Diminished Ovarian Reserve: A Narrative Review of Etiologies and Possible Therapeutic Approaches

What is diminished ovarian reserve? There is no clear and universal definition of dimin - ished ovarian reserve (DOR). Since ovarian reserve is defined as the number of oocytes in the ovary or oo - cyte quantity [1], DOR usually means a condition in which women have fewer oocytes compared to women in the same age. Clinically, DOR can be characterized by poor fertility outcomes even with assisted reproduc- tive technology (ART) [2]. In this respect, DOR is close to poor ovarian response (POR) and DOR and POR are commonly used interchangeably, but unlike DOR, POR has a clear definition. In the Bologna European Society of Human Reproduction and Embryology con- sensus [3], POR is defined when women have at least two of three following features: (1) advanced maternal age (≥ 40 years) or any of the risk factors for POR, (2) a previous POR (≤ 3 oocytes with a conventional stimu- lation protocol), and (3) an abnormal ovarian reserve test (i.e., antral follicular count [AFC] < 5–7 follicles or anti-Müllerian hormone [AMH] < 0.5–1.1 ng/mL). In addition, in the Patient-Oriented Strategies Encom- passing IndividualizeD Oocyte Number (POSEIDON) stratification [4], women are classified into 4 groups of POR in ART according to age (35 years), ovarian re - serve parameters (AFC = 5 ng/mL and AMH = 1.2 ng/ mL), and unexpected poor or suboptimal ovarian re - sponse. It means, by definition, age or at least one pre- vious controlled ovarian stimulation is important for a diagnosis of POR in both the Bologna criteria and the POSEIDON stratification, whereas DOR is a more gen- eral diagnosis with clinical judgement based on abnor- mal ovarian reserve testing results. However, besides of ovarian reserve tests such as serum follicle-stimulating hormone (FSH), AMH, AFC, and clomiphene citrate challenge test, age or a prior cycle performance are also used to define DOR in the research [2] and the cut-offs of ovarian reserve markers are arbitrary. This heteroge- neity in the definition produces confusion and difficul- https://doi.org/10.6118/jmm.25109 J Menopausal Med 2025;31:85-94 pISSN: 2288-6478, eISSN: 2288-6761 Diminished Ovarian Reserve: A Narrative Review of Etiologies and Possible Therapeutic Approaches Dong-Yun Lee Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Diminished ovarian reserve (DOR) occurs unintentionally during treatment or spontaneously. Despite its significant clinical manifestations, such as infertility and early menopause, and its high prevalence, most studies on DOR have focused on premature ovarian insufficiency, and reviews specifically addressing DOR remain scarce. This narrative review aims to provide insight into the diverse etiologies of DOR while discussing promising therapeutic approaches. Iatrogenic DOR can occur during chemotherapy, pelvic radiation, and ovarian surgery. Spontaneous DOR may result from ovarian tumors as well as idiopathic or genetic causes. DOR also inevitably occurs during ovarian fragment transplantation. Stem cell transplantation, in vitro activation, and platelet-rich plasma injection have shown some positive results as therapeutic approaches to DOR; however, more high-quality studies are needed to establish their broader applications in clinical practice. Key Words: Diminished ovarian reserve, Etiology, Poor ovarian response, Premature ovarian insufficiency, Therapeutic approach Dong-Yun Lee 86 www.e-jmm.org ty in interpreting results from studies. Although there are no definitive criteria to differentiate DOR from pre- mature ovarian insufficiency (POI), a brief comparison between the two conditions is summarized in Table 1. Why do we need to pay attention to diminished ovarian reserve? Regardless of definition or cause, DOR is associated with a higher risk of a variety of health problems which can reduce quality of life. Infertility As DOR implies diminution of normal reproductive potential, it can cause infertility. Pregnancy and live birth rates are expected to be low even with repetitive ARTs in a woman with DOR [5] and indeed many fertility centers use POR criteria to diagnose DOR in clinical practice. Furthermore, DOR is common in in- fertile women. Therefore, DOR is of great importance in terms of fertility. Early menopausal change DOR is not necessarily a matter of pregnancy. At any given age, DOR can be translated into shortened repro- ductive life. Considering that women reach a meno - pausal state when having fewer than 1,000 remaining follicles [6], women with DOR are at higher risk of developing POI or early menopause according to their age. The more the number of oocytes decreases, the greater the risk of menopause. It is well known that young women without ovarian function would experi- ence a variety of short-term (vasomotor symptoms) and long-term health problems (osteoporosis, cardio - vascular disease, and cognitive dysfunction) [7]. Mean- while, even DOR in young premenopausal women is significantly associated with low bone mineral density, increased bone turnover, sexual dysfunction, and sleep disturbance [8]. What should we know about diminished ovarian reserve research in humans? Normal aging is the most common cause of DOR, but DOR is also induced unintentionally by treatment, es- pecially during cancer treatment. Although the occur- rence of DOR after treatment in women with normal ovarian function varies according to age and methods of treatment, any women who will receive possibly gonadotoxic treatment have some degrees of risk of de- veloping DOR. Since DOR is an important reason for ART and the success rate does not improve dramati - cally in spite of recent developments in technologies in assisted reproduction, novel treatment options to over- come or reverse DOR is warranted. Despite its clinical importance and prevalence, review literature on DOR is still limited, while most reviews focus on POI. This narrative review will present various causes of DOR in human and also will discuss possible therapeutic approaches to DOR. Since ovarian reserve reflects ovarian function at a specific time point, DOR is not a permanent but an intermediate step towards becoming POI. Moreover, DOR and POI can share etiologies and features. Therefore, it is difficult to think of POI and DOR separately and POI also will be ad - dressed along with DOR in some parts of this review. ETIOLOGIES OF DIMINISHED OVARIAN RESERVE Iatrogenic diminished ovarian reserve Chemotherapy Iatrogenic DOR occurs exclusively after cancer treat- ment, especially chemotherapy. The ovaries are sensi- tive to chemotherapy, and alkylating agents are most likely to cause damage on the ovarian reserve [9]. Cy- clophosphamide, an alkylating agent, is regarded as one of the most gonadotoxic chemotherapies. It binds alkyl groups to DNA covalently, induces DNA crosslinking, and consequently prevents DNA replication. This drug can damage primordial follicle population directly by inducing granulosa cell apoptosis and follicular atresia [10] or indirectly by accelerating primordial follicle activation [11]. In addition, inflammation and vascu - lature damage also can contribute to loss of ovarian Table 1. Comparison of DOR and POI based on the international guidelines and reviews DOR POI Menstrual cycle Usually regular Amenorrhea or irregular Ovarian reserve tests AMH (ng/mL) < 1.1 or 1.2 Very low AFC (n) 10 > 25 DOR: diminished ovarian reserve, POI: premature ovarian insufficiency, AMH: anti-Müllerian hormone, AFC: antral follicular count, FSH: follicle-stimulating hormone. 87 Diminished Ovarian Reserve reserve [12]. Meanwhile, cisplatin, a platinum-based compound, interferes with DNA repair mechanisms and produces apoptotic cell death [13]. It has been re- ported that this drug has moderate risk of amenorrhea when combined with bleomycin [14], but clinical data regarding ovarian toxicity is still limited in human. Like cyclophosphamide, cisplatin also produces the loss of primordial follicles in both direct and indirect ways. Doxorubicin is another chemotherapeutic agent that can produce ovarian toxicity. It prevents topoisomerase II-DNA complex formation which leads to accumula- tion of DNA fragments and induction of cell death. It also stimulates the oxidative stress [15]. The likelihood that POI will develop after chemo - therapy can vary enormously, and sensitivity to go - nadotoxic chemotherapy is age- and dose-dependent. In a meta-analysis of 74 studies in patients with breast cancer, the rate of chemotherapy-induced amenorrhea was increased by age showing that older age of > 40 years old was a strong risk factor for the occurrence of chemotherapy-induced amenorrhea [16] . In addi - tion, it has been suggested that higher doses of chemo- therapy correspond with higher rates of amenorrhea, although this correlation may not be consistent and a possible threshold dose for amenorrhea is not clear [17]. Of note, the risk of ovarian failure was assessed as risk of amenorrhea after chemotherapy in most clinical studies and guidelines, since initial work of American Society of Clinical Oncology [9]. However, regular menstruation does not guarantee normal ovarian func- tion, because AMH or AFC can be significantly lower in these women which support some degrees of follicle depletion [18]. In a recent study in young breast can - cer patients who underwent ovarian protection using GnRH agonist during chemotherapy [19], 95% women experienced resumption of menstruation at 1 year after doxorubicin/cyclophosphamide-based chemotherapy. However, serum AMH level was reduced by over 70% after treatment, which means the ovarian reserve did not return to the baseline. In this aspect, it can be spec- ulated that some women may have DOR after gonado- toxic chemotherapy irrespective of having resumed menstruation. Radiation therapy It is well known that radiation to the female pelvis has detrimental effects on the ovaries. Non-growing fol - licles or primordial follicles are sensitive to radiation, although quiescent follicles are generally more resistant to radiotherapy that larger maturing follicles [20]. Di- viding granulosa cells are the initial target of radiation damage, and cell death presents within hours of radia- tion [21]. In addition, radiation can produce vascular damage in the stroma leading to atrophy and fibrosis of tissue [22] and it also stimulates oxidative stress [23]. The degree of the damage by radiation differs by dose, field and schedule of radiation as well as age or ovar - ian reserve at the time of treatment [24]. Among them, dose is the most important determining factor for ovar- ian damage. High dose of radiation such as total body irradiation and whole abdominal irradiation usually induces POI, even during childhood [25]. LD50 (the dose destroying about 50% of non-growing follicles) is conservatively estimated to be less than 2 Gy [20] and a single oocyte is highly radiosensitive with the Do of 0.12 Gy (reciprocal of the slope on the exponential portion of a survival curve). It can be translated that sterilization is predicted in 5% by 2–3 Gy and 50% by 6–12 Gy in women whose ovaries are exposed to radia- tion therapy [26]. Meanwhile, age (or ovarian reserve at the initiation of radiation) is also related to the de - gree of radiation-induced damage. Doses of radiation which would result in ovarian failure were calculated to be 20.3 Gy at birth, 18.4 Gy at age of 10, 16.5 Gy at age of 20, and 14.3 Gy at age of 30, with a probability of 97.5% [27]. In addition, women of < 40 years old need more radiation dose for permanent damage than older women (20 Gy vs. 6 Gy) [28]. There have been several developments in the tech - niques to decrease the exposure of radiation to the ovaries such as novel beam arrangements, fraction - ation schedules, highly conformational radiotherapy, intensity modification, and shielding or transposing ovaries during radiotherapy. However, it is not possible to avoid the whole damage from radiation and doses reaching the ovaries remain high during the treatment of cancers [29] , and consequently, radiation therapy can induce DOR and POI immediately or subsequently. Ovarian surgery Endometriotic cystectomy can cause damage on ovar- ian reserve by removing primordial follicles adjacent to the cyst [30]. In addition, tearing, bleeding, and co- agulation during operations also cause loss of ovarian reserve [31]. Even experienced surgeons using accurate techniques cannot avoid ovarian damage completely [32]. Many studies have demonstrated the detrimental effects of endometriotic cystectomy on ovarian reserve, https://doi.org/10.6118/jmm.25109 Dong-Yun Lee 88 www.e-jmm.org mainly evaluated by serum AMH level [33,34]. In a recent meta-analysis including 14 studies [35], endo - metriotic cystectomies are associated with a significant reduction of serum AMH level by 54.2% at the late- postoperative time point (9–18 months). It is not surprising that excision of a non-endometri- otic ovarian cyst such as cystadenomas also can cause ovarian damage. In a prospective study, serum AMH level at postoperative 1 week declined by 33.9% com - pared with preoperative level, although the amount of decrease was smaller and recovery was faster than en - dometrioma [36]. In another study, the median serum AMH level was also significantly reduced at 1 month after operation in both endometrioma and non-endo- metrioma group [37]. Moreover, in a meta-analysis of 367 patients from 10 studies, serum AMH level sig - nificantly decreased by 38% after excision of unilateral non-endometriotic ovarian cyst [38]. Although the risk of removing or injuring ovarian tissue is greater for en- dometrioma and a significant decrease in residual ovar- ian volume compared with the untreated contralateral ovary was not found after dermoid cystectomies [39], a possibility of ovarian damage should be considered during operations of non-endometriotic ovarian cyst as well as ovarian endometriomas. Of note, the mean serum AMH level after surgeries was above 1.2 ng/mL in most studies, which means that many women does not meet the criteria for POR based on serum AMH level [3,4]. However, some of them surely have DOR or higher risk of developing DOR, es- pecially when they are at advanced age or already have relatively lower ovarian reserve compared to the same age before surgery. Spontaneous diminished ovarian reserve Genetic As ovarian reserve diminishes naturally with age, all women should experience DOR even without any iatrogenic cause at some point in the reproductive age. Indeed, AMH declines by approximately 5% per year in women in their third decade [40]. Apart from these natural phenomena, it is estimated that 10% of women in the general population might be at risk of early- onset DOR during their early reproductive life [41] , but the cause of this “premature” DOR remains largely unknown and no specific cause is identified in most cases. Although various factors such as environmental, psychological, or physical can affect ovarian reserve, genetic defects such as chromosome or gene abnor - malities play an important role in the loss of ovarian reserve [42]. Tuner syndrome is the most common sex chromo - some abnormality in women. Accelerated loss of germ cells and subsequent early depletion of ovarian reserve in childhood or early adolescence is an important characteristic of Turner syndrome, although the initial migration of primordial cells may not be impaired [43]. Since ovarian reserve would be determined by the pro- portion of 46,XX cells in the ovary in Turner syndrome [44], patients with mosaicism such as 45,X/46,XX or 45,X/47,XXX more frequently experience spontaneous menstruation [45] and most spontaneous pregnancies (up to 5%) are observed in 45,X/46,XX mosaicism [46]. Nevertheless, patients with Turner syndrome only have a very short period for fertility, more likely in DOR state, until they are becoming POI due to the limited and rapidly decreasing ovarian reserve. BRCA1/2 are tumor suppressor genes and BRCA mutations are associated with high risks of breast and ovarian cancer. In addition to cancer risk, BRCA muta- tions are also associated with decreased ovarian reserve or an earlier age of menopause [47]. As BRCA repairs double-strand DNA break and maintains embryogen- esis and telomere length [48-50], BRCA mutations ac- cumulate DNA damage in the oocytes which triggers apoptosis [51] and BRCA-related ataxia telangiectasia mutated-mediated repair functions a regulator of ovar- ian aging [52]. In 316 young women (≤ 40 years) with breast cancer, women with any BRCA mutation had a significantly lower median serum AMH level by 32%, showing a negative correlation between mutation and serum AMH level [53]. In a meta-analysis in 250 germ- line BRCA mutation carriers and 578 controls, women with BRCA mutation had a significantly lower serum AMH levels (23%) after adjustments, and this differ - ence mostly resulted from BRCA1 mutation [54]. Based on these findings, possibilities of shorter fertile period and a tendency to DOR or POI should be considered in reproductive-aged women with BRCA mutations [55]. The fragile X mental retardation 1 (FMR1) gene, a regulator gene in the X chromosome, is associated with DOR as well as neuropsychiatric disorders. The FMR1 gene contains a CGG trinucleotide repeated site at the 5’ untranslated region, and this region may change repeat number during meiosis due to errors in DNA replica- tion, repair, and recombination, and loss of oocytes oc- curs due to impaired granulosa cell mitosis [56]. Gene 89 Diminished Ovarian Reserve expression vary according to the number of CGG re - peats, and premutation with the range of 55–200 CGG repeats causes excessive FMR1 RNA transcription and decreased protein translation, and consequently women with premutation experience a significant de - crease in ovarian reserve. It has been shown that age of menopause is 5 years earlier than general population [57] and estimated incidence of POI is up to 30% [56] in women with a fragile X premutation. Even though many women with premutation will not develop POI, they probably have DOR or are at higher risk of devel- oping DOR [58]. In addition to these known genetic disorders, various genetic variabilities such as single-nucleotide polymor- phisms and non-coding RNA molecules are also associ- ated with DOR or POI [42]. Recently whole-exome se- quencing detected 79 heterozygous variants overlapped between DOR and POI, which are likely to be involved in the decline of ovarian function [59]. However, not much is known about genetic causes for spontaneous DOR with early-onset, and more research is needed. Ovarian endometrioma Ovarian endometriomas per se can affect ovarian reserve negatively [60]. Focal inflammation by endo - metrioma induces fibrosis and loss of cortex-specific stroma, and finally, recruitment and atresia of follicles are enhanced (burnout hypothesis) [61]. In addition, it has been proposed that endometrioma contains higher concentrations of free iron, reactive oxygen species, proteolytic enzymes, and inflammatory molecules which cause significant changes affecting the surround- ing ovarian tissue negatively [62]. Impaired circulation by the compression of the cyst is also possible [63]. In a meta-analysis of 17 studies evaluating the effects of endometrioma on the serum AMH level, AMH was significantly lower in women with endometrioma than in women with non-endometriotic ovarian cyst or with healthy ovaries [64]. In addition, the longitudinal de - cline of serum AMH level was faster over 6 months in women with endometrioma compared to controls [65]. Moreover, numbers of oocytes and metaphase II oo - cytes retrieved were significantly lower in women with endometrioma [66,67], although it may result from technical difficulty during oocyte pick-up procedure. Taken together, current evidence indicates that endo - metriomas themselves are associated with a decrease in ovarian reserve which can increase the risk of develop- ing DOR. Diminished ovarian reserve after transplantation of frozen-thawed ovarian tissue Ovarian tissue cryopreservation and transplantation is a safe and effective fertility preservation option now, but there has been a concern about massive depletion of follicle and becoming DOR after reimplantation of ovarian tissue [68]. Loss of ovarian reserve can occur at any stages of the cryopreservation and transplantation procedures, but it is estimated that the 80% loss of pri- mordial follicles occurs in the post-grafting stage [69]. Ischemia and activation are two main mechanisms which contribute to the massive post-grafting follicle loss. As blood supply is stopped after removal of ovar- ian tissue, ischemia and hypoxia persist until neovascu- larization following transplantation which can take up to 10 days to provide sufficient oxygen and nutrients to the graft [70]. During this period, the grafted tissue is exposed to ischemic injury causing follicle loss [71]. In addition, massive activation of the primordial follicle pool such as significant increases in early growing fol- licle populations and proliferations of granulosa cells in transitional and early growing follicles, occurs shortly after transplantation, and it also contributes to loss of ovarian reserve of the graft [72]. A recent study in 285 European women who under - went transplantation of cryopreserved ovarian tissue [73] reported promising results that 88.7% had re - sumption of menstruation and about one-fourth gave a birth. However, a 5-year graft survival rate was 55%. In addition, the empty follicle rate was 31% and embryo transfer was possible in only 50% in women undergo- ing frozen-thawed ovarian tissue transplantation fol - lowed by in vitro fertilization. Based on these clinical data as well as physiology, transplantation of frozen- thawed ovarian tissue should be supposed to DOR or condition at higher risk of developing DOR. POSSIBLE THERAPEUTIC APPROACHES Currently there is no reliable and established treat - ment for DOR which can reverse loss of ovarian re - serve. Although a variety of protocols and adjuvant therapies for in vitro fertilization are introduced to improve ovarian response to controlled ovarian stimu- lation and clinical outcomes such as pregnancy and live birth rates in infertile women with DOR [74], these

cannot reverse DOR, and therefore, cannot be considered as a definite treatment. Following methods are now showing a possibility of being considered as https://doi.org/10.6118/jmm.25109 Dong-Yun Lee 90 www.e-jmm.org therapeutic approaches in women with DOR. Stem cell transplantation Due to its regenerative nature of self-renewal and dif- ferentiation into various cells, stem cells are considered as a potential therapeutic option for many diseases and effects of stem cell transplantation also have been re - searched in POI [75]. When human amnion–derived mesenchymal stem cells were injected into tail vein or directly into ovary in cyclophosphamide and busulfan- induced POI rats [76], AMH increased in both trans - plantation methods and FSH levels did not differ by the route of administration. In addition, the numbers of follicles at the various stages were significantly in - creased in both groups compared with the POI group. In another study using menstrual-derived stem cells, the number of healthy follicles substantially increased and FSH decreased in cisplatin-induced mouse POI model [77]. A meta-analyses of 16 pre-clinical stud - ies reported that stem cell-based therapy significantly improved FSH and estradiol levels, ovarian weight, follicle count, and the number of pregnancies in ani - mal models of POI, mostly induced by chemotherapy [78]. However, large-scale and high-quality studies are warranted in the future due to a considerable degree of heterogeneity among the studies. Regarding DOR, infusion of human bone marrow–derived stem cells resulted in higher numbers of follicles, metaphase II oocytes, and embryos in mice DOR models, possibly mediated by promoting ovarian vascularization and follicular growth [79]. In humans, treatment using stem cells derived from several sources also has been tested for this purpose in several studies. Despite some positive results, the num- ber of participants is small and the selection criteria are unclear [80,81]. In vitro activation The balance between activation (PI3K pathway) and inhibition (Hippo pathway) is important in the early folliculogenesis [82], and disruption of the Hippo pathway by fragmentation of ovarian tissue with (con- ventional) or without (drug-free) incubation with Akt stimulants has been introduced as in vitro activation technique [83]. In a small study (n = 11), some DOR and POI patients can get pregnant using this technique [84]. Although in vitro activation might increase the num- ber of follicles for ART and improve the pregnancy rate in women with DOR or POI, the pregnancy rate is usually very low based on case series [83]. In addi - tion, ovarian reserve may not restore by conventional in vitro activation, and rather, this technique may have a deleterious effect on the ovarian reserve because a massive follicular activation can compromise the de - velopment of growing follicles leading to atresia [85]. Moreover, in vitro culture may trigger some damages such as necrosis or apoptosis on the ovarian tissue [86]. Platelet-rich plasma Platelet-rich plasma is plasma with high concentra - tions of platelets which contains various proteins, hor- mones, growth factors, and cytokines [87]. Considering its regenerative potential, autologous platelet-rich plas- ma intraovarian injection has been studied for POR or even POI, but only in small case series [88,89]. In a re- cent pilot study including 120 women with POR, POI, perimenopause and menopause (30 per each group), a significant improvement on AMH and AFC was ob- served in POR and POI patients and menstruation was recovered in some POI and menopausal patients [89]. A recent meta-analysis of 2,256 women from 38 stud - ies, mostly observational, reported that PRP treatment improved the main fertility parameters such as AMH and AFC, but the incidence of spontaneous pregnancy following PRP treatment was very low (7%) [90]. Fur- ther randomized trials with large numbers and a longer follow-up period are warranted. Ovarian tissue transplantation Re-implanted ovarian tissue after freezing and thaw- ing could be considered as a new source of ovarian reserve as well as sex hormones [91]. This concept has been tested in two small studies with transplantation of ovarian cortical tissue into the abdominal wall [92,93] but evidence supporting use for this purpose is still scarce. Recently, duration of ovarian activity after transplan- tation is getting longer and can be extended over 10 year by repeating reimplantation [94]. The better the ovarian function upon freezing (at younger age), the better the function after transplantation is expected. However, this approach is still conceptual and experi- mental for women with DOR or POI. Clinical application Despite some positive results, research is still limited to draw a clear conclusion on the application of these 91 Diminished Ovarian Reserve novel techniques in women with DOR. Most studies have shown the beneficial effects from animals, and reliable human studies are sparse. Therefore, results from uncontrolled case-series should be interpreted with caution, and these methods should be considered experimental until much more evidence can support the effects. Meanwhile, more studies on the underlying mechanisms and risks of each treatment are needed for clinical applications in human.

In human, iatrogenic DOR mostly develops during cancer treatment such as chemotherapy or pelvic radia- tion. As DOR is irreversible once it occurs and it has negative impact on fertility potential and even general health, attention and efforts are required to reduce the risk of occurrence. For cancer therapy-induced DOR, choosing less gonadotoxic treatment modality and us- ing the minimum effective dose is the best strategy. Fertility preservation should be considered when the occurrence of iatrogenic or even spontaneous DOR is expected in young women desiring the future fertility. Meanwhile, reduction of ischemic injury and follicle activation will be beneficial for less prominent loss of ovarian reserve after transplantation of ovarian tissue. Several possible therapeutic approaches to DOR have been proposed with logical reasons and positive results. However, due to lack and low quality of the available evidence, these results should be interpreted with cau- tion, and further research is warranted to be widely ap- plied in clinical practice. FUNDING No funding to declare. CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported.

1. Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril 2020; 114: 1151-7. 2. Cohen J, Chabbert-Buffet N, Darai E. Diminished ovarian re- serve, premature ovarian failure, poor ovarian responder—a plea for universal definitions. J Assist Reprod Genet 2015; 32: 1709-12. 3. Ferraretti AP , La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L; ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna crite- ria. Hum Reprod 2011; 26: 1616-24. 4. Humaidan P , Alviggi C, Fischer R, Esteves SC. The novel POSEI- DON stratification of 'Low prognosis patients in Assisted Re- productive Technology' and its proposed marker of successful outcome. F1000Res 2016; 5: 2911. 5. Oudendijk JF , Y arde F , Eijkemans MJ, Broekmans FJ, Broer SL. The poor responder in IVF: is the prognosis always poor?: a sys- tematic review. Hum Reprod Update 2012; 18: 1-11. 6. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF . Accelerated disappearance of ovarian follicles in mid-life: implica- tions for forecasting menopause. Hum Reprod 1992; 7: 1342-6. 7. Stuenkel CA, Gompel A. Primary ovarian insufficiency. N Engl J Med 2023; 388: 154-63. 8. Pal L, Bevilacqua K, Zeitlian G, Shu J, Santoro N. Implications of diminished ovarian reserve (DOR) extend well beyond reproduc- tive concerns. Menopause 2008; 15: 1086-94. 9. Lee SJ, Schover LR, Partridge AH, Patrizio P , Wallace WH, Hagerty K, et al.; American Society of Clinical Oncology. Ameri- can Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006; 24: 2917-31. 10. Yuksel A, Bildik G, Senbabaoglu F , Akin N, Arvas M, Unal F , et al. The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells. Hum Reprod 2015; 30: 2926-35. 11. Lande Y , Fisch B, Tsur A, Farhi J, Prag-Rosenberg R, Ben-Haroush A, et al. Short-term exposure of human ovarian follicles to cyclo- phosphamide metabolites seems to promote follicular activation in vitro. Reprod Biomed Online 2017; 34: 104-14. 12. Dolmans MM, Taylor HS, Rodriguez-Wallberg KA, Blumenfeld Z, Lambertini M, von Wolff M, et al. Utility of gonadotropin- releasing hormone agonists for fertility preservation in women re- ceiving chemotherapy: pros and cons. Fertil Steril 2020; 114: 725- 38. 13. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 2014; 740: 364-78. 14. Maneschi F , Benedetti-Panici P , Scambia G, Salerno MG, D'Agostino G, Mancuso S. Menstrual and hormone patterns in women treated with high-dose cisplatin and bleomycin. Gynecol Oncol 1994; 54: 345-8. 15. Spears N, Lopes F , Stefansdottir A, Rossi V , De Felici M, Anderson RA, et al. Ovarian damage from chemotherapy and current ap- proaches to its protection. Hum Reprod Update 2019; 25: 673-93. 16. Zavos A, Valachis A. Risk of chemotherapy-induced amenor- https://doi.org/10.6118/jmm.25109 Dong-Yun Lee 92 www.e-jmm.org rhea in patients with breast cancer: a systematic review and meta- analysis. Acta Oncol 2016; 55: 664-70. 17. Walshe JM, Denduluri N, Swain SM. Amenorrhea in premeno- pausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol 2006; 24: 5769-79. 18. Gracia CR, Sammel MD, Freeman E, Prewitt M, Carlson C, Ray A, et al. Impact of cancer therapies on ovarian reserve. Fertil Steril 2012; 97: 134-40.e1. 19. Kim SE, Kim WJ, Choi D, Lee DY . Comparison of goserelin and leuprorelin for ovarian protection during chemotherapy in young patients with breast cancer. Breast Cancer Res Treat 2023; 198: 231-7. 20. Wallace WH, Thomson AB, Kelsey TW . The radiosensitivity of the human oocyte. Hum Reprod 2003; 18: 117-21. 21. Stroud JS, Mutch D, Rader J, Powell M, Thaker PH, Grigsby PW . Effects of cancer treatment on ovarian function. Fertil Steril 2009; 92: 417-27. 22. Wo JY , Viswanathan AN. Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients. Int J Radiat Oncol Biol Phys 2009; 73: 1304-12. 23. Alhumaidha KA, Saleh DO, Abd El Fattah MA, El-Eraky WI, Moawad H. Cardiorenal protective effect of taurine against cyclophosphamide-induced toxicity in albino rats. Can J Physiol Pharmacol 2016; 94: 131-9. 24. Meirow D, Biederman H, Anderson RA, Wallace WH. Toxicity of chemotherapy and radiation on female reproduction. Clin Obstet Gynecol 2010; 53: 727-39. 25. Wallace WH, Shalet SM, Hendry JH, Morris-Jones PH, Gatta- maneni HR. Ovarian failure following abdominal irradiation in childhood: the radiosensitivity of the human oocyte. Br J Radiol 1989; 62: 995-8. 26. Duncan FE, Kimler BF , Briley SM. Combating radiation therapy- induced damage to the ovarian environment. Future Oncol 2016; 12: 1687-90. 27. Wallace WH, Thomson AB, Saran F , Kelsey TW . Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys 2005; 62: 738-44. 28. Lushbaugh CC, Casarett GW . The effects of gonadal irradiation in clinical radiation therapy: a review. Cancer 1976; 37(2 Suppl): 1111-25. 29. Moss EL, Taneja S, Munir F , Kent C, Robinson L, Potdar N, et al. Iatrogenic menopause after treatment for cervical cancer. Clin Oncol (R Coll Radiol) 2016; 28: 766-75. 30. Roman H, Tarta O, Pura I, Opris I, Bourdel N, Marpeau L, et al. Direct proportional relationship between endometrioma size and ovarian parenchyma inadvertently removed during cystectomy, and its implication on the management of enlarged endometrio- mas. Hum Reprod 2010; 25: 1428-32. 31. Saridogan E, Becker CM, Feki A, Grimbizis GF , Hummelshoj L, Keckstein J, et al. Recommendations for the surgical treatment of endometriosis. Part 1: ovarian endometrioma. Hum Reprod Open 2017; 2017: hox016. 32. Biacchiardi CP , Piane LD, Camanni M, Deltetto F , Delpiano EM, Marchino GL, et al. Laparoscopic stripping of endometriomas negatively affects ovarian follicular reserve even if performed by experienced surgeons. Reprod Biomed Online 2011; 23: 740-6. 33. Raffi F , Metwally M, Amer S. The impact of excision of ovarian endometrioma on ovarian reserve: a systematic review and meta- analysis. J Clin Endocrinol Metab 2012; 97: 3146-54. 34. Muzii L, Di Tucci C, Di Feliciantonio M, Marchetti C, Perniola G, Panici PB. The effect of surgery for endometrioma on ovarian reserve evaluated by antral follicle count: a systematic review and meta-analysis. Hum Reprod 2014; 29: 2190-8. 35. Y ounis JS, Shapso N, Ben-Sira Y , Nelson SM, Izhaki I. Endome- trioma surgery-a systematic review and meta-analysis of the effect on antral follicle count and anti-Müllerian hormone. Am J Obstet Gynecol 2022; 226: 33-51.e7. 36. Chang HJ, Han SH, Lee JR, Jee BC, Lee BI, Suh CS, et al. Impact of laparoscopic cystectomy on ovarian reserve: serial changes of serum anti-Müllerian hormone levels. Fertil Steril 2010; 94: 343-9. 37. Iwase A, Hirokawa W , Goto M, Takikawa S, Nagatomo Y , Na- kahara T, et al. Serum anti-Müllerian hormone level is a useful marker for evaluating the impact of laparoscopic cystectomy on ovarian reserve. Fertil Steril 2010; 94: 2846-9. 38. Mohamed AA, Al-Hussaini TK, Fathalla MM, El Shamy TT, Abdelaal, II, Amer SA. The impact of excision of benign nonen- dometriotic ovarian cysts on ovarian reserve: a systematic review. Am J Obstet Gynecol 2016; 215: 169-76. 39. Exacoustos C, Zupi E, Amadio A, Szabolcs B, De Vivo B, Marconi D, et al. Laparoscopic removal of endometriomas: sonographic evaluation of residual functioning ovarian tissue. Am J Obstet Gy- necol 2004; 191: 68-72. 40. Nelson SM, Iliodromiti S, Fleming R, Anderson R, McConnachie A, Messow CM. Reference range for the antimüllerian hormone Generation II assay: a population study of 10,984 women, with comparison to the established Diagnostics Systems Laboratory nomogram. Fertil Steril 2014; 101: 523-9. 41. Nikolaou D, Templeton A. Early ovarian ageing: a hypothesis. De- tection and clinical relevance. Hum Reprod 2003; 18: 1137-9. 42. Moiseeva AV , Kudryavtseva V A, Nikolenko VN, Gevorgyan MM, Unanyan AL, Bakhmet AA, et al. Genetic determination of the ovarian reserve: a literature review. J Ovarian Res 2021; 14: 102. 43. Oktay K, Bedoschi G, Berkowitz K, Bronson R, Kashani B, Mc- Govern P , et al. Fertility preservation in women with turner syn- drome: a comprehensive review and practical guidelines. J Pediatr Adolesc Gynecol 2016; 29: 409-16. 44. Grynberg M, Bidet M, Benard J, Poulain M, Sonigo C, Cédrin- Durnerin I, et al. Fertility preservation in Turner syndrome. Fertil 93 Diminished Ovarian Reserve Steril 2016; 105: 13-9. 45. Aso K, Koto S, Higuchi A, Ariyasu D, Izawa M, Miyamoto Igaki J, et al. Serum FSH level below 10 mIU/mL at twelve years old is an index of spontaneous and cyclical menstruation in Turner syn- drome. Endocr J 2010; 57: 909-13. 46. Bernard V , Donadille B, Zenaty D, Courtillot C, Salenave S, Brac de la Perrière A, et al.; CMERC Center for Rare Disease. Sponta- neous fertility and pregnancy outcomes amongst 480 women with Turner syndrome. Hum Reprod 2016; 31: 782-8. 47. Lin WT, Beattie M, Chen LM, Oktay K, Crawford SL, Gold EB, et al. Comparison of age at natural menopause in BRCA1/2 muta- tion carriers with a non-clinic-based sample of women in north- ern California. Cancer 2013; 119: 1652-9. 48. Keefe DL, Marquard K, Liu L. The telomere theory of reproduc- tive senescence in women. Curr Opin Obstet Gynecol 2006; 18: 280-5. 49. Venkitaraman AR. Beyond cancer genomics: after the end of the beginning. Curr Opin Genet Dev 2012; 22: 1-2. 50. Daum H, Peretz T, Laufer N. BRCA mutations and reproduction. Fertil Steril 2018; 109: 33-8. 51. Shapira M, Raanani H, Feldman B, Srebnik N, Dereck-Haim S, Manela D, et al. BRCA mutation carriers show normal ovarian re- sponse in in vitro fertilization cycles. Fertil Steril 2015; 104: 1162- 7. 52. Turan V , Oktay K. BRCA-related ATM-mediated DNA double- strand break repair and ovarian aging. Hum Reprod Update 2020; 26: 43-57. 53. Son KA, Lee DY , Choi D. Association of BRCA mutations and anti-müllerian hormone level in young breast cancer patients. Front Endocrinol (Lausanne) 2019; 10: 235. 54. Turan V , Lambertini M, Lee DY , Wang E, Clatot F , Karlan BY , et al. Association of germline BRCA pathogenic variants with di- minished ovarian reserve: a meta-analysis of individual patient- level data. J Clin Oncol 2021; 39: 2016-24. 55. Baltacı E, Kazancı F , Şahin F . BRCA, infertility, and fertility pres- ervation: a review for counseling. J Assist Reprod Genet 2023; 40: 465-72. 56. Rose BI, Brown SE. An explanation of the mechanisms underly- ing fragile X-associated premature ovarian insufficiency. J Assist Reprod Genet 2020; 37: 1313-22. 57. Sullivan SD, Welt C, Sherman S. FMR1 and the continuum of primary ovarian insufficiency. Semin Reprod Med 2011; 29: 299- 307. 58. Nolin SL, Glicksman A, Ding X, Ersalesi N, Brown WT, Sherman SL, et al. Fragile X analysis of 1112 prenatal samples from 1991 to 2010. Prenat Diagn 2011; 31: 925-31. 59. Tang R, Yu Q. Novel variants in women with premature ovarian function decline identified via whole-exome sequencing. J Assist Reprod Genet 2020; 37: 2487-502. 60. Kitajima M, Defrère S, Dolmans MM, Colette S, Squifflet J, Van Langendonckt A, et al. Endometriomas as a possible cause of re- duced ovarian reserve in women with endometriosis. Fertil Steril 2011; 96: 685-91. 61. Kitajima M, Dolmans MM, Donnez O, Masuzaki H, Soares M, Donnez J. Enhanced follicular recruitment and atresia in cortex derived from ovaries with endometriomas. Fertil Steril 2014; 101: 1031-7. 62. Sanchez AM, Viganò P , Somigliana E, Panina-Bordignon P , Ver- cellini P , Candiani M. The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to the ovary. Hum Reprod Update 2014; 20: 217-30. 63. The effect of surgery for endometriomas on fertility: scientific im- pact paper no. 55. BJOG 2018; 125: e19-28. 64. Muzii L, Di Tucci C, Di Feliciantonio M, Galati G, Di Donato V , Musella A, et al. Antimüllerian hormone is reduced in the pres- ence of ovarian endometriomas: a systematic review and meta- analysis. Fertil Steril 2018; 110: 932-40.e1. 65. Kasapoglu I, Ata B, Uyaniklar O, Seyhan A, Orhan A, Yildiz Oguz S, et al. Endometrioma-related reduction in ovarian reserve (ER- ROR): a prospective longitudinal study. Fertil Steril 2018; 110: 122-7. 66. Hamdan M, Dunselman G, Li TC, Cheong Y . The impact of endometrioma on IVF/ICSI outcomes: a systematic review and meta-analysis. Hum Reprod Update 2015; 21: 809-25. 67. Alshehre SM, Narice BF , Fenwick MA, Metwally M. The impact of endometrioma on in vitro fertilisation/intra-cytoplasmic injec- tion IVF/ICSI reproductive outcomes: a systematic review and meta-analysis. Arch Gynecol Obstet 2021; 303: 3-16. 68. Dolmans MM, Martinez-Madrid B, Gadisseux E, Guiot Y , Yuan WY , Torre A, et al. Short-term transplantation of isolated human ovarian follicles and cortical tissue into nude mice. Reproduction 2007; 134: 253-62. 69. Roness H, Meirow D. FERTILITY PRESERV ATION: follicle re- serve loss in ovarian tissue transplantation. Reproduction 2019; 158: F35-44. 70. Cacciottola L, Manavella DD, Amorim CA, Donnez J, Dolmans MM. In vivo characterization of metabolic activity and oxidative stress in grafted human ovarian tissue using microdialysis. Fertil Steril 2018; 110: 534-44.e3. 71. Demeestere I, Simon P , Emiliani S, Delbaere A, Englert Y . Ortho- topic and heterotopic ovarian tissue transplantation. Hum Reprod Update 2009; 15: 649-65. 72. Meirow D, Roness H, Kristensen SG, Andersen CY . Optimizing outcomes from ovarian tissue cryopreservation and transplanta- tion; activation versus preservation. Hum Reprod 2015; 30: 2453- 6. 73. Dolmans MM, von Wolff M, Poirot C, Diaz-Garcia C, Cacciottola https://doi.org/10.6118/jmm.25109 Dong-Yun Lee 94 www.e-jmm.org L, Boissel N, et al. Transplantation of cryopreserved ovarian tissue in a series of 285 women: a review of five leading European cen- ters. Fertil Steril 2021; 115: 1102-15. 74. Giannelou P , Simopoulou M, Grigoriadis S, Makrakis E, Kon- togeorgi A, Pantou A, et al. The conundrum of poor ovarian re- sponse: from diagnosis to treatment. Diagnostics (Basel) 2020; 10: 687. 75. Wang S, Yu L, Sun M, Mu S, Wang C, Wang D, et al. The thera- peutic potential of umbilical cord mesenchymal stem cells in mice premature ovarian failure. Biomed Res Int 2013; 2013: 690491. 76. Feng X, Ling L, Zhang W , Liu X, Wang Y , Luo Y , et al. Effects of human amnion-derived mesenchymal stem cell (hAD-MSC) transplantation in situ on primary ovarian insufficiency in SD rats. Reprod Sci 2020; 27: 1502-12. 77. Wang Z, Wang Y , Y ang T, Li J, Y ang X. Study of the reparative ef- fects of menstrual-derived stem cells on premature ovarian failure in mice. Stem Cell Res Ther 2017; 8: 11. 78. Chen L, Guo S, Wei C, Li H, Wang H, Xu Y . Effect of stem cell transplantation of premature ovarian failure in animal models and patients: a meta-analysis and case report. Exp Ther Med 2018; 15: 4105-18. 79. Herraiz S, Buigues A, Díaz-García C, Romeu M, Martínez S, Gómez-Seguí I, et al. Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion. Fertil Steril 2018; 109: 908-18.e2. 80. Herraiz S, Pellicer N, Romeu M, Pellicer A. Treatment potential of bone marrow-derived stem cells in women with diminished ovarian reserves and premature ovarian failure. Curr Opin Obstet Gynecol 2019; 31: 156-62. 81. Salvatore G, De Felici M, Dolci S, Tudisco C, Cicconi R, Campag- nolo L, et al. Human adipose-derived stromal cells transplantation prolongs reproductive lifespan on mouse models of mild and severe premature ovarian insufficiency. Stem Cell Res Ther 2021; 12: 537. 82. Hsueh AJ, Kawamura K, Cheng Y , Fauser BC. Intraovarian con- trol of early folliculogenesis. Endocr Rev 2015; 36: 1-24. 83. Devenutto L, Quintana R, Quintana T. In vitro activation of ovar- ian cortex and autologous transplantation: a novel approach to primary ovarian insufficiency and diminished ovarian reserve. Hum Reprod Open 2020; 2020: hoaa046. 84. Kawamura K, Ishizuka B, Hsueh AJW . Drug-free in-vitro activa- tion of follicles for infertility treatment in poor ovarian response patients with decreased ovarian reserve. Reprod Biomed Online 2020; 40: 245-53. 85. Dolmans MM, Cordier F , Amorim CA, Donnez J, Vander Linden C. In vitro activation prior to transplantation of human ovarian tissue: is it truly effective? Front Endocrinol (Lausanne) 2019; 10: 520. 86. Griesinger G, Fauser B. Drug-free in-vitro activation of ovarian cortex; can it really activate the 'ovarian gold reserve'? Reprod Biomed Online 2020; 40: 187-9. 87. Qureshi AH, Chaoji V , Maiguel D, Faridi MH, Barth CJ, Salem SM, et al. Proteomic and phospho-proteomic profile of human platelets in basal, resting state: insights into integrin signaling. PLoS One 2009; 4: e7627. 88. Pantos K, Simopoulou M, Pantou A, Rapani A, Tsioulou P , Nitsos N, et al. A case series on natural conceptions resulting in ongoing pregnancies in menopausal and prematurely menopausal women following platelet-rich plasma treatment. Cell Transplant 2019; 28: 1333-40. 89. Sfakianoudis K, Simopoulou M, Grigoriadis S, Pantou A, Tsiou- lou P , Maziotis E, et al. Reactivating ovarian function through autologous platelet-rich plasma intraovarian infusion: pilot data on premature ovarian insufficiency, perimenopausal, menopausal, and poor responder women. J Clin Med 2020; 9: 1809. 90. Éliás M, Kónya M, Kekk Z, Turan C, das Virgens IPA, Tóth R, et al. Platelet-rich plasma (PRP) treatment of the ovaries signifi- cantly improves fertility parameters and reproductive outcomes in diminished ovarian reserve patients: a systematic review and meta-analysis. J Ovarian Res 2024; 17: 104. 91. Donnez J, Dolmans MM. Natural hormone replacement therapy with a functioning ovary after the menopause: dream or reality? Reprod Biomed Online 2018; 37: 359-66. 92. Callejo J, Salvador C, Miralles A, Vilaseca S, Lailla JM, Balasch J. Long-term ovarian function evaluation after autografting by im- plantation with fresh and frozen-thawed human ovarian tissue. J Clin Endocrinol Metab 2001; 86: 4489-94. 93. Kiran G, Kiran H, Coban YK, Guven AM. Ovarian cortical trans- plantation may be an alternative to hormone therapy in patients with early climacterium. Fertil Steril 2005; 84: 1509. 94. Donnez J, Dolmans MM. Ovarian cortex transplantation: 60 reported live births brings the success and worldwide expansion of the technique towards routine clinical practice. J Assist Reprod Genet 2015; 32: 1167-70.