{"paper_id":"42129ed6-b1b2-4641-8577-98309c43550e","body_text":"85\nReceived: April 17, 2025  Revised: July 10, 2025  Accepted: July 21, 2025\nAddress for Correspondence: Dong-Yun Lee, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University \nSchool of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea \nTel: 82-2-3410-0726, E-mail: dongyun0406.lee@samsung.com, ORCID: https://orcid.org/0000-0002-7540-0522\nREVIEW ARTICLE\nCopyright © by The Korean Society of Meno pause\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License  (http://creativecommons.org/licenses/by-nc/4.0/).\nINTRODUCTION\nWhat is diminished ovarian reserve?\nThere is no clear and universal definition of dimin -\nished ovarian reserve (DOR). Since ovarian reserve is \ndefined as the number of oocytes in the ovary or oo -\ncyte quantity [1], DOR usually means a condition in \nwhich women have fewer oocytes compared to women \nin the same age. Clinically, DOR can be characterized \nby poor fertility outcomes even with assisted reproduc-\ntive technology (ART) [2]. In this respect, DOR is close \nto poor ovarian response (POR) and DOR and POR \nare commonly used interchangeably, but unlike DOR, \nPOR has a clear definition. In the Bologna European \nSociety of Human Reproduction and Embryology con-\nsensus [3], POR is defined when women have at least \ntwo of three following features: (1) advanced maternal \nage (≥ 40 years) or any of the risk factors for POR, (2) a \nprevious POR (≤ 3 oocytes with a conventional stimu-\nlation protocol), and (3) an abnormal ovarian reserve \ntest (i.e., antral follicular count [AFC] < 5–7 follicles \nor anti-Müllerian hormone [AMH] < 0.5–1.1 ng/mL). \nIn addition, in the Patient-Oriented Strategies Encom-\npassing IndividualizeD Oocyte Number (POSEIDON) \nstratification [4], women are classified into 4 groups of \nPOR in ART according to age (35 years), ovarian re -\nserve parameters (AFC = 5 ng/mL and AMH = 1.2 ng/\nmL), and unexpected poor or suboptimal ovarian re -\nsponse. It means, by definition, age or at least one pre-\nvious controlled ovarian stimulation is important for a \ndiagnosis of POR in both the Bologna criteria and the \nPOSEIDON stratification, whereas DOR is a more gen-\neral diagnosis with clinical judgement based on abnor-\nmal ovarian reserve testing results. However, besides of \novarian reserve tests such as serum follicle-stimulating \nhormone (FSH), AMH, AFC, and clomiphene citrate \nchallenge test, age or a prior cycle performance are also \nused to define DOR in the research [2] and the cut-offs \nof ovarian reserve markers are arbitrary. This heteroge-\nneity in the definition produces confusion and difficul-\nhttps://doi.org/10.6118/jmm.25109\nJ Menopausal Med 2025;31:85-94\npISSN: 2288-6478, eISSN: 2288-6761\nDiminished Ovarian Reserve: A Narrative Review of \nEtiologies and Possible Therapeutic Approaches\nDong-Yun Lee\nDepartment of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea\nDiminished ovarian reserve (DOR) occurs unintentionally during treatment or spontaneously. Despite its significant clinical \nmanifestations, such as infertility and early menopause, and its high prevalence, most studies on DOR have focused on premature \novarian insufficiency, and reviews specifically addressing DOR remain scarce. This narrative review aims to provide insight into the \ndiverse etiologies of DOR while discussing promising therapeutic approaches. Iatrogenic DOR can occur during chemotherapy, pelvic \nradiation, and ovarian surgery. Spontaneous DOR may result from ovarian tumors as well as idiopathic or genetic causes. DOR also \ninevitably occurs during ovarian fragment transplantation. Stem cell transplantation, in vitro activation, and platelet-rich plasma injection \nhave shown some positive results as therapeutic approaches to DOR; however, more high-quality studies are needed to establish their \nbroader applications in clinical practice.\nKey Words: Diminished ovarian reserve, Etiology, Poor ovarian response, Premature ovarian insufficiency, Therapeutic approach\n\nDong-Yun Lee\n86\nwww.e-jmm.org\nty in interpreting results from studies. Although there \nare no definitive criteria to differentiate DOR from pre-\nmature ovarian insufficiency (POI), a brief comparison \nbetween the two conditions is summarized in Table 1.\nWhy do we need to pay attention to diminished \novarian reserve?\nRegardless of definition or cause, DOR is associated \nwith a higher risk of a variety of health problems which \ncan reduce quality of life.\nInfertility\nAs DOR implies diminution of normal reproductive \npotential, it can cause infertility. Pregnancy and live \nbirth rates are expected to be low even with repetitive \nARTs in a woman with DOR [5] and indeed many \nfertility centers use POR criteria to diagnose DOR in \nclinical practice. Furthermore, DOR is common in in-\nfertile women. Therefore, DOR is of great importance \nin terms of fertility.\nEarly menopausal change\nDOR is not necessarily a matter of pregnancy. At any \ngiven age, DOR can be translated into shortened repro-\nductive life. Considering that women reach a meno -\npausal state when having fewer than 1,000 remaining \nfollicles [6], women with DOR are at higher risk of \ndeveloping POI or early menopause according to their \nage. The more the number of oocytes decreases, the \ngreater the risk of menopause. It is well known that \nyoung women without ovarian function would experi-\nence a variety of short-term (vasomotor symptoms) \nand long-term health problems (osteoporosis, cardio -\nvascular disease, and cognitive dysfunction) [7]. Mean-\nwhile, even DOR in young premenopausal women is \nsignificantly associated with low bone mineral density, \nincreased bone turnover, sexual dysfunction, and sleep \ndisturbance [8].\nWhat should we know about diminished ovarian \nreserve research in humans?\nNormal aging is the most common cause of DOR, but \nDOR is also induced unintentionally by treatment, es-\npecially during cancer treatment. Although the occur-\nrence of DOR after treatment in women with normal \novarian function varies according to age and methods \nof treatment, any women who will receive possibly \ngonadotoxic treatment have some degrees of risk of de-\nveloping DOR. Since DOR is an important reason for \nART and the success rate does not improve dramati -\ncally in spite of recent developments in technologies in \nassisted reproduction, novel treatment options to over-\ncome or reverse DOR is warranted.\nDespite its clinical importance and prevalence, review \nliterature on DOR is still limited, while most reviews \nfocus on POI. This narrative review will present various \ncauses of DOR in human and also will discuss possible \ntherapeutic approaches to DOR. Since ovarian reserve \nreflects ovarian function at a specific time point, DOR \nis not a permanent but an intermediate step towards \nbecoming POI. Moreover, DOR and POI can share \netiologies and features. Therefore, it is difficult to think \nof POI and DOR separately and POI also will be ad -\ndressed along with DOR in some parts of this review.\nETIOLOGIES OF DIMINISHED  \nOVARIAN RESERVE\nIatrogenic diminished ovarian reserve\nChemotherapy\nIatrogenic DOR occurs exclusively after cancer treat-\nment, especially chemotherapy. The ovaries are sensi-\ntive to chemotherapy, and alkylating agents are most \nlikely to cause damage on the ovarian reserve [9]. Cy-\nclophosphamide, an alkylating agent, is regarded as one \nof the most gonadotoxic chemotherapies. It binds alkyl \ngroups to DNA covalently, induces DNA crosslinking, \nand consequently prevents DNA replication. This drug \ncan damage primordial follicle population directly by \ninducing granulosa cell apoptosis and follicular atresia \n[10] or indirectly by accelerating primordial follicle \nactivation [11]. In addition, inflammation and vascu -\nlature damage also can contribute to loss of ovarian \nTable 1. Comparison of DOR and POI based on the international \nguidelines and reviews\nDOR POI\nMenstrual cycle Usually regular Amenorrhea or irregular\nOvarian reserve tests\n   AMH (ng/mL) < 1.1 or 1.2 Very low\n   AFC (n) < 5–7 Not specified  \n(few or none)\n   FSH (IU/L) > 10 > 25\nDOR: diminished ovarian reserve, POI: premature ovarian insufficiency, AMH: \nanti-Müllerian hormone, AFC: antral follicular count, FSH: follicle-stimulating \nhormone.\n\n87\nDiminished Ovarian Reserve\nreserve [12]. Meanwhile, cisplatin, a platinum-based \ncompound, interferes with DNA repair mechanisms \nand produces apoptotic cell death [13]. It has been re-\nported that this drug has moderate risk of amenorrhea \nwhen combined with bleomycin [14], but clinical data \nregarding ovarian toxicity is still limited in human. Like \ncyclophosphamide, cisplatin also produces the loss of \nprimordial follicles in both direct and indirect ways. \nDoxorubicin is another chemotherapeutic agent that \ncan produce ovarian toxicity. It prevents topoisomerase \nII-DNA complex formation which leads to accumula-\ntion of DNA fragments and induction of cell death. It \nalso stimulates the oxidative stress [15].\nThe likelihood that POI will develop after chemo -\ntherapy can vary enormously, and sensitivity to go -\nnadotoxic chemotherapy is age- and dose-dependent. \nIn a meta-analysis of 74 studies in patients with breast \ncancer, the rate of chemotherapy-induced amenorrhea \nwas increased by age showing that older age of > 40 \nyears old was a strong risk factor for the occurrence \nof chemotherapy-induced amenorrhea [16] . In addi -\ntion, it has been suggested that higher doses of chemo-\ntherapy correspond with higher rates of amenorrhea, \nalthough this correlation may not be consistent and \na possible threshold dose for amenorrhea is not clear \n[17]. Of note, the risk of ovarian failure was assessed as \nrisk of amenorrhea after chemotherapy in most clinical \nstudies and guidelines, since initial work of American \nSociety of Clinical Oncology [9]. However, regular \nmenstruation does not guarantee normal ovarian func-\ntion, because AMH or AFC can be significantly lower \nin these women which support some degrees of follicle \ndepletion [18]. In a recent study in young breast can -\ncer patients who underwent ovarian protection using \nGnRH agonist during chemotherapy [19], 95% women \nexperienced resumption of menstruation at 1 year after \ndoxorubicin/cyclophosphamide-based chemotherapy. \nHowever, serum AMH level was reduced by over 70% \nafter treatment, which means the ovarian reserve did \nnot return to the baseline. In this aspect, it can be spec-\nulated that some women may have DOR after gonado-\ntoxic chemotherapy irrespective of having resumed \nmenstruation.\nRadiation therapy\nIt is well known that radiation to the female pelvis has \ndetrimental effects on the ovaries. Non-growing fol -\nlicles or primordial follicles are sensitive to radiation, \nalthough quiescent follicles are generally more resistant \nto radiotherapy that larger maturing follicles [20]. Di-\nviding granulosa cells are the initial target of radiation \ndamage, and cell death presents within hours of radia-\ntion [21]. In addition, radiation can produce vascular \ndamage in the stroma leading to atrophy and fibrosis of \ntissue [22] and it also stimulates oxidative stress [23].\nThe degree of the damage by radiation differs by dose, \nfield and schedule of radiation as well as age or ovar -\nian reserve at the time of treatment [24]. Among them, \ndose is the most important determining factor for ovar-\nian damage. High dose of radiation such as total body \nirradiation and whole abdominal irradiation usually \ninduces POI, even during childhood [25]. LD50 (the \ndose destroying about 50% of non-growing follicles) is \nconservatively estimated to be less than 2 Gy [20] and \na single oocyte is highly radiosensitive with the Do \nof 0.12 Gy (reciprocal of the slope on the exponential \nportion of a survival curve). It can be translated that \nsterilization is predicted in 5% by 2–3 Gy and 50% by \n6–12 Gy in women whose ovaries are exposed to radia-\ntion therapy [26]. Meanwhile, age (or ovarian reserve \nat the initiation of radiation) is also related to the de -\ngree of radiation-induced damage. Doses of radiation \nwhich would result in ovarian failure were calculated \nto be 20.3 Gy at birth, 18.4 Gy at age of 10, 16.5 Gy at \nage of 20, and 14.3 Gy at age of 30, with a probability of \n97.5% [27]. In addition, women of < 40 years old need \nmore radiation dose for permanent damage than older \nwomen (20 Gy vs. 6 Gy) [28].\nThere have been several developments in the tech -\nniques to decrease the exposure of radiation to the \novaries such as novel beam arrangements, fraction -\nation schedules, highly conformational radiotherapy, \nintensity modification, and shielding or transposing \novaries during radiotherapy. However, it is not possible \nto avoid the whole damage from radiation and doses \nreaching the ovaries remain high during the treatment \nof cancers [29] , and consequently, radiation therapy \ncan induce DOR and POI immediately or subsequently.\nOvarian surgery\nEndometriotic cystectomy can cause damage on ovar-\nian reserve by removing primordial follicles adjacent \nto the cyst [30]. In addition, tearing, bleeding, and co-\nagulation during operations also cause loss of ovarian \nreserve [31]. Even experienced surgeons using accurate \ntechniques cannot avoid ovarian damage completely \n[32]. Many studies have demonstrated the detrimental \neffects of endometriotic cystectomy on ovarian reserve, \nhttps://doi.org/10.6118/jmm.25109\n\nDong-Yun Lee\n88\nwww.e-jmm.org\nmainly evaluated by serum AMH level [33,34]. In a \nrecent meta-analysis including 14 studies [35], endo -\nmetriotic cystectomies are associated with a significant \nreduction of serum AMH level by 54.2% at the late-\npostoperative time point (9–18 months).\nIt is not surprising that excision of a non-endometri-\notic ovarian cyst such as cystadenomas also can cause \novarian damage. In a prospective study, serum AMH \nlevel at postoperative 1 week declined by 33.9% com -\npared with preoperative level, although the amount of \ndecrease was smaller and recovery was faster than en -\ndometrioma [36]. In another study, the median serum \nAMH level was also significantly reduced at 1 month \nafter operation in both endometrioma and non-endo-\nmetrioma group [37]. Moreover, in a meta-analysis of \n367 patients from 10 studies, serum AMH level sig -\nnificantly decreased by 38% after excision of unilateral \nnon-endometriotic ovarian cyst [38]. Although the risk \nof removing or injuring ovarian tissue is greater for en-\ndometrioma and a significant decrease in residual ovar-\nian volume compared with the untreated contralateral \novary was not found after dermoid cystectomies [39], \na possibility of ovarian damage should be considered \nduring operations of non-endometriotic ovarian cyst as \nwell as ovarian endometriomas.\nOf note, the mean serum AMH level after surgeries \nwas above 1.2 ng/mL in most studies, which means that \nmany women does not meet the criteria for POR based \non serum AMH level [3,4]. However, some of them \nsurely have DOR or higher risk of developing DOR, es-\npecially when they are at advanced age or already have \nrelatively lower ovarian reserve compared to the same \nage before surgery.\nSpontaneous diminished ovarian reserve\nGenetic\nAs ovarian reserve diminishes naturally with age, \nall women should experience DOR even without any \niatrogenic cause at some point in the reproductive age. \nIndeed, AMH declines by approximately 5% per year \nin women in their third decade [40]. Apart from these \nnatural phenomena, it is estimated that 10% of women \nin the general population might be at risk of early-\nonset DOR during their early reproductive life [41] , \nbut the cause of this “premature” DOR remains largely \nunknown and no specific cause is identified in most \ncases. Although various factors such as environmental, \npsychological, or physical can affect ovarian reserve, \ngenetic defects such as chromosome or gene abnor -\nmalities play an important role in the loss of ovarian \nreserve [42].\nTuner syndrome is the most common sex chromo -\nsome abnormality in women. Accelerated loss of germ \ncells and subsequent early depletion of ovarian reserve \nin childhood or early adolescence is an important \ncharacteristic of Turner syndrome, although the initial \nmigration of primordial cells may not be impaired [43]. \nSince ovarian reserve would be determined by the pro-\nportion of 46,XX cells in the ovary in Turner syndrome \n[44], patients with mosaicism such as 45,X/46,XX or \n45,X/47,XXX more frequently experience spontaneous \nmenstruation [45] and most spontaneous pregnancies \n(up to 5%) are observed in 45,X/46,XX mosaicism [46]. \nNevertheless, patients with Turner syndrome only have \na very short period for fertility, more likely in DOR \nstate, until they are becoming POI due to the limited \nand rapidly decreasing ovarian reserve.\nBRCA1/2  are tumor suppressor genes and BRCA  \nmutations are associated with high risks of breast and \novarian cancer. In addition to cancer risk, BRCA muta-\ntions are also associated with decreased ovarian reserve \nor an earlier age of menopause [47]. As BRCA repairs \ndouble-strand DNA break and maintains embryogen-\nesis and telomere length [48-50], BRCA mutations ac-\ncumulate DNA damage in the oocytes which triggers \napoptosis [51] and BRCA-related ataxia telangiectasia \nmutated-mediated repair functions a regulator of ovar-\nian aging [52]. In 316 young women (≤ 40 years) with \nbreast cancer, women with any BRCA mutation had a \nsignificantly lower median serum AMH level by 32%, \nshowing a negative correlation between mutation and \nserum AMH level [53]. In a meta-analysis in 250 germ-\nline BRCA mutation carriers and 578 controls, women \nwith BRCA mutation had a significantly lower serum \nAMH levels (23%) after adjustments, and this differ -\nence mostly resulted from BRCA1 mutation [54]. Based \non these findings, possibilities of shorter fertile period \nand a tendency to DOR or POI should be considered in \nreproductive-aged women with BRCA mutations [55].\nThe fragile X mental retardation 1  (FMR1) gene, a \nregulator gene in the X chromosome, is associated with \nDOR as well as neuropsychiatric disorders. The FMR1 \ngene contains a CGG trinucleotide repeated site at the 5’ \nuntranslated region, and this region may change repeat \nnumber during meiosis due to errors in DNA replica-\ntion, repair, and recombination, and loss of oocytes oc-\ncurs due to impaired granulosa cell mitosis [56]. Gene \n\n89\nDiminished Ovarian Reserve\nexpression vary according to the number of CGG re -\npeats, and premutation with the range of 55–200 CGG \nrepeats causes excessive FMR1  RNA transcription \nand decreased protein translation, and consequently \nwomen with premutation experience a significant de -\ncrease in ovarian reserve. It has been shown that age of \nmenopause is 5 years earlier than general population \n[57] and estimated incidence of POI is up to 30% [56] \nin women with a fragile X premutation. Even though \nmany women with premutation will not develop POI, \nthey probably have DOR or are at higher risk of devel-\noping DOR [58].\nIn addition to these known genetic disorders, various \ngenetic variabilities such as single-nucleotide polymor-\nphisms and non-coding RNA molecules are also associ-\nated with DOR or POI [42]. Recently whole-exome se-\nquencing detected 79 heterozygous variants overlapped \nbetween DOR and POI, which are likely to be involved \nin the decline of ovarian function [59]. However, not \nmuch is known about genetic causes for spontaneous \nDOR with early-onset, and more research is needed.\nOvarian endometrioma\nOvarian endometriomas per se can affect ovarian \nreserve negatively [60]. Focal inflammation by endo -\nmetrioma induces fibrosis and loss of cortex-specific \nstroma, and finally, recruitment and atresia of follicles \nare enhanced (burnout hypothesis) [61]. In addition, it \nhas been proposed that endometrioma contains higher \nconcentrations of free iron, reactive oxygen species, \nproteolytic enzymes, and inflammatory molecules \nwhich cause significant changes affecting the surround-\ning ovarian tissue negatively [62]. Impaired circulation \nby the compression of the cyst is also possible [63].\nIn a meta-analysis of 17 studies evaluating the effects \nof endometrioma on the serum AMH level, AMH was \nsignificantly lower in women with endometrioma than \nin women with non-endometriotic ovarian cyst or with \nhealthy ovaries [64]. In addition, the longitudinal de -\ncline of serum AMH level was faster over 6 months in \nwomen with endometrioma compared to controls [65]. \nMoreover, numbers of oocytes and metaphase II oo -\ncytes retrieved were significantly lower in women with \nendometrioma [66,67], although it may result from \ntechnical difficulty during oocyte pick-up procedure. \nTaken together, current evidence indicates that endo -\nmetriomas themselves are associated with a decrease in \novarian reserve which can increase the risk of develop-\ning DOR.\nDiminished ovarian reserve after transplantation of \nfrozen-thawed ovarian tissue\nOvarian tissue cryopreservation and transplantation \nis a safe and effective fertility preservation option now, \nbut there has been a concern about massive depletion \nof follicle and becoming DOR after reimplantation of \novarian tissue [68]. Loss of ovarian reserve can occur at \nany stages of the cryopreservation and transplantation \nprocedures, but it is estimated that the 80% loss of pri-\nmordial follicles occurs in the post-grafting stage [69]. \nIschemia and activation are two main mechanisms \nwhich contribute to the massive post-grafting follicle \nloss. As blood supply is stopped after removal of ovar-\nian tissue, ischemia and hypoxia persist until neovascu-\nlarization following transplantation which can take up \nto 10 days to provide sufficient oxygen and nutrients to \nthe graft [70]. During this period, the grafted tissue is \nexposed to ischemic injury causing follicle loss [71]. In \naddition, massive activation of the primordial follicle \npool such as significant increases in early growing fol-\nlicle populations and proliferations of granulosa cells in \ntransitional and early growing follicles, occurs shortly \nafter transplantation, and it also contributes to loss of \novarian reserve of the graft [72].\nA recent study in 285 European women who under -\nwent transplantation of cryopreserved ovarian tissue \n[73] reported promising results that 88.7% had re -\nsumption of menstruation and about one-fourth gave a \nbirth. However, a 5-year graft survival rate was 55%. In \naddition, the empty follicle rate was 31% and embryo \ntransfer was possible in only 50% in women undergo-\ning frozen-thawed ovarian tissue transplantation fol -\nlowed by in vitro fertilization. Based on these clinical \ndata as well as physiology, transplantation of frozen-\nthawed ovarian tissue should be supposed to DOR or \ncondition at higher risk of developing DOR.\nPOSSIBLE THERAPEUTIC APPROACHES\nCurrently there is no reliable and established treat -\nment for DOR which can reverse loss of ovarian re -\nserve. Although a variety of protocols and adjuvant \ntherapies for in vitro fertilization are introduced to \nimprove ovarian response to controlled ovarian stimu-\nlation and clinical outcomes such as pregnancy and live \nbirth rates in infertile women with DOR [74], these \nmethods cannot reverse DOR, and therefore, cannot be \nconsidered as a definite treatment. Following methods \nare now showing a possibility of being considered as \nhttps://doi.org/10.6118/jmm.25109\n\nDong-Yun Lee\n90\nwww.e-jmm.org\ntherapeutic approaches in women with DOR.\nStem cell transplantation\nDue to its regenerative nature of self-renewal and dif-\nferentiation into various cells, stem cells are considered \nas a potential therapeutic option for many diseases and \neffects of stem cell transplantation also have been re -\nsearched in POI [75]. When human amnion–derived \nmesenchymal stem cells were injected into tail vein or \ndirectly into ovary in cyclophosphamide and busulfan-\ninduced POI rats [76], AMH increased in both trans -\nplantation methods and FSH levels did not differ by \nthe route of administration. In addition, the numbers \nof follicles at the various stages were significantly in -\ncreased in both groups compared with the POI group. \nIn another study using menstrual-derived stem cells, \nthe number of healthy follicles substantially increased \nand FSH decreased in cisplatin-induced mouse POI \nmodel [77]. A meta-analyses of 16 pre-clinical stud -\nies reported that stem cell-based therapy significantly \nimproved FSH and estradiol levels, ovarian weight, \nfollicle count, and the number of pregnancies in ani -\nmal models of POI, mostly induced by chemotherapy \n[78]. However, large-scale and high-quality studies are \nwarranted in the future due to a considerable degree \nof heterogeneity among the studies. Regarding DOR, \ninfusion of human bone marrow–derived stem cells \nresulted in higher numbers of follicles, metaphase II \noocytes, and embryos in mice DOR models, possibly \nmediated by promoting ovarian vascularization and \nfollicular growth [79].\nIn humans, treatment using stem cells derived from \nseveral sources also has been tested for this purpose in \nseveral studies. Despite some positive results, the num-\nber of participants is small and the selection criteria are \nunclear [80,81].\nIn vitro activation\nThe balance between activation (PI3K pathway) and \ninhibition (Hippo pathway) is important in the early \nfolliculogenesis [82], and disruption of the Hippo \npathway by fragmentation of ovarian tissue with (con-\nventional) or without (drug-free) incubation with Akt \nstimulants has been introduced as in vitro activation \ntechnique [83]. In a small study (n = 11), some DOR \nand POI patients can get pregnant using this technique \n[84].\nAlthough in vitro activation might increase the num-\nber of follicles for ART and improve the pregnancy \nrate in women with DOR or POI, the pregnancy rate \nis usually very low based on case series [83]. In addi -\ntion, ovarian reserve may not restore by conventional \nin vitro activation, and rather, this technique may have \na deleterious effect on the ovarian reserve because a \nmassive follicular activation can compromise the de -\nvelopment of growing follicles leading to atresia [85]. \nMoreover, in vitro culture may trigger some damages \nsuch as necrosis or apoptosis on the ovarian tissue [86].\nPlatelet-rich plasma\nPlatelet-rich plasma is plasma with high concentra -\ntions of platelets which contains various proteins, hor-\nmones, growth factors, and cytokines [87]. Considering \nits regenerative potential, autologous platelet-rich plas-\nma intraovarian injection has been studied for POR or \neven POI, but only in small case series [88,89]. In a re-\ncent pilot study including 120 women with POR, POI, \nperimenopause and menopause (30 per each group), \na significant improvement on AMH and AFC was ob-\nserved in POR and POI patients and menstruation was \nrecovered in some POI and menopausal patients [89]. \nA recent meta-analysis of 2,256 women from 38 stud -\nies, mostly observational, reported that PRP treatment \nimproved the main fertility parameters such as AMH \nand AFC, but the incidence of spontaneous pregnancy \nfollowing PRP treatment was very low (7%) [90]. Fur-\nther randomized trials with large numbers and a longer \nfollow-up period are warranted.\nOvarian tissue transplantation\nRe-implanted ovarian tissue after freezing and thaw-\ning could be considered as a new source of ovarian \nreserve as well as sex hormones [91]. This concept has \nbeen tested in two small studies with transplantation of \novarian cortical tissue into the abdominal wall [92,93] \nbut evidence supporting use for this purpose is still \nscarce.\nRecently, duration of ovarian activity after transplan-\ntation is getting longer and can be extended over 10 \nyear by repeating reimplantation [94]. The better the \novarian function upon freezing (at younger age), the \nbetter the function after transplantation is expected. \nHowever, this approach is still conceptual and experi-\nmental for women with DOR or POI.\nClinical application\nDespite some positive results, research is still limited \nto draw a clear conclusion on the application of these \n\n91\nDiminished Ovarian Reserve\nnovel techniques in women with DOR. Most studies \nhave shown the beneficial effects from animals, and \nreliable human studies are sparse. Therefore, results \nfrom uncontrolled case-series should be interpreted \nwith caution, and these methods should be considered \nexperimental until much more evidence can support \nthe effects. Meanwhile, more studies on the underlying \nmechanisms and risks of each treatment are needed for \nclinical applications in human.\nCONCLUSION\nIn human, iatrogenic DOR mostly develops during \ncancer treatment such as chemotherapy or pelvic radia-\ntion. As DOR is irreversible once it occurs and it has \nnegative impact on fertility potential and even general \nhealth, attention and efforts are required to reduce the \nrisk of occurrence. For cancer therapy-induced DOR, \nchoosing less gonadotoxic treatment modality and us-\ning the minimum effective dose is the best strategy. \nFertility preservation should be considered when the \noccurrence of iatrogenic or even spontaneous DOR is \nexpected in young women desiring the future fertility. \nMeanwhile, reduction of ischemic injury and follicle \nactivation will be beneficial for less prominent loss of \novarian reserve after transplantation of ovarian tissue.\nSeveral possible therapeutic approaches to DOR have \nbeen proposed with logical reasons and positive results. \nHowever, due to lack and low quality of the available \nevidence, these results should be interpreted with cau-\ntion, and further research is warranted to be widely ap-\nplied in clinical practice.\nFUNDING\nNo funding to declare.\nCONFLICT OF INTEREST\nNo potential conflict of interest relevant to this article \nwas reported.\nREFERENCES\n 1. 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