MINI REVIEW published: 17 May 2021 doi: 10.3389/fendo.2021.653857 The Role of Androgen Supplementation in Women With Diminished Ovarian Reserve: Time to Randomize, Not Meta-Analyze Ana Raquel Neves 1,2, Pedro Montoya-Botero 3 and Nikolaos P. Polyzos 1,4* 1 Department of Obstetrics, Gynecology and Reproductive Medicine, Dexeus University Hospital, Barcelona, Spain, 2 Faculty of Medicine, Autonomous University of Barcelona, Cerdanyola del Vallès, Spain, 3 Department of Reproductive Medicine, Conceptum – Unidad de Fertilidad del Country, Bogotá, Colombia, 4 Faculty of Medicine and Health Sciences, Ghent University (UZ Gent), Gent, Belgium The management of patients with diminished ovarian reserve (DOR) remains one of the most challenging tasks in IVF clinical practice. Despite the promising results obtained from animal studies regarding the importance of androgens on folliculogenesis, the evidence obtained from clinical studies remains inconclusive. This is mainly due to the lack of an evidence-based methodology applied in the available trials and to the heterogeneity in the Edited by: inclusion criteria and IVF treatment protocols. In this review, we analyze the available Antonio La Marca, evidence obtained from animal studies and highlight the pitfalls from the clinical studies University of Modena and Reggio that prevent us from closing the chapter of this line of research. Emilia, Italy Reviewed by: Keywords: androgens, testosterone, DHEA, poor ovarian response (POR), diminished ovarian response (DOR) Fulvio Zullo, University of Naples Federico II, Italy Bulent Urman, Koç University, Turkey INTRODUCTION *Correspondence: Nikolaos P. Polyzos In women, testosterone and dihydrotestosterone (DHT), the bioactive androgens that bind directly nikpol@dexeus.com to the androgen receptor (AR), are produced by peripheral conversion of androgen precursors (androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate) that are secreted Specialty section: from both the ovary and adrenal gland (1, 2). This article was submitted to The AR is expressed at all levels of the female hypothalamic-pituitary-gonadal axis (2). In the Reproduction, ovary, the AR has been detected in several stages of oocyte development from the primary stage a section of the journal onwards, as well as in the ovarian stroma (3). The fact that hyperandrogenic women present an Frontiers in Endocrinology increased number of small antral follicles suggests a role for androgens in both follicular Received: 15 January 2021 development and follicular arrest. Clinical examples of this effect include polycystic ovarian Accepted: 23 April 2021 syndrome (PCOS) and congenital adrenal hyperplasia patients (4). On the other hand, although Published: 17 May 2021 initial studies using histomorphologic criteria suggested that exposure to exogenous testosterone Citation: treatment in female-to-male transexual patients induced polycystic ovary morphology (5, 6), more Neves AR, Montoya-Botero P and recent studies using both histologic and ultrasound criteria have not confirmed these findings (7–9). Polyzos NP (2021) The Role of Circulating androgen levels have been reported to decline with age, especially during the earlier Androgen Supplementation in Women With Diminished Ovarian Reserve: Time reproductive years (10). Similarly, the reproductive aging process consists of a gradual reduction in to Randomize, Not Meta-Analyze. oocyte quantity and quality, with a consequent age-related decrease in the reproductive potential Front. Endocrinol. 12:653857. (11, 12). In the light of these findings, IVF centers have initiated androgen pretreatment in patients doi: 10.3389/fendo.2021.653857 with diminished ovarian reserve, intending to improve their reproductive outcomes. In fact, a recent Frontiers in Endocrinology | www.frontiersin.org 1 May 2021 | Volume 12 | Article 653857 Neves et al. Androgens and Diminished Ovarian Response survey has shown that more than 40% of physicians in Europe contributing to follicle survival, and improve sensitivity to and Australia are prescribing off-label androgens in this FSH-induced follicle growth and progression to the antral subgroup of patients (13). However, the evidence for including stage (22). On the other hand, when AR signaling is blocked, this approach in our clinical practice is scarce. preantral follicles cannot progress to antral follicles and, instead, The aim of this review is to analyze the available evidence are subjected to an increased rate of atresia. from animal studies regarding the impact of androgen supplementation on folliculogenesis, as well as the drawbacks The Peri-Ovulatory Stage from clinical studies that might preclude the obtention of The effect of androgens in later stages of follicle development, definitive conclusions to guide an evidence-based approach for namely in the pre- and peri-ovulatory stage, is controversial. such a challenging population. Studies in primates have shown that testosterone treatment did not increase the number of preovulatory follicles (14). However, experiments in pigs have shown that androgens might have regulatory functions during late follicular development (23). In METHODS fact, DHT treatment resulted in an increase in the amount of The Cochrane Central Register of Controlled Trials FSH receptor mRNA in preovulatory follicles and increased (CENTRAL), MEDLINE via PubMed, the Web of Science and ovulation rate (23). Similarly, experiments in mice have also Scopus were screened with a combination of keywords related to shown that testosterone has a role in the maturation of oocytes ART, poor responders, diminished ovarian response, androgens, arrested in prophase I of meiosis (24) and that DHT significantly testosterone and DHEA in various combinations. The search increased the number of ovulated oocytes (22). On the other period was from the date of inception of each database until 1 hand, Romero and Smitz reported that elevated levels of December 2020. Only full text papers published in English androstenedione and testosterone negatively affected meiotic were included. resumption (25). These conflicting findings regarding the role of androgens in the late stages of follicular development suggest that further studies are needed to clarify the physiopathology behind such complex interactions. THE PROMISING EVIDENCE FROM Figure 1 highlights the main androgen effects on folliculogenesis. ANIMAL STUDIES Primordial Follicle Initiation Genetic Studies Previous studies in primates have shown that androgens increase Finally, data from genetic models have also reaffirmed the role of the numbers of small- and medium-sized follicles but not large AR-mediated activity in the regulation of ovarian function. preovulatory follicles (14). In particular, testosterone and DHT Studies using female mouse models homozygous for an pretreatment increased the number of primary follicles. Also, inactivated AR (ARKO) have revealed reduced fertility and a they resulted in a significant increase in insulin growth factor I defective folliculogenesis (26–28), as well as a reduced litter size (IGF-I) and IGF-I receptor mRNAs in the oocytes of primordial (27), increased follicular atresia and premature ovarian failure follicles, suggesting that androgen-induced activation of oocyte (21). Together, these data suggest the AR signaling pathway IGF-I signaling may trigger primordial follicle growth (15). More mediates both intra and extra-ovarian actions, with an essential recently, mouse studies have corroborated that testosterone role in maintaining normal ovarian function and fertility. promotes primordial follicle to primary follicle transition via an AR-mediated pathway rather than by transformation into estradiol (16). THE PITFALLS FROM CLINICAL STUDIES Preantral to Antral Stage Transition All these promising data obtained from animal studies and the Besides the effect on primordial follicle initiation, androgens also fact that both androgens and ovarian reserve decline steeply with seem to have a role in the preantral to antral stage transition. In age, led to the speculation that androgen replacement in women vivo studies in ovine models have shown that DHEA exposure with DOR might delay these age-related effects. However, despite stimulates early follicular growth during the preantral and early several lines of evidence supporting a role for androgens in antral follicular stages (17). Studies in mouse models have also folliculogenesis, the available data from clinical studies remains shown that both DHT and testosterone stimulate granulosa cell unconvincing. This might be related to the methodological (GC) proliferation and both secondary and preantral follicle inconsistencies observed in the available trials (Tables 1 and 2). growth (18). Moreover, androgens seem to support follicle development during the FSH-dependent preantral stage by Dehydroepiandrosterone increasing the expression of FSH receptor mRNA levels and, A case series of five patients with unexplained infertility and therefore, enhancing FSH action (19, 20). GC-specific AR-null previous poor response to ovarian stimulation was the first study mice experiments have also shown that AR signaling in GCs is to analyze the effect of DHEA pretreatment on ovarian response necessary for progression beyond the preantral stage (21). (51). In this study, 80 mg/day of oral micronized DHEA was Androgens enhance antiapoptotic pathways, thereby given for 2 months, after which ovarian stimulation was started Frontiers in Endocrinology | www.frontiersin.org 2 May 2021 | Volume 12 | Article 653857 Neves et al. Androgens and Diminished Ovarian Response FIGURE 1 | Androgen effects on folliculogenesis. with recombinant follicle stimulating hormone (rFSH) for Also noteworthy is the fact that oral DHEA formulations are intrauterine insemination. The authors concluded that oral dietary supplements and therefore are not regulated by the US DHEA supplementation might improve ovarian response and Food and Drug Administration (FDA) nor by the European reduce gonadotrophin consumption. Five years later, a case Medicines Agency (EMA) and are exempt from pharmaceutical report of a 43-years old patient seeking embryo accumulation quality standards. Consequently, the true standardization of the for preimplantation genetic screening draw the scientific formulations used cannot be guaranteed (78). community’s attention to the role of androgens in ovarian response to stimulation (52). After her first stimulation cycle, Testosterone the patient started self-administering 75 mg/day of oral Numerous observational and randomized controlled trials have micronized DHEA and initiated acupuncture treatment. In also been published on the use of testosterone pre-treatment on total, the patient performed 9 stimulation cycles with different POR and DOR patients (Tables 1 and 2). Most studies report the stimulation protocols, and a significant increase in ovarian use of transdermal testosterone, both in gel and patches, with response was reported after four months of DHEA doses of treatment based on Vendola’s studies on primates (14, pretreatment. Since then, multiple observational and 15). In these studies, an effect on follicular development was randomized controlled trials have followed, with varying DOR reported with transdermal testosterone 20 µg/Kg/day, obtained and poor ovarian reserve (POR) definitions, with DHEA doses with a 12.5mg/day gel application or a 2.5mg/day patch. ranging from 50 to 90 mg/day and a treatment duration ranging Importantly, however, pharmacokinetics studies performed in from 1 to 12 months, both before and during controlled ovarian postmenopausal women revealed that the administration of 4.4-5 stimulation (Tables 1 and 2). Importantly, no pharmacological mg testosterone gel or cream raised free testosterone levels studies have been performed to determine the optimal dose, within the reference range for reproductive-aged women duration or timing of DHEA supplementation in DOR patients. whereas higher doses increased testosterone levels above the Another key limitation regarding many studies on DHEA physiological range (79, 80). These findings question the pre-treatment is the frequent use of patients as their own potential clinical benefit (or harm) of using the high doses that controls, comparing ovarian response after DHEA have been reported so far. supplementation with a previous cycle. This study design does The issue of the duration of treatment has also been another not take into account the importance of biological variability in point of conflict in the published studies, ranging from 5 days, the response to ovarian stimulation and the natural process of based on Vendola’s studies (14, 15), to 21-28 days, based on a RCT the regression to the mean, precluding definitive conclusions that reported that testosterone effects at the follicular level occurred regarding the true effect of such treatment (77). after at least three weeks of testosterone pre-treatment (32). Frontiers in Endocrinology | www.frontiersin.org 3 May 2021 | Volume 12 | Article 653857 Frontiers in Endocrinology | www.frontiersin.org Neves et al. TABLE 1 | Published randomized controlled trials on the use of DHEA and Testosterone in DOR and POR patients. Author Year Definition of POR Number Dose Duration Stimulation Primary outcome of protocol patients Testosterone Massin et al. (29) 2006 * Previous POR (Peak E2<1200pg/mL and ≤5 oocytes) and D3 FSH > 12 IU/L 49 10 mg/d 15-20 d NR Total number of retrieved oocytes or E2 > 70pg/mL or Inhibin B <45ng/mL Fá bregues et al. (30) 2009 Previous POR and 31-39y 62 20 ug/kg/d 5d Long GnRH agonist Incidence of low responders Kim et al. (31) 2011 Previous cycle with ≤3 oocytes retrieved despite high Gn dose 110 12.5 mg/d 21 d GnRH antagonist Number of MII oocytes retrieved Kim et al. (32) 2014 Previous cycle with ≤3 oocytes retrieved despite high Gn dose 120 12.5 mg/d I1: 14 d/ GnRH antagonist Number of MII oocytes retrieved I2: 21 d/ I3: 28 d Marzal Escrivá et al. (33) ≥2: ≥38y, AFC ≤6, FSH ≥10 IU/L, AMH ≤5pg/mL AND ≤4 follicles of ≥16 mm 66 20 ug/kg/d 7d GnRH antagonist Number of MII oocytes retrieved 2015 on the day of trigger or E2 ≤500 pg/mL on the day of trigger or ≤ 4 MII Bosdou et al. (34) 2016 Bologna criteria 50 10 mg/d 21 d Long GnRH agonist Total number of retrieved oocytes Saharkhiz et al. (35) 2018 * Bologna criteria 48 25 mg/d During COS GnRH antagonist NR DHEA Wiser et al. (36) 2010 <5 oocytes retrieved in previous cycle; poor quality embryos; previous cycle 33 75 mg/d > 6 weeks Long GnRH agonist Peak estradiol levels, the number of cancelation due to poor response with rFSH 300IU retrieved oocytes, embryo quality and number of embryos reserved for transfer Artini et al. (37) 2012 Bologna criteria 24 75 mg/d 12 weeks GnRH antagonist HIF1 and VEGF concentrations in the FF and the number of MII oocytes Moawad and Shaeer (38) <40y; <5 oocytes retrieved in previous cycle; previous cycle cancelation due 133 75 mg/d >12 weeks GnRH antagonist Peak E2 levels, number of retrieved 2012 to poor response with rFSH 300IU; AMH<1.7ng/mL oocytes and number of embryos Yeung et al. (39) 2013 * POI 22 75 mg/d 16 weeks NA Serum AMH level 4 Yeung et al. (40) 2014 * <40y, subfertility >1y and AFC<5 32 75 mg/d 12 weeks GnRH antagonist The primary outcome was the AFC at 12 weeks Kara et al. (41) 2014 AMH<1ng/mL or FSH>15IU/L and AFC < 4 208 75 mg/d 12 weeks Microdose flare NR Zhang et al. (42) 2014 D3 FSH ≥ 10IU/L or FSH/LH>3; AFC<5; previous cycle with <5 oocytes 95 75 mg/d 12 weeks HMG + Clomiphene Follicular fluid BMP- 15 and GDF-9 and retrieved or previous cancelled cycle due to POR citrate serum AMH, FSH and E2 Kotb et al. (43) 2016 Bologna criteria 25-40y 140 75 mg/d 3 months GnRH antagonist Clinical pregnancy rate Agarwal et al. (44) 2017 * 18-45y with DOR: (1) FSH levels >7 mIU/ml for age<33y; >7.9 mIU/ml for age 40 75 mg/d 12 weeks NA AMH, FSH and AFC 33–37y; >8.4 mIU/ml for age >38 years. (2) AMH < 1.05 ng/ml. (3) AFC<4 Narkwichean et al. (45) AFC<10 and/or AMH <5 pmol/L 52 75 mg/d >12 weeks Long GnRH agonist Number of oocytes retrieved 2017 * Elprince et al. (46) 2020 * (1) serum AMH < 1.1 ng/mL, (2) FSH ≥ 10 mIU/L and ≤ 15 mIU/L on cycle 50 75 mg/d 2 Ovulation induction NR D3, and (3) AFC ≤ 4 Continuous Androgens and Diminished Ovarian Response cycles May 2021 | Volume 12 | Article 653857 * Placebo controlled. AFC, antral follicle count; AMH, antimullerian hormone; BMP-15, bone morphogenetic protein-15; d, day(s); E2, estradiol; FF, follicular fluid; FSH, follicle stimulating hormone; GDF-9, growth differentiation factor-9; Gn, gonadotropin; GnRH, gonadotropin releasing hormone; HIF, Hypoxia inducible factor; MII, mature oocytes; NR, not reported; NA, not applicable; POI, premature ovarian insufficiency; POR, poor ovarian responders; VEGF, vascular endothelial growth factor; y, years. Frontiers in Endocrinology | www.frontiersin.org Neves et al. TABLE 2 | Published observational trials on the use of DHEA and Testosterone in DOR and POR patients. Author Year Study design Definition of POR Number Dose Duration Stimulation Main outcome measure of protocol patients Testosterone Balasch et al. (47) 2006 Prospective 31-39y patients undergoing their third IVF 25 2.5mg/d 5d Long GnRH agonist NR self-controlled attempt with 1 or 2 previous IVF cycles Patch cancelled because of poor follicular response, with basal FSH <10IU/L Mitri et al. (48) 2016 Retrospective At least one previous failed or cancelled 26 25mg/d gel variable Microflare GnRH NR IVF cycle with suspected Gn resistance agonist with (serum FSH ≥20 mIU/L on D7) and interrupted FSH absent or minimal follicular growth during the current cycle. Doan et al. (49) 2017 Prospective History or probability of POR: AFC<5–7 or 110 12.5mg/d gel 28 d GnRH antagonist NR AMH≤ 1.26 ng/ml) Fabregues et al. (50) 2019 Retrospective Bologna criteria 141 2.5mg/d Patch 5d GnRH antagonist NR and Long GnRH agonist DHEA Casson et al. (51) 2000 Case series Previous POR to vigorous Gn stimulation 5 80mg/d 2 months Ovulation induction NR (peak estradiol ≤500 pg/ml, MII ≤2) Barad and Gleicher (52) 2005 Case report 43y patient 1 75 mg/d 11 months GnRH agonist Peak E2 concentration, oocytes retrieved, and cyropreservable embryos. Barad and Gleicher (53) 2006 Retrospective Prior IVF cycle with age-appropriate COS, 25 75 mg/d 17.6 ± 2.13 GnRH agonist NR 5 self-controlled and < 4 oocytes retrieved, uniformly poor weeks embryo quality and FSH >10 mIU/ml or E2 >75 pg/ml Barad et al. (54) 2007 Retrospective Basal FSH <12 mIU/ml, but exceeding the 190 75 mg/d 3.8 ± 0.3 Microflare GnRH Clinical pregnancy rate 95% CI of the mean value for the patient’s months agonist age group or vasal FSH ≥12 mIU/ml and/ or a baseline estradiol level ≥75 pg/ml Mamas and Mamas (55) Case series POI 5 50-75 mg/d 2-6 months NA NR 2009 Mamas and Mamas (56) Case series POI 14 50-75 mg/d 3-7 months NA NR 2009 Sonmezer et al. (57) 2009 Prospective (i) cycle cancellation due to E2<130 pg/ml 19 75 mg/d 90-180 d GnRH antagonist Antral follicle count, number of follicles >14 and Androgens and Diminished Ovarian Response self-controlled on cycle D6 or <450 pg/ml on the day of >17 mm on the day of HCG administration, E2 on trigger, (ii) <4 retrieved oocytes despite the day of HCG administration, number of retrieved May 2021 | Volume 12 | Article 653857 vigorous ovarian stimulation. oocytes, mean number of MII, number of transferred embryos and rates of fertilization, implantation, pregnancy, and clinical pregnancy. Gleicher et al. (58) 2009 Retrospective Definition of POR changed over the study 73 75 mg/d > 2 months NR Miscarriage rate period Gleicher et al. (59) 2010 Retrospective Elevated age-specific baseline FSH or 66 75 mg/d >4 weeks Microflare GnRH Number and percentage of aneuploid embryos abnormally low age-specific AMH agonist Gleicher et al. (60) 2010 Retrospective Elevated age-specific baseline FSH or 120 75 mg/d 73 ± 27 d NA AMH universal AMH < 0.8 ng/ml (Continued) Frontiers in Endocrinology | www.frontiersin.org Neves et al. TABLE 2 | Continued Author Year Study design Definition of POR Number Dose Duration Stimulation Main outcome measure of protocol patients Weissman et al. (61) 2011 Retrospective >1 of the following characteristics in a 15 75 mg/d ~3 months NR Progesterone concentration on day 5 of stimulation self-controlled previous cycle with high-dose Gn and on the day of hCG administration. stimulation:< 5 oocytes retrieved, ≤ 3 follicles ≥ 16 mm on the day of cycle cancelation, or E2 level <500 pg/ml on the day of trigger Fusi et al. (62) 2013 Prospective Cohort 1: Previous IVF cycle with POR 101 75 mg/d > 3 months Long GnRH agonist Spontaneous pregnancies Cohort 2: > 40y and DOR (AFC < 4, FSH > 10 IU/ml, AMH < 1 ng/ml Hyman et al. (63) 2013 Prospective At least one previous IVF cycle with ≤ 4 43 75 mg/d >3 months NR NR self-controlled oocytes retrieved despite high dose Gn (≥ 450IU/day) Singh et al. (64) 2013 Prospective Poor ovarian response in the previous IVF 31 75 mg/d 4 months NR AMH, FSH and antral follicle count self-controlled cycle(s) Yilmaz et al. (65) 2013 Prospective AFC <5 or AMH <1.1 ng/ml and a 41 75 mg/d > 6 weeks GnRH antagonist AMH, Inhibin B and antral follicle count previous poor ovarian response Jirge et al. (66) 2014 Prospective Bologna criteria <40ys with 1 previously 31 75 mg/d > 2 months GnRH antagonist Dose and duration of gonadotropin therapy, oocyte self-controlled failed IVF cycle yield, embryo number and quality, pregnancy and live birth rate. Xu et al. (67) 2014 Retrospective Bologna criteria 386 75 mg/d 90 d GnRH antagonist Ongoing pregnancy rate and implantation rate Zangmo et al. (68) 2014 Prospective <42 years, with <5 oocytes retrieved in 50 75 mg/d 4 months NR Oocyte and embryo number and quality 6 self-controlled previous IVF cycles, D2 FSH 10–20 mIU/ ml Tsui et al. (69) 2015 Prospective Bologna criteria 10 90 mg/d 12.2 weeks GnRH antagonist Total doses of rFSH, days of stimulation, oocytes self-controlled retrieved, fertilized oocytes, Day 3 embryos, and transferred embryos Vlahos et al. (70) 2015 Prospective At least 2 of the following: >40 years, D2 161 75 mg/d > 3 months GnRH antagonist Live birth rate FSH >9.5 mIU/ml, AMH< 2 ng/ml, at least one previous cycle of COS with < 3 oocytes retrieved, at least one cancelled attempt owing to POR and E2 < 500 pg/ ml on the day of trigger Hu et al. (71) 2017 Prospective <40 years, subfertility >1 year, and DOR 106 75 mg/d 8 weeks GnRH antagonist NR Androgens and Diminished Ovarian Response (two or more items such as FSH 10-25 IU/L, E2 >80 pg/ml, AMH <0.5-1.1 ng/ml May 2021 | Volume 12 | Article 653857 and AFC ≤5 on cycle D2-3 Chern et al. (72) 2018 Retrospective Bologna criteria or 2 episodes of a 151 90 mg/d 3 months GnRH antagonist Number of oocytes retrieved and clinical pregnancy previous POR after maximal stimulation rate alone Al-Turki et al. (73) 2018 Prospective Bologna criteria, 25-40y with previously 62 50 mg/d 3 months GnRH antagonist Number of oocytes retrieved, fertilization rate, failed IVF cycle number of embryos and pregnancy rate Wong et al. (74) 2018 Prospective POI 31 75 mg/d 12 months NA AMH Chen et al. (75) 2019 Retrospective POSEIDON group 4 297 90 mg/d 3 months GnRH antagonist Number of oocytes retrieved and MII Ozcil (76) 2020 Retrospective 6 POI and 28 POR according to the 34 50 mg/d 5 months NA Spontaneous clinical pregnancy rate Bologna criteria AFC, antral follicle count; AMH, antimullerian hormone; CI, confidence interval; COS, controlled ovarian stimulation; d, day(s); E2, estradiol; FSH, follicle stimulating hormone; Gn, gonadotropin; GnRH, gonadotropin releasing hormone; HCG, human chorionic gonadotropin; IVF, in vitro fertilization; MII, mature oocytes; NR, not reported; NA, not applicable; POI, premature ovarian insufficiency; POR, poor ovarian responders; y, years. Neves et al. Androgens and Diminished Ovarian Response This should come as no surprise, if we consider that the progression from a primordial follicle to a periovulatory follicle takes approximately 3 months (81). Too Much Is Not Enough The vast bulk of published original studies and meta-analysis on the use of androgens pre-treatment in DOR and POR patients is depicted in Figure 2. One of the limitations in analyzing the effect of these adjuvant strategies in DOR/POR patients is the definition of diminished and poor response itself. In this context, the Poseidon Group introduced the concept of ‘low prognosis patients’ and highlighted the need for tailored evidence-based clinical algorithms for each of the four proposed risk groups (82, 83). Standardizing the inclusion criteria offuture studies based on these risk groups might be a further step in minimizing study heterogeneity. Despite the above-mentioned methodological limitations and the heterogeneity among the inclusion criteria and treatment protocols, original studies continue to be published in an attempt to optimize the clinical management of such a challenging population. With the same goal, a disproportionate number of meta-analysis has been published, especially when considering the FIGURE 2 | Published original studies and meta-analysis on the use of DHEA number of original studies. Table 3 describes the meta-analysis or testosterone supplementation in POR and DOR patients. published on the use of DHEA and testosterone supplementation in IVF and the study design of the included trials. If we consider the low level of evidence of some of the included study designs, the DOR/POR from the beginning. In order to do so, evidence from lack of evidence-based protocols for both DHEA and testosterone pharmacokinetics studies (79) as well as from the timespan of supplementation, the heterogeneity in the definition of POR and human folliculogenesis (97) must be taken into account in what DOR and the diversity in the IVF protocols used in the different concerns the optimal dose and duration of treatment. In this trials, the clinical impact of the conclusions drawn from these respect, the currently ongoing multicenter double-blind placebo- meta-analysis might be called into question. In this regard, an controlled randomized controlled trial T-TRANSPORT individual patient data approach could be of use in increasing the (NCT02418572, available at http://clinicaltrials.gov/ct2/show/ strength of the available evidence. NCT02418572) might shed some light on this subject. With an However, to break this vicious cycle, we are left with the need intervention group undergoing 5.5 mg daily transdermal to write the story of androgens supplementation in patients with testosterone for two months prior to an IVF cycle and powered TABLE 3 | Published meta-analysis on the use of DHEA and Testosterone in IVF. Author Year Number of studies Population Study design DHEA Narckwichean et al. (84) 2013 3 DOR/POR 1 RCT, 2 Retrospective Li et al. (85) 2015 8 DOR/POR 2 RCT, 2 Prospective, 4 Retrospective Qin et al. (86) 2016 9 DOR/POR 4 RCT, 2 Prospective, 3 Retrospective Liu et al. (87) 2017 6 NOR/DOR/POR 6 RCT Schwarze et al. (88) 2018 5 DOR/POR 2 RCT, 1 Prospective, 2 Retrospective Xu et al. (89) 2019 9 NOR/DOR/POR 9 RCT Testosterone Gonzá lez-Comadran et al. (90) 2012 3 DOR/POR 3 RCT Luo et al. (91) 2014 3 DOR/POR 3 RCT Noventa et al. (92) 2019 7 DOR/POR 7 RCT Testosterone and DHEA Sunkara et al. (93) 2011 5 DOR/POR 4 RCT, 1 Retrospective Bosdou et al. (94) 2012 3 DOR/POR 3 RCT Nagels et al. (95) 2015 17 NOR/DOR/POR/POI 17 RCT Zhang et al. (96) 2019 4 POR 4 RCT DHEA, dehydroepiandrosterone; DOR, diminished ovarian reserve; NOR, normoresponders; POI, premature ovarian insufficiency; POR, poor ovarian responders; RCT, randomized controlled trials. Frontiers in Endocrinology | www.frontiersin.org 7 May 2021 | Volume 12 | Article 653857 Neves et al. Androgens and Diminished Ovarian Response with clinical pregnancy rate as the primary outcome measure, this AUTHOR CONTRIBUTIONS trial is expected to clarify the role of androgens in IVF. AN designed the study, performed the literature review, CONCLUSION contributed to the interpretation of the findings, wrote the manuscript and critically revised it. PM-B contributed to Despite the vast amount of available literature on the use of DHEA the interpretation of the findings and critically revised the and testosterone in POR patients, the bulk of evidence is still limited manuscript. NP designed the study, supervised the writing of to draw definite conclusions. More than reviewing the available data the manuscript, contributed to the interpretation of the findings and publishing new studies based on the same pitfalls, we urge to and critically revised the manuscript. 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An drogen s Conflict of Interest: NP is the principal investigator of the T-TRANSPORT trial. (Dehydroepiandrosterone or Testosterone) for Women Undergoing The remaining authors declare that the research was conducted in the absence of Assisted Reproduction. Cochrane Database Syst Rev (2015) (11):CD009749. any commercial or financial relationships that could be construed as a potential doi: 10.1002/14651858.CD009749.pub2 conflict of interest. 96. Zhang Y, Zhang C, Shu J, Guo J, Chang HM, Leung PCK, et al. Adjuvant Treatment Strategies in Ovarian Stimulation for Poor Responders Undergoing IVF: A Systematic Review and Network Meta- Copyright © 2021 Neves, Montoya-Botero and Polyzos. This is an open-access article Analysis. Hum Reprod Update (2020) 26(2):247–63. doi: 10.1093/humupd/ distributed under the terms of the Creative Commons Attribution License (CC BY). dmz046 The use, distribution or reproduction in other forums is permitted, provided the 97. Baerwald AR, Adams GP, Pierson RA. Ovarian Antral Folliculogenesis original author(s) and the copyright owner(s) are credited and that the original During the Human Menstrual Cycle: A Review. Hum Reprod Update (2012) publication in this journal is cited, in accordance with accepted academic practice. No 18(1):73–91. doi: 10.1093/humupd/dmr039 use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Endocrinology | www.frontiersin.org 11 May 2021 | Volume 12 | Article 653857