MEDLINE (clarivate.com.cn/solutions/medline/) was searched for relevant studies published between January 1960 and December 2023 by using title/abstract terms including 'stress', 'psychological stress', 'mental stress', 'anxiety', 'depression', 'distress', 'cortisol', 'alpha amylase', 'primary ovarian insufficiency', 'Functional hypothalamic amenorrhea', 'polycystic ovary syndrome', 'IVF', 'assisted reproductive technology', 'menopause', 'ovarian reserve', 'anti-Müllerian hormone', 'antral follicle count', 'Chronic stress', 'chronic unpredictable stress', 'restraint stress', 'chronic restraint stress', 'cold stress', 'follicles', 'oocytes', 'granulosa cells', 'ovulation', 'estrous cycle', 'ovarian hormone', 'HPA', 'SAM', 'CRH', 'metabolic syndrome', 'insulin resistance', 'diabetes', 'obesity', 'sleep disorders', 'melatonin', 'psychological intervention', 'cognitive behavioral therapy', 'mindfulness-based stress reduction', 'music therapy', 'yoga', 'caloric restriction', 'metformin', 'resveratrol' or in combination, applying AND and OR operators. To obtain more comprehensive retrieval results, the references of relevant papers were also searched.

Research and review articles focusing on the role of stress on ovarian function were included. By contrast, research and review articles focusing on the effect of disorders associated with ovarian dysfunction on mental stress, including communications, case reports, guidelines, comments and protocols, were excluded from the present review. Articles written not in English or without available full text were also excluded.

The title and abstract of every article were checked by two authors (YH and WW). Disagreements were resolved by a third author (FF). A total of 7,623 articles were found by the initial search; 7,316 papers were removed after checking the title and abstract. Next, 307 papers were filtered for full text, of which 183 met the inclusion criteria; 36 were population studies on the effect of stress on ovarian function, 71 were animal models and 26 were psychological and 50 were metabolic intervention studies.

In assisted reproductive medicine, one of the most controversial areas is the underlying influence of psychological factors on pregnancy outcomes. Infertility is a serious health problem around the world and female infertility factors account for at least 35% of all infertility cases (27). The risk of anxiety, depression and distress is generally high in infertile patients (28,29). A 2004 study that interviewed 122 patients before their first infertility clinic visit utilizing a structured psychiatric interview found that 40.2% had a psychiatric disorder, including major depressive, generalized anxiety and dysthymic disorder (30). Volgsten et al (31) reported that, of 413 infertile patients undergoing IVF treatment, 127 (30.8%) were diagnosed with psychiatric disorders, with major depression being the most common. In a study involving 352 female and 274 male patients attending infertility clinics in northern California, 56.5% of patients exhibited notable symptoms of depression and 76% showed notable symptoms of anxiety (32). Infertile patients have higher Beck Depression Inventory (BDI) (14.94±12.90 vs. 8.95±10.49, P<0.0001) and Spielberger Trait Anxiety Inventory (STAI-T) score (48.76±10.96 vs. 41.18±11.26, P<0.0001), indicating a greater experience of anxiety and depression compared with fertile individuals (33).

Numerous studies have explored the link between psychological symptoms before and during ART cycles and subsequent pregnancy rates, yielding conflicting results: Certain studies suggest that higher distress/anxiety/depression levels before and during treatment are associated with lower pregnancy rates (8,9,11,34-39), while others do not (10,40-50). These inconsistencies may be attributed to challenges in accurately assessing stress levels in female patients with infertility and heterogeneity of studies (5,28). Future research should therefore focus on developing more precise psychological assessment methods and establishing consistent time points for data collection to enhance quality of research findings.

POI is characterized by premature loss of ovarian function and permanent cessation of menstruation before the age of 40 years (51). Demographic studies confirm that psychological stress, such as emotional trauma, major life events or chronic stress, may be as a potential trigger for POI in certain cases (52,53). Individuals with POI report continuous exposure to family and work stress and sleep problems, suggesting that adverse life events may contribute to development of POI (52).

Among mental disorders associated with POI, depression is most closely associated to POI. A population study involving 290 patients found that 43% of those with POI had a history of depression, with 26% receiving a depression diagnosis before being diagnosed with POI (15). Depression typically emerges following signs of altered ovarian function but before POI diagnosis (54), possibly due to a more fragile stress system. Female patients are more likely than male patients to develop depression and changes in estrogen levels can increase susceptibility to this condition (18,55). Given the lack of prospective studies on pre-diagnosis stress in patients with POI, more conclusive evidence is needed to determine whether there is an overlapping process or causal association between POI and psychological stress.

Various indicators are used to assess ovarian reserve (OR), with AFC and AMH being particularly promising (51). A study on 979 premenopausal patients aged 25-45 years used AFC measured via transvaginal ultrasound to evaluate OR; the finding indicated a positive association between higher stress levels and AFC in younger patients (β=0.545, P=0.005), and stress accelerates age-related AFC decline (β=−0.036, P=0.031), suggesting women with higher stress experienced faster AFC loss (56). Environmental stress might enhance fertility temporarily by increasing the volume of growing follicles, potentially depleting OR in the long-term (56). Additionally, a cross-sectional study suggested that psychological stress accelerates AFC decline (β=−0.070, P=0.021), implying that low positive affectivity may aggravate the adverse impact of stress on AFC decline (57). Consistent findings across populations reveal that higher levels of perceived stress are linked to decreased AFC and AMH levels (13). A cross-sectional study on 576 infertile patients demonstrated a negative association between salivary α amylase (SAA), a stress marker, and AMH levels (r=−0.315, P<0.001; adjusted for age, r=−0.336, P<0.001) (58). Another study noted modest inverse associations between depression and low AMH among patients aged 36-40 years (adjusted P=0.75, 95%CI, 0.52, 1.09) and nulliparous patients (adjusted P=0.77, 95%CI, 0.59, 1.00) (14). Taken together, data from the aforementioned population studies suggested that elevated levels of perceived stress, as well as biomarkers of stress, are associated with reduced OR.

FHA or anovulation is characterized by the absence of menstruation and ovulation without an identifiable organic cause. The main determinant of the disease is a combination of psychosocial and metabolic stress (59). Predisposing factors include low energy use, nutritional deficiencies, abnormal sleep, emotional and chronic severe stress and overexertion or physical activity (59,60). More severe depressive and anxious symptoms contribute to onset of FHA (16,61-63). Patients with FHA often exhibit dysfunctional attitudes, such as perfectionism, higher need for approval, and struggle to cope with daily stressors (59). Cognitive behavioral therapy accelerates the recovery of ovarian function in patients with FHA, underscoring the role of mental stress in development of this condition (59). As with POI, more prospective studies are needed to explore the effect of psychological stress on FHA.

PCOS is a prevalent endocrine disorder in patients of reproductive age, characterized by systemic metabolic issue and disruptions in neuroendocrine-immune function (64). Patients with PCOS are at a higher risk of developing cardiovascular risk factors and associated insulin resistance, dyslipidemia and diabetes (65). Patients with PCOS also face an elevated likelihood of mood and anxiety disorders (17,66,67). There is a notable prevalence of psychiatric issues among patients with PCOS, including depression (26-40%), anxiety (11.6%) and binge-eating (23.3%) (17), indicating a potential role of psychological factors in pathophysiology of PCOS. Psychological aspects have been identified as a notable risk factor for PCOS (68) and emotional distress potentially stems from psychosocial and/or pathophysiological origins (66). Moreover, patients with PCOS may perceive symptom such as hirsutism and acne or potential outcomes such as infertility and obesity as stigmatizing, leading to distress and potentially exacerbating progression of the disease (67). However, as meta-analysis has indicated, few studies have focused on the effect of psychological stress on disease and PCOS (17).

The HPA axis serves a key role in the functioning of the neuroendocrine system, overseeing responses to stress and managing bodily functions such as digestion, immunity, mood, sexual behavior and energy regulation (68). Activation of the HPA axis impacts ovarian function by boosting the levels of cortisol and CRH. Additionally, it can suppress release of gonadotropins, such as FSH and LH, thereby affecting synthesis of steroid hormones, ovulation and menstrual cycle (155). Previous research has indicated that the surge in cortisol and CRH resulting from HPA axis activation, along with the inhibition of the HPO axis, are key factors in impairing ovarian function (156).

In a CRS model, activation of the HPA axis results in impaired oocyte developmental potential and decreased fertility (21,93-95). Previous studies indicated that patients undergoing IVF experienced higher levels of state anxiety and serum cortisol (39,157). Additionally, patients with high anticipatory state anxiety and cortisol concentrations have lower pregnancy rates (158), supporting the link between HPA axis activation and decreased fertility. However, a cross-sectional study of 89 infertile patients revealed that increased perceived mental stress is an independent predictor of increasing FSH levels (β=0.22, P=0.045) and likelihood for DOR (OR=9.97, 95%CI, 1.66, 55.99, P=0.012), but there was no significant difference in serum cortisol levels between patients with DOR and normal OR (r=−0.176, P=0.287), which suggests that serum cortisol levels, representing current stress, may not significantly be associated with ovarian reserve or infertility (159). In direct exposure studies, mouse oocytes exposed to physiological or stress-induced levels of cortisol during in vitro maturation did not show any impact on nuclear maturation or embryo development (94,160). Conversely, injection of cortisol into female mice resulted in impaired oocyte development, decreased mitochondrial membrane potential and increased oxidative stress and granulosa cell apoptosis through activating the TNF-α system (128). These effects may be linked to decreased expression of insulin-like growth factor 1 (IGF-1) and BDNF in granulosa cells and decreased FasL/Fas secretion in ovaries and oocytes (161). The differing impacts of cortisol in vivo and in vitro may be attributed to the indirect influence of cortisol on oocytes via the NEM network. In rats, exposure to CRS leads to increased expression of hypothalamic RFamide-related peptide-3 (RFRP3) and levels of circulating corticosterone, resulting in decreased HPG axis function (95). However, following a complete estrous cycle, female rats exhibit decreased inclination towards mating; the stress-induced reproductive dysfunction in female rats is alleviated by suppressing RFRP3 expression using a cytomegalovirus promoter-driven lentivirus vector. This indicates that elevated levels of RFRP3 under stress may have enduring detrimental impacts on fertility (95).

During stress, the hypothalamus produces a neuropeptide known as CRH, which serves a vital role in the regulation of ovarian functions, as its receptors have been identified in reproductive organs, including ovary, uterus and placenta (162). Previous research has shown that CRH is responsible for activation of primordial follicles in cultured newborn mouse ovaries in vitro (21). Furthermore, CRS could result in a decrease in oocyte competence and an increase in both CRH and CRH receptor (CRH-R) expression in the ovary (97). Co-culturing mouse granulosa cells with CRH activates the Fas/FasL and TNF-α systems, leading to heightened apoptosis of granulosa cells and oocytes, as well as impaired early embryonic development (97,103). CRH-R antagonists such as antalarmin are effective in inhibiting these damaging effects (97). In another study, injection of CRH in female rats for 12 days post-mating resulted in a 40% disruption in pregnancy (163). These findings suggest that CRH negatively impacts reproductive function.

Stress-induced activation of the HPA axis results in increased levels of glucocorticoids in the bloodstream, along with disrupted functioning of the HPO axis and ovarian cycle. In female mice, chronic stress reduces the synthesis and release of LH mediated by GnRH (164). One explanation for decreased LH secretion may be the elevated levels of cortisol due to stress. A previous study on mice exposed to long-term corticosterone demonstrated a notable decrease in LH levels, accompanied by alteration in neuronal activity in the pituitary gonadotroph cells (165). CRS in rats inhibits the preovulatory LH surge (166), while CUS has been shown to raise cortisol levels and SOD activity (87), both of which impact ovulation. Moreover, patients diagnosed with FHA exhibit high activation of the HPA axis, indicated by increased levels of cortisol in the blood (167). Furthermore, patients with FHA who experience spontaneous recovery of ovarian function show lower serum cortisol levels post-recovery compared with those who do not recover from FHA (168).

Ovarian function is regulated by the autonomic nervous system, which cooperates with the HPO axis (169). Sympathetic fibers from the celiac ganglia extend to ovarian follicles, mainly targeting the theca layer, where NE, the principal neurotransmitter, interacts with β-adrenergic receptors situated in the theca and granulosa cells (170-172). Neural and hormonal signals integrate to control steroid production and development of ovarian follicles (173). Notably, during stressful conditions, excessive activation of the SAM axis disrupts this equilibrium, leading to compromised ovarian function (174).

Previous research on rats has shown that normal aging process is associated with elevated NE levels and increased sympathetic activity within the ovary (175), implying that SAM axis activation promotes ovarian aging. Chronic exposure to cold stress activates the sympathetic nervous system, causing prolonged estrous cycle, decreased levels of estrogen and progesterone and corpus luteum count and heightened follicular atresia in rats (114,115,117,176).

Surgical denervation of the ovary and blocking the β-adrenergic receptor using propranolol decrease ovarian sympathetic activity, leading to a decrease in ovarian kisspeptin (KISS1) and an increase in FSH receptor (FSHR) expression. This may enhance follicle growth, suggesting activation of the SAM axis could hinder ovarian function by elevating ovarian KISS1 levels (177). NE is detected in human follicular fluid (178). However, physiological levels of NE are unable to trigger NE receptor activation but can induce the generation of ROS in granulosa cells (178). In vitro, rat granulosa cells display increased apoptosis upon co-culture with NE (179). Furthermore, following recovery from cold stress model, rats exhibited sustained elevated levels of ovarian NE, disrupted estrous cycle and reduced fertility, indicating that SAM axis activation may have lasting impacts on ovarian function in rats (111).

Data from population studies also corroborate the harm caused by SAM axis activation on ovarian function (12,58,180,181). A previous population-based study including 274 patients showed significant decreases in the likelihood of conceiving during the fertile window in the first cycle of attempting pregnancy for patients with high SAA levels compared with those with low levels (fecundability odds ratio, FOR=0.85, 95%CI, 0.67, 1.09) (12). Although SAA is a marker for stress and SAM activity, these findings support the idea that stress impacts female fertility through the SAM pathway (12). Similarly, a study on 401 patients found that those in the top tertile for SAA levels had a 29% decrease in fecundity (longer time to pregnancy) compared with those in the bottom tertile (FOR=0.71, 95%CI, 1.04, 4.11), and this decrease in fecundity leads to an increased risk of infertility (Relative Risk, RR=2.07, 95%CI=1.04, 4.11) (181). Aside from its potential impact on fertility rates, SAM axis activation may also influence OR. A study on 576 infertile patients found that higher levels of SAA were linked to lower serum AMH (r=−0.315; adjusted r=−0.336, both P<0.0001) (58). Another population study involving 107 patients revealed that follicular NE levels had a negative association with proportion of good quality embryos (r=−0.62, P<0.05) but not with clinical pregnancy rates (180).

The activation of stress-associated neuroendocrine systems plays a key role in maintaining body equilibrium, yet excessive stress can disrupt homeostasis (148). Previous studies indicate that life stress poses a risk and has prognostic implications for metabolic conditions such as obesity, T2DM and metabolic syndrome (3,182). Moreover, involvement of the HPA and SAM axes due to mental stress is linked to increased metabolic disorder (183,184). Notably, patients with metabolic syndrome or T2DM exhibit lower OR compared with healthy counterparts (185,186), highlighting the connection between stress, metabolic disorder and ovarian function.

Previous research suggests that stressors such as stressful life events, emotional distress, anger, poor sleep and work stress disrupt glucose balance and promote insulin resistance (187). As a result, these stressors are considered independent risk factors for T2DM (188,189) and individuals experiencing chronic stress are at a higher risk of developing T2DM compared with non-stressed individuals (190). T2DM is a chronic metabolic disorder characterized by hyperglycemia and insulin resistance, both of which may contribute to ovarian dysfunction (191,192).

As reviewed by Dri et al (193), granulosa, theca and stromal compartments of the ovary express insulin receptors, which bind to insulin and IGF-1, dysregulating dynamics of OR and/or impairing the survival and competence of the oocytes. Previous studies in vitro have demonstrated that insulin can stimulate these receptors in granulosa and theca cells, resulting in elevated levels of androgen, estrogen and progesterone (194-196). Prolonged stress and insulin resistance can lead to reduced β-cell function, necessitating exogenous insulin administration (197). Chronic exposure to high systemic insulin levels stimulates ovarian insulin and IGF-1 receptors, resulting in follicle stimulation and increased production of ovarian androgens (198). Persistent hyperglycemia can negatively impact folliculogenesis and ovarian function, potentially via advanced glycation end-products (AGEs) and their receptors (191,199). AGEs decrease oocyte developmental competence and vascularization, induce hypoxia and decrease glucose uptake (200). Insulin resistance can also disrupt ovulation by impeding recruitment of dominant follicles, leading to anovulatory states and menstrual irregularity (201). Moreover, in T1DM, folliculogenesis, oogenesis and embryo development are impaired in mice (202), but the underlying mechanism needs to be further investigated.

Previous population studies have indicated an association between abnormal glucose metabolism, insulin resistance and ovarian function (173-180). The incidence of oligomenorrhea is notably higher in patients with T2DM compared with those with normal blood glucose levels (203,204). Additionally, Study of Women's Health Across the Nation Bone, a longitudinal and ethnically diverse research project (n=2,171), observed that patients with diabetes at the start of the study reached menopause ~3 years sooner than non-diabetic counterparts (P=0.002) (205). Similarly, Sekhar et al (206) reported that the mean age of menopause is lower in patients with T2DM (44.65 years) compared with those without T2DM (48.2 years; P<0.01). A retrospective cohort study by Qin et al (207) found that patients with T2DM had significantly decreased AMH levels (2.43±2.31 vs. 3.58±2.58 μg/l, P<0.001), and T2DM was an independent risk factor for clinical pregnancy rate (adjusted OR=0.458, adjusted 95% CI, 0.235, 0.891, P=0.022) and live birth rate (adjusted OR=0.227, adjusted 95%CI, 0.101, 0.513, P<0.001). Furthermore, early menopause (onset at <45 years of age) was found to be more prevalent among patients with T2DM compared with those without T2DM (206). Decreased estrogen secretion post-menopause can increase visceral fat deposition and insulin resistance, significantly elevating risk of T2DM (208), and hormone replacement therapy has been shown to mitigate this risk (209,210). Similarly, decreased insulin sensitivity and impaired glucose metabolism are observed in animal models that underwent ovariectomy, but these effects are reversed by chronic estrogen administration (211,212). These findings highlight the key role of estrogens in maintaining glucose homeostasis. Consequently, stress-induced impaired glucose metabolism may lead to ovarian dysfunction, which can cause further abnormal glucose metabolism.

In summary, stress-induced abnormal glucose metabolism has detrimental effects on ovarian function throughout the reproductive lifecycle. However, more animal studies and cohort studies are required to elucidate the interplay between these factors.

Obesity has emerged as a growing health crisis with notable repercussions for public health. In recent years, accumulating evidence indicated that stress, notably increased levels of cortisol, plays a crucial role in the onset of obesity (213-216). Chronic stress activates the HPA axis, which results in elevated circulating cortisol levels. This causes the redistribution of white adipose tissue towards the abdominal area, and also increases appetite, particularly for calorie-dense foods (217). Notably, the obesity epidemic coincides with factors such as elevated cortisol production, prolonged stress, consumption of high glycemic index foods and poor sleep quality (3). The Prospective Urban and Rural Epidemiological study involving 120,000 individuals found that participants with higher life stress scores (encompassing work, family and financial stress and major life events) exhibited a higher prevalence of abdominal obesity compared with those with lower life stress (218). Moreover, in elderly female patients, central obesity becomes common due to redistribution of adipose tissue associated with aging (219). Similar patterns observed in fat redistribution due to chronic stress and aging in female patients suggest a potential connection between these factors (220). Recent studies increasingly highlight that obesity is associated not only with stress but also with diminished ovarian function (221-223).

Population-based studies have demonstrated an inverse association between obesity and OR (186-192). A cross-sectional study on 36 healthy patients aged 40-52 years showed that AMH and inhibin levels of obese patients were reduced by 77 (0.06, 95%CI, 0.12, 0.67 vs. 0.02 ng/ml, 95%CI, 0.12, 0.67, P=0.02) and 24% (12.5, 95%CI, 10.1, 15.4 ng/ml vs. 9.5 ng/ml, 95% CI, 8.0, 11.3, P=0.08), respectively, compared with normal-weight patients after adjusting for age, body mass index (BMI), race, smoking status and alcohol use (224). In a previous study involving 1,654 African American patients aged 23-35 years, it was observed that obese participants exhibited 23.7% lower AMH concentration (2.9 vs. 3.8 ng/ml) compared with those with a BMI ≤25 kg/m² (225). This finding has been corroborated by several other research studies (226-228). Additionally, obesity is linked to anovulatory cycles, irregular menstrual period and, diminished implantation and pregnancy rate and it may also be associated with PCOS (229,230). Research on the effects of a high-fat diet (HFD) on ovarian follicular development has indicated a decrease in number of primordial follicles (231). Exposure to HFD results in follicular atresia, and accelerated follicle loss in rats via the activation of mTOR and the inhibition of sirtuin 1 (SIRT1) signaling, leading to premature ovarian failure (POF) (232). Previous studies on diet-induced obesity in mice reveal increased oocyte apoptosis (233), the presence of multiple spindles (double spindles) (234) and oocyte mitochondrial dysfunction such as decreased mitochondrial membrane potential, mitochondrial distribution and ATP levels (235). These findings are supported by population studies: For example, Machtinger et al (236) found that severe obesity is associated with a higher incidence of spindle anomalies in failed fertilized oocytes, with observations of double spindles (OR=2.68, 95%CI, 1.39-5.15, P=0.003) and disorganized single spindles (OR=4.58, 95%CI, 1.05-19.86, P=0.04). A recent study reported that an increase in BMI was negatively associated with OR measured by AMH levels in patients with PCOS (β=−0.03, 95%CI, −0.06-0.00, P=0.034) (237). Although direct evidence linking stress-induced obesity with impaired ovarian function is lacking, the aforementioned indirect evidence supports this connection.

Sleep disorder caused by mental stress are widely hypothesized to be associated with infertility and ovarian dysfunction (238-240). Previous studies on animals have indicated that sleep deprivation (SD) disrupts the regularity of the estrous cycle and results in anovulation, potentially leading to reproductive dysfunction (241,242). Negative effects of SD may impede follicular development during ovarian hyperstimulation due to an increase in corticosterone levels in rats (243). SD has been shown to significantly elevate serotonin levels, which decreases estradiol production induced by FSH and FSH-driven expression of StAR protein in follicles, resulting in decreased estrogen levels in the bloodstream (244). This is also supported by population-based research: A large-scale prospective cohort study that monitored 80,840 patients from the Nurses' Health Study between 1991 and 2013 discovered that working rotating night shifts for 2 or >10 years is associated with earlier onset of menopause (245).

Melatonin secretion decreases with age, which serves a crucial role in regulating sleep and metabolic balance, with its lipophilic nature giving it potent antioxidant properties (246). Melatonin is a key player in combating aging by protecting cells from oxidative damage, a process exacerbated by the natural decline in melatonin levels over time (247,248). Previous findings linked CUS to increased ovarian ROS levels, with ROS-induced oxidative stress being a notable contributor to ovarian damage and aging (85). Previous studies have demonstrated that melatonin safeguards mouse ovarian granulosa cells by mitigating oxidative stress-induced DNA damage, mitochondrial dysfunction, lipid peroxidation and apoptosis (249), which are associated with the SIRT1/FOXO1 and FOS pathways (249-252). Moreover, melatonin improves oocyte quality by neutralizing ROS generated during follicle maturation and ovulation and fertilization via NADPH, glutathione (GSH), bone Morphogenetic Protein 15 (BMP15) and SIRT1/SOD2-associated mechanisms (253-256). On the other hand, melatonin supplements also significantly alleviated spindle/chromosome disorganization, which may involve the SIRT2-dependent H4K16 deacetylation pathway (257,258). Clinical trials have indicated that melatonin treatment in infertile patients can elevate follicular melatonin levels, reduce oxidative damage and enhance fertilization and pregnancy rates (253,257,259). Importantly, decreased melatonin secretion has been linked to a higher risk of diabetes (260), underscoring the association between melatonin levels, metabolic health and ovarian function.

The likelihood of depression, anxiety and distress is notably high among patients experiencing infertility and psychological symptoms adversely affect fertility (261). Additionally, onset of depression often occurs before the diagnosis of POI, implying that depression and/or its treatment may contribute to development of POI (15).

The effectiveness of psychological interventions in decreasing psychological distress and association with significant increases in pregnancy rates has been shown (5). After receiving antidepressant medication and psychotherapy, infertile patients with depression have higher pregnancy rates (262). Patients with POF/POI may benefit from psychological interventions, as emotional and other menopausal symptoms may be prolonged and not always alleviated by hormone therapy (15). Stress management and psychological therapy have been linked to spontaneous pregnancy in certain infertile couples. Multiple studies have documented cases of infertile couples conceiving naturally after adopting a child (263,264). The aforementioned data suggests that psychological interventions may be a promising approach for these individuals to enhance quality of life.

CBT can help patients alleviate stress and achieve relaxation by identifying and analyzing problems, recognizing unproductive thoughts and behaviors, creating and implementing replacement thoughts and behaviors, regular review and adjustment of strategies, and applying learned skills to daily life (265). CBT has been demonstrated to be an effective approach in treating depressive disorder, with meta-analyses of randomized controlled trials corroborating its efficacy for both anxiety (266-268) and depression (269,270).

A randomized controlled trial involving 56 pregnant patients with a history of primary infertility indicated that CBT counseling alleviates perceived stress, and anxiety, as well as enhancing the quality of life score (271). Domar et al (272) showed that infertile patients assigned to either structured CBT or standard support groups had a higher pregnancy rate (52 vs. 20%, P=0.05), compared with those who did not participate in these programs during their second IVF cycle; however, P-value decreased slightly to 0.038 after adjusting for intracytoplasmic sperm injection (ICSI) through logistic regression. Mean stress scores after CBT treatment in infertile patients were significantly decreased compared with before (2.7±0.62 vs. 3.5±0.62; P<0.05) (273), which was confirmed by a previous web-based CBT study (274). Researchers have identified CBT as an effective treatment for enhancing the quality of life (vasomotor symptoms, physical, psychosocial, sexual and total domain) of perimenopausal patients (275-280). A randomized controlled trial conducted with 50 patients with POI revealed mean scores of stress [adjusted mean difference (AMD), −10.97; 95%CI, −11.64, −10.29; P<0.001], state anxiety (AMD, −14.76; 95%CI, −15.77, −13.74; P<0.001), trait anxiety (AMD, −14.41; 95%CI, −15.47, −13.74; P<0.001) and depression (AMD, −7.44; 95%CI, −8.41, −6.46; P<0.001) were significantly lower in the CBT group compared with control group receiving routine care (281), suggesting healthcare providers should employ this method to enhance mental health in these patients.

A study allocated 16 patients with FHA equally to CBT group or an observation group for 20 weeks; 6/8 patients in the CBT group experienced recovery of ovarian activity compared with 2/88 in the observation group (87.5 vs. 25.0%, χ²=7.14) (282). Besides promoting ovulation, CBT has also been shown to lower cortisol levels in patients with FHA (283). CBT not only reinstates ovarian function but also impacts metabolic processes (284). A pilot study on 12 adolescents with PCOS demonstrated that CBT notably decreases weight (104±26 vs. 93±18 kg, P<0.05) and improves depression score (17±3 vs. 9.6±2, P<0.01) (285). Another study involving 15 overweight/obese adolescents with PCOS revealed that weekly CBT + lifestyle modification sessions (LS) for 8 weeks significantly led to weight loss, enhanced quality of life and reduced depressive symptoms compared with those only receiving LS intervention (286).

MBSR, a strategy of lessening stress and anxiety through meditation, breathwork and body awareness, is a methodical mindfulness meditation plan that is progressively accessible in medical and healthcare environments to boost mental health and general wellbeing (287). MBSR has been demonstrated to decrease mental suffering and enhance life quality in patients with cancer, heart disease and depressions (288,289).

Individuals diagnosed with POF or POI often experience prolonged mood disturbance and other menopausal symptoms that may not be effectively alleviated by hormone therapy (15), indicating that MBSR may offer potential benefits. A randomized controlled trial including 197 symptomatic peri- and postmenopausal patients found that both MBSR and menopause education control (MEC) decreases total Greene Climacteric Scale score and symptom score reduction of anxiety and depression is significant in the MBSR compared with the MEC group (anxiety, 5.97±2.49 vs. 6.97±2.57, P=0.07; depression, 4.78±2.60 vs. 5.39±2.41, P=0.031) (290). In patients with POI, mindfulness practices have been shown to decrease scores of menopause-specific quality of life (compared with baseline, 48.32±4.96 vs. 95.6±9.77, P<0.0001; compared with control, 48.32±4.96 vs. 102.6±14.9, P<0.0001) and the frequency of hot flushes (6.74±6.34 vs. 23.4±13.9, P<0.0001) (291). MBSR improves emotional wellbeing and biological outcomes in infertile patients (292-294).

Previous research has shown that music therapy has the potential to decrease stress, improve quality of life and alleviate depression and anxiety (295). In a randomized-controlled study of 48 postmenopausal patients, music therapy significantly decreased BDI score (11.81±8.62 vs. 16.44±6.09, P=0.031) compared with control and the Menopause Rating Scale (MRS) total and sub-scale scores were significantly decreased when comparing before and after intervention (296).

In a study of 40 patients with perimenopause syndrome, music therapy was more likely to improve psychological and emotional symptoms compared with CBT (MRS total, 9.2 vs. 3.5, P=0.008; MRS-psychological, 6.5 vs. 0.9, P=0.004; Patient Health Questionnaire 9 score, 4.3 vs. 1.6, P=0.009) (297). A comprehensive meta-analysis indicated that music therapy decreases the anxiety (MD=−3.09, 95%CI, −5.57, −0.61, P=0.01) and pain score (MD=−2.93, 95%CI, −3.86, −2.00, P<0.0001) and increased the satisfaction score (MD=1.51, 95%CI, 0.40, 2.61, P=0.008) in infertile patients undergoing ART (298). While music therapy increases the clinical pregnancy rates, the difference is not statistically significant (RR=1.08, 95%CI, 0.94, 1.26, P=0.28) (298,299).

Alongside seeking advice from professional psychologists, individuals may opt for self-care. An evaluation of 166 patients undergoing first-time IVF through a randomized controlled prospective study, examining the effectiveness of a cognitive coping and relaxation intervention (CCRI) that could be self-administered indicated that patients who engaged in the CCRI demonstrated enhanced positive reappraisal coping, better Fertility Quality of Life score and reduced levels of anxiety (300). Another randomized controlled prospective pilot study explored the impact of an online version of the mind/body program (301), where patients assigned to the intervention group showed significant decreases in anxiety and depression, along with an increased likelihood of pregnancy.

Yoga has been shown to be a beneficial intervention for anxiety and depression, stress reduction and enhancement of the overall wellbeing among the general public (302). Furthermore, yoga can alleviate anxiety and depression in individuals undergoing IVF treatment and increase the ART success rate (303). Yoga can enhance the quality of life in relation to infertility, with a specific focus on diminishing adverse emotions and cognition linked to infertility (304). A separate study investigating yoga as a complementary approach for patients receiving IVF treatment yielded comparable results (305). Yoga alleviates the menopausal symptoms, anxiety and depression of menopausal patients and decreases the levels of FSH and LH (306,307).

Frederiksen et al (308) assessed advantages of expressive writing for individuals with from infertility; male and female patients exhibited a noticeable decrease in depressive symptoms. In addition, adhering to a balanced diet, leading a healthy lifestyle and managing work-life balance are potential strategies to alleviate stress and safeguard ovarian function (309).

As aforementioned, the activation of stress-associated neuroendocrine systems causes metabolic imbalance in the body, and metabolic disorders lead to ovary dysfunction.

CR refers to a reduction in calorie consumption without eliminating essential nutrients (310). CR is hypothesized to extend the lifespan of rodents, yeast, worms, flies and primates by decreasing body weight and slowing aging process (311). CR has been shown to mitigate age-associated diseases such as neurodegeneration, hepatic steatosis and T2DM (312).

Notably, recent studies have shown that CR can protect ovarian function. CR decreases aneuploidy, chromosomal misalignment and meiotic spindle abnormality in oocytes in aged mice (313-315). CR can attenuate aging-associated decrease in chromosomal cohesion and protect the normal progress of meiosis (315). CR enhances ovarian estrogen sensitivity and inhibits ovulation, thereby extending reproductive lifespan (316,317). CR can also reduce primordial follicle activation and lead to increased ovarian Forkhead box O3 (Foxo3a) expression, activation of the SIRT1 signaling pathway and suppression of the mTOR signaling pathway, which may increase preservation of the ovarian primordial follicular reserve and delay menopause onset (318-322).

Obesity impairs ovarian function and obese patients are often encouraged to lose weight before conception to increase the chances of a successful pregnancy (323). However, the protective effect of CR on ovarian function lacks large-scale multicenter clinical trials and CR is a long-term dietary adjustment process that is difficult to maintain (324). Recently, there has been considerable interest in identifying drugs that can mimic the effects of CR. CR mimetics (CRMs) promote lifespan and sustain the health benefits of CR without requiring dietary restriction (325-329). CRMs have good clinical prospects because they do not require long-term dietary restriction and have better patient compliance.

Metformin is a widely prescribed medication for management of T2DM (330) that reduces blood glucose by decreasing glucose absorption, enhancing peripheral glucose uptake and increasing insulin sensitivity (331). Metformin can decrease the risk of all-cause mortality and cardiovascular death in patients with T2DM (332). Moreover, metformin is also known for anti-aging (333) and anticancer (334) effects.

Metformin has been demonstrated to increase OR and protect ovarian function through regulatory mechanisms such as inhibiting the mTOR pathway, enhancing SIRT1 expression and decreasing oxidative stress damage (335,336). Furthermore, in aged mice, metformin decreases mitochondrial ROS via SIRT3-mediated acetylation of SOD2K68 in oocytes (337). For chemotherapy-induced ovarian damage, metformin may attenuate carboplatin-induced ovarian damage, potentially through its antioxidative effects (338). In addition, metformin decreases aging-related ovarian fibrosis. Metformin-responsive macrophage subpopulations appear in aged mice treated with metformin, which may decrease ovarian fibrosis by clearing fibroblasts that produce the senescence-associated secretory phenotype in aged ovaries (339). Therefore, metformin may serve as a promising drug to protect reproductive function.

Resveratrol is a derivative of stilbene produced by >70 species of plants (340) in response to external adverse stimuli. Resveratrol has multiple protective effects in mammal models of T2DM, metabolic syndrome, cancer and neurodegenerative and cardiovascular diseases (341). For example, resveratrol increases SIRT1 levels and improves insulin resistance in a HFD rat model, indicating resveratrol has the potential to combat insulin resistance and maintain glucose metabolism homeostasis (342). Furthermore, resveratrol induces a CR-like transcriptional signature in mice and mimics metabolic changes of human CR (343).

In humans, resveratrol can improve the follicular microenvironment to improve IVF outcomes (344). Intraperitoneal injection of resveratrol during superovulation improves oocyte quality in both young and old mice, and increased the number of oocytes retrieved from old mice (345). Resveratrol improves fertility of reproductive age female mice, which may be achieved by activating SIRT1 and increasing the expression of Foxo3a (346-349). In vitro, resveratrol increased first polar body emission rates and improves oocyte mitochondrial function (350-352). In vitro, resveratrol protects granulosa cells by activating autophagy to resist oxidative stress (353,354). In conclusion, resveratrol is beneficial to ovarian function and protects oocytes.