case of seizure after taking DHEA in one patient. The long-term safety of taking DHEA is still unknown, and the main safety concern is that DHEA as an androgen precursor may increase estrogen or androgen-related malignancies.DHEA is currently used in the reproductive field as a rare indication (orphanindications), and many reproductive centers require patients to sign an informed consent form before using this drug.5. Outlook: Clinicians have used many different treatments for patients with low ovarian response in IVF, and DHEA supplementation is certainly one of the most widely used. Unfortunately, to date, with the exception of a small prospective randomized controlled trial (level 1 evidence) by Wiser et al, studies of the effectiveness of DHEA have largely been of low level of evidence. Therefore, there is an imminent need to conduct multicenter randomized prospective controlled studies with large samples. Given the lack of sufficient data to support the clinical effectiveness of DHEA, its widespread use cannot yet be fully recommended, but this does not appear to have dampened the enthusiasm for its use in IVF centers worldwide in any way. This is not only because it can significantly reduce the dose of relatively expensive ovulation-promoting drugs and improve pregnancy rates, but more importantly, if the speculation that the ovarian microenvironment is aging and the oocytes are not, once verified to be correct, then it will undoubtedly offer great hope for pregnancy in DOR patients. One can expect a significant prolongation of the reproductive age by reconstructing the ovarian environment in young people, and DHEA could be the first drug to "rejuvenate" the ovaries.