The first step in in vitro fertilization-embryo transfer (IVF-ET) is to obtain a sufficient number of high-quality oocytes; however, patients with reduced ovarian reserve (DOR) often have difficulty obtaining ideal oocytes due to poor response to gonadotropins, which ultimately leads to low pregnancy rates. Studies have found that patients with DOR account for 9%-24% of IVF [[i]]. Therefore, ways to improve ovarian reserve function in women with DOR are increasingly becoming a hot topic of research. Since Casson [[ii]] 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 [[iii]] that approximately 25.8% of centers used DHEA as pre-IVF pretreatment for patients with poor ovarian response with some efficacy. In this article, we will review the use of DHEA in patients with DOR. 1. Physiological functions of DHEA DHEA is the most abundant steroid in 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 [[iv]]. Although it has been more than 80 years since the first isolation and purification of DHEA by Butenandt in 1931, its physiological functions and role in the ovary are still not fully elucidated. What is certain is that DHEA is an important precursor hormone for steroid hormone synthesis in the follicle, but the biological role of DHEA is 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 a protective effect on cardiovascular [[v]]. The clinical efficacy of DHEA in patients with DOR was first reported by Casson in 2000 in a case study of five patients with a diagnosis of ovarian hyporesponsiveness who were given oral DHEA before gonadotropin and were found to have significantly improved ovarian responsiveness [[vi]], although only one of these five patients ended up with a double pregnancy. In 2006, Barad et al. [[vii]] compared IVF cycles before and after DHEA in 25 DOR patients 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 [[viii]] reported another study including 190 women with low ovarian reserve function on DHEA, in which 89 cases in the study group were given oral micronized DHEA, 75 mg/d, for 4 months before 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 ± 0.4 years), 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 a lack of sufficient high-level evidence based on medical evidence. 2012 Meta-analysis by Bosdou [[ix]] on the use of androgens and androgen modulators in patients with ovarian hyporesponsiveness showed that testosterone transdermal patches increased the pregnancy rate in patients with ovarian hyporesponsiveness. IVF pregnancy rates (RD:15%, 95% CI: 0.03 to 0.26) and live birth rates (RD:0.11, 95% CI: 0.003 to 0.22) in responding patients, but oral DHEA pretreatment was not found to be associated with higher pregnancy and live birth rates. In addition, recent studies have shown different clinical outcomes with DHEA in patients with premature ovarian failure of different FMR1 genotypes or subtypes [[x]]. Therefore, it is inconclusive whether the use of DHEA or other androgenic drugs necessarily increases 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 3.1 Steroid hormone synthesis substrate DHEA is an important precursor hormone for steroid hormone synthesis in the follicle. Therefore, Mcnatty et al. concluded [[xi]] 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, Increase follicle recruitment Low doses of androgens can increase follicle recruitment and promote follicle growth and development, the exact mechanism is not well understood, it may be that androgens promote the secretion of insulin-like growth factor-1 (IGF-1), which increases ovarian responsiveness by amplifying the action of gonadotropins. in 1998, Casson [2] et al. reported that prior to ovulatory cycles DHEA was administered and after 8 weeks the patients showed an instant increase in IGF-1. Increased levels of intrafollicular androgens also promote the secretion of anti-mullerian hormone (AMH) and inhibin B by granulosa cells [[xii]]. Follicular fluid androgen levels and granulosa cell AR mRNA were positively correlated with FSH receptor mRNA levels [[xiii]]. Androgens induce granulosa cell FSH receptor production and increase the sensitivity of granulosa cells to FSH, thus promoting estrogen synthesis and follicular development. Based on these theories, 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 [[xiv]]. Other studies have suggested that androgens have apoptosis-inhibiting effects and that the period of peak DHEA action coincides with the follicular recruitment cycle [[xv]]. 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 [[xvi]]. Immunohistochemical studies have confirmed the expression of AR in human follicles [[xvii]].High expression of AR on the surface of antral and early sinus follicles and its subsequent decrease [[xviii]] may suggest that androgens play a very important role in follicular development at this stage.Sen and Hammer [[xix]] showed that androgen receptor knockout (ARKO) is the most important pathway for the development of human follicles. The ARKO model further confirmed the role of granulosa cell-specific AR in pre-sinus follicle ElBeltagy et al [[xx]] found that the expression of granulosa cell AR was significantly increased after in vitro culture of granulosa cells using DHEA. Therefore, it is speculated that as an androgenic agent, DHEA could be involved in follicle recruitment and growth and development through upregulation of AR expression or direct signaling with androgen receptors. 3.4, Reduced embryonic aneuploidy rate and miscarriage rate Human embryonic chromosomal aneuploidy rate increases with increasing age [[xxi]. [xxii]]. The decrease in aneuploidy rate can be explained, at least in part, by improved embryo quality and increased pregnancy rates. A study of subgroups of patients with low ovarian function at different ages found that although all showed elevated FSH, decreased AMH and low response to ovarian stimulation, significantly more aneuploidy was demonstrated in older patients compared to younger ones [[xxiii]]. in a case-control study in 2007 [[xxiv]], eight cases of aging ovarian function on DHEA ( In 2010, in a 1:2 matched case-control study [[xxv]], the preimplantation genetic screening (PGS) method was used to screen for X, Y, and 13 embryos.) method was used to screen for chromosomes X, Y, 13, 16, 18, 21, and 22. The results showed that the application of DHEA significantly reduced the number and proportion of chromosomal aneuploidies in embryos, with the most significant aneuploidy-reducing effect being seen with 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 [[xxvi]]. 3.5. Improving the ovarian microenvironment It is indisputable that the number of remaining follicles gradually decreases with age, and it is generally assumed that oocyte quality decreases at the same time, but the effects of DHEA addition question this traditional theory. It was found that young DOR women did not have an increase in embryonic aneuploidy, although they also showed typical signs of ovarian aging [[xxvii]]; on the other hand, Gleicher et al [25] showed that the addition of DHEA significantly reduced age-related embryonic aneuploidy. It can therefore be speculated that DHEA might 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 ovaries of young DOR patients 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 certain key components within the normal ovarian environment that are not yet known. Bentov et al.'s [[xxviii]] study of older mice with a significant increase in follicle number after administration of the mitochondrial nutrient coenzyme Q10 (CoQ10) provides another perspective on the aging microenvironment, follicle immortality speculation. 3.6, Immunomodulatory effects Belgorosky et al [[xxix]] 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. studies by Luchetti [[xxx]] and Sander [[xxxi]] et al also found the same results, and in the latter study a concomitant increase in tumor necrosis factor-α (TNF-α) was also found, while CD4+, CD8+ T lymphocytes, and TNF-α are undoubtedly involved in the development of autoimmune diseases. A study by Shi [[xxxii]] et al. found that androgens significantly improved the condition of mice with autoimmune premature ovarian failure as well as glucocorticoids. Since moderate amounts of androgens have fewer side effects and better compliance compared to glucocorticoids, androgens may become an effective treatment for autoimmune infertility. In a study by Barad [8], the degree of increase in cumulative pregnancy rate with DHEA was positively correlated with the duration of administration, and the fastest increase in pregnancy rate was found after 2 months of continuous DHEA administration, with the peak occurring after 4 to 5 months of administration. The Center for Human Reproduction in New York, NY, USA, recommends that DOR patients take DHEA for at least 6 weeks, with appropriate extensions for younger patients [[xxxiii]]. DHEA is approved by the Food and Drug Administration (FDA) as a health food in the United States and is available for purchase as a supplement. It has relatively rare side effects, mainly androgen-related such as acne, facial hair growth, and low voice, however, Karp et al [[xxxiv]] also reported one case of seizures in a patient taking DHEA. The long-term safety of taking DHEA is still unknown, and the most significant safety concern is that DHEA as an androgen precursor may increase estrogenic or androgen-related malignancies [[xxxv]]. DHEA is currently used as a rare indication (orphan indications) in the reproductive field [[xxxvi]], and many reproductive centers require patients to sign an informed consent form before using this drug. Many fertility centers require patients to sign an informed consent form before using this drug. 5. Outlook: Clinicians have used many different treatments for patients with ovarian hyporesponsiveness 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 [[xxxvii]] et al, studies on 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 supporting the clinical effectiveness of DHEA, its widespread use cannot yet be fully recommended [[xxxviii]], but this does not appear to have dampened in any way the enthusiasm for its use in IVF centers worldwide. 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 give 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.