Connecting the dots: the role of fatigue in female infertility

Infertility is a condition characterized by the inability of a woman to conceive after a year of regular, unprotected intercourse. It poses a significant global health concern, affecting approximately 15% of couples worldwide, with female factors alone accounting for at least 35% [ 1– 3]. Beyond the physiological challenges, long-term infertil - ity can lead to emotional distress, strained relationships, and societal stigma, impacting the overall well-being of couples aspiring to have children [4]. Fatigue, commonly described as extreme tiredness, diminished energy, and reduced physical and mental capacity, is a prevalent symptom in various chronic con - ditions [ 5]. While there is no consensus definition, and it overlaps with factors such as chronic pain, physical exertion, sleep disorders, and psychological stress [ 6, 7]. Under the bio-psycho-social medical model, the concept Reproductive Biology and Endocrinology †Wenzhu Li, Xiaoyan Huang and Yiqiu Wei contributed equally to this work and share first authorship. *Correspondence: Tailang Yin [email protected] Lianghui Diao [email protected] 1Reproductive Medical Center, Renmin Hospital of Wuhan University and Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan 430060, China 2Department of Rheumatology, The University of Hong Kong- Shenzhen Hospital, Shenzhen 518053, China 3Shenzhen Key Laboratory of Reproductive Immunology for Peri- implantation, Shenzhen Zhongshan Institute for Reproductive Medicine and Genetics, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), Shenzhen 518045, China 4Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri- implantation, Shenzhen 518045, China

Fatigue, an increasingly acknowledged symptom in various chronic diseases, has garnered heightened attention, during the medical era of bio-psycho-social model. Its persistence not only significantly compromises an individual’s quality of life but also correlates with chronic organ damage. Surprisingly, the intricate relationship between fatigue and female reproductive health, specifically infertility, remains largely unexplored. Our exploration into the existing body of evidence establishes a compelling link between fatigue with uterine and ovarian diseases, as well as conditions associated with infertility, such as rheumatism. This observation suggests a potentially pivotal role of fatigue in influencing overall female fertility. Furthermore, we propose a hypothetical mechanism elucidating the impact of fatigue on infertility from multiple perspectives, postulating that neuroendocrine, neurotransmitter, inflammatory immune, and mitochondrial dysfunction resulting from fatigue and its co-factors may further contribute to endocrine disorders, menstrual irregularities, and sexual dysfunction, ultimately leading to infertility. In addition to providing this comprehensive theoretical framework, we summarize anti-fatigue strategies and accentuate current knowledge gaps. By doing so, our aim is to offer novel insights, stimulate further research, and advance our understanding of the crucial interplay between fatigue and female reproductive health.

Female infertility, Fatigue, Stress, HPA axis, Inflammation Connecting the dots: the role of fatigue in female infertility Wenzhu Li1†, Xiaoyan Huang2†, Yiqiu Wei1†, Tailang Yin1* and Lianghui Diao3,4* Page 2 of 13 Li et al. Reproductive Biology and Endocrinology (2024) 22:66 of “whole-person care” has been increasingly accepted and applied, and patient-reported outcomes (PROs) have received more attention in clinical research, with fatigue being an important indicator of disease [ 8– 10]. This phenomenon has also appeared in the field of gynecol - ogy, thus, we began to focus on the impact of fatigue on infertility. There is growing recognition of the potential link between fatigue and female infertility, but scientific evi - dence remains limited. Fatigue could impact fertility through complex mechanisms involving the neuroen - docrine system [ 11], inflammatory-immune response [12], energy metabolism, and oxidative stress [ 13]. Fur- thermore, the development of fatigue is associated with changes in neurotransmitter metabolism and neuronal plasticity [14]. These alterations, in turn, may affect cru - cial reproductive processes like ovulation, implantation, and embryonic development. What’s more, managing chronic fatigue can exact a significant emotional toll, potentially leading to stress, anxiety, and depression, which may further impact fertility through hormonal imbalances [ 15], disrupted menstrual cycles [ 16], and decreased sexual desire [17]. In this review, we aim to provide a comprehensive overview of the link between fatigue and female infertil - ity, delving into the potential mechanisms through which fatigue impacts reproductive health (Fig.  1). By connect - ing the dots between fatigue and factors closely tied to infertility, we endeavor to unveil the complex interac - tions and indirect effects of fatigue on female fertility. Our objective is to offer novel insights, stimulate further research, and propel the advancement of our comprehen- sion in this pivotal realm of female reproductive health for the benefit of graduate students in medicine and prac- ticing physicians. Epidemiology of fatigue Fatigue is a multifaceted symptom experienced by both healthy and unhealthy individuals, lacking a clear-cut definition. Self-reported scales are the primary measure - ment tools [ 18]. Current research suggests a key distin - guishing factor between healthy and disease-related fatigue is the inability to alleviate fatigue with rest [ 19]. Fatigue often occurs as a comorbidity alongside various psychophysical factors, such as anxiety, depression, and pain, as demonstrated by multivariate analyses [ 20– 26]. Therefore, exploring the influence of these co-factors on infertility is vital. Though not life-threatening, fatigue severely affects the quality of life (QoL) of infertile women [ 27]. Despite regional variations in reported incidence [ 28– 32], a recent meta-analysis estimated the global prevalence of general fatigue at 20.4% in adults and 11.7% in minors [33]. Studies from 2011 highlighted that 7–45% of the U.S. population experiences persistent fatigue [ 34]. A cross-sectional study involving 2063 individuals showed that over 50% of patients were troubled by fatigue in Saudi Arabia [ 35]. Importantly, women appear to be more susceptible to fatigue than men, with a pooled odds ratio [33]. Further, studies support that female sex may be an independent risk factor for persistent fatigue [28, 36]. Fatigue can manifest throughout a woman’s reproduc - tive life cycle, impacting sexual maturity, pregnancy, post-partum, and perimenopause. Postpartum fatigue is well-documented [ 37, 38], but there’s a paucity of research on fatigue in infertile women. However, fatigue in women of reproductive age, especially in infertile women, has only begun to be mentioned in recent years. Approximately 25–60% of infertile patients are reported to be disturbed by psychological factors, including anxi - ety and depression [ 39], but the prevalence of fatigue in infertility is understudied. An observational study showed that 52 out of 140 infertile women had self- reported fatigue, and the severity of fatigue negatively affected their QoL [ 40]. Similarly, a study involving 149 infertile patients showed that fatigue was the most influ - ential factor in the QoL of infertile women [ 41]. Taken together, more research is critically needed to address this gap. Current state-of-the-art of fatigue in female infertility Research on how fatigue directly impacts female infer - tility remains limited. However, fatigue is discussed for several chronic conditions affecting the uterus and ova - ries (Table  1). Additionally, emerging studies suggest that autoimmune diseases, characterized prominently by fatigue, may adversely affect female fertility. Overall, research on fatigue associated with infertility faces mul - tiple challenges and barriers. Fatigue in Uterine and Ovarian diseases Endometriosis Endometriosis (EMT), defined as the presence of endo - metriotic lesions outside the uterus, is a greatly disturb - ing gynecologic disease that affects about 10% of women of reproductive age [ 42]. As early as 2018, a multicenter cross-sectional study sponsored by Wright and his col - leagues found fatigue as a frequent symptom of EMT and was closely associated with insomnia, depression, pain, and occupational stress [ 43]. Subsequently, many observational studies have documented similar results [44]. Several evidence have indicated that the severity of EMT is associated with increased fatigue. A matched pair case-control study revealed that women with pain - ful endometriosis reported significantly greater fatigue than those without significant pain symptoms and con - trols [ 45]. Ashrafi et al. found fatigue to be a predic - tor of risk for EMT through multiple logistic regression Page 3 of 13 Li et al. Reproductive Biology and Endocrinology (2024) 22:66 [46]. EMT-related fatigue seriously undermines women’s sense of life well-being and even their relationships with partners [47]. A scale-based observational study in Spain emphasized that moderate to severe fatigue contributed to psychological impairment, such as higher anxiety and depression, poorer sleep quality, and lower sexual func - tion [48]. The above studies showed that fatigue is a com- mon, secondary symptom of EMT, and is related to other somatic and psychological impairments, ultimately sig - nificantly decreasing patients’ QoL and sexual function [49]. Polycystic ovary syndrome Polycystic ovary syndrome (PCOS) is the most common chronic endocrine disease characterized by menstrual dysfunction and ovulation disorders affecting 5–13% of women in the general population [ 50]. Studies have found that PCOS women often suffer from increased anxiety and depression, causing psychological fatigue and further impairing QoL [ 51, 52]. It is noted that patients with lower QoL parameters showed more worse marital sexual functioning [53]. A randomized clinical trial found that a psychological treatment named cognitive behav - ioral therapy (CBT) can significantly reduce the sever - ity of fatigue in PCOS patients compared to the control Fig. 1 Potential mechanisms by which fatigue influences female infertility. The relationship between fatigue and female infertility is under-recognized, and it has complex crosstalk with co-factors (for example, pain and depression) through the activation of in vivo stress-responsive systems (HPA-axis, neurotransmitter system) and inflammation stimulated by different stress signals, and then contributing to hormonal dysregulation, oxidative stress, and mitochondrial metabolic dysfunction, which may be an underlying mechanism that affects female infertility. The solid lines represent reported studies, and the dotted lines represent studies that need to be developed. Double arrows represent interconnections. HPA, hypothalamic-pituitary-adrenal; 5-HT, 5-hydroxytryptamine; ROS, reactive oxygen species Page 4 of 13 Li et al. Reproductive Biology and Endocrinology (2024) 22:66 group [51]. On the whole, fatigue almost goes unnoticed in patients with PCOS [54]. Premature Ovarian Insufficiency. Premature ovarian insufficiency (POI) develops the breakdown of ovarian function and menopause before the age of 40, affects about 1% of women, and is one of the main causes of female infertility [ 55]. A cross- sectional study showed fatigue was a highly prevalent symptom closely associated with menopause in the recruited Chinese women with POI [ 56]. A few cross- sectional studies supported that the POI group had a higher fatigue index than controls [ 56, 57]. In another study, POI patients were more likely to suffer from sleep disturbance and depression, but not fatigue compared to age-matched healthy individuals [ 58]. Similar results were also obtained in an earlier study on premature ovar- ian failure [ 59]. Thus, the available evidence on whether patients with POI are at higher risk for fatigue is hetero - geneous and needs to be studied extensively. Fatigue in Autoimmune diseases affecting fertility Autoimmune diseases are a large group of chronic dis - orders mediated by immune responses to self-antigens, such as rheumatoid arthritis (RA) [ 19], antiphospho - lipid syndrome [ 60], systemic lupus erythematosus [ 61], multiple sclerosis (MS) [ 62], autoimmune hypothyroid - ism [ 63]. A range of mental and somatic symptoms are present in these disorders, with fatigue being one of the most common and challenging symptoms to man - age [ 64]. Fatigue is often indicative of disease activity in these disorders [ 19], while disease activity raises the risk of adverse pregnancy outcomes, particularly mis - carriage [ 65– 67]. MS patients with fatigue had signifi - cantly higher levels of C-reactive protein (CRP) during pregnancy than those without fatigue, suggesting that Table 1 Characteristics of the Typical Studies Included in the Review Chronic Conditions Author Information Study Type/ Sample Size the Role of Fatigue Fatigue Measurement Endometriosis Facchin et al. 2021 [45] Matched pair case-control study (EMT, N = 123; Control, N = 123) Women with painful EMT reported significantly greater fatigue 5-point Likert scale Álvarez-Salvago et al. 2020 [49] Matched pair case-control study (EMT, N = 25; Control, N = 25) Women with higher endometriosis-related fatigue had a lower QoL. The Spanish ver- sion of the Piper Fatigue Scale Mundo-López et al. 2020 [48] Cross-sectional study (EMT, N = 230) One-third and one-half of the recruited patients with EMT showed moderate to severe fatigue, which is closely related to higher anxiety and depression, poorer sleep quality, lower sexual function, and so on by regression analysis. Piper Fatigue Scale Ramin-Wright et al. 2018 [43] Multi-center matched case- control study (EMT, N = 560; Control, N = 560) More women diagnosed with EMT experienced frequent fatigue than control women. Fatigue in EMT was associated with insomnia, depression, pain, and occupational stress by regression analysis. The self-admin- istered question- naire developed by endometriosis and psychosomat- ic specialists from the universities of Zurich and Berlin. Polycystic Ovary Syndrome Boivin et al. 2020 [52] NA 120(PCOS, N = 11; PCOS screen- positive, N = 25; PCOS screen- negative, N = 74) The PCOS-confirmed women scored more poorly than control groups on physical, emotional, social, and spiritual well-being indexs, like fatigue and depression. Fatigue Symptom Inventory Abdollahi et al. 2019 [51] Randomized controlled clinical trial (PCOS with CBT, N = 37; PCOS, N = 37) Cognitive-behavioral therapy (CBT) significantly reduced psychological fatigue in PCOS patients. The Fatigue Impact Scale Premature Ovar- ian Insufficiency Benetti-Pinto et al. 2019 [57] Cross-sectional study (POI with HT therapy, N = 61; Control, N = 62) The POI group had a higher fatigue index than controls. Chalder Fatigue Scale Huang et al. 2021 [56] Cross-sectional study (POI, N = 293; Control, N = 471) Fatigue is one of the 13 items of menopause. 168 of 293 women with POI suffered from fatigue (57.3%). The modified Kup- perman Meno- pausal Index Ates et al. 2022 [58] Matched pair study (POI, N = 62; Control, N = 62) Fatigue did not differ significantly between the groups Fatigue Severity Scale Premature Ovar- ian Failure Stege et al. 2008 [59] Case-control study (POF, N = 81; Control, N = 68) Fatigue did not differ significantly between the groups The Short- ened Fatigue Questionnaire Page 5 of 13 Li et al. Reproductive Biology and Endocrinology (2024) 22:66 higher CRP , an indicator of systemic inflammation, may be somewhat predictive of pregnancy-related comor - bidities [ 68]. A small single-center retrospective study revealed that more patients with MS underwent elective cesarean deliveries due to fatigue [ 69]. Additionally, the state of chronic fatigue directly impairs sexual function of women, which contributes significantly to the probabil - ity of fertility [17, 70], For instance, some studies showed sexual function in women with RA may be affected by pain and fatigue, potentially impacting fertility [ 71, 72]. Despite the shared occurrence of fatigue and female infertility in autoimmune diseases, high-quality research investigating the impact of fatigue on infertility in these conditions is needed. Challenges of Fatigue Research in female infertility The underrepresentation of fatigue research within female infertility remains a significant obstacle. This can be attributed to several factors: Subjective and difficult measurement The qualitative assessment of fatigue is relatively difficult and often subjective, and relies on the use of subjective self-report questionnaires [ 18, 73]. Moreover, experts in different fields may develop professional-specific ques - tionnaires [ 74, 75]. The lack of standardized fatigue measurement across studies, including variations in the specific scales, recall periods, and wording, makes it challenging to compare results and draw definitive conclusions. Focus on cross-sectional designs Most of the studies on fatigue and infertility utilizes cross-sectional designs [ 76– 78], which typically estab - lishes causality through multiple regression analysis. The cross-sectional designs limit the ability to establish clear cause-and-effect relationships. Potential confounding factors Difficulties in fatigue research also arise from potential confounders of fatigue, such as emotional distress and pain [19, 79], suggesting that fatigue is not a single symp - tom of infertility, but rather is accompanied by a number of psychological and physical symptoms [ 40]. It is para - mount to consider these interconnected factors to fully understand the complex relationship between fatigue and infertility. Putative mechanisms of fatigue on female infertility Longstanding fatigue serves as a catalyst for pathophysi - ologic changes in numerous systems and organs [ 11], posing detrimental effects on health [ 80], which may become the key force driving infertility. The pathogen - esis of fatigue, involves the central nervous system (CNS) and autonomic nervous system (ANS), immune and inflammation, mitochondrial oxidative stress [ 81– 83]. Simultaneously, the mechanisms of infertility are closely related to neuro-endocrine dysregulation, inflammatory and immune imbalances, and oxidative stress activation [62, 84]. It is clear that there are shared mechanisms for fatigue and infertility, which is worth exploring. Conse - quently, the forthcoming section presents evidence in support of a hypothesized mechanism illustrating overlap between fatigue and infertility. Neuroendocrine disruption and Hormonal Imbalance The CNS and endocrine system collaborate to maintain daily activities and keep up energy. Structural and func - tional dysfunctions in different regions of the brain may disrupt motor cortical excitability, hormone secretion, and the signal to the working muscles, which in turn cause fatigue [ 85, 86]. In particular, abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis have been identified as a cause of fatigue. Notably, adrenal hormone dysregulation, such as hypocortisolemia, is frequently found in fatigued individuals, representing one facet of the imbalance of the HPA axis [ 87]. For instance, one study found MS patients with fatigue had significantly higher pituitary heights and widths, along with increased secretion of adrenocorticotropic hormone compared to patients without fatigue. These findings suggest CNS and endocrine systems are involved in the pathogenesis of fatigue through sophisticated regulation of brain struc- ture and function [75]. More importantly, it is closely tied to maintaining reproductive function. First of all, gonadotrophin-releas - ing hormone (GnRH) from the hypothalamus, along with luteinizing hormone (LH) and follicle-stimulating hor - mone (FSH) from the pituitary gland, regulates follicular development and the ovarian cycle [88]. What’s more, the HPA axis has a direct inhibitory action on the hypotha - lamic-pituitary-ovarian axis in certain ways [ 15], impact- ing the cyclical patterns in central and ovarian hormones, including FSH, LH, E2, and P4. Besides, one early study found that uterine cortisol deficiency may mediate ele - vated levels of NK cells, which further impaired decidual- ization [89]. Dehydroepiandrosterone (DHEA), a kind of adrenal hormone, is linked to fatigue and turns out to be an important contributor to reproductive function [ 90]. DHEA deficiency can severely impact ovarian hormone synthesis and ovarian reserve, potentially leading to pre - mature ovarian insufficiency (POI) [91]. Supplementation with DHEA has demonstrated positive effects on preg - nancy rates, emphasizing its role in maintaining fertility [92– 95]. Beyond the HPA axis, hormonal changes asso - ciated with fatigue extend to estrogen, progesterone and thyroid hormone [96– 99]. Moreover, untreated maternal hypothyroidism is associated with adverse pregnancy Page 6 of 13 Li et al. Reproductive Biology and Endocrinology (2024) 22:66 outcomes such as miscarriage, preeclampsia, and many neonatal disorders [100]. In fact, although fatigue is a rather ill-defined physi - cal manifestation and the relationship with female infertility has not been directly studied, evidence of neu - roendocrine disruption and hormonal imbalance found in fatigue-related disorders supports their relevance to the maintenance of female fertility. Stress and nervous system response Perhaps, it is reasonable to suggest that fatigue and its co-factors can contribute to infertility via shared mech - anistic pathways. Organisms are required to respond and adapt adequately to ubiquitous stress in an ever- changing environment, such as viral infections, trauma, and adverse life events. In the first place, the onset of fatigue and its co-factors is regulated by the in-vivo stress response system [ 101, 102]. When subjected to internal and external stress, the biological stress response system immediately makes corresponding alterations, including the HPA axis and the ANS system, as well as the neuro - immune system [14, 103– 105]. Sustained stress may lead to maladaptive responses manifested as dysregulation of the above systems [ 106], which is specifically manifested as abnormal levels of serum catecholamines and gluco - corticoids and persistent low-grade inflammation based on findings such as microglial activation in the brain and increased pro-inflammatory cytokines in the periph - ery [ 107]. Moreover, stress and stress hormones inhibit the release of GnRH, and glucocorticoids suppress LH secretion [ 108]. These abnormal alterations may further disrupt ovarian steroidogenesis and exacerbate inflam - matory storms, ultimately being detrimental to female fertility. Anhedonia attributed to deficits in reward processing is a shared feature in many neuropsychiatric symptoms, including fatigue, depression, and chronic pain [ 62]. The processing ability of brain reward circuits is disrupted by inappropriate levels of monoaminergic neurotransmis - sion, mainly including serotonin (5-HT), norepinephrine, and dopamine with their degenerate mesocorticolimbic pathways from the midbrain to the basal ganglia, the lim- bic system, and the prefrontal cortex [ 62, 109, 110]. The lack of neurotransmitters, including 5-HT, can cause sex- ual dysfunction, thereby reducing fertility opportunities [15, 111]. Overall, hormonal imbalances and incorrect release of neurotransmitters caused by the nervous response sys - tem could result in infertility. Additionally, fatigue could reduce sexual desire and cause sexual dysfunction, ulti - mately declining the chance of pregnancy [48]. The above evidence suggests that fatigue mediate neurologic dys - regulation that can aggravate infertility. Low-grade inflammatory activation Of great interest, fatigue is common in chronic autoim - mune, inflammatory diseases [ 112, 113]. A recent cross- sectional study found elevating fatigue severity is closely linked to stronger signs of monocyte activation, includ - ing increased inflammatory gene expression in mono - cytes, higher CD8 + T-lymphocyte counts, and increased serum pro-inflammatory cytokines [ 114]. There is a strong correlation between fatigue severity and pro - duction of pro-inflammatory cytokines [ 19]. Women with fatigue often show multiple immune dysfunctions rendering them susceptible to upper respiratory tract infection, chronic lymphadenopathy, and high body tem - perature [ 115]. These dysregulations involve cell-medi - ated immunity, including impairment of the function of NK cells, hypo-reactivity of T cells to the antigen, the activation of monocyte macrophages, and the persistence of autoreactive cells [ 116]. Concurrently, they manifest as changes in many inflammation-related markers, such as increased CRP levels [ 68], elevation in pro-inflamma - tory factors like interleukin-1β, interleukin-6, interleu - kin-12, interleukin-2, tumor necrosis factor-alpha and interferon-gamma, increased expression of nuclear factor kappa-B, as well as decreased levels of anti-inflammatory factors like interleukin-8, interleukin-13, interleukin-15, and interleukin-23 [ 117]. The changes in inflammation- related profile support that patients experiencing fatigue are in a low-grade inflammatory state. In a word, inflam - matory activation is undoubtedly a key step in the onset of fatigue [118]. It was reported that the increased infertility rate in RA with fatigue symptoms is due to an imbalance of inflam - matory factors [ 72]. Indeed, the immune system serves as a crucial bridge connecting various systems within the organism, with cytokine and immune cells distributed in both in center and periphery systems. The homeostasis of immunity and inflammation is necessary to maintain a successful pregnancy. The imbalance of inflammatory factors and immune cell profiles is a notable phenom - enon in patients with adverse pregnancy history [ 119, 120]. Such abnormalities could significantly impact preg - nancy outcomes by damaging ovarian function [ 121], inhibiting endometrial receptivity [ 122], hindering tro - phoblast development, and interfering with immune tol - erance at the maternal-fetal interface [65]. In short, inflammation is one of the most common mechanisms underlying fatigue and is also a known con - tributor to infertility. Fatigue may indicate active inflam - mation that needs to be managed in the reproductive field. Mitochondrial dysfunction and Cellular stress Fatigue is defined as “a lack of energy” , indicating a close relationship with energy metabolism [ 13], which is Page 7 of 13 Li et al. Reproductive Biology and Endocrinology (2024) 22:66 manifested as impacted adenosine triphosphate produc - tion [ 123]. Mitochondria are core organelles that have existed in most cells since biological evolution. They pro- vide continuous energy for biological survival and func - tion, produce adenosine triphosphate and lactic acid, and maintain the production level of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the bal - ance of calcium and iron in cells, removing peroxides in time. Dysfunctional mitochondria can generate and release mitochondrial components, including cardio - lipin, mitochondrial DNA, and mitochondrial formylated peptides. These components, once released, can act as damage-associated molecular patterns, triggering an inflammatory response through the activation of pattern recognition receptors [ 124]. In addition, mitochondria play a rate-limiting role in controlling steroidogenesis, and mitochondrial impairment in neurons further affects the synthesis of neuroactive steroid hormones in the brain [ 125]. And the collapse of mitochondria at neu - ronal synapse impedes the release of neurotransmitters [126, 127]. In summary, loss of neuroendocrine-immune homeostasis due to mitochondrial disruption may par - tially explain infertility. Furthermore, mitochondria function as the primary origin of ROS/RNS as byproducts of nutrient metabo - lism. This occurrence is concomitant with various indica- tors of oxidative stress, including diminished activity of antioxidant enzymes such as superoxide dismutase and plasma-like glucose peroxidase, as well as reduced lev - els of zinc. Conversely, there is an elevation in the activ - ity of pro-oxidative enzymes like myeloperoxidase, along with increased levels of nitro-tyrosine and heightened nitric oxide production [ 118]. The heightened presence of ROS/RNS assumes a pivotal role in the manifestation of fatigue. A study demonstrated that the accumulation of ROS/RNS during exercise had a detrimental impact on Na+/K+- ATPase activity, calcium conversion and sensi - tivity in myofibrils, and actin-myosin dynamics. These effects collectively resulted in a reduction in the genera - tion of muscle energy, ultimately culminating in the onset of muscle fatigue [128]. Similarly, it has been proved that many experimental drugs with antioxidant properties can improve and alleviate chronic fatigue-like behaviors by changing ROS signaling pathways [ 129, 130]. How - ever, excessive oxidative stress could impair the female reproductive system by destroying oocyte quality [ 131, 132], damaging endometrial receptivity [ 133], promoting trophoblast apoptosis, medicating implantation failure, and early pregnancy loss [ 134]. Thereby, we believe mito- chondrial dysfunction and cellular stress, closely linked with fatigue, exert a profound influence on the func - tion of the reproductive system, but need to be further studied. Taken together, although explained from multiple perspectives, the current evidence is still insufficient to prove whether fatigue is a result or a predisposing fac - tor for female infertility. The above hypothesized mech - anisms regarding the impacts of fatigue on infertility perhaps only provide new viewpoints for researchers in the future. The potential benefits of fatigue management on infertility Given the potential connection between fatigue and infertility, it’s reasonable to consider whether fatigue management could benefit those experiencing infertil - ity. An early intervention for fatigue is recommended, as a systematic review pointed out health risks associ - ated with fatigue can occur earlier than hospitalization, illness, and death [ 135]. Current treatments for fatigue include dietary supplement/nutritional interventions, medications, exercise, physical therapy, and psychologi - cal interventions [ 136– 140] (Fig.  2). Among them, some strategies have been reported to be beneficial for treating infertility, while others may be in favor of the health of female reproduction. Anti-inflammatory and antioxidant nutrients These nutrients, such as coenzyme Q10, L-carnitine, iron, zinc, methionine, nicotinamide adenine dinucleo - tide, and vitamins, help relieve fatigue [ 141– 143]. Some studies have shown that supplementation with iron can significantly improve fatigue in women of reproductive age, potentially contributing to achieving successful preg- nancy [ 144, 145]. Meanwhile, they belong to mitochon - dria-targeted nutrient therapy, which improves oxidative damage to ovarian and uterus. For instance, coenzyme Q10 is a key component of ATP production via oxidative phosphorylation, and improves mitochondrial membrane potential and superoxide levels, thereby rescuing ovarian reserve deficiency [ 146]. Zinc supplementation has been reported to significantly improve oocyte glutathione and mitochondrial activity, as well as reduce ROS levels, which facilitates oocyte maturation [ 147]. Vitamins have been shown to increase mitochondrial biosynthesis [148], and restore endocrine and metabolic homeostasis [ 149], which in turn improves follicular development and sub - sequent follicular quality in the PCOS model. Medications Some synthetic and natural drugs can combat fatigue. Glucocorticoids, relieve fatigue due to hypocortisolism and may improve ovarian function to treat infertility through regulating neuroendocrine function [ 150, 151]. Synbiotics, a bio-mixture of probiotics and nutrients, show potential in treating multiple symptoms of fatigue, including improving inflammation and stress responses mediated by the cytokine-HPA axis, along with mental Page 8 of 13 Li et al. Reproductive Biology and Endocrinology (2024) 22:66 and physical health [ 152], and enhance energy metabo - lism effectively [139]. Exercise and Physical Therapy In addition to medication, exercise rehabilitation is used to reduce fatigue. A recent meta-analysis found that physical therapy was efficacious and safe in reduc - ing fatigue in people with inflammatory rheumatic and musculoskeletal diseases [ 64]. It is believed that practic - ing yoga has a positive effect on reproductive organs and increases blood circulation [153]. Acupuncture treatment for infertile patients can regulate menstrual cycle and reduce fatigue, thus facilitating the process of ART cycles [154]. Psychological interventions Furthermore, psychological interventions, particularly CBT, are applied in the management of people with fatigue [ 155]. The psychological vulnerability screening and additional psychological consultation for infertile women are endorsed to mitigate these mixed symptoms that are not conducive to pregnancy, such as fatigue, depression, and anxiety [ 156]. A quasi-experimental study found psychological interventions significantly reduced depression and fatigue of infertility women, in turn, improved their intimacy and sexual satisfaction [157]. Two randomized controlled trials from Brunei found that Nursing care reduced depression and fatigue, and improved feelings of social support and sleep qual - ity among infertile women [ 158, 159]. It can be seen that psychotherapy is one of the recommended treatments for infertility patients. Herein, it is conceivable that measures to alleviate fatigue may be beneficial in treating infertility and improving reproductive outcomes. Current gaps and future perspectives The direct connection between fatigue and female infer - tility remains weak in evidence. Considering our pre - vious discussion, it is apparent that fatigue alone is not the singular determining factor in female infertility. Fig. 2 Strategies as well as mechanisms to alleviate fatigue. There are four main measures of fatigue alleviation: dietary supplements, medication, exercise and physical therapy, and psychological interventions. Relief of fatigue is achieved through anti-inflammatory, antioxidant, improved energy metabolism, and neurological modulation. The circular arrows indicate that the anti-fatigue mechanisms interact with each other and do not correspond to specific anti-fatigue measures Page 9 of 13 Li et al. Reproductive Biology and Endocrinology (2024) 22:66 Unfortunately, the current concept of fatigue is vague [160], and the diagnostic criteria are not unified [ 161]. In different studies, fatigue can serve as an experimen - tal concept, a symptom, a risk, a cause, and a result [ 6]. Moreover, the scales for assessing fatigue are varied [ 74, 75] and relatively subjective. There are three models for inducing fatigue, including exhaustive exercise-induced fatigue, and chemotherapy or radiotherapy-induced fatigue [162, 163]. These heterogeneities increase the dif- ficulty of conducting research, thus making it challenging to explore fatigue in female infertility. Unlike depression, fatigue is often a concomitant symptom and is not sub - jectively valued, despite its significant impact on women’s QoL and reproductive health. While anti-fatigue interventions might benefit female infertility, current studies lack thorough mechanistic exploration. The rational use of anti-fatigue approaches and their impact on female infertility and pregnancy out - comes need to be further investigated [139, 164]. In summary, the understanding of “fatigue” is weak when it comes to reproduction. Exploring the relation - ships between fatigue, female infertility, and adverse pregnancy outcomes is crucial, requiring more investiga - tion in clinical trials and basic research. In clinical trials, utilizing established fatigue assessment scales and com - prehensive recording of influencing factors are advised. Rigorous statistical methods, including machine learning and multivariate logistic regression, should be employed to analyze the relationship between fatigue and female infertility or pregnancy outcomes, under the premise of eliminating confounding factors. It is important to develop strict inclusion criteria for clinical populations with fatigue symptoms, implement subgroup analysis, and explore the benefits of fatigue management on fer - tility outcomes. Additionally, biomarker detection in blood and other humor, such as uterine fluid, may reveal insights into fatigue and pregnancy outcomes. In basic research, the use of well-established fatigue-related ani - mal models is essential to investigate their potential impacts on reproduction.

Fatigue, a perplexing and disabling symptom, has gained more recognition in the medical era of bio-psycho-social model amid heightened individual psychological stress. It is thought to arise from endocrine imbalance and neu - rotransmitter changes in the central nervous system, immune-inflammation disruption, mitochondrial dys - function, and excessive oxidative stress during viral infec- tions or social-environmental stress. It is closely linked to both psychological and somatic factors, indirectly affect - ing female infertility. Prolonged fatigue can significantly diminish women’s quality of life and reproductive health, yet public awareness and understanding of this issue remain limited. Our study highlights the associations between fatigue and several common chronic conditions, and proposes hypotheses regarding the impact of fatigue on female infertility with the hope of calling attention to the issue of fatigue in infertile women in alignment with the whole-life care concept and providing insights for future study in this topic. Abbreviations HPA Axis: Hypothalamic-Pituitary-Adrenal Axis QoL Quality of Life MS Multiple Sclerosis IVF In Vitro Fertilization EMT Endometriosis PCOS Polycystic Ovary Syndrome CBT Cognitive Behavioral Therapy POI Premature Ovarian Insufficiency CRP C-Reactive Protein GnRH Gonadotrophin-Releasing Hormone LH Luteinizing Hormone FSH Follicle-Stimulating Hormone NK cells Natural Killer Cells DHEA Dehydroepiandrosterone CNS Central Nervous System ANS Autonomic Nervous System 5-HT Serotonin ECS Endocannabinoid System ROS/RNS Reactive Oxygen Species/ Reactive Nitrogen Species RA Rheumatoid Arthritis

The authors thank Dr. Shaolin Liang and Mrs. Yuan Sheng (STI-Zhilian Research Institute for Innovation and Digital Health, Beijing, China) for optimizing the schema graph. Author contributions L.H.D. conceptualized the idea. T.L.Y. discussed and refined the framework. W.Z.L. drafted and revised the manuscript. X.Y.H. critically reviewed the manuscript with a focus on the autoimmune aspects. Y.Q.W. contributed to manuscript revision and language editing. All authors reviewed and approved the final manuscript. Funding The writing of this review was made possible by grants from the General Program of the National Natural Science Foundation of China (82371684, 82271672), the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University (JCRCWL-2022-001), and the General Program of the Natural Science Foundation of Guangdong Province (2022A1515010650, 2023A1515011675). Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Received: 30 January 2024 / Accepted: 21 May 2024 Page 10 of 13 Li et al. Reproductive Biology and Endocrinology (2024) 22:66

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