The risk factors, pathogenesis and treatment of premature ovarian insufficiency

Abstract

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Premature ovarian insufficiency (POI) is a prevalent condition that impacts female reproductive health and overall well-being. It is characterized by ovarian dysfunction, estrogen deficiency, and increased gonadotropin levels in women under 40 years old. The exact etiology and pathogenesis of POI remain incompletely understood, posing significant challenges for its treatment and prevention. This review article examines the pathogenic factors and mechanisms involved in POI, with a particular focus on the impact of environmental toxicants such as atmospheric particulate matter, endocrine-disrupting chemicals, pesticides, microplastics, heavy metals, and cigarette smoke on the development of POI. Furthermore, the treatments for POI are outlined, encompassing hormone replacement therapy, stem cell and exosome therapy, melatonin therapy, traditional Chinese medicine, in vitro activation, platelet-rich plasma therapy, and ovarian tissue cryopreservation. The primary objective is to raise awareness about the potential detrimental effects of environmental toxicant exposure on ovarian function and reserve, urging individuals to minimize their exposure to harmful substances and advocate for environmental protection. This review also aims to serve as a valuable resource for the prevention and management of POI.

Introduction

Premature ovarian insufficiency (POI) is a gynecological endocrine disorder characterized by menstrual irregularities, infertility, elevated serum gonadotropins, and low estradiol levels in women younger than 40 years old [1]. The global incidence of POI is estimated to be around 3.7% [2], and it significantly affects female reproductive capacity and leads to severe health implications [3]. Studies have shown that women with POI face an increased risk of osteoporosis, cardiovascular disease, mental health disorders, and type 2 diabetes [4,5,6,7]. Additionally, POI not only diminishes oocyte quality and quantity but also correlates with reduced clinical pregnancy rates and heightened miscarriage risks [8]. Due to its complexities, the exact etiology and pathogenesis of POI, particularly the involvement of environmental toxicants (ETs) in its onset and progression, remain incompletely understood. This article aims to comprehensively examine the etiology and pathological mechanisms of POI, with a specific focus on the interplay between ETs exposure and POI. Furthermore, it consolidates various treatment modalities for POI to offer insights for its management and prevention.

Etiology of POI

The etiology of POI is heterogeneous, with a significant portion of cases remaining unidentified. Recognized and prevalent causes of POI encompass genetic, iatrogenic, autoimmune, infectious diseases, and environment [9]. Besides idiopathic influences, genetic factors are deemed primary contributors to POI, constituting approximately 20–25% [10]. Turner syndrome and fragile X premutation, stemming from X chromosome abnormalities, are the most frequent genetic triggers of POI [11]. Turner syndrome affects around 64 per 100,000 newborns [12], with over 80% of patients experiencing absent spontaneous menstruation; even among those with spontaneous menstruation, about one-third are diagnosed with POI [13]. In women carrying fragile X premutation, the incidence of POI ranges from 15–24% [14]. The genetic basis of POI is highly diverse, with various gene mutations, such as cytoplasmic polyadenylation element-binding protein 3 (CPEB3), transmembrane and coiled-coil domains 1 (TMCO1), bone morphogenetic protein-15 (BMP15), basonuclin 1 (BNC1), and others, linked to POI development [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]. Additionally, a recent cohort study has identified twenty more POI-associated genes involved in gonadogenesis, meiosis, follicular development, and ovulation [32]. Similarly, epigenetic modifications play a crucial role in POI pathogenesis [33, 34]. Epigenetics refers to heritable gene expression modifications that do not alter the DNA sequence [35], encompassing DNA methylation, histone modification, non-coding RNAs, and chromatin remodeling [36]. Olsen KW et al. have demonstrated that ovarian granular cells (GCs) in women with diminished ovarian reserve (DOR) exhibit distinct epigenetic features, including increased DNA methylation variability [37, 38]. What’s more, aberrant DNA methylation [39, 40], Tet1 demethylase deficiency [41], dysfunction in polycomb repressive complex 1 [42], and various non-coding RNAs, including long noncoding RNA, microRNA-127-5p, miR-379-5p, and miR-15b [43,44,45,46,47,48] may contribute to POI development by disrupting epigenetic processes. (Table 1).

Table 1 Gene defects in POI

Iatrogenic factors play a significant role in the etiology of POI, accounting for approximately 25% of POI cases resulting from radiotherapy, chemotherapy, and surgery [77]. Treatment with cisplatin, cyclophosphamide, or adriamycin can trigger the accelerated activation or death of primordial follicles, increase follicular atresia, damage ovarian blood vessels and stroma, ultimately leading to POI [78, 79]. It is worth noting that the impact of chemotherapeutic drugs on reproductive health varies based on the specific drug, dosage, and treatment duration [80]. Similarly, both radiotherapy, especially pelvic radiotherapy, and laparoscopic ovarian cystectomy elevate the risk of POI [81,82,83,84,85].

Autoimmune diseases such as Hashimoto's thyroiditis, Addison's disease, systemic lupus erythematosus, celiac disease, antiphospholipid syndrome, and rheumatoid arthritis contribute to approximately 4–30% of POI cases [86,87,88,89,90]. Other factors linked to POI include chronic stress, galactosemia, viral infections like mumps and HIV, and unhealthy lifestyles [91,92,93,94,95]. In addition, although controversial [96], papillomavirus vaccines are also potentially associated with an increased risk of POI [97, 98]. Additionally, environmental agents represent another significant aspect. With the ongoing global industrialization, environmental pollution has emerged as a pressing global concern. Consequently, individuals are inevitably exposed to various ETs in their daily lives. Unfortunately, the detrimental effects of ETs exposure on female reproductive health may not be fully recognized. Recent studies have highlighted the substantial role of ETs exposure in POI development [99], including atmospheric particulate matter (PM), endocrine disrupting chemicals (EDCs), pesticides, induced microplastics, heavy metals, and cigarette smoke [100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121]. Hence, a comprehensive understanding of the pathological mechanism underlying POI, particularly those by ETs exposure, could aid in the prevention and management of POI. (Fig. 1 and Table 2).

Fig.1

The risk factors of POI

Table 2 Effects of ETs on ovarian function

Pathological mechanisms of POI

The quantity and quality of oocytes in the ovaries, also called ovarian reserve, serve as indicators of female reproductive capacity [216]. Theoretically, women are born with a restricted number of follicles, with approximately 7 million dormant follicles present in the female fetal ovaries at around 20 weeks of gestation, representing the peak number of follicles. Over time, this number gradually lessens. At birth, the ovary typically contains one million to two million primordial follicles, which diminish to 400,000 to 500,000 by menarche. Throughout the reproductive lifespan, the majority of follicles undergo atresia, with only about 400 follicles maturing and ovulating in sequence. Menopause occurs when the number of primordial follicles in the ovary drops below 1000, triggering a series of physiological changes [217,218,219,220]. The female reproductive lifespan mostly depends on the delicate interplay between dormancy, activation and apoptosis of primordial follicles [94, 221]. Research suggests that the incidence of POI may be caused by premature primordial follicle activation, increased activation rate of primordial follicles, follicular maturation inhibition, or apoptosis acceleration [94, 222]. Therefore, protecting the quantity and quality of follicles is essential for female reproductive health. The pathological mechanisms of POI mainly involve DNA damage, oxidative stress, epigenetic modification, endocrine disorders, ovarian inflammation and ovarian cell death. (Fig. 2).

Fig.2

Follicular development process and premature ovarian insufficiency

The development of follicles will go through the stages of primordial follicles, primary follicles, secondary follicles to antral follicles. the dominant follicles will be excluded and other follicles in the same period will be atresia. Various factors, including idiopathic factors, genetic factors, iatrogenic factor, autoimmune diseases, infectious diseases, environmental toxicants, can induce accelerated activation or death of primordial follicles and accelerated atretic follicles, leading to premature ovarian insufficiency.

DNA damage

DNA is the fundamental basis of genetic information, and its integrity is essential for sustaining life and maintaining health. However, the genome is inevitably under threat from various forms of DNA damage, including base damage and glycosyl destruction, base mismatch, covalent cross-linking of DNA strands, and DNA strand breaks [223]. DNA damage plays a significant role in the pathogenesis and progression of POI [224, 225]. A genetic analysis involving nearly 70,000 women identified 44 genes associated with POI, many of which are associated with DNA damage and repair processes [226, 227]. Numerous endogenous or exogenous factors can induce or aggravate DNA damage [228]. Reactive oxygen species (ROS) and reactive nitrogen are thought to be the primary endogenous chemicals responsible for DNA damage [229]. Similarly, metabolites such as acetaldehyde or S-adenosylmethionine have the similar effect [230, 231]. ROS are implicated in oxidative assaults on DNA, resulting in oxidized base fragments, oxidized sugar fragments, apurinic/apyrimidinic sites, and strand breaks [232], with DNA double-strand breaks (DSBs) being the most damaging [233]. Exogenous factors that induce DNA damage or DSBs include ionizing radiation, chemotherapy, and ETs [234,235,236,237]. For example, treatment with cyclophosphamide, adriamycin, and cisplatin can induce DSBs in primordial follicle oocytes, ultimately resulting in oocyte death [238, 239]. X-rays and gamma-rays cause DNA damage in oocytes within primordial follicles by either directly oxidizing bases or indirectly generating ROS [235]. Furthermore, various ETs exposure leads to DNA damage in oocytes, GCs, and even entire ovarian cells, including polystyrene microplastics [122,123,124,125], pesticides (such as captan, acrylonitrile, thiamethoxam, azadirachtin-based biopesticide, malathion, glyphosate, methoxychlor [110, 127,128,129,130, 132, 135]), heavy metals (for instance nickel oxide nanoparticles, silver nanoparticles, mercury chloride, strontium, aluminum, iron, cadmium, arsenic, and copper [145, 146, 148, 150, 152, 160, 240] [163]), EDCs (like di-(2-ethylhexyl) phthalate (DEHP), butylparaben, aroclor 1254, 4-vinylcyclohexene diepoxide (VCD), perfluorohexane sulfonate nonylphenol [116, 182, 183, 199, 212, 213]), cigarette smoke, dibenzo[def,p]chrysene, nicotine [170, 175, 176], and PM [241]. In daily life, exposure to one or more ETs is unavoidable, which potentially induce DNA damage through various mechanisms, including direct harm to DNA molecules, induction of DNA oxidative damage by increasing ROS levels, or interference with DNA damage repair pathways, which may overlap. For example, bisphenol A, dibutyl phthalate, perfluorooctanoic acid, DEHP, or PM not only induce DNA oxidative damage but also impact the expression of DNA damage response genes [103, 186,187,188,189, 200, 201, 205, 242, 243].

In response to DNA damage, cells activate various DNA repair pathways, including base‐excision repair, nucleotide excision repair, homologous recombination, and non-homologous end joining pathways [244]. Notably, while DNA repair mechanisms are essential for maintaining genomic stability, they produce intermediate products such as apurinic/apyrimidinic sites that can exacerbate DNA damage [245], implying that DNA damage can set off a vicious cycle of DNA damage and potentially leading to cell death. Furthermore, when DNA damage is too severe to repair or DNA repair mechanisms are overwhelmed, various cellular responses are activated, including cell cycle arrest, senescence, apoptosis, autophagy or necrosis [246,247,248], which are at least partially achieved by regulating the HUS-1-CEP-1-EGL-1-CED-9-CED-4-CED-3 pathway [122] or the PI3K/Akt pathway [138]. Turan V et al. demonstrated that the accumulation of DSBs in primordial follicles accelerates follicular apoptosis, diminishes ovarian reserve, and ultimately accelerates ovarian aging [227]. (Fig. 3).

Fig.3

DNA damage and premature ovarian insufficiency

Various factors, including DNA repair deficiency, chemotherapy, radiation, reactive oxygen species and environmental toxicants, can induce DNA damage. To response DNA damage, DNA repair pathways are triggered. The DNA repair intermediate products may exacerbate DNA damage. When DNA damage is too severe to repair or DNA repair mechanisms are overwhelmed, cell cycle arrest, senescence, apoptosis, autophagy or necrosis is triggered.

Oxidative stress

Oxidative stress is a state of imbalance between oxidation and anti-oxidation caused by the overproduction of oxidants [249]. ROS are widely recognized as prevalent oxidants, including superoxide anion, hydrogen peroxide, hydroxyl radical, ozone, and singlet oxygen [250]. Studies have shown that physiological ROS levels are critical in embryonic and follicular development, steroidogenesis, and oocyte maturation [251,252,253,254]. However, excessive ROS cause oxidative damage to DNA, proteins, lipids, organelles, and cell membranes, which may trigger cell death pathways such as apoptosis, autophagy, ferroptosis, pyroptosis, necrosis, and ultimately lead to follicular atresia and reproductive aging [115, 116, 249, 255,256,257,258].

Oxidative stress is one of the culprits of POI, with various pathogenic factors of POI leading to ovarian damage via this pathway. For example, BNC1 is important in maintaining the redox homeostasis and lipid metabolism balance of oocytes. Mutation or deficiency of BNC1 causes an increase in mitochondrial membrane potential, ROS, and mitochondrial superoxide indicator levels in oocytes, ultimately triggering oocyte ferroptosis via the NF2-YAP signal pathway [18]. CPEB3 regulates mitochondrial activity, intracellular ROS concentration, mitochondrial activity, cell proliferation, and apoptosis in cumulus cells [259], whereas CPEB3 deficiency disrupts follicular development and leads to POI [15]. In addition, deficiencies or mutations in TMCO1, BMP15, and the follicle-stimulating hormone receptor are also linked to increased ovarian ROS and oxidative stress [16, 260,261,262]. Similarly, chemotherapy induces excessive ROS production and oxidative stress in the ovaries, which leads to mitochondrial dysfunction, lipid peroxidation, ovarian cell death, and follicle loss [53, 257, 263,264,265]. Radiation exposure also caused ovarian oxidative damage by increasing ROS levels, inhibiting glutathione peroxidase activity, and elevating NADPH oxidase subunits [266,267,268]. ETs exposure is a significant contributor to ovarian oxidative stress. Studies have demonstrated that PM exposure not only induces high levels of ROS and oxidative stress in the ovary by activating the NF-κB/IL-6 signaling pathway [215, 241, 269], but also lowers the ovarian reserve of offspring mice by activating ROS-dependent NF-κB and PI3K/Akt/FoxO3a signaling pathways [270]. Similarly, microplastic exposure raises ROS levels in oocytes or GCs, causing DNA oxidation, mitochondrial dysfunction, cell cycle arrest, apoptosis, and necrosis [114,115,116, 124, 125, 271]. Furthermore, pesticides (including captan, organochlorine pesticides, acrylonitrile, thiamethoxam, organophosphorus insecticide diazinon, malathion, acetochlor, allethrin, pyriproxyfen, mancozeb, imidacloprid, glyphosate [108, 110, 127, 128, 130, 131, 133, 134, 137,138,139,140,141,142]), heavy metals (including iron overload, silver nanoparticle, cadmium, copper nanoparticle, lead, mercury, sodium arsenite [147, 149, 153,154,155, 160, 164, 166,167,168,169, 272, 273]), EDCs (including nonylphenol, VCD, bisphenol A, bisphenol S, bisphenol F, and bisphenol AF, fluorene-9-bisphenol, DEHP, butylparaben, perfluorooctanoic acid, propylparaben [116, 182, 183, 190, 191, 198, 199, 202, 203, 210, 274]), cigarette smoke, 3-monochloro-1,2-propanediol, and nicotine [170, 171, 177, 181] can induce oxidative damage in ovarian cells through different mechanisms, including increasing levels of ROS, reducing antioxidant enzyme activity, increasing oxidase activity, triggering endoplasmic reticulum stress, and impairing mitochondrial function, ultimately resulting in decreased oocyte quality, cell death, follicular atresia, and ovarian dysfunction. Paradoxically, Shi L et al. suggested that long-term moderate oxidative stress induced by ROS may only impact the quality of oocytes and follicles, but not the quantity of oocytes [275]. The contradictory conclusion could be attributed to differences in ROS levels and the specific context of the study. Notably, it is critical to recognize that oxidative stress is multifaceted, making its extent and potential hazards difficult to precisely control. (Fig. 4).

Fig.4

Oxidative stress and premature ovarian insufficiency

Gene mutation or deficiency, chemotherapy, radiation or environmental toxicants can decrease glutathione peroxidase activity, increase NADPH oxidase subunits activity and induce the high level of ROS, leading to lipids/proteins peroxidation, endoplasmic reticulum stress, mitochondrial dysfunction, apoptosis, autophagy, ferroptosis, pyroptosis, necrosis, which ultimately lead to follicular atresia and premature ovarian insufficiency.

Epigenetic modifications and pathophysiology of POI

Epigenetic modification regulates gene expression through DNA methylation, histone modification, and RNA interference, playing a crucial role in establishing primordial follicle pools [42], oogenesis, and embryonic development [276]. Abnormal epigenetic modifications, such as significantly increased H3K9ac and H3K9me2 modifications in the regulatory region of the FMR1 gene in GCs [277], epitope mutations in mural GCs, increased DNA methylation variability, and predicted telomere length, are common in patients with POI [37].

Various pathogenic factors of POI may induce ovarian damage through interfering with epigenetic modification. Roy et al. found that the histone demethylase JMJD3 in ovarian GCs is associated with the demethylation of H3K27, and conditional deletion of JMJD3 will lead to a decreased number of healthy follicles, estrous cycle disorders, and increased follicular atresia, eventually resulting in POI and subfertility [278]. Yang et al. demonstrated that cyclophosphamide alters DNA methylation and histone modifications in germinal vesicle oocytes, exhibited as increased H3K9me3 levels, decreased H3K4me3 levels, and 5hmC/5mC ratio, resulting in poor oocyte quality [279]. Pre-conceptional maternal exposure to cyclophosphamide can alter the methylation levels of imprinted genes (H19, Igf2r and Peg3) in offspring oocytes, impairing oocyte quality and function [280]. Furthermore, ionizing radiation alters epigenetic modifications in female germ cells, which are primarily mediated by chromatin remodeling and telomere function changes [281]. Similarly, ETs exposure causes abnormal epigenetic alteration, which contributes to the onset and progression of POI [104]. For example, bisphenol A exposure affects steroidogenesis and reproductive function by interfering with DNA methylation and histone trimethylation levels (H3K4me3, H3K27me3 and H3K9me3) in the ovary [192, 193]. Acute low-dose exposure to bisphenol S increases 5-methylcytosine and H3K27me2 in immature oocytes or 5-methylcytosine during oocyte maturation, resulting in lower oocyte quality [196]. DEHP exposure affects the expression of LIM homeobox 8 and SOHLH1 in oocytes and primordial follicle assembly via inhibiting the expression of Smyd3-H3K4me3 in ovaries [206]. Perinatal propylparaben exposure causes steroidogenesis dysfunction and ovarian aging in offspring mice, which may be linked to Cyp1a1 hypermethylation and changes in Peg3 and H19 methylation levels [211]. According to Li et al., ovarian damage and POI produced by VCD exposure were associated with lower levels of N6-methyladenosine, its regulator demethylase ALKBH5, and ALKBH5-mediated YAP activity [184]. Low-dose chlordecone exposure during pregnancy decreases ovarian reserve and increases follicular atresia in female offspring, which may be attributed to an increase in H2Aub and H3K27me3, a decrease in H4ac and H3K4me3 in embryonic oocytes, and a decrease in histone H3 trimethylation and H4 acetylation in growing oocytes [143]. Furthermore, heavy metal cadmium impairs follicular development, steroidogenesis, and GCs function by interfering with DNA methylation, miRNAs (miR-27a-3p, miR-27b-3p, miR-146, miR-10b-5p, and miR-211-3p), or m6A [156,157,158]. Long-term arsenic exposure causes genotoxicity and reproductive harm by reducing DNA methylation levels in the ovary [161]. Meanwhile, arsenic exposure raises the level of DNA methylation in the promoter region of steroidogenic factor-1 in GCs, resulting in aberrant steroidogenesis [162]. Cigarette smoke exposure can alter the methylation of interleukin-6 gene in cumulus cells, potentially affecting oocyte maturation [171]. Furthermore, prenatal nicotine exposure promotes ovarian dysplasia and interferes with estradiol synthesis in offspring rats, which may be associated with reduced H3K27ac and H3K9ac levels in the promotor region of the cytochrome P450 aromatase via nicotinic acetylcholine receptors [178].

Endocrine disruption, altered steroidogenesis and POI

Estradiol, androgens, FSH, and anti-Müllerian hormone, as well as their interactions, play a crucial role in folliculogenesis and the maintenance of ovarian reserve [95]. Consequently, disorders in their synthesis and secretion potentially impact ovarian reserve. EDCs are a type of natural or synthetic compounds that interferes or disrupts the normal endocrine function. Numerous studies have confirmed that EDCs exposure is a significant environmental risk factor and determinant of POI [282]. These substances disrupt the endocrine system by interfering with hormone synthesis or receptor expression, altering circulating hormone levels or distribution, interacting with hormone receptors, affecting signal transduction, inducing epigenetic modification, and altering hormone metabolism or clearance [283]. For example, bisphenol A exhibits a strong affinity for estrogen-related receptor-γ and G protein-coupled receptor-30, potentially disrupting the interaction between estradiol and its receptors [194]. Polycyclic aromatic hydrocarbons not only interact with estradiol receptor α and G protein-coupled receptors to inhibit estradiol production in GCs but also induce the expression of Bax in oocytes through the aryl hydrocarbon receptor, ultimately leading to apoptosis [214]. Hao et al. indicated that exposure to chlorothalonil reduces the level of estrogen receptor α in the ovary, potentially resulting in endocrine disorders [144]. Thiamethoxam exposure disrupts the levels of female hormone receptors, including anti-Müllerian hormone receptor, estrogen receptor β, follicle-stimulating hormone receptor, and luteinizing hormone receptor in mouse ovaries [128]. Furthermore, substances like phthalates, parabens, perfluorooctanoic acid/perfluorooctane sulphonic acid, diethylstilbestrol, 2,3,7,8-tetrachlorodibenzo-p-dioxin, triclosan can interfere with ovarian steroidogenesis and function [104, 204, 207]. Interestingly, EDCs can also impact non-estrogen pathways by interfering with the expression of genes relevant to primordial germ cell development and affecting oocyte meiosis to impair follicular development [284, 285]. Cigarette smoking causes endocrine disorders by reducing estrogen expression, accelerating estrogen clearance, and increasing serum androgen levels to antagonize estrogen [95]. PM2.5 exposure disrupts ovarian endocrine function, as evidenced by a significant decrease in estradiol and steroid synthase (including Cyp11a, Cyp19a, Cyp17a, and Hsd3b) and a considerable increase in FSH [215]. Furthermore, cadmium exposure alters hormone synthesis function in offspring GCs by modulating miRNAs and DNA methylation modifications [159].

Ovarian inflammation and POI

Animal studies have demonstrated a significantly increase in pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and iNOS) in the ovaries of POI models, with anti-inflammatory and anti-oxidative stress treatments showing efficacy in improving ovarian function [82, 286, 287]. Meanwhile, clinical studies have indicated that helper T cell 1 levels in POI females'peripheral blood and ovaries are significantly higher [288], and the cell-mediated immune response is positively associated with inflammatory response [289]. In addition, an increasing number of studies have demonstrated that inflammatory aging, a chronic low-grade inflammation status with aging, plays an important role in the pathogenesis of POI [289, 290], confirming the strong association between ovarian inflammation and POI. It is possible that any factor contributing to ovarian inflammation could lead to POI.

Autoimmune diseases are one of the most important pathogenic factors in POI, since they induce inflammatory autoimmune responses in tissues and increase pro-inflammatory signals [291, 292]. It is plausible to suggest that POI induced by autoimmune diseases is largely connected to ovarian inflammation. Al-Shahat et al. indicated that cisplatin induces ovarian inflammation by activating the p38/MAPK and JNK signaling pathways, as evidenced by the upregulation of pro-inflammatory markers (IL1β, IL6, TNF-α, NF-κβ, and TGF-β1) and the downregulation of anti-inflammatory markers (IL10), ultimately leading to ovarian dysfunction [293]. Moreover, the binding of TNF-α to its receptor activates MAPKs and NF-κB pathways, initiating an inflammatory signal amplification loop that leads to more severe tissue damage [294]. Similarly, cyclophosphamide or radiotherapy treatment can induce ovarian inflammation and upregulate the expression of pro-inflammatory factor (TNF-α) [78, 295, 296]. High levels of TNF-α may promote intracellular calcium accumulation and activate endonucleases, ultimately inducing apoptosis of growing follicles [297]. What’s more, ovarian inflammation induced by ETs contributes to the development POI. For example, PM2.5 triggers ovarian oxidative stress and inflammation by activating the NF-κB/IL-6 signaling pathway, leading to ovarian dysfunction and decreased ovarian reserve [215]. Concurrently, it promotes GCs apoptosis and follicular atresia by inducing an inflammatory response [102]. Saeed et al. showed that microplastic-induced ovarian damage is linked to increased levels of pro-inflammatory factors (IL-6 and NF-κB) [126]. Exposure to bisphenol S can induce an ovarian inflammatory response via SIRT-1/Nrf2/NF-κB pathway, leading to increased levels of inflammatory mediators such as TNF-α, CRP, iNOS, and COX-2 [197]. Additionally, perinatal BPA exposure can impair female offspring's reproductive function, possibly through inflammatory response and abnormal autophagy mediated by the TLR4/NF-κB and mTOR signaling pathways [195]. DEHP induces inflammation-related cell death (pyroptosis) in GCs via SLC39A5/NF-κB/NLRP3 pathway [208]. Meanwhile, DEHP-induced ovarian inflammation is associated with intestinal flora imbalances and alterations in fecal metabolites [209]. Moreover, ovarian dysfunction caused by captan [110], thiamethoxam [128], organochlorine pesticides [137], and 3-monochloro-1,2-propanediol [181] is also associated with the induction of ovarian inflammation.

Ovarian cell death and POI

Throughout the reproductive lifespan, regulated cell death plays a vital role in follicular formation, follicular development, follicular atresia, dominant follicle excretion, and removal of damaged oocytes. However, endogenous or exogenous factors may trigger the regulated cell death pathway and lead to follicular loss [298], which may be closely associated with the occurrence and progression of POI.

Apoptosis is the most extensively studied pathway of regulatory cell death in the ovary [299]. It is primarily triggered by two pathways: the mitochondrial pathway and the death receptor pathway. The mitochondrial pathway is regulated by members of the B-cell lymphoma 2 protein family, while the death receptor pathway is mainly initiated by extracellular ligands that bind to death receptors and trigger apoptosis [298, 300, 301]. However, it is worth noting that the two pathways are not completely independent [301]. Several studies have shown that gene deletion or abnormality (including CPEB3, TMCO1, BMP15), ionizing radiation, chemotherapy, and ETs cause ovarian dysfunction and POI by inducing apoptosis of ovarian somatic cells or oocytes [15, 16, 79, 191, 267, 270, 302, 303].

In addition to apoptosis, ferroptosis, autophagy and autophagic cell death, pyroptosis, necrosis, and necroptosis also play an important role in the development of POI [304,305,306,307,308,309]]. For example, BNC1 deficiency induces oocyte ferroptosis through the NF2-YAP pathway [18]. Cisplatin induces ferroptosis in GCs by regulating the expression of ferroptosis-related molecules, including glutathione peroxidase 4, acetyl CoA synthetase long chain family member 4, arachidonic acid 15-lipoxygenase, and solute carrier family 7 member 11, leading to follicular development disorders and POI [304]. Delcour et al. found that mutations in autophagy-related genes ATG7 and ATG9A reduce autophagosome synthesis and impair autophagy, which is closely related to decreased ovarian reserve [310]. In addition, Liu et al. showed that Tet1 deficiency causes a declined in autophagy and ubiquitination, elevating organelle fission in oocytes [41]. VCD triggers autophagy to induce POI after inactivating the Akt/mTOR pathway by inhibiting miR-144 [185]. In addition, abnormalities in autophagy caused by cyclophosphamide, tripterygium glycosides, diazinon, malathion, and acrylonitrile are closely associated with ovarian dysfunction [48, 127, 131, 138, 311, 312]. Meanwhile, cyclophosphamide or microplastics exposure can also cause POI by inducing pyroptosis, which may be related to the NLRP3/Caspase-1 signaling pathway [115, 306, 313].

Treatment strategies

In recent years, considerable efforts have been devoted to exploring effective treatments for POI. Unfortunately, no entirely effective and optimal treatment has yet been identified. Current therapeutic approaches for POI include hormone replacement therapy (HRT), stem cell and exosome therapy, melatonin therapy, traditional Chinese medicine therapy, in vitro activation, platelet-rich plasma (PRP) therapy, and ovarian tissue cryopreservation. (Fig. 5).

Fig.5

The treatment of POI

Hormone replacement therapy

HRT, the predominant clinical intervention for POI, aims to raise sex hormone levels to premenopausal levels through exogenous supplementation. This approach effectively alleviates symptoms associated with POI and lowers the risk of chronic diseases such as osteoporosis and cardiovascular disease [314,315,316]. Regrettably, HRT treatment does not fundamentally restore ovarian reserve in patients, and long-term HRT treatment may even increase the risk of breast cancer and venous thrombosis [317, 318]. Conversely, there isn't any solid proof yet that HRT increases the risk of cancer recurrence in those who have survived cancer [319, 320]. Therefore, HRT can be administered to POI patients without a contraindication to alleviate menopausal symptoms and mitigate the risk of disease stemming from hormone deficiency.

Stem cell and exosome therapy

Stem cells are undifferentiated cells that have the potential to multi-differentiate, proliferate indefinitely, and self-renew. According to the source, stem cells are classified as adult stem cells, induced pluripotent stem cells, and embryonic stem cells [321]. Mesenchymal stem cells (MSCs), a type of adult stem cells, are the most extensively investigated in POI stem cell therapy [289, 322]. MSCs are extensively derived from bone marrow, fat, umbilical cord, amniotic membrane, menstrual blood, and embryos, and they benefit from low immunogenicity and easy access [323]. Animal studies have confirmed that MSCs transplantation effectively restores the ovarian function of the POI model [324,325,326,327]. Its mechanism may be related to homing, differentiation, paracrine, angiogenesis, immune regulation, anti-inflammatory, anti-apoptosis, anti-fibrosis, and anti-oxidative stress [322, 323, 328]. Meanwhile, clinical studies have been conducted gradually [323]. However, while MSCs have a strong therapeutic potential in POI, their safety has aroused concerns. First, MSCs production and preparation have not yet been standardized, which may result in uneven quality of cells; second, there is still a lack of standards to characterize the safety, biological distribution, and effectiveness of MSCs, making it difficult to evaluate the therapeutic effect; and finally, MSCs therapy may have potential risks of tumorigenicity, immune rejection, and chromosomal aberrations [329,330,331]. To prevent the potential hazards of MSCs treatment, exosome therapy is being investigated progressively.

Exosomes are nano-sized vesicles secreted by cells that contain proteins, lipids, nucleic acids, and other substances [331]. Similar to MSCs, exosomes improve ovarian function in POI animals by inhibiting apoptosis, promoting angiogenesis, reducing oxidative stress, preventing fibrosis, and promoting cell proliferation, implying that exosomes represent a promising cell-free treatment for POI. However, it is worth noting that the generation of exosomes requires standardized production and purifying techniques. Meanwhile, the disadvantages of exosome therapy, such as low targeting, low retention, and immunogenicity, require improved solutions [332].

Melatonin treatment

Melatonin was originally assumed to be an amine hormone secreted by the pineal gland [333]. Recent studies have shown that it can also be synthesized in other tissues such as ovary, testis, placenta, and skin [305]. Melatonin has a beneficial effect in POI, reducing cyclophosphamide-induced primordial follicle loss and inhibiting GC apoptosis by regulating the PTEN/Akt/FoxO3a pathway [334, 335]. Meanwhile, it regulates the ERK pathway, which protects ovarian cells from excessive autophagy-induced ovarian reserve loss and mitochondrial dysfunction [305]. In addition, the DNA protective properties and antioxidant activities of melatonin aid to protect ovarian function and fertility in POI patients [336]. In summary, melatonin supplementation is thought to be a treatment for improving ovarian function in women with POI.

Traditional Chinese medicine treatment

Traditional Chinese medicine has a definite effect in the treatment of POI [337,338,339,340]. The mechanism includes anti-apoptosis [341,342,343], antioxidative stress [344], immunological regulation [337], angiogenesis [345], autophagy regulation [346], DNA damage repair [347], and epigenetic modification [348, 349]. Si-Wu-tang therapy improves follicular development, ovarian function, antioxidant capacity, and angiogenesis in POI mice, possibly through regulating the PI3K/Akt, Nrf2/HO-1, and STAT3/HIF-1α/VEGF signaling pathways [345, 350]. Jian-Pi-Yi-Shen decoction improves mitochondrial activity by regulating the ASK1/JNK signaling pathway, which inhibits GC apoptosis [342]. Similarly, Huyang yangkun formula promote follicular development by regulating AQP8/Bcl-2 family-related apoptosis [341], as well as the Hippo/JAK2/STAT3 pathway to improve ovarian function in POI rats [351]. Zigui-Yichong-Fang is involved in mediating Foxo3 a deacetylation by regulating SIRT1/FoxO3a pathway, which improvs ovarian reserve in POI mice [348]. Bushen-Culuan Decoction may improve ovarian oxidative stress and ovarian reserve by activating the Nrf2/ARE signaling pathway [352]. Similarly, Bu Shen Huo Xue Tang effectively protects the ovarian function of autoimmune POI mice by activating the Nrf2/Keap1 pathway and enhancing antioxidant capacity [344]. Furthermore, it protected ovarian reserve and function in POI animals, maybe connected with promoting endogenous BMSC proliferation and homing [353]. Clinical studies have also shown that Zishen Yutai Pills has a positive effect on patients with DOR undergoing in vitro fertilization and embryo transfer, as evidenced by an increase in the number of oocytes and embryos [354]. Traditional Chinese medicine monomers, such as resveratrol, quercetin, (-)-epicatechin, polysaccharides, honokiol, lycium barbarum polysaccharide, red ginseng, icariin, ginsenoside Rg1, and chrysin, play an excellent role in POI treatment [286, 287, 306, 347, 355,356,357,358,359,360,361,362,363].

Although Chinese herbal compounds have great therapeutic potential in POI, their safety has always been a concern due to the potential toxic components in Chinese herbal medicines, such as aristolochic acid, aconitine, triptolide, brucine, aconite, and metals [364,365,366], which severely limit the global development of traditional Chinese medicine [367, 368]. As a result, how to capitalize on the benefits of traditional Chinese medicine therapy and advance toward internationalization remains a huge challenge for the development of traditional Chinese medicine.

Acupuncture is more generally acknowledged than Chinese herbal medicine treatment. It not only effectively improves the hormone disorder in POI model and inhibits GC apoptosis [369,370,371,372], but it also protects ovarian function by regulating intestinal microflora alterations and inhibiting ovarian oxidative stress and Fe²⁺ accumulation [373]. Similarly, clinical studies have shown that acupuncture has a considerable effect on inhibiting apoptosis, increasing the number of antral follicles, and improving sex hormone levels and ovarian function in patients with DOR or POI [374]. In addition, moxibustion can effectively protect the ovarian function of POI models or patients [375, 376], which may be achieved by inhibiting PI3K/Akt/mTOR signaling pathway [375] or mitigating NLRP3 inflammatory activation and mitochondrial dysfunction [377].

In vitro activation

In vitro activation (IVA) is a technique that stimulates the growth of residual primordial follicles and promotes their development into functional oocytes, hence improving the oocyte retrieval rate of POI patients [378, 379]. The activation of PTEN/PI3K/Akt/Foxo3 signaling pathway, as well as the inhibition of the Hippo signaling pathway, play critical roles in IVA-induced follicular activation and development [380, 381]. Clinical studies have also confirmed that drug-free IVA combined with laparoscopic ovarian incision treatment can disrupt the Hippo signaling pathway and promote the growth of residual follicles in the ovaries of POI patients [382, 383]. In addition, ovarian biopsy and ovarian scraping techniques can promote follicular development in vivo [384]. Interestingly, Lunding et al. found that, while more than half of POI patients became pregnant after undergoing ovarian biopsying, fragmentation, and autotransplantation, there is no conclusive evidence that this treatment increases the number of retrieved oocytes for IVF/ICSI after 10 weeks [385]. In addition, while Zhai et al. showed that no side effects from the IVA operation after 2–4 years of follow-up [379], the long-term implications of IVA procedure remained unknown. Therefore, the safety and efficacy of IVA treatment still need further exploration.

Platelet-rich plasma therapy

PRP is a biological product derived from autologous blood that contains various growth factors, cytokines, proteins, and hormones [386]. Studies have shown that intraovarian PRP injection may be an effective strategy for treating POI. It can improve sex hormone levels, restore the menstrual cycle, promote primordial follicle development, and increase oocyte retrieval rates, all while improving the reproductive potential of POI patients [386,387,388]. However, the mechanism of PRP, particularly in POI, remains mostly unexplained. Ahmadian et al. showed that PRP stimulated ovarian angiogenesis while inhibiting follicular degeneration and atresia induced by ovotoxic substances. Meanwhile, it has considerable potential to inhibit inflammation, restore tissue damage, and stimulate tissue regeneration [389]. In addition, the protective effect of PRP may be linked to apoptosis inhibition and mTOR signaling activation [390]. Although PRP has great potential for treating POI, there are also potential risks, including infection, tumorigenesis, immunological rejection, and embryo safety [380, 391, 392]. Moreover, the preparation technique, quality evaluation, dosage, and duration of PRP have yet to be standardized, limiting its use significantly. Therefore, future research still needs to further clarify the molecular mechanism of PRP in the treatment of POI, as well as develop a standardized process for PRP preparation and administration.

Other treatments

Ovarian tissue cryopreservation and autologous transplantation effectively restore the reproductive endocrine function and fertility in POI patients [393, 394]. In addition, coenzyme Q10, tissue engineering techniques are also expected to protect the ovarian function in POI patients [395, 396]. Meanwhile, it is also crucial to keep a healthy lifestyle [95, 397].

Discussion

POI is a complex gynecological endocrine disease, and its etiology is highly heterogeneous, including genetic defects, epigenetic changes, iatrogenic injuries, autoimmune diseases, and environmental factors [2]. They may cause ovarian dysfunction and ovarian reserve depletion by inducing DNA damage and oxidative stress, changing epigenetic modification, disrupting endocrine function, causing ovarian inflammation and ovarian cell death. Nowadays, although people are gradually aware of the potential harm of environmental factors on ovarian function, it is far from enough compared with genetic defects and iatrogenic factors [78, 398,399,400]. The reasons may be as follows: firstly, ovarian damage induced by ETs may be caused by prolonged and continuous exposure, while current studies mostly focus on a single time point, which may lead to the inability to identify ovotoxic substances in time; secondly, the diagnosis of POI is mostly concentrated in women aged 30–40 years old, but the time point of ETs exposure may have occurred many years ago, which also makes it difficult for us to find the exact cause; thirdly, The complexity and unknown of POI pathological mechanism and oogenesis process. Therefore, more prospective and retrospective cohort studies and experimental studies are needed to find the ovotoxic ETs and their effects on ovarian function, as well as elucidate the related molecular mechanism.

However, in the face of known ETs, how to avoid the potential harm remains a difficult problem. As we all know, there are many kinds of ETs, and they are everywhere in our lives. For example, bisphenol A is widely used in the manufacture of polycarbonate, acrylate and epoxy resin [401, 402]. Phthalate is often used in the manufacture of toys and food packaging materials [403, 404]. Parabens are widely found in preservatives in pharmaceuticals, food, industrial products and personal care products [405]. Plastic products are widely used in packaging, construction, automobile, furniture, agriculture and cosmetics [406]. Furthermore, pesticide is an indispensable part of the development of agriculture, forestry and animal husbandry [407]. These mean that it is very difficult to completely avoid these ovotoxic substances. Therefore, it is urgent to reduce the production, use and distribution of these ETs, as well as to research and development safer and more effective alternatives. Meanwhile, people should also consciously stay away from harmful ETs. Last but not least, ETs exposure not only impairs reproductive health [284, 408, 409], but also affects the health of offspring through changing epigenetic modification [410, 411]. Therefore, it is necessary to study the genetic variation of exposed populations in the future.

Conclusion

In a word, this paper reviews the risk factors, pathogenesis and treatment strategies of POI. Meanwhile, various ovotoxic ETs and their mechanism leading to ovarian reserve decline and ovarian dysfunction are described in detail. It is hoped to provide better strategies for the treatment and prevention of POI, and to make people aware of the potential harm of ETs exposure to female reproductive health.