{"paper_id":"3b8e4394-8a58-4690-81f9-6acd9941cb81","body_text":"REVIEW Open Access\n© The Author(s) 2024. Open Access  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, \nsharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and \nthe source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this \narticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included \nin the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will \nneed to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The \nCreative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available \nin this article, unless otherwise stated in a credit line to the data.\nLi et al. Reproductive Biology and Endocrinology           (2024) 22:66 \nhttps://doi.org/10.1186/s12958-024-01235-5\nIntroduction\nInfertility is a condition characterized by the inability of \na woman to conceive after a year of regular, unprotected \nintercourse. It poses a significant global health concern, \naffecting approximately 15% of couples worldwide, with \nfemale factors alone accounting for at least 35% [ 1– 3]. \nBeyond the physiological challenges, long-term infertil -\nity can lead to emotional distress, strained relationships, \nand societal stigma, impacting the overall well-being of \ncouples aspiring to have children [4].\nFatigue, commonly described as extreme tiredness, \ndiminished energy, and reduced physical and mental \ncapacity, is a prevalent symptom in various chronic con -\nditions [ 5]. While there is no consensus definition, and \nit overlaps with factors such as chronic pain, physical \nexertion, sleep disorders, and psychological stress [ 6, 7]. \nUnder the bio-psycho-social medical model, the concept \nReproductive Biology \nand Endocrinology\n†Wenzhu Li, Xiaoyan Huang and Yiqiu Wei contributed equally to this \nwork and share first authorship.\n*Correspondence:\nTailang Yin\nreproductive@whu.edu.cn\nLianghui Diao\ndiaolianghui@gmail.com\n1Reproductive Medical Center, Renmin Hospital of Wuhan University and \nHubei Clinic Research Center for Assisted Reproductive Technology and \nEmbryonic Development, Wuhan 430060, China\n2Department of Rheumatology, The University of Hong Kong- Shenzhen \nHospital, Shenzhen 518053, China\n3Shenzhen Key Laboratory of Reproductive Immunology for Peri-\nimplantation, Shenzhen Zhongshan Institute for Reproductive Medicine \nand Genetics, Shenzhen Zhongshan Obstetrics & Gynecology Hospital \n(formerly Shenzhen Zhongshan Urology Hospital), Shenzhen  \n518045, China\n4Guangdong Engineering Technology Research Center of Reproductive \nImmunology for Peri- implantation, Shenzhen 518045, China\nAbstract\nFatigue, an increasingly acknowledged symptom in various chronic diseases, has garnered heightened attention, \nduring the medical era of bio-psycho-social model. Its persistence not only significantly compromises an \nindividual’s quality of life but also correlates with chronic organ damage. Surprisingly, the intricate relationship \nbetween fatigue and female reproductive health, specifically infertility, remains largely unexplored. Our exploration \ninto the existing body of evidence establishes a compelling link between fatigue with uterine and ovarian diseases, \nas well as conditions associated with infertility, such as rheumatism. This observation suggests a potentially pivotal \nrole of fatigue in influencing overall female fertility. Furthermore, we propose a hypothetical mechanism elucidating \nthe impact of fatigue on infertility from multiple perspectives, postulating that neuroendocrine, neurotransmitter, \ninflammatory immune, and mitochondrial dysfunction resulting from fatigue and its co-factors may further \ncontribute to endocrine disorders, menstrual irregularities, and sexual dysfunction, ultimately leading to infertility. \nIn addition to providing this comprehensive theoretical framework, we summarize anti-fatigue strategies and \naccentuate current knowledge gaps. By doing so, our aim is to offer novel insights, stimulate further research, and \nadvance our understanding of the crucial interplay between fatigue and female reproductive health.\nKeywords Female infertility, Fatigue, Stress, HPA axis, Inflammation\nConnecting the dots: the role of fatigue \nin female infertility\nWenzhu Li1†, Xiaoyan Huang2†, Yiqiu Wei1†, Tailang Yin1* and Lianghui Diao3,4*\n\nPage 2 of 13\nLi et al. Reproductive Biology and Endocrinology            (2024) 22:66 \nof “whole-person care” has been increasingly accepted \nand applied, and patient-reported outcomes (PROs) have \nreceived more attention in clinical research, with fatigue \nbeing an important indicator of disease [ 8– 10]. This \nphenomenon has also appeared in the field of gynecol -\nogy, thus, we began to focus on the impact of fatigue on \ninfertility.\nThere is growing recognition of the potential link \nbetween fatigue and female infertility, but scientific evi -\ndence remains limited. Fatigue could impact fertility \nthrough complex mechanisms involving the neuroen -\ndocrine system [ 11], inflammatory-immune response \n[12], energy metabolism, and oxidative stress [ 13]. Fur-\nthermore, the development of fatigue is associated with \nchanges in neurotransmitter metabolism and neuronal \nplasticity [14]. These alterations, in turn, may affect cru -\ncial reproductive processes like ovulation, implantation, \nand embryonic development. What’s more, managing \nchronic fatigue can exact a significant emotional toll, \npotentially leading to stress, anxiety, and depression, \nwhich may further impact fertility through hormonal \nimbalances [ 15], disrupted menstrual cycles [ 16], and \ndecreased sexual desire [17].\nIn this review, we aim to provide a comprehensive \noverview of the link between fatigue and female infertil -\nity, delving into the potential mechanisms through which \nfatigue impacts reproductive health (Fig.  1). By connect -\ning the dots between fatigue and factors closely tied to \ninfertility, we endeavor to unveil the complex interac -\ntions and indirect effects of fatigue on female fertility. \nOur objective is to offer novel insights, stimulate further \nresearch, and propel the advancement of our comprehen-\nsion in this pivotal realm of female reproductive health \nfor the benefit of graduate students in medicine and prac-\nticing physicians.\nEpidemiology of fatigue\nFatigue is a multifaceted symptom experienced by both \nhealthy and unhealthy individuals, lacking a clear-cut \ndefinition. Self-reported scales are the primary measure -\nment tools [ 18]. Current research suggests a key distin -\nguishing factor between healthy and disease-related \nfatigue is the inability to alleviate fatigue with rest [ 19]. \nFatigue often occurs as a comorbidity alongside various \npsychophysical factors, such as anxiety, depression, and \npain, as demonstrated by multivariate analyses [ 20– 26]. \nTherefore, exploring the influence of these co-factors on \ninfertility is vital.\nThough not life-threatening, fatigue severely affects \nthe quality of life (QoL) of infertile women [ 27]. Despite \nregional variations in reported incidence [ 28– 32], a \nrecent meta-analysis estimated the global prevalence of \ngeneral fatigue at 20.4% in adults and 11.7% in minors \n[33]. Studies from 2011 highlighted that 7–45% of the \nU.S. population experiences persistent fatigue [ 34]. A \ncross-sectional study involving 2063 individuals showed \nthat over 50% of patients were troubled by fatigue in \nSaudi Arabia [ 35]. Importantly, women appear to be \nmore susceptible to fatigue than men, with a pooled odds \nratio [33]. Further, studies support that female sex may be \nan independent risk factor for persistent fatigue [28, 36].\nFatigue can manifest throughout a woman’s reproduc -\ntive life cycle, impacting sexual maturity, pregnancy, \npost-partum, and perimenopause. Postpartum fatigue \nis well-documented [ 37, 38], but there’s a paucity of \nresearch on fatigue in infertile women. However, fatigue \nin women of reproductive age, especially in infertile \nwomen, has only begun to be mentioned in recent years. \nApproximately 25–60% of infertile patients are reported \nto be disturbed by psychological factors, including anxi -\nety and depression [ 39], but the prevalence of fatigue \nin infertility is understudied. An observational study \nshowed that 52 out of 140 infertile women had self-\nreported fatigue, and the severity of fatigue negatively \naffected their QoL [ 40]. Similarly, a study involving 149 \ninfertile patients showed that fatigue was the most influ -\nential factor in the QoL of infertile women [ 41]. Taken \ntogether, more research is critically needed to address \nthis gap.\nCurrent state-of-the-art of fatigue in female infertility\nResearch on how fatigue directly impacts female infer -\ntility remains limited. However, fatigue is discussed for \nseveral chronic conditions affecting the uterus and ova -\nries (Table  1). Additionally, emerging studies suggest \nthat autoimmune diseases, characterized prominently \nby fatigue, may adversely affect female fertility. Overall, \nresearch on fatigue associated with infertility faces mul -\ntiple challenges and barriers.\nFatigue in Uterine and Ovarian diseases\nEndometriosis\nEndometriosis (EMT), defined as the presence of endo -\nmetriotic lesions outside the uterus, is a greatly disturb -\ning gynecologic disease that affects about 10% of women \nof reproductive age [ 42]. As early as 2018, a multicenter \ncross-sectional study sponsored by Wright and his col -\nleagues found fatigue as a frequent symptom of EMT \nand was closely associated with insomnia, depression, \npain, and occupational stress [ 43]. Subsequently, many \nobservational studies have documented similar results \n[44]. Several evidence have indicated that the severity \nof EMT is associated with increased fatigue. A matched \npair case-control study revealed that women with pain -\nful endometriosis reported significantly greater fatigue \nthan those without significant pain symptoms and con -\ntrols [ 45]. Ashrafi et al. found fatigue to be a predic -\ntor of risk for EMT through multiple logistic regression \n\nPage 3 of 13\nLi et al. Reproductive Biology and Endocrinology            (2024) 22:66 \n[46]. EMT-related fatigue seriously undermines women’s \nsense of life well-being and even their relationships with \npartners [47]. A scale-based observational study in Spain \nemphasized that moderate to severe fatigue contributed \nto psychological impairment, such as higher anxiety and \ndepression, poorer sleep quality, and lower sexual func -\ntion [48]. The above studies showed that fatigue is a com-\nmon, secondary symptom of EMT, and is related to other \nsomatic and psychological impairments, ultimately sig -\nnificantly decreasing patients’ QoL and sexual function \n[49].\nPolycystic ovary syndrome\nPolycystic ovary syndrome (PCOS) is the most common \nchronic endocrine disease characterized by menstrual \ndysfunction and ovulation disorders affecting 5–13% \nof women in the general population [ 50]. Studies have \nfound that PCOS women often suffer from increased \nanxiety and depression, causing psychological fatigue and \nfurther impairing QoL [ 51, 52]. It is noted that patients \nwith lower QoL parameters showed more worse marital \nsexual functioning [53]. A randomized clinical trial found \nthat a psychological treatment named cognitive behav -\nioral therapy (CBT) can significantly reduce the sever -\nity of fatigue in PCOS patients compared to the control \nFig. 1 Potential mechanisms by which fatigue influences female infertility. The relationship between fatigue and female infertility is under-recognized, \nand it has complex crosstalk with co-factors (for example, pain and depression) through the activation of in vivo stress-responsive systems (HPA-axis, \nneurotransmitter system) and inflammation stimulated by different stress signals, and then contributing to hormonal dysregulation, oxidative stress, and \nmitochondrial metabolic dysfunction, which may be an underlying mechanism that affects female infertility. The solid lines represent reported studies, \nand the dotted lines represent studies that need to be developed. Double arrows represent interconnections. HPA, hypothalamic-pituitary-adrenal; 5-HT, \n5-hydroxytryptamine; ROS, reactive oxygen species\n \n\nPage 4 of 13\nLi et al. Reproductive Biology and Endocrinology            (2024) 22:66 \ngroup [51]. On the whole, fatigue almost goes unnoticed \nin patients with PCOS [54].\nPremature Ovarian Insufficiency.\nPremature ovarian insufficiency (POI) develops the \nbreakdown of ovarian function and menopause before \nthe age of 40, affects about 1% of women, and is one \nof the main causes of female infertility [ 55]. A cross-\nsectional study showed fatigue was a highly prevalent \nsymptom closely associated with menopause in the \nrecruited Chinese women with POI [ 56]. A few cross-\nsectional studies supported that the POI group had a \nhigher fatigue index than controls [ 56, 57]. In another \nstudy, POI patients were more likely to suffer from sleep \ndisturbance and depression, but not fatigue compared \nto age-matched healthy individuals [ 58]. Similar results \nwere also obtained in an earlier study on premature ovar-\nian failure [ 59]. Thus, the available evidence on whether \npatients with POI are at higher risk for fatigue is hetero -\ngeneous and needs to be studied extensively.\nFatigue in Autoimmune diseases affecting fertility\nAutoimmune diseases are a large group of chronic dis -\norders mediated by immune responses to self-antigens, \nsuch as rheumatoid arthritis (RA) [ 19], antiphospho -\nlipid syndrome [ 60], systemic lupus erythematosus [ 61], \nmultiple sclerosis (MS) [ 62], autoimmune hypothyroid -\nism [ 63]. A range of mental and somatic symptoms are \npresent in these disorders, with fatigue being one of \nthe most common and challenging symptoms to man -\nage [ 64]. Fatigue is often indicative of disease activity \nin these disorders [ 19], while disease activity raises the \nrisk of adverse pregnancy outcomes, particularly mis -\ncarriage [ 65– 67]. MS patients with fatigue had signifi -\ncantly higher levels of C-reactive protein (CRP) during \npregnancy than those without fatigue, suggesting that \nTable 1 Characteristics of the Typical Studies Included in the Review\nChronic \nConditions\nAuthor \nInformation\nStudy Type/ Sample Size the Role of Fatigue Fatigue \nMeasurement\nEndometriosis Facchin et al. \n2021 [45]\nMatched pair case-control study\n(EMT, N = 123; Control, N = 123)\nWomen with painful EMT\nreported significantly greater fatigue\n5-point Likert \nscale\nÁlvarez-Salvago \net al. 2020 [49]\nMatched pair case-control study\n(EMT, N = 25; Control, N = 25)\nWomen with higher endometriosis-related fatigue had \na lower QoL.\nThe Spanish ver-\nsion of the Piper \nFatigue Scale\nMundo-López et \nal. 2020 [48]\nCross-sectional study\n(EMT, N = 230)\nOne-third and one-half of the recruited patients \nwith EMT showed moderate to severe fatigue, which \nis closely related to higher anxiety and depression, \npoorer sleep quality, lower sexual function, and so on \nby regression analysis.\nPiper Fatigue Scale\nRamin-Wright et \nal. 2018 [43]\nMulti-center matched case-\ncontrol study\n(EMT, N = 560; Control, N = 560)\nMore women diagnosed with EMT experienced \nfrequent fatigue than control women. Fatigue in EMT \nwas associated with insomnia, depression, pain, and \noccupational stress by regression analysis.\nThe self-admin-\nistered question-\nnaire developed \nby endometriosis \nand psychosomat-\nic specialists from \nthe universities of \nZurich and Berlin.\nPolycystic Ovary \nSyndrome\nBoivin et al. 2020 \n[52]\nNA\n120(PCOS, N = 11; PCOS screen-\npositive, N = 25; PCOS screen-\nnegative, N = 74)\nThe PCOS-confirmed women scored\nmore poorly than control groups on physical, \nemotional, social, and spiritual well-being indexs, like \nfatigue and depression.\nFatigue Symptom \nInventory\nAbdollahi et al. \n2019 [51]\nRandomized controlled clinical \ntrial\n(PCOS with CBT, N = 37; PCOS, \nN = 37)\nCognitive-behavioral therapy (CBT)\nsignificantly reduced psychological fatigue in PCOS \npatients.\nThe Fatigue \nImpact Scale\nPremature Ovar-\nian Insufficiency\nBenetti-Pinto et \nal. 2019 [57]\nCross-sectional study\n(POI with HT therapy, N = 61; \nControl, N = 62)\nThe POI group had a higher fatigue\nindex than controls.\nChalder Fatigue \nScale\nHuang et al. \n2021 [56]\nCross-sectional study\n(POI, N = 293; Control, N = 471)\nFatigue is one of the 13 items of menopause. 168 of \n293 women with POI suffered from fatigue (57.3%).\nThe modified Kup-\nperman Meno-\npausal Index\nAtes et al. 2022 \n[58]\nMatched pair study\n(POI, N = 62; Control, N = 62)\nFatigue did not differ significantly\nbetween the groups\nFatigue Severity \nScale\nPremature Ovar-\nian Failure\nStege et al. 2008 \n[59]\nCase-control study\n(POF, N = 81; Control, N = 68)\nFatigue did not differ significantly\nbetween the groups\nThe Short-\nened Fatigue \nQuestionnaire\n\nPage 5 of 13\nLi et al. Reproductive Biology and Endocrinology            (2024) 22:66 \nhigher CRP , an indicator of systemic inflammation, may \nbe somewhat predictive of pregnancy-related comor -\nbidities [ 68]. A small single-center retrospective study \nrevealed that more patients with MS underwent elective \ncesarean deliveries due to fatigue [ 69]. Additionally, the \nstate of chronic fatigue directly impairs sexual function of \nwomen, which contributes significantly to the probabil -\nity of fertility [17, 70], For instance, some studies showed \nsexual function in women with RA may be affected by \npain and fatigue, potentially impacting fertility [ 71, 72]. \nDespite the shared occurrence of fatigue and female \ninfertility in autoimmune diseases, high-quality research \ninvestigating the impact of fatigue on infertility in these \nconditions is needed.\nChallenges of Fatigue Research in female infertility\nThe underrepresentation of fatigue research within \nfemale infertility remains a significant obstacle. This can \nbe attributed to several factors:\nSubjective and difficult measurement\nThe qualitative assessment of fatigue is relatively difficult \nand often subjective, and relies on the use of subjective \nself-report questionnaires [ 18, 73]. Moreover, experts in \ndifferent fields may develop professional-specific ques -\ntionnaires [ 74, 75]. The lack of standardized fatigue \nmeasurement across studies, including variations in \nthe specific scales, recall periods, and wording, makes \nit challenging to compare results and draw definitive \nconclusions.\nFocus on cross-sectional designs\nMost of the studies on fatigue and infertility utilizes \ncross-sectional designs [ 76– 78], which typically estab -\nlishes causality through multiple regression analysis. The \ncross-sectional designs limit the ability to establish clear \ncause-and-effect relationships.\nPotential confounding factors\nDifficulties in fatigue research also arise from potential \nconfounders of fatigue, such as emotional distress and \npain [19, 79], suggesting that fatigue is not a single symp -\ntom of infertility, but rather is accompanied by a number \nof psychological and physical symptoms [ 40]. It is para -\nmount to consider these interconnected factors to fully \nunderstand the complex relationship between fatigue and \ninfertility.\nPutative mechanisms of fatigue on female infertility\nLongstanding fatigue serves as a catalyst for pathophysi -\nologic changes in numerous systems and organs [ 11], \nposing detrimental effects on health [ 80], which may \nbecome the key force driving infertility. The pathogen -\nesis of fatigue, involves the central nervous system (CNS) \nand autonomic nervous system (ANS), immune and \ninflammation, mitochondrial oxidative stress [ 81– 83]. \nSimultaneously, the mechanisms of infertility are closely \nrelated to neuro-endocrine dysregulation, inflammatory \nand immune imbalances, and oxidative stress activation \n[62, 84]. It is clear that there are shared mechanisms for \nfatigue and infertility, which is worth exploring. Conse -\nquently, the forthcoming section presents evidence in \nsupport of a hypothesized mechanism illustrating overlap \nbetween fatigue and infertility.\nNeuroendocrine disruption and Hormonal Imbalance\nThe CNS and endocrine system collaborate to maintain \ndaily activities and keep up energy. Structural and func -\ntional dysfunctions in different regions of the brain may \ndisrupt motor cortical excitability, hormone secretion, \nand the signal to the working muscles, which in turn \ncause fatigue [ 85, 86]. In particular, abnormalities in the \nhypothalamic-pituitary-adrenal (HPA) axis have been \nidentified as a cause of fatigue. Notably, adrenal hormone \ndysregulation, such as hypocortisolemia, is frequently \nfound in fatigued individuals, representing one facet of \nthe imbalance of the HPA axis [ 87]. For instance, one \nstudy found MS patients with fatigue had significantly \nhigher pituitary heights and widths, along with increased \nsecretion of adrenocorticotropic hormone compared \nto patients without fatigue. These findings suggest CNS \nand endocrine systems are involved in the pathogenesis \nof fatigue through sophisticated regulation of brain struc-\nture and function [75].\nMore importantly, it is closely tied to maintaining \nreproductive function. First of all, gonadotrophin-releas -\ning hormone (GnRH) from the hypothalamus, along with \nluteinizing hormone (LH) and follicle-stimulating hor -\nmone (FSH) from the pituitary gland, regulates follicular \ndevelopment and the ovarian cycle [88]. What’s more, the \nHPA axis has a direct inhibitory action on the hypotha -\nlamic-pituitary-ovarian axis in certain ways [ 15], impact-\ning the cyclical patterns in central and ovarian hormones, \nincluding FSH, LH, E2, and P4. Besides, one early study \nfound that uterine cortisol deficiency may mediate ele -\nvated levels of NK cells, which further impaired decidual-\nization [89]. Dehydroepiandrosterone (DHEA), a kind of \nadrenal hormone, is linked to fatigue and turns out to be \nan important contributor to reproductive function [ 90]. \nDHEA deficiency can severely impact ovarian hormone \nsynthesis and ovarian reserve, potentially leading to pre -\nmature ovarian insufficiency (POI) [91]. Supplementation \nwith DHEA has demonstrated positive effects on preg -\nnancy rates, emphasizing its role in maintaining fertility \n[92– 95]. Beyond the HPA axis, hormonal changes asso -\nciated with fatigue extend to estrogen, progesterone and \nthyroid hormone [96– 99]. Moreover, untreated maternal \nhypothyroidism is associated with adverse pregnancy \n\nPage 6 of 13\nLi et al. Reproductive Biology and Endocrinology            (2024) 22:66 \noutcomes such as miscarriage, preeclampsia, and many \nneonatal disorders [100].\nIn fact, although fatigue is a rather ill-defined physi -\ncal manifestation and the relationship with female \ninfertility has not been directly studied, evidence of neu -\nroendocrine disruption and hormonal imbalance found \nin fatigue-related disorders supports their relevance to \nthe maintenance of female fertility.\nStress and nervous system response\nPerhaps, it is reasonable to suggest that fatigue and its \nco-factors can contribute to infertility via shared mech -\nanistic pathways. Organisms are required to respond \nand adapt adequately to ubiquitous stress in an ever-\nchanging environment, such as viral infections, trauma, \nand adverse life events. In the first place, the onset of \nfatigue and its co-factors is regulated by the in-vivo stress \nresponse system [ 101, 102]. When subjected to internal \nand external stress, the biological stress response system \nimmediately makes corresponding alterations, including \nthe HPA axis and the ANS system, as well as the neuro -\nimmune system [14, 103– 105]. Sustained stress may lead \nto maladaptive responses manifested as dysregulation of \nthe above systems [ 106], which is specifically manifested \nas abnormal levels of serum catecholamines and gluco -\ncorticoids and persistent low-grade inflammation based \non findings such as microglial activation in the brain and \nincreased pro-inflammatory cytokines in the periph -\nery [ 107]. Moreover, stress and stress hormones inhibit \nthe release of GnRH, and glucocorticoids suppress LH \nsecretion [ 108]. These abnormal alterations may further \ndisrupt ovarian steroidogenesis and exacerbate inflam -\nmatory storms, ultimately being detrimental to female \nfertility.\nAnhedonia attributed to deficits in reward processing \nis a shared feature in many neuropsychiatric symptoms, \nincluding fatigue, depression, and chronic pain [ 62]. The \nprocessing ability of brain reward circuits is disrupted by \ninappropriate levels of monoaminergic neurotransmis -\nsion, mainly including serotonin (5-HT), norepinephrine, \nand dopamine with their degenerate mesocorticolimbic \npathways from the midbrain to the basal ganglia, the lim-\nbic system, and the prefrontal cortex [ 62, 109, 110]. The \nlack of neurotransmitters, including 5-HT, can cause sex-\nual dysfunction, thereby reducing fertility opportunities \n[15, 111].\nOverall, hormonal imbalances and incorrect release of \nneurotransmitters caused by the nervous response sys -\ntem could result in infertility. Additionally, fatigue could \nreduce sexual desire and cause sexual dysfunction, ulti -\nmately declining the chance of pregnancy [48]. The above \nevidence suggests that fatigue mediate neurologic dys -\nregulation that can aggravate infertility.\nLow-grade inflammatory activation\nOf great interest, fatigue is common in chronic autoim -\nmune, inflammatory diseases [ 112, 113]. A recent cross-\nsectional study found elevating fatigue severity is closely \nlinked to stronger signs of monocyte activation, includ -\ning increased inflammatory gene expression in mono -\ncytes, higher CD8 + T-lymphocyte counts, and increased \nserum pro-inflammatory cytokines [ 114]. There is a \nstrong correlation between fatigue severity and pro -\nduction of pro-inflammatory cytokines [ 19]. Women \nwith fatigue often show multiple immune dysfunctions \nrendering them susceptible to upper respiratory tract \ninfection, chronic lymphadenopathy, and high body tem -\nperature [ 115]. These dysregulations involve cell-medi -\nated immunity, including impairment of the function of \nNK cells, hypo-reactivity of T cells to the antigen, the \nactivation of monocyte macrophages, and the persistence \nof autoreactive cells [ 116]. Concurrently, they manifest \nas changes in many inflammation-related markers, such \nas increased CRP levels [ 68], elevation in pro-inflamma -\ntory factors like interleukin-1β, interleukin-6, interleu -\nkin-12, interleukin-2, tumor necrosis factor-alpha and \ninterferon-gamma, increased expression of nuclear factor \nkappa-B, as well as decreased levels of anti-inflammatory \nfactors like interleukin-8, interleukin-13, interleukin-15, \nand interleukin-23 [ 117]. The changes in inflammation-\nrelated profile support that patients experiencing fatigue \nare in a low-grade inflammatory state. In a word, inflam -\nmatory activation is undoubtedly a key step in the onset \nof fatigue [118].\nIt was reported that the increased infertility rate in RA \nwith fatigue symptoms is due to an imbalance of inflam -\nmatory factors [ 72]. Indeed, the immune system serves \nas a crucial bridge connecting various systems within the \norganism, with cytokine and immune cells distributed in \nboth in center and periphery systems. The homeostasis \nof immunity and inflammation is necessary to maintain \na successful pregnancy. The imbalance of inflammatory \nfactors and immune cell profiles is a notable phenom -\nenon in patients with adverse pregnancy history [ 119, \n120]. Such abnormalities could significantly impact preg -\nnancy outcomes by damaging ovarian function [ 121], \ninhibiting endometrial receptivity [ 122], hindering tro -\nphoblast development, and interfering with immune tol -\nerance at the maternal-fetal interface [65].\nIn short, inflammation is one of the most common \nmechanisms underlying fatigue and is also a known con -\ntributor to infertility. Fatigue may indicate active inflam -\nmation that needs to be managed in the reproductive \nfield.\nMitochondrial dysfunction and Cellular stress\nFatigue is defined as “a lack of energy” , indicating a close \nrelationship with energy metabolism [ 13], which is \n\nPage 7 of 13\nLi et al. Reproductive Biology and Endocrinology            (2024) 22:66 \nmanifested as impacted adenosine triphosphate produc -\ntion [ 123]. Mitochondria are core organelles that have \nexisted in most cells since biological evolution. They pro-\nvide continuous energy for biological survival and func -\ntion, produce adenosine triphosphate and lactic acid, and \nmaintain the production level of reactive oxygen species \n(ROS) and reactive nitrogen species (RNS) and the bal -\nance of calcium and iron in cells, removing peroxides \nin time. Dysfunctional mitochondria can generate and \nrelease mitochondrial components, including cardio -\nlipin, mitochondrial DNA, and mitochondrial formylated \npeptides. These components, once released, can act as \ndamage-associated molecular patterns, triggering an \ninflammatory response through the activation of pattern \nrecognition receptors [ 124]. In addition, mitochondria \nplay a rate-limiting role in controlling steroidogenesis, \nand mitochondrial impairment in neurons further affects \nthe synthesis of neuroactive steroid hormones in the \nbrain [ 125]. And the collapse of mitochondria at neu -\nronal synapse impedes the release of neurotransmitters \n[126, 127]. In summary, loss of neuroendocrine-immune \nhomeostasis due to mitochondrial disruption may par -\ntially explain infertility.\nFurthermore, mitochondria function as the primary \norigin of ROS/RNS as byproducts of nutrient metabo -\nlism. This occurrence is concomitant with various indica-\ntors of oxidative stress, including diminished activity of \nantioxidant enzymes such as superoxide dismutase and \nplasma-like glucose peroxidase, as well as reduced lev -\nels of zinc. Conversely, there is an elevation in the activ -\nity of pro-oxidative enzymes like myeloperoxidase, along \nwith increased levels of nitro-tyrosine and heightened \nnitric oxide production [ 118]. The heightened presence \nof ROS/RNS assumes a pivotal role in the manifestation \nof fatigue. A study demonstrated that the accumulation \nof ROS/RNS during exercise had a detrimental impact on \nNa+/K+- ATPase activity, calcium conversion and sensi -\ntivity in myofibrils, and actin-myosin dynamics. These \neffects collectively resulted in a reduction in the genera -\ntion of muscle energy, ultimately culminating in the onset \nof muscle fatigue [128]. Similarly, it has been proved that \nmany experimental drugs with antioxidant properties \ncan improve and alleviate chronic fatigue-like behaviors \nby changing ROS signaling pathways [ 129, 130]. How -\never, excessive oxidative stress could impair the female \nreproductive system by destroying oocyte quality [ 131, \n132], damaging endometrial receptivity [ 133], promoting \ntrophoblast apoptosis, medicating implantation failure, \nand early pregnancy loss [ 134]. Thereby, we believe mito-\nchondrial dysfunction and cellular stress, closely linked \nwith fatigue, exert a profound influence on the func -\ntion of the reproductive system, but need to be further \nstudied.\nTaken together, although explained from multiple \nperspectives, the current evidence is still insufficient to \nprove whether fatigue is a result or a predisposing fac -\ntor for female infertility. The above hypothesized mech -\nanisms regarding the impacts of fatigue on infertility \nperhaps only provide new viewpoints for researchers in \nthe future.\nThe potential benefits of fatigue management on infertility\nGiven the potential connection between fatigue and \ninfertility, it’s reasonable to consider whether fatigue \nmanagement could benefit those experiencing infertil -\nity. An early intervention for fatigue is recommended, \nas a systematic review pointed out health risks associ -\nated with fatigue can occur earlier than hospitalization, \nillness, and death [ 135]. Current treatments for fatigue \ninclude dietary supplement/nutritional interventions, \nmedications, exercise, physical therapy, and psychologi -\ncal interventions [ 136– 140] (Fig.  2). Among them, some \nstrategies have been reported to be beneficial for treating \ninfertility, while others may be in favor of the health of \nfemale reproduction.\nAnti-inflammatory and antioxidant nutrients\nThese nutrients, such as coenzyme Q10, L-carnitine, \niron, zinc, methionine, nicotinamide adenine dinucleo -\ntide, and vitamins, help relieve fatigue [ 141– 143]. Some \nstudies have shown that supplementation with iron can \nsignificantly improve fatigue in women of reproductive \nage, potentially contributing to achieving successful preg-\nnancy [ 144, 145]. Meanwhile, they belong to mitochon -\ndria-targeted nutrient therapy, which improves oxidative \ndamage to ovarian and uterus. For instance, coenzyme \nQ10 is a key component of ATP production via oxidative \nphosphorylation, and improves mitochondrial membrane \npotential and superoxide levels, thereby rescuing ovarian \nreserve deficiency [ 146]. Zinc supplementation has been \nreported to significantly improve oocyte glutathione \nand mitochondrial activity, as well as reduce ROS levels, \nwhich facilitates oocyte maturation [ 147]. Vitamins have \nbeen shown to increase mitochondrial biosynthesis [148], \nand restore endocrine and metabolic homeostasis [ 149], \nwhich in turn improves follicular development and sub -\nsequent follicular quality in the PCOS model.\nMedications\nSome synthetic and natural drugs can combat fatigue. \nGlucocorticoids, relieve fatigue due to hypocortisolism \nand may improve ovarian function to treat infertility \nthrough regulating neuroendocrine function [ 150, 151]. \nSynbiotics, a bio-mixture of probiotics and nutrients, \nshow potential in treating multiple symptoms of fatigue, \nincluding improving inflammation and stress responses \nmediated by the cytokine-HPA axis, along with mental \n\nPage 8 of 13\nLi et al. Reproductive Biology and Endocrinology            (2024) 22:66 \nand physical health [ 152], and enhance energy metabo -\nlism effectively [139].\nExercise and Physical Therapy\nIn addition to medication, exercise rehabilitation is \nused to reduce fatigue. A recent meta-analysis found \nthat physical therapy was efficacious and safe in reduc -\ning fatigue in people with inflammatory rheumatic and \nmusculoskeletal diseases [ 64]. It is believed that practic -\ning yoga has a positive effect on reproductive organs and \nincreases blood circulation [153]. Acupuncture treatment \nfor infertile patients can regulate menstrual cycle and \nreduce fatigue, thus facilitating the process of ART cycles \n[154].\nPsychological interventions\nFurthermore, psychological interventions, particularly \nCBT, are applied in the management of people with \nfatigue [ 155]. The psychological vulnerability screening \nand additional psychological consultation for infertile \nwomen are endorsed to mitigate these mixed symptoms \nthat are not conducive to pregnancy, such as fatigue, \ndepression, and anxiety [ 156]. A quasi-experimental \nstudy found psychological interventions significantly \nreduced depression and fatigue of infertility women, in \nturn, improved their intimacy and sexual satisfaction \n[157]. Two randomized controlled trials from Brunei \nfound that Nursing care reduced depression and fatigue, \nand improved feelings of social support and sleep qual -\nity among infertile women [ 158, 159]. It can be seen that \npsychotherapy is one of the recommended treatments for \ninfertility patients. Herein, it is conceivable that measures \nto alleviate fatigue may be beneficial in treating infertility \nand improving reproductive outcomes.\nCurrent gaps and future perspectives\nThe direct connection between fatigue and female infer -\ntility remains weak in evidence. Considering our pre -\nvious discussion, it is apparent that fatigue alone is not \nthe singular determining factor in female infertility. \nFig. 2 Strategies as well as mechanisms to alleviate fatigue. There are four main measures of fatigue alleviation: dietary supplements, medication, exercise \nand physical therapy, and psychological interventions. Relief of fatigue is achieved through anti-inflammatory, antioxidant, improved energy metabolism, \nand neurological modulation. The circular arrows indicate that the anti-fatigue mechanisms interact with each other and do not correspond to specific \nanti-fatigue measures\n \n\nPage 9 of 13\nLi et al. Reproductive Biology and Endocrinology            (2024) 22:66 \nUnfortunately, the current concept of fatigue is vague \n[160], and the diagnostic criteria are not unified [ 161]. \nIn different studies, fatigue can serve as an experimen -\ntal concept, a symptom, a risk, a cause, and a result [ 6]. \nMoreover, the scales for assessing fatigue are varied [ 74, \n75] and relatively subjective. There are three models for \ninducing fatigue, including exhaustive exercise-induced \nfatigue, and chemotherapy or radiotherapy-induced \nfatigue [162, 163]. These heterogeneities increase the dif-\nficulty of conducting research, thus making it challenging \nto explore fatigue in female infertility. Unlike depression, \nfatigue is often a concomitant symptom and is not sub -\njectively valued, despite its significant impact on women’s \nQoL and reproductive health.\nWhile anti-fatigue interventions might benefit female \ninfertility, current studies lack thorough mechanistic \nexploration. The rational use of anti-fatigue approaches \nand their impact on female infertility and pregnancy out -\ncomes need to be further investigated [139, 164].\nIn summary, the understanding of “fatigue” is weak \nwhen it comes to reproduction. Exploring the relation -\nships between fatigue, female infertility, and adverse \npregnancy outcomes is crucial, requiring more investiga -\ntion in clinical trials and basic research. In clinical trials, \nutilizing established fatigue assessment scales and com -\nprehensive recording of influencing factors are advised. \nRigorous statistical methods, including machine learning \nand multivariate logistic regression, should be employed \nto analyze the relationship between fatigue and female \ninfertility or pregnancy outcomes, under the premise \nof eliminating confounding factors. It is important to \ndevelop strict inclusion criteria for clinical populations \nwith fatigue symptoms, implement subgroup analysis, \nand explore the benefits of fatigue management on fer -\ntility outcomes. Additionally, biomarker detection in \nblood and other humor, such as uterine fluid, may reveal \ninsights into fatigue and pregnancy outcomes. In basic \nresearch, the use of well-established fatigue-related ani -\nmal models is essential to investigate their potential \nimpacts on reproduction.\nConclusion\nFatigue, a perplexing and disabling symptom, has gained \nmore recognition in the medical era of bio-psycho-social \nmodel amid heightened individual psychological stress. \nIt is thought to arise from endocrine imbalance and neu -\nrotransmitter changes in the central nervous system, \nimmune-inflammation disruption, mitochondrial dys -\nfunction, and excessive oxidative stress during viral infec-\ntions or social-environmental stress. It is closely linked to \nboth psychological and somatic factors, indirectly affect -\ning female infertility. Prolonged fatigue can significantly \ndiminish women’s quality of life and reproductive health, \nyet public awareness and understanding of this issue \nremain limited.   Our study highlights the associations \nbetween fatigue and several common chronic conditions, \nand proposes hypotheses regarding the impact of fatigue \non female infertility with the hope of calling attention to \nthe issue of fatigue in infertile women in alignment with \nthe whole-life care concept and providing insights for \nfuture study in this topic.\nAbbreviations\nHPA  Axis: Hypothalamic-Pituitary-Adrenal Axis\nQoL  Quality of Life\nMS  Multiple Sclerosis\nIVF  In Vitro Fertilization\nEMT  Endometriosis\nPCOS  Polycystic Ovary Syndrome\nCBT  Cognitive Behavioral Therapy\nPOI  Premature Ovarian Insufficiency\nCRP  C-Reactive Protein\nGnRH  Gonadotrophin-Releasing Hormone\nLH  Luteinizing Hormone\nFSH  Follicle-Stimulating Hormone\nNK cells  Natural Killer Cells\nDHEA  Dehydroepiandrosterone\nCNS  Central Nervous System\nANS  Autonomic Nervous System\n5-HT  Serotonin\nECS  Endocannabinoid System\nROS/RNS  Reactive Oxygen Species/ Reactive Nitrogen Species\nRA  Rheumatoid Arthritis\nAcknowledgements\nThe authors thank Dr. Shaolin Liang and Mrs. Yuan Sheng (STI-Zhilian Research \nInstitute for Innovation and Digital Health, Beijing, China) for optimizing the \nschema graph.\nAuthor contributions\nL.H.D. conceptualized the idea. T.L.Y. discussed and refined the framework. \nW.Z.L. drafted and revised the manuscript. X.Y.H. critically reviewed the \nmanuscript with a focus on the autoimmune aspects. Y.Q.W. contributed to \nmanuscript revision and language editing. All authors reviewed and approved \nthe final manuscript.\nFunding\nThe writing of this review was made possible by grants from the General \nProgram of the National Natural Science Foundation of China (82371684, \n82271672), the Interdisciplinary Innovative Talents Foundation from Renmin \nHospital of Wuhan University (JCRCWL-2022-001), and the General Program of \nthe Natural Science Foundation of Guangdong Province (2022A1515010650, \n2023A1515011675).\nData availability\nNo datasets were generated or analysed during the current study.\nDeclarations\nEthics approval and consent to participate\nNot applicable.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare no competing interests.\nReceived: 30 January 2024 / Accepted: 21 May 2024\n\n\nPage 10 of 13\nLi et al. Reproductive Biology and Endocrinology            (2024) 22:66 \nReferences\n1. Ga R, Muvvala SPR. Access to infertility care and ART treatment in India: a \nclinician’s perspective. Best Pract Res Clin Obstet Gynaecol. 2023;86:102302.\n2. Sang Q, Ray PF, Wang L. Understanding the genetics of human infertility. Sci-\nence. 2023;380:158–63.\n3. Yatsenko SA, Rajkovic A. Genetics of human female infertility†. Biol Reprod. \n2019;101:549–66.\n4. Swift A, Reis P , Swanson M. Infertility-related stress and quality of life in \nwomen experiencing concurrent reproductive trauma. J Psychosom Obstet \nGynaecol. 2022;43:171–6.\n5. Zhao S, Shibata K, Hellyer PJ, Trender W, Manohar S, Hampshire A, Husain M. \nRapid vigilance and episodic memory decrements in COVID-19 survivors. \nBrain Commun. 2022;4:fcab295.\n6. Pattyn N, Van Cutsem J, Dessy E, Mairesse O. Bridging Exercise Science, cogni-\ntive psychology, and Medical Practice: is cognitive fatigue a remake of the \nEmperor’s New clothes? Front Psychol. 2018;9:1246.\n7. Goërtz YMJ, Braamse AMJ, Spruit MA, Janssen DJA, Ebadi Z, Van Herck M, \nBurtin C, Peters JB, Sprangers MAG, Lamers F, et al. Fatigue in patients with \nchronic disease: results from the population-based lifelines Cohort Study. Sci \nRep. 2021;11:20977.\n8. Heesen C, Berger T, Riemann-Lorenz K, Krause N, Friede T, Pöttgen J, Meyer B, \nLühmann D. Mobile health interventions in multiple sclerosis: a systematic \nreview. Mult Scler. 2023;29:1709–20.\n9. Cruz Rivera S, Aiyegbusi OL, Piani Meier D, Dunne A, Harlow DE, Henke C, \nKamudoni P , Calvert MJ. The effect of disease modifying therapies on fatigue \nin multiple sclerosis. Mult Scler Relat Disord. 2023;79:105065.\n10. Terwee CB, Elders PJM, Blom MT, Beulens JW, Rolandsson O, Rogge AA, Rose \nM, Harman N, Williamson PR, Pouwer F, et al. Patient-reported outcomes for \npeople with diabetes: what and how to measure? A narrative review. Diabe-\ntologia. 2023;66:1357–77.\n11. Thomas N, Gurvich C, Huang K, Gooley PR, Armstrong CW. The underlying \nsex differences in neuroendocrine adaptations relevant to myalgic encepha-\nlomyelitis chronic fatigue syndrome. Front Neuroendocrinol. 2022;66:100995.\n12. Lanser L, Kink P , Egger EM, Willenbacher W, Fuchs D, Weiss G, Kurz K. Inflam-\nmation-Induced Tryptophan Breakdown is related with Anemia, fatigue, and \nDepression in Cancer. Front Immunol. 2020;11:249.\n13. Zhong H, Shi J, Zhang J, Wang Q, Zhang Y, Yu P , Guan R, Feng F. Soft-Shelled \nTurtle Peptide Supplementation Modifies Energy Metabolism and Oxidative \nStress, Enhances Exercise Endurance, and Decreases Physical Fatigue in Mice. \nFoods. 2022; 11.\n14. Baker AME, Maffitt NJ, Del Vecchio A, McKeating KM, Baker MR, Baker SN, \nSoteropoulos DS. Neural dysregulation in post-COVID fatigue. Brain Com-\nmun. 2023;5:fcad122.\n15. Valsamakis G, Chrousos G, Mastorakos G. Stress, female reproduction and \npregnancy. Psychoneuroendocrinology. 2019;100:48–57.\n16. Pollack B, von Saltza E, McCorkell L, Santos L, Hultman A, Cohen AK, Soares L. \nFemale reproductive health impacts of long COVID and associated illnesses \nincluding ME/CFS, POTS, and connective tissue disorders: a literature review. \nFront Rehabil Sci. 2023;4:1122673.\n17. Zhang L, Wu B, Ye J. Fatigue have impact on the sexual problems in \nChinese females with systemic lupus erythematosus. BMC Womens Health. \n2022;22:266.\n18. Hewlett S, Dures E, Almeida C. Measures of fatigue: Bristol rheumatoid arthri-\ntis fatigue multi-dimensional questionnaire (BRAF MDQ), Bristol rheumatoid \narthritis fatigue Numerical Rating scales (BRAF NRS) for severity, effect, and \ncoping, chalder fatigue questionnaire (CFQ), Checklist Individual Strength \n(CIS20R and CIS8R), fatigue severity scale (FSS), Functional Assessment \nChronic illness therapy (fatigue) (FACIT-F), Multi-dimensional Assessment of \nfatigue (MAF), multi-dimensional fatigue inventory (MFI), Pediatric Quality of \nLife (PedsQL) multi-dimensional fatigue Scale, Profile of fatigue (ProF), short \nform 36 vitality Subscale (SF-36 VT), and Visual Analog scales (VAS). Arthritis \nCare Res (Hoboken). 2011;63(Suppl 11):S263–286.\n19. Davies K, Dures E, Ng WF. Fatigue in inflammatory rheumatic diseases: \ncurrent knowledge and areas for future research. Nat Rev Rheumatol. \n2021;17:651–64.\n20. Möller MC, Berginström N, Ghafouri B, Holmqvist A, Löfgren M, Nordin L, \nStålnacke BM. Cognitive and mental fatigue in chronic pain: cognitive func-\ntions, emotional aspects, biomarkers and neuronal correlates-protocol for a \ndescriptive cross-sectional study. BMJ Open. 2023;13:e068011.\n21. Valentine TR, Alschuler KN, Ehde DM, Kratz AL. Prevalence, co-occurrence, \nand trajectories of pain, fatigue, depression, and anxiety in the year following \nmultiple sclerosis diagnosis. Mult Scler. 2022;28:620–31.\n22. Clark NL, Kainth GS, Johnson M, Rangan A, Kottam L, Swainston K. Psycho-\nlogical interventions to improve pain, fatigue, anxiety, depression, and quality \nof life in children and adults with hypermobility spectrum disorders and \nEhlers-Danlos syndrome: a systematic review. Rheumatol Int. 2023.\n23. Renna ME, Shrout MR, Madison AA, Alfano CM, Povoski SP , Lipari AM, Carson \nWE 3rd, Malarkey WB, Kiecolt-Glaser JK. Depression and anxiety in colorectal \ncancer patients: ties to pain, fatigue, and inflammation. Psychooncology. \n2022;31:1536–44.\n24. Murphy HM, Fetter CM, Snow NJ, Chaves AR, Downer MB, Ploughman \nM. Lower corticospinal excitability and greater fatigue among people \nwith multiple sclerosis experiencing pain. Mult Scler J Exp Transl Clin. \n2023;9:20552173221143398.\n25. Manning K, Kauffman BY, Rogers AH, Garey L, Zvolensky MJ. Fatigue severity \nand fatigue sensitivity: relations to anxiety, depression, pain catastrophizing, \nand pain severity among adults with severe fatigue and chronic low back \npain. Behav Med. 2022;48:181–9.\n26. Holten KIA, Bernklev T, Opheim R, Johansen I, Olsen BC, Lund C, Strande V, \nMedhus AW, Perminow G, Bengtson MB, et al. Fatigue in patients with newly \ndiagnosed inflammatory bowel disease: results from a prospective inception \ncohort, the IBSEN III Study. J Crohns Colitis. 2023;17:1781–90.\n27. Nho JH, Kim EJ. Relationships among Type-D personality, fatigue, and Quality \nof Life in Infertile Women. Asian Nurs Res. 2022;16:208–14.\n28. Sunata K, Miyata J, Terai H, Matsuyama E, Watase M, Namkoong H, Asakura \nT, Masaki K, Chubachi S, Ohgino K et al. Asthma is a risk factor for general \nfatigue of long COVID in Japanese nation-wide cohort study. Allergol Int. \n2023.\n29. Amiot A, Chaibi S, Bouhnik Y, Serrero M, Filippi J, Roblin X, Bourrier A, \nBouguen G, Franchimont D, Savoye G, et al. Prevalence and determinants \nof fatigue in patients with IBD: a cross-sectional survey from the GETAID. J \nCrohns Colitis. 2023;17:1418–25.\n30. Al Maqbali M, Al Sinani M, Al Naamani Z, Al Badi K, Tanash MI. Prevalence of \nfatigue in patients with Cancer: a systematic review and Meta-analysis. J Pain \nSymptom Manage. 2021;61:167–e189114.\n31. Zhan J, Zhang P , Wen H, Wang Y, Yan X, Zhan L, Chen H, Xu N, Lu L. Global \nprevalence estimates of poststroke fatigue: a systematic review and meta-\nanalysis. Int J Stroke. 2023;18:1040–50.\n32. Lilleholt L, Zettler I, Betsch C, Böhm R. Development and validation of the \npandemic fatigue scale. Nat Commun. 2023;14:6352.\n33. Yoon JH, Park NH, Kang YE, Ahn YC, Lee EJ, Son CG. The demographic features \nof fatigue in the general population worldwide: a systematic review and \nmeta-analysis. Front Public Health. 2023;11:1192121.\n34. Junghaenel DU, Christodoulou C, Lai JS, Stone AA. Demographic correlates \nof fatigue in the US general population: results from the patient-reported \noutcomes measurement information system (PROMIS) initiative. J Psychosom \nRes. 2011;71:117–23.\n35. Al-Johani MS, Khalil R, Al-Mohaimeed YA, Al-Mundarij OM, Al-Samani AS, \nAl-Saqry OS, Al-Saawi AA, Al-Dhali IK, Al-Essa WA. Post-COVID-19 fatigue and \nhealth-related quality of life in Saudi Arabia: a population-based study. Front \nPublic Health. 2023;11:1254723.\n36. Hechenberger S, Helmlinger B, Penner IK, Pirpamer L, Fruhwirth V, Heschl \nB, Ropele S, Wurth S, Damulina A, Eppinger S, et al. Psychological factors \nand brain magnetic resonance imaging metrics associated with fatigue in \npersons with multiple sclerosis. J Neurol Sci. 2023;454:120833.\n37. Corwin EJ, Arbour M. Postpartum fatigue and evidence-based interventions. \nMCN Am J Matern Child Nurs. 2007;32:215–20. quiz 221 – 212.\n38. Odabas RK, Sökmen Y, Taspinar A. The effect of acupressure on postpartum \nfatigue in women delivering by caesarean section: a randomized controlled \nstudy. Explore (NY). 2023;19:293–9.\n39. Boivin J, Oguz M, Duong M, Cooper O, Filipenko D, Markert M, Samuelsen \nC, Lenderking WR. Emotional reactions to infertility diagnosis: thematic and \nnatural language processing analyses of the 1000 dreams survey. Reprod \nBiomed Online. 2023;46:399–409.\n40. Kim YM, Nho JH. [Factors influencing infertility-related quality of life in infer-\ntile women]. Korean J Women Health Nurs. 2020;26:49–60.\n41. Nho JH, Kim EJ. Relationships among type-D personality, fatigue, and quality \nof life in infertile women. Asian Nurs Res (Korean Soc Nurs Sci). 2022.\n42. Maddern J, Grundy L, Castro J, Brierley SM. Pain in Endometriosis. Front Cell \nNeurosci. 2020;14:590823.\n43. Ramin-Wright A, Schwartz ASK, Geraedts K, Rauchfuss M, Wölfler MM, \nHaeberlin F, von Orelli S, Eberhard M, Imthurn B, Imesch P , et al. Fatigue - a \nsymptom in endometriosis. Hum Reprod. 2018;33:1459–65.\n\nPage 11 of 13\nLi et al. Reproductive Biology and Endocrinology            (2024) 22:66 \n44. DiBenedetti D, Soliman AM, Gupta C, Surrey ES. Patients’ perspectives of \nendometriosis-related fatigue: qualitative interviews. J Patient-Reported \nOutcomes. 2020; 4.\n45. Facchin F, Buggio L, Roncella E, Somigliana E, Ottolini F, Dridi D, Roberto A, \nVercellini P . Sleep disturbances, fatigue and psychological health in women \nwith endometriosis: a matched pair case-control study. Reprod Biomed \nOnline. 2021;43:1027–34.\n46. Ashrafi M, Sadatmahalleh SJ, Akhoond MR, Talebi M. Evaluation of risk \nfactors Associated with endometriosis in Infertile Women. Int J Fertil Steril. \n2016;10:11–21.\n47. Alvarez-Salvago F, Lara-Ramos A, Cantarero-Villanueva I, Mazheika M, \nMundo-López A, Galiano-Castillo N, Fernández-Lao C, Arroyo-Morales M, \nOcón-Hernández O, Artacho-Cordón F. Chronic fatigue, physical impairments \nand quality of life in women with endometriosis: a case-control study. Int J \nEnviron Res Public Health. 2020; 17.\n48. Mundo-López A, Ocón-Hernández O, San-Sebastián AP , Galiano-Castillo N, \nRodríguez-Pérez O, Arroyo-Luque MS, Arroyo-Morales M, Cantarero-Villan-\nueva I, Fernández-Lao C, Artacho-Cordón F. Contribution of chronic fatigue \nto Psychosocial Status and Quality of Life in Spanish Women diagnosed with \nendometriosis. Int J Environ Res Public Health. 2020; 17.\n49. Álvarez-Salvago F, Lara-Ramos A, Cantarero-Villanueva I, Mazheika M, \nMundo-López A, Galiano-Castillo N, Fernández-Lao C, Arroyo-Morales M, \nOcón-Hernández O, Artacho-Cordón F. Chronic fatigue, physical impairments \nand quality of life in women with endometriosis: a case-control study. Int J \nEnviron Res Public Health. 2020; 17.\n50. Guan C, Zahid S, Minhas AS, Ouyang P , Vaught A, Baker VL, Michos ED. \nPolycystic ovary syndrome: a risk-enhancing factor for cardiovascular disease. \nFertil Steril. 2022;117:924–35.\n51. Abdollahi L, Mirghafourvand M, Babapour JK, Mohammadi M. Effectiveness \nof cognitive-behavioral therapy (CBT) in improving the quality of life and psy-\nchological fatigue in women with polycystic ovarian syndrome: a random-\nized controlled clinical trial. J Psychosom Obstet Gynaecol. 2019;40:283–93.\n52. Boivin MJ, Fatehi F, Phillips-Chan AE, Richardson JR, Summers AN, Foley SA. \nExploratory study of a screening measure for polycystic ovarian syndrome, \nquality of life assessment, and neuropsychological evaluation. BMC Womens \nHealth. 2020;20:132.\n53. Drosdzol A, Skrzypulec V, Mazur B, Pawlińska-Chmara R. Quality of life and \nmarital sexual satisfaction in women with polycystic ovary syndrome. Folia \nHistochem Cytobiol. 2007;45(Suppl 1):S93–97.\n54. Ee C, Pirotta S, Mousa A, Moran L, Lim S. Providing lifestyle advice to women \nwith PCOS: an overview of practical issues affecting success. BMC Endocr \nDisord. 2021;21:234.\n55. Shekari S, Stankovic S, Gardner EJ, Hawkes G, Kentistou KA, Beaumont RN, \nMörseburg A, Wood AR, Prague JK, Mishra GD, et al. Penetrance of patho-\ngenic genetic variants associated with premature ovarian insufficiency. Nat \nMed. 2023;29:1692–9.\n56. Huang Y, Qi T, Ma L, Li D, Li C, Lan Y, Chu K, Chen P , Xu W, Cao Y, et al. \nMenopausal symptoms in women with premature ovarian insufficiency: \nprevalence, severity, and associated factors. Menopause. 2021;28:529–37.\n57. Benetti-Pinto CL, Menezes C, Yela DA, Cardoso TM. Sleep quality and fatigue \nin women with premature ovarian insufficiency receiving hormone therapy: \na comparative study. Menopause. 2019;26:1141–5.\n58. Ates S, Aydın S, Ozcan P , Bakar RZ, Cetin C. Sleep, depression, anxiety and \nfatigue in women with premature ovarian insufficiency. J Psychosom Obstet \nGynaecol. 2022;43:482–7.\n59. van der Stege JG, Groen H, van Zadelhoff SJ, Lambalk CB, Braat DD, van \nKasteren YM, van Santbrink EJ, Apperloo MJ, Weijmar Schultz WC, Hoek \nA. Decreased androgen concentrations and diminished general and \nsexual well-being in women with premature ovarian failure. Menopause. \n2008;15:23–31.\n60. Bearne LM, Bieles J, Georgopoulou S, Andrews J, Tully A, Stolarchuk-Prowting \nK, Williamson T, Suarez BS, Nel L, D’Cruz D, et al. Fatigue in adults with primary \nantiphospholipid syndrome: findings from a mixed-methods study. Lupus. \n2020;29:924–33.\n61. Stamm B, Barbhaiya M, Siegel C, Lieber S, Lockshin M, Sammaritano L. Infertil-\nity in systemic lupus erythematosus: what rheumatologists need to know in \na new age of assisted reproductive technology. Lupus Sci Med. 2022; 9.\n62. Heitmann H, Andlauer TFM, Korn T, Mühlau M, Henningsen P , Hemmer B, \nPloner M. Fatigue, depression, and pain in multiple sclerosis: how neuroin-\nflammation translates into dysfunctional reward processing and anhedonic \nsymptoms. Mult Scler. 2022;28:1020–7.\n63. Louwerens M, Appelhof BC, Verloop H, Medici M, Peeters RP , Visser TJ, Boelen \nA, Fliers E, Smit JW, Dekkers OM. Fatigue and fatigue-related symptoms in \npatients treated for different causes of hypothyroidism. Eur J Endocrinol. \n2012;167:809–15.\n64. Santos EJF, Farisogullari B, Dures E, Geenen R, Machado PM. Efficacy of \nnon-pharmacological interventions: a systematic review informing the 2023 \nEULAR recommendations for the management of fatigue in people with \ninflammatory rheumatic and musculoskeletal diseases. RMD Open 2023; 9.\n65. Tan Y, Liu Q, Li Z, Yang S, Cui L. Pyroptosis-triggered pathogenesis: new \ninsights on antiphospholipid syndrome. Front Immunol. 2023;14:1155222.\n66. Tańska K, Gietka-Czernel M, Glinicki P , Kozakowski J. Thyroid autoimmunity \nand its negative impact on female fertility and maternal pregnancy out-\ncomes. Front Endocrinol (Lausanne). 2022;13:1049665.\n67. Kaplan TB, Bove R, Galetta K, Healy B, Chitnis C, Houtchens M. Effect of preg-\nnancy loss on MS disease activity. J Neurol Sci. 2019;397:58–60.\n68. Jalkanen A, Kauko T, Koskinen JO, Waris ME, Airas L. Elevated concentration of \nC-reactive protein is associated with pregnancy-related co-morbidities but \nnot with relapse activity in multiple sclerosis. Neurol Sci. 2015;36:441–7.\n69. Biringer K, Sivak S, Sivakova J, Ružiňák R, Martiníková M, Kantorova E, Biring -\nerová Z, Kudela E, Kurca E. Fatigue as the limiting factor for vaginal birth in \npatients with multiple sclerosis. Neuro Endocrinol Lett. 2021;42:222–8.\n70. Ghasemi V, Simbar M, Ozgoli G, Nabavi SM, Alavi Majd H. Prevalence, dimen-\nsions, and predictor factors of sexual dysfunction in women of Iran multiple \nsclerosis society: a cross-sectional study. Neurol Sci. 2020;41:1105–13.\n71. Provost M, Eaton JL, Clowse MEB. Fertility and infertility in rheumatoid arthri-\ntis. Curr Opin Rheumatol. 2014;26:308–14.\n72. Fattah A, Asadi A, Shayesteh MRH, Hesari FH, Jamalzehi S, Abbasi M, Mousavi \nMJ, Aslani S. Fertility and infertility implications in rheumatoid arthritis; state \nof the art. Inflamm Res. 2020;69:721–9.\n73. Beckers E, Hermans K, Van Tubergen A, Boonen A. Fatigue in patients with \nrheumatic and musculoskeletal diseases: a scoping review on definitions, \nmeasurement instruments, determinants, consequences and interventions. \nRMD Open 2023; 9.\n74. Cohen ET, Matsuda PN, Fritz NE, Allen DD, Yorke AM, Widener GL, Jewell ST, \nPotter K. Self-report measures of fatigue for people with multiple sclerosis: a \nsystematic review. J Neurol Phys Ther. 2023.\n75. Eren F, Demir A, Yilmaz SE, Ozturk S. Evaluation of the relationship between \nthe morphometric structure of the pituitary gland and fatigue in patients \nwith multiple sclerosis. Mult Scler Relat Disord. 2023;69:104470.\n76. Reece JC, Neate SL, Davenport RA, Milanzi E, Nag N, Bevens W, Yu M, Jelinek \nGA, Simpson-Yap S. Stressful life events and depression and fatigue in people \nwith multiple sclerosis: a cross-sectional analysis of an international cohort. \nActa Neurol Belg. 2023.\n77. Uhlir V, Stallmach A, Grunert PC. Fatigue in patients with inflammatory bowel \ndisease-strongly influenced by depression and not identifiable through labo-\nratory testing: a cross-sectional survey study. BMC Gastroenterol. 2023;23:288.\n78. Walker S, Goodfellow H, Pookarnjanamorakot P , Murray E, Bindman J, Bland-\nford A, Bradbury K, Cooper B, Hamilton FL, Hurst JR, et al. Impact of fatigue \nas the primary determinant of functional limitations among patients with \npost-COVID-19 syndrome: a cross-sectional observational study. BMJ Open. \n2023;13:e069217.\n79. Onate-Figuérez A, Avendaño-Coy J, Fernández-Canosa S, Soto-León V, López-\nMolina MI, Oliviero A. Factors Associated with fatigue in people with spinal \ncord Injury: a systematic review and Meta-analysis. Arch Phys Med Rehabil. \n2023;104:132–42.\n80. Lock AM, Bonetti DL, Campbell ADK. The psychological and physiological \nhealth effects of fatigue. Occup Med (Lond). 2018;68:502–11.\n81. García-González D, Medino-Muñoz J, Romero-Elías M, García-Foncillas J, Ruiz-\nCasado A. Biological mechanisms of cancer-related fatigue in breast cancer \nsurvivors after treatment: a scoping review. J Cancer Surviv. 2023.\n82. Penson A, Walraven I, Bronkhorst E, Grootenhuis MA, Maurice-Stam H, de \nBeijer I, der Loo M, Tissing WJE, van der Pal HJH, de Vries ACH, et al. Chronic \nfatigue in childhood cancer survivors is associated with lifestyle and psycho-\nsocial factors; a DCCSS LATER study. ESMO Open. 2023;8:102044.\n83. Åkerstedt T, Schwarz J, Theorell-Haglöw J, Lindberg E. What do women mean \nby poor sleep? A large population-based sample with polysomnographi-\ncal indicators, inflammation, fatigue, depression, and anxiety. Sleep Med. \n2023;109:219–25.\n84. Chitnis T, Vandercappellen J, King M, Brichetto G. Symptom Interconnectiv-\nity in multiple sclerosis: a narrative review of potential underlying Biological \nDisease processes. Neurol Ther. 2022;11:1043–70.\n\nPage 12 of 13\nLi et al. Reproductive Biology and Endocrinology            (2024) 22:66 \n85. Siemionow V, Fang Y, Calabrese L, Sahgal V, Yue GH. Altered central nervous \nsystem signal during motor performance in chronic fatigue syndrome. Clin \nNeurophysiol. 2004;115:2372–81.\n86. Gottschalk M, Kümpfel T, Flachenecker P , Uhr M, Trenkwalder C, Holsboer F, \nWeber F. Fatigue and regulation of the hypothalamo-pituitary-adrenal axis in \nmultiple sclerosis. Arch Neurol. 2005;62:277–80.\n87. Huang YM, Chi CW, Wu PS, Tai HC, Chien MN, Chen YJ. Adrenal gland irradia-\ntion causes fatigue accompanied by reactive changes in cortisol levels. J Clin \nMed. 2022; 11.\n88. Coss D. Regulation of reproduction via tight control of gonadotropin hor-\nmone levels. Mol Cell Endocrinol. 2018;463:116–30.\n89. Kuroda K, Venkatakrishnan R, James S, Šucurovic S, Mulac-Jericevic B, Lucas \nES, Takeda S, Shmygol A, Brosens JJ, Quenby S. Elevated periimplantation \nuterine natural killer cell density in human endometrium is associated with \nimpaired corticosteroid signaling in decidualizing stromal cells. J Clin Endo-\ncrinol Metab. 2013;98:4429–37.\n90. Wronka KM, Wunsch E, Kozłowska-Petriczko K, Wójcicki M, Kruk B, Milkiewicz \nP . Dehydroepiandrosterone sulfate indicates decreased sulfation capacity and \nimpaired quality of life in patients with primary sclerosing cholangitis. Pol \nArch Intern Med. 2021;131:790–6.\n91. Gleicher N, Darmon S, Molinari E, Zhang L, Hu J, Albertini DF, Barad DH. A \nform of secondary ovarian insufficiency (SOI) due to adrenal hypoandrogen-\nism as new infertility diagnosis. Endocrine. 2021;72:260–7.\n92. Ozcil MD. Dehydroepiandrosterone supplementation improves ovarian \nreserve and pregnancy rates in poor responders. Eur Rev Med Pharmacol Sci. \n2020;24:9104–11.\n93. Gao H, Gao L, Wang W. Advances in the cellular immunological pathogenesis \nand related treatment of primary ovarian insufficiency. Am J Reprod Immu-\nnol. 2022;88:e13622.\n94. Gibson DA, Simitsidellis I, Kelepouri O, Critchley HOD, Saunders PTK. \nDehydroepiandrosterone enhances decidualization in women of advanced \nreproductive age. Fertil Steril. 2018;109:728–e734722.\n95. Mandal S, Mukhopadhyay P , Ghosh S. DHEA on sexual function in Sheehan \nSyndrome: a Randomized double-blind placebo-controlled crossover trial. J \nClin Endocrinol Metab. 2022;107:e3395–402.\n96. Cabelka CA, Baumann CW, Collins BC, Nash N, Le G, Lindsay A, Spangen-\nburg EE, Lowe DA. Effects of ovarian hormones and estrogen receptor α on \nphysical activity and skeletal muscle fatigue in female mice. Exp Gerontol. \n2019;115:155–64.\n97. Kanamori T, Suzuki M, Kaneko Y, Yamada K, Kubo H, Uchiyama M. Severe \nfatigue due to valproate-induced hypothyroidism in a case of bipolar disor-\nder. Ann Gen Psychiatry. 2020;19:49.\n98. Sunada N, Honda H, Nakano Y, Yamamoto K, Tokumasu K, Sakurada Y, \nMatsuda Y, Hasegawa T, Otsuka Y, Obika M, et al. Hormonal trends in patients \nsuffering from long COVID symptoms. Endocr J. 2022;69:1173–81.\n99. Sun Q, Oltra E, Dijck-Brouwer DAJ, Chillon TS, Seemann P , Asaad S, Demircan \nK, Espejo-Oltra JA, Sánchez-Fito T, Martín-Martínez E, et al. Autoantibodies \nto selenoprotein P in chronic fatigue syndrome suggest selenium transport \nimpairment and acquired resistance to thyroid hormone. Redox Biol. \n2023;65:102796.\n100. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, \nNixon A, Pearce EN, Soldin OP , Sullivan S, et al. Guidelines of the American \nthyroid Association for the diagnosis and management of thyroid disease \nduring pregnancy and postpartum. Thyroid. 2011;21:1081–125.\n101. Wu Z, Qu J, Zhang W, Liu GH. Stress, epigenetics, and aging: unraveling the \nintricate crosstalk. Mol Cell. 2023.\n102. Rosenberg AGW, Dingemans VDA, Bos-Roubos AG, Luijks S, Dessens AB, \nDykgraaf R, Roos-Hesselink JW, Van Rossum EFC, Van Der Lely AJ, De Graaff \nLCG. Associations between fatigue and endocrine and non-endocrine health \nproblems in Turner Syndrome: Cohort Study and Review. J Clin Endocrinol \nMetab. 2023;108:e1649–59.\n103. Tsigos C, Chrousos GP . Hypothalamic-pituitary-adrenal axis, neuroendocrine \nfactors and stress. J Psychosom Res. 2002;53:865–71.\n104. Strahler J, Skoluda N, Rohleder N, Nater UM. Dysregulated stress signal sensi-\ntivity and inflammatory disinhibition as a pathophysiological mechanism of \nstress-related chronic fatigue. Neurosci Biobehav Rev. 2016;68:298–318.\n105. Van Booven DJ, Gamer J, Joseph A, Perez M, Zarnowski O, Pandya M, Collado \nF, Klimas N, Oltra E, Nathanson L. Stress-Induced Transcriptomic changes in \nfemales with myalgic Encephalomyelitis/Chronic fatigue syndrome reveal \ndisrupted Immune signatures. Int J Mol Sci. 2023; 24.\n106. Vignjević Petrinović S, Milošević MS, Marković D, Momčilović S. Inter-\nplay between stress and cancer-A focus on inflammation. Front Physiol. \n2023;14:1119095.\n107. Li R, Zhou Y, Zhang S, Li J, Zheng Y, Fan X. The natural (poly)phenols as modu-\nlators of microglia polarization via TLR4/NF-κB pathway exert anti-inflamma-\ntory activity in ischemic stroke. Eur J Pharmacol. 2022;914:174660.\n108. Sakurada Y, Matsuda Y, Motohashi K, Hasegawa T, Otsuka Y, Nakano Y, \nTokumasu K, Yamamoto K, Sunada N, Honda H et al. Clinical characteristics of \nfemale long COVID patients with menstrual symptoms: a retrospective study \nfrom a Japanese outpatient clinic. J Psychosom Obstet Gynecol. 2024; 45.\n109. Park Y, Lee JJ, Koh JH, Kim MJ, Park SH, Kwok SK. Kynurenine pathway can \nbe a potential biomarker of fatigue in primary Sjögren’s syndrome. Clin Exp \nRheumatol. 2023.\n110. Langley C, Masuda N, Godwin S, De Marco G, Smith AD, Jones R, Bruce J, \nThai NJ. Dysfunction of basal ganglia functional connectivity associated \nwith subjective and cognitive fatigue in multiple sclerosis. Front Neurosci. \n2023;17:1194859.\n111. Rasmussen AL, Larsen SV, Ozenne B, Köhler-Forsberg K, Stenbæk DS, \nJørgensen MB, Giraldi A, Frokjaer VG. Sexual health and serotonin 4 receptor \nbrain binding in unmedicated patients with depression-a NeuroPharm study. \nTransl Psychiatry. 2023;13:247.\n112. Milrad SF, Hall DL, Jutagir DR, Lattie EG, Czaja SJ, Perdomo DM, Fletcher MA, \nKlimas N, Antoni MH. Depression, evening salivary cortisol and inflamma-\ntion in chronic fatigue syndrome: a psychoneuroendocrinological structural \nregression model. Int J Psychophysiol. 2018;131:124–30.\n113. Slavich GM, Sacher J. Stress, sex hormones, inflammation, and major depres-\nsive disorder: extending Social Signal Transduction Theory of Depression \nto account for sex differences in mood disorders. Psychopharmacology. \n2019;236:3063–79.\n114. Berentschot JC, Drexhage HA, Aynekulu Mersha DG, Wijkhuijs AJM, Geurts-\nvanKessel CH, Koopmans MPG, Voermans JJC, Hendriks RW, Nagtzaam NMA, \nde Bie M, et al. Immunological profiling in long COVID: overall low grade \ninflammation and T-lymphocyte senescence and increased monocyte \nactivation correlating with increasing fatigue severity. Front Immunol. \n2023;14:1254899.\n115. Kłysiak M, Wieder-Huszla S, Branecka-Woźniak D, Karakiewicz-Krawczyk K, \nNapieracz-Trzosek I, Owsianowska J, Jurczak A, Cymbaluk-Płoska A. Analysis \nof the occurrence of Predicative Factors of Chronic Fatigue in female patients \nwith Cancer of the Reproductive organs with respect to stage of treatment. \nInt J Environ Res Public Health. 2023; 20.\n116. Brenu EW, Huth TK, Hardcastle SL, Fuller K, Kaur M, Johnston S, Ramos SB, \nStaines DR, Marshall-Gradisnik SM. Role of adaptive and innate immune \ncells in chronic fatigue syndrome/myalgic encephalomyelitis. Int Immunol. \n2014;26:233–42.\n117. Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG. Plasma cytokines in \nwomen with chronic fatigue syndrome. J Transl Med. 2009;7:96.\n118. Al-Hakeim HK, Al-Rubaye HT, Al-Hadrawi DS, Almulla AF, Maes M. Long-\nCOVID post-viral chronic fatigue and affective symptoms are associated with \noxidative damage, lowered antioxidant defenses and inflammation: a proof \nof concept and mechanism study. Mol Psychiatry. 2023;28:564–78.\n119. Liang PY, Diao LH, Huang CY, Lian RC, Chen X, Li GG, Zhao J, Li YY, He XB, Zeng \nY. The pro-inflammatory and anti-inflammatory cytokine profile in peripheral \nblood of women with recurrent implantation failure. Reprod Biomed Online. \n2015;31:823–6.\n120. Qin D, Xu H, Chen Z, Deng X, Jiang S, Zhang X, Bao S. The peripheral and \ndecidual immune cell profiles in women with recurrent pregnancy loss. Front \nImmunol. 2022;13:994240.\n121. Zhu X, Liu J, Pan H, Geng Z, Huang W, Liu T, Zhang B. Thymopentin treatment \nof murine premature ovarian failure via attenuation of immune cell activ-\nity and promotion of the BMP4/Smad9 signalling pathway. Int J Med Sci. \n2021;18:3544–55.\n122. Jain M, Mladova E, Shichanina A, Kirillova K, Povarova A, Scherbakova L, \nSamokhodskaya L, Panina O. Microbiological and cytokine profiling of \nmenstrual blood for the Assessment of Endometrial receptivity: a pilot study. \nBiomedicines. 2023; 11.\n123. Xu J, Potter M, Tomas C, Elson JL, Morten KJ, Poulton J, Wang N, Jin H, Hou Z, \nHuang WE. A new approach to find biomarkers in chronic fatigue syndrome/\nmyalgic encephalomyelitis (CFS/ME) by single-cell Raman Micro-spectros-\ncopy. Analyst. 2019;144:913–20.\n124. Barrera MJ, Aguilera S, Castro I, Carvajal P , Jara D, Molina C, González \nS, González MJ. Dysfunctional mitochondria as critical players in the \n\nPage 13 of 13\nLi et al. Reproductive Biology and Endocrinology            (2024) 22:66 \ninflammation of autoimmune diseases: potential role in Sjögren’s syndrome. \nAutoimmun Rev. 2021;20:102867.\n125. Zhou YX, Wei J, Deng G, Hu A, Sun PY, Zhao X, Song BL, Luo J. Delivery of \nlow-density lipoprotein from endocytic carriers to mitochondria supports \nsteroidogenesis. Nat Cell Biol. 2023;25:937–49.\n126. Verma H, Gangwar P , Yadav A, Yadav B, Rao R, Kaur S, Kumar P , Dhiman M, \nTaglialatela G, Mantha AK. Understanding the neuronal synapse and chal-\nlenges associated with the mitochondrial dysfunction in mild cognitive \nimpairment and Alzheimer’s disease. Mitochondrion. 2023;73:19–29.\n127. Trigo D, Avelar C, Fernandes M, Sá J, da Cruz ESO. Mitochondria, energy, and \nmetabolism in neuronal health and disease. FEBS Lett. 2022;596:1095–110.\n128. Supruniuk E, Górski J, Chabowski A. Endogenous and exogenous antioxi-\ndants in skeletal muscle fatigue development during Exercise. Antioxid \n(Basel). 2023; 12.\n129. Bai L, Tan C, Ren J, Liu J, Zou W, Liu G, Sheng Y. Cordyceps Militaris acidic poly-\nsaccharides improve learning and memory impairment in mice with exercise \nfatigue through the PI3K/NRF2/HO-1 signalling pathway. Int J Biol Macromol. \n2023;227:158–72.\n130. Ma C, Deng Y, Xiao R, Xu F, Li M, Gong Q, Gao J. Anti-fatigue effect of phlorizin \non exhaustive exercise-induced oxidative injury mediated by Nrf2/ARE \nsignaling pathway in mice. Eur J Pharmacol. 2022;918:174563.\n131. Wang L, Tang J, Wang L, Tan F, Song H, Zhou J, Li F. Oxidative stress in oocyte \naging and female reproduction. J Cell Physiol. 2021;236:7966–83.\n132. Lai XL, Xiong WJ, Li LS, Lan MF, Zhang JX, Zhou YT, Niu D, Duan X. Zinc \ndeficiency compromises the maturational competence of porcine oocyte by \ninducing mitophagy and apoptosis. Ecotoxicol Environ Saf. 2023;252:114593.\n133. Shan H, Luo R, Guo X, Li R, Ye Z, Peng T, Liu F, Yang Z. Abnormal endometrial \nreceptivity and oxidative stress in polycystic ovary syndrome. Front Pharma-\ncol. 2022;13:904942.\n134. Mauchart P , Vass RA, Nagy B, Sulyok E, Bódis J, Kovács K. Oxidative stress in \nassisted Reproductive techniques, with a focus on an underestimated risk \nfactor. Curr Issues Mol Biol. 2023;45:1272–86.\n135. Knoop V, Cloots B, Costenoble A, Debain A, Vella Azzopardi R, Vermeiren S, \nJansen B, Scafoglieri A, Bautmans I. Fatigue and the prediction of negative \nhealth outcomes: a systematic review with meta-analysis. Ageing Res Rev. \n2021;67:101261.\n136. Katznelson L, Gadelha M. Glucocorticoid use in patients with adrenal insuf-\nficiency following administration of the COVID-19 vaccine: a pituitary society \nstatement. Pituitary. 2021;24:143–5.\n137. Vandenbulcke L, Erard M, Van Assche D, De Langhe E. The effect of physical \nexercise on fatigue in systemic lupus erythematosus: a systematic review. \nActa Clin Belg. 2023;78:342–57.\n138. Maunick B, Skvarc D, Olive L, Mikocka-Walus A. Effects of acceptance and \ncommitment therapy on fatigue for patients with cancer and other chronic \nhealth conditions: a systematic review and meta-analysis. J Psychosom Res. \n2023;171:111366.\n139. Wan JJ, Qin Z, Wang PY, Sun Y, Liu X. Muscle fatigue: general understanding \nand treatment. Exp Mol Med. 2017;49:e384.\n140. Spinelli FR, Berti R, Farina G, Ceccarelli F, Conti F, Crescioli C. Exercise-induced \nmodulation of Interferon-signature: a therapeutic route toward management \nof systemic Lupus Erythematosus. Autoimmun Rev. 2023;22:103412.\n141. Turk MA, Liu Y, Pope JE. Non-pharmacological interventions in the treatment \nof rheumatoid arthritis: a systematic review and meta-analysis. Autoimmun \nRev. 2023;22:103323.\n142. Maksoud R, Balinas C, Holden S, Cabanas H, Staines D, Marshall-Gradisnik S. A \nsystematic review of nutraceutical interventions for mitochondrial dysfunc-\ntions in myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. \n2021;19:81.\n143. Barnish M, Sheikh M, Scholey A. Nutrient therapy for the improvement of \nfatigue symptoms. Nutrients. 2023; 15.\n144. Avery H, Jackson P , Haskell-Ramsay C. The effect of iron supplementation on \ncognition, subjective mood, well-being and fatigue in women of reproduc-\ntive age: a systematic review. Proceedings of the Nutrition Society. 2020; \n79:E330-E330.\n145. Garzon S, Cacciato PM, Certelli C, Salvaggio C, Magliarditi M, Rizzo G. Iron \nDeficiency Anemia in pregnancy: Novel approaches for an old problem. \nOman Med J. 2020;35:e166.\n146. Shelling AN, Ahmed Nasef N. The role of lifestyle and dietary factors in the \ndevelopment of premature ovarian insufficiency. Antioxid (Basel). 2023; 12.\n147. Yao Y, Tang Y, Qin H, Meng R, Zhang C, Zhang Y, Yang Y, Qiao P , Liu J, Su J. Zinc \nsupplementation promotes oocyte maturation and subsequent embryonic \ndevelopment in sheep. Theriogenology. 2023;206:161–9.\n148. Safaei Z, Bakhshalizadeh SH, Nasr Esfahani MH, Akbari Sene A, Najafzadeh \nV, Soleimani M, Shirazi R. Effect of vitamin D3 on mitochondrial Biogenesis \nin Granulosa cells derived from polycystic ovary syndrome. Int J Fertil Steril. \n2020;14:143–9.\n149. Izadi A, Ebrahimi S, Shirazi S, Taghizadeh S, Parizad M, Farzadi L, Gargari \nBP . Hormonal and metabolic effects of Coenzyme Q10 and/or vitamin \nE in patients with polycystic ovary syndrome. J Clin Endocrinol Metab. \n2019;104:319–27.\n150. Cleare AJ. Glucocorticoids and glucocorticoid receptors: mediators of \nfatigue? Acta Neuropsychiatr. 2003;15:341–53.\n151. Sasson R, Winder N, Kees S, Amsterdam A. Induction of apoptosis in \ngranulosa cells by TNF alpha and its attenuation by glucocorticoids involve \nmodulation of Bcl-2. Biochem Biophys Res Commun. 2002;294:51–9.\n152. Hinchado MD, Quero-Calero CD, Otero E, Gálvez I, Ortega E. Synbiotic supple-\nmentation improves Quality of Life and Inmunoneuroendocrine Response \nin patients with Fibromyalgia: influence of codiagnosis with chronic fatigue \nsyndrome. Nutrients. 2023; 15.\n153. Demir Yıldırım A, Güngör Satılmış İ. The effects of yoga on pregnancy, stress, \nand anxiety in infertile individuals: a systematic review. Holist Nurs Pract. \n2022;36:275–83.\n154. Min ES, Lee MS, Lee MK, Lee M, Kim E, Song E, Hur MH. A qualitative study on \nthe experience of acupuncture treatment in infertile women. Integr Med Res. \n2021; 10.\n155. Regev S, Schwartz D, Sarid O, Goren G, Slonim-Nevo V, Friger M, Sergienko R, \nGreenberg D, Monsonego A, Nemirovsky A, et al. Randomised clinical trial: \npsychological intervention improves work productivity and daily activity by \nreducing abdominal pain and fatigue in Crohn’s disease. Aliment Pharmacol \nTher. 2023;57:861–71.\n156. Szatmári A, Helembai K, Zádori J, Kovács I. Paramedical counselling in infertil-\nity treatment: its effects on anxio-depressive symptom severity, perceived \nstress and self-esteem. Heliyon. 2022;8:e09827.\n157. Kim M, Moon SH, Kim JE. Effects of psychological intervention for Korean \ninfertile women under in Vitro fertilization on infertility stress, depression, \nintimacy, sexual satisfaction and fatigue. Arch Psychiatr Nurs. 2020;34:211–7.\n158. Ozcan S, Kirca N. Effects of care given in line with Levine’s conservation \nmodel on the quality of life of women receiving infertility treatment: a single \nblind randomized controlled trial. Health Care Women Int. 2023;44:418–39.\n159. Kirca N, Özcan S. The effects of nursing care based on Levine’s conserva-\ntion model on fatigue, depression, perceived social support, and sleep \nquality in infertile women: a randomized controlled trial. Int J Nurs Knowl. \n2023;34:284–96.\n160. Skau S, Sundberg K, Kuhn HG. A proposal for a Unifying Set of definitions of \nfatigue. Front Psychol. 2021;12:739764.\n161. Kluger BM, Krupp LB, Enoka RM. Fatigue and fatigability in neurologic ill-\nnesses: proposal for a unified taxonomy. Neurology. 2013;80:409–16.\n162. Yang X, Xue Y, Liu R, Zhao X, Li K, Wang J, Hou L. Dopamine release impair-\nments Accompany Movement Vigor Deficiency in an Exercise-Induced \nfatigue mouse model. ACS Chem Neurosci. 2023;14:2443–9.\n163. Dougherty JP , Wolff BS, Cullen MJ, Saligan LN, Gershengorn MC. Taltirelin \nalleviates fatigue-like behavior in mouse models of cancer-related fatigue. \nPharmacol Res. 2017;124:1–8.\n164. Wersocki E, Bedson J, Chen Y, LeResche L, Dunn KM. Comprehensive system-\natic review of long-term opioids in women with chronic noncancer pain and \nassociated reproductive dysfunction (hypothalamic-pituitary-gonadal axis \ndisruption). Pain. 2017;158:8–16.\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in \npublished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}