Lifestyle factors and oxidative stress in female ...€¦ · Center for Reproductive Medicine Cleveland Clinic, 9500 Euclid Avenue, Desk A19, Cleveland, OH 44195, USA *Author for

Lifestyle factors and oxidativestress in female infertility: isthere an evidence base tosupport the linkage?Expert Rev. Obstet. Gynecol. 8(6), 607–624 (2013)

Sajal Gupta*,Jennifer Fedor,Kelly Biedenharn andAshok AgarwalCenter for Reproductive Medicine

Cleveland Clinic, 9500 Euclid Avenue,

Desk A19, Cleveland, OH 44195, USA

*Author for correspondence:

Tel.: + 12 164 449 485

Fax: + 12 164 456 049

[email protected]

At present, between 10 to 15% of couples are infertile, and half of all infertility cases arecredited to a female factor. Determination of the source of the problem may hold the key toimproving fertility for women. Emerging research demonstrates that reactive oxygen speciesand oxidative stress (OS) have strong connections with female reproductive function;increases in OS which is associated with certain lifestyle factors can negatively impact femalefertility. Lifestyle factors including being obese or underweight, exercising, cigarette smoking,alcohol and caffeine consumption, drug use, psychological stress and environmental andoccupational exposures can all have adverse effects on fertility due to their complexinteractions and impact exerted via OS on female reproductive processes. Our reviewhighlights these linkages to explain their impact on female fertility, as well as providesuggestions to reduce OS and improve reproductive potential in women.

KEYWORDS: antioxidants • assisted reproductive techniques • female reproduction • infertility • lifestyle factors

• oxidative stress • reactive oxygen species.

The prevalence of lifestyle factors detrimentalto fertility has increased significantly in the21st century, particularly among women inthe reproductive age. There has been a dra-matic shift in the risk factors for infertilityover the last few decades including delayedconception and advanced maternal age. Theseshifts have probably further brought to forethe impact of oxidative stress (OS) on femaleinfertility by influencing the oxidative micro-environment within follicles with increasingage. Many lifestyle factors are reported to beassociated with the generation of OS, whichrenders the physiological processes of femalereproduction and embryo development vulner-able to damage. The present research aims toidentify the complex relationship between life-styles and OS-induced infertility, in order toprovide recommendations for enhancement ofnatural and assisted fertility. OS may contrib-ute to several disease states affecting female fer-tility, including endometriosis and polycysticovary syndrome (PCOS). In addition,extremes of body weight, excessive physical

activity, maternal smoking, alcohol and caf-feine consumption, recreational drug abuse,psychological stress and environmental pollu-tants may negatively affect female fertilitythrough OS mechanisms. The prevalence ofsome of those factors, such as smoking, haveactually decreased while others, like obesity,have such a wide range of metabolic conse-quences that it is impossible to attribute theireffect on fertility to OS.

Antioxidants, lifestyle modification and inte-grated treatment approaches may be viableoptions to improve fecundity. Currently, thereis a gap in the literature with few studies report-ing the OS-mediated effects of multiple lifestylefactors on female fertility – an issue-this researchaims to address. This review is beneficial forboth the women in reproductive age facing sub-fertility and their physicians, who wish toimprove fertility potential. Infertility affects 10–15% of couples [1,2], and half of all infertilitycases are attributed to female factors [3]. There-fore, understanding the negative impact of life-style and OS on female fertility is critical.

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Free radicals, antioxidants & oxidative stressFree radicals are reactive, unstable molecules that may be gener-ated as the result of normal metabolic processes, or may comefrom exogenous sources. Free radicals can be classified as eitherreactive nitrogen species or reactive oxygen species (ROS). Thethree main types of ROS are superoxide (O2•-), hydrogen per-oxide (H2O2) and hydroxyl radical (OH•). The superoxide rad-ical is dismutated and converted into H2O2. H2O2 can also beformed directly by oxidase enzymes. The hydroxyl radical isgenerated by the conversion of H2O2 or superoxide by a metalion catalyst.

Antioxidants are protective mechanisms that scavenge excessROS and neutralize these radicals into molecules of water.These molecules maintain ROS at physiologically compatiblelevels. There are two main types of antioxidants. Enzymaticantioxidants or natural antioxidants include superoxide dismu-tase (SOD), catalase and glutathione (GSH). Non-enzymaticantioxidants or synthetic antioxidants include vitamins Cand E, selenium, zinc, taurine, hypotaurine, glutathione, b-carotene and carotene. These nutrients are not actually ‘often’obtained in dietary supplements. There is a great geographicand cultural variation in supplement access and use, and thisvariation is often correlated with lifestyle factors and healthylifestyle in general. In the USA, female smokers are more likelyto take multivitamins than non-smokers. Thus, there are bothendogenous and exogenous contributors to theantioxidant milieu.

Normally, there exists a delicate balance between levels ofROS and antioxidants. However, OS is a condition that ariseswhen the production of ROS exceeds the scavenging capabil-ities of the antioxidants. This imbalance can be caused by anincrease in ROS or a decrease in antioxidant activity. OS isdetrimental to the entire system, because high levels of ROScan damage biological molecules such as lipids, proteins andDNA, resulting in damage and dysfunction of the cell. ROSare produced by the mitochondria during glucose metabolismand the ROS, that is generated, can cause alterations of themitochondria and depletion of ATP. Although an overabun-dance of these species can result in pathology, ROS are neces-sary for a variety of physiologic functions in the body,including those of the female reproductive system [4].

Redox pathways in the female reproductive systemEach month within the ovarian follicles, a group of oocytesbegins to develop. Meiosis I resumes only in the dominantoocyte. This stage in oocyte development is characterized by anincrease in ROS; antioxidants retard this process. Antioxidants,however, are beneficial to meiosis II [5]. Within the pre-ovulatory follicles, ROS stimulates programmed cell death,although this is offset by the actions of GSH and follicularstimulating hormone (FSH) in the dominant follicle [5]. Addi-tionally, the ROS produced by the follicles contributes to theinduction of ovulation. Ovulation is induced by the LH surge,and results in the release of a secondary oocyte from the ovary.Post-LH surge inflammatory precursors are necessary for the

process of ovulation, although an excessive amount leads to theproduction of ROS [6]. Following ovulation, the corpus luteumdevelops from the remnants of an ovarian follicle. Within thecorpus luteum, the mitochondrial electron transport chain hasbeen found to leak electrons, leading to the generation of thesuperoxide radical, when these electrons combine with oxygen.In order to cope with the increase in ROS within the corpusluteum, levels of SOD also increase. The corpus luteum willregress if no pregnancy takes place, and will persist if a preg-nancy does occur. Pregnancy is considered to be a state of OS.During the first trimester of pregnancy, an inflammatoryresponse is produced as a result of leukocyte activation, and theproduction of superoxide radicals increases. OS is supported byincreases in lipid peroxides, free radicals and vitamin E in theplacental mitochondria as the pregnancy progresses [7,8].

Reactive oxygen species in oocytes & embryosLevels of OS are related to oocyte and embryo quality, pro-grammed cell death, permanent meiosis arrest, age-relateddefects and chromosomal abnormalities. The excessive produc-tion of ROS in oocytes and embryos can affect mitochondrialfunction, and lead to OS-induced arrest of cell division andcell death [9]. In 2010, Liu et al. found that H2O2 treatmentinduced programmed cell death in mouse zygotes, and thatmitochondrial damage caused by OS was associated with cellcycle arrest [9]. Studies in mouse and rat embryos have demon-strated that the antioxidant defense system develops graduallywith increasing embryonic age, peaking at the neonatal period[10]. Because the antioxidant system remains immature duringthe early development of the embryo, and since high concen-trations of ROS are produced during the early developmentalstages, this leaves the embryo susceptible to oxidative damageto DNA, proteins and lipid membranes. There is a role for OSin impairing mitochondrial function and the production ofATP during embryogenesis. Cell division requires the contrac-tion of non-muscular myosin II, the energy needed for thiscontraction is produced by the mitochondria. OS may reducethe ATP production and render cell division problematic. Thisprocess can have severe consequences for organogenesis andmay result in embryonic damage.

An elevated concentration of homocysteine has been reportedin follicular fluid after ovarian hyperstimulation [11]. There arereported evidence that elevated homocysteine can cause epige-nomic changes in the embryos. There is a potential that ele-vated homocysteine levels will induce epigenetic changes andcorrelate with poor embryo quality [12].

There are several endogenous mechanisms in place to guarddeveloping oocytes and embryos from OS-induced damage.Many aspects of development in the gamete and embryo natu-rally occur in low oxygen environments, which may help toprotect from free radical damage by ROS [13]. Developing fol-licles and embryos are also protected from toxicity and OS byantioxidant molecules, although as discussed previously, there isa lag time before these antioxidants become sufficiently active.Internal sources of protection within the embryo include

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antioxidant enzymes such as SOD and g-glutamylcysteine syn-thetase [14]. Human follicular fluid contains antioxidant pro-teins such as SOD, GST and paraxonase [15]. Follicular fluidalso includes non-enzymatic antioxidants such as hypotaurineand ascorbic acid which can act as external sources of protec-tion against ROS for the embryo [14]. Higher concentrations ofmelatonin, a direct free-radical scavenger, have been found infollicular fluid as compared with serum, suggesting that thismolecule may also protect maturing oocytes and developingembryos from OS [16]. In fact, exogenous melatonin adminis-tration has been found to reduce oxidative damage to the fol-licle and to improve fertilization rates [16]. Treatment withexogenous antioxidants and other substances can also improveoocyte and embryo quality. The addition of polyethyleneglycol-catalase to embryos having been treated with H2O2 atte-nuated the ROS-induced apoptosis and arrest, resulting inincreased development [17]. Vitamins C and E, carotenoids andfolic acid may be effective in abating both embryonic andmaternal OS, and thus reducing congenital anomalies, althoughfurther clinical investigation is needed [10].

Role of oxidative stress in female infertilityInfertility is defined as the inability to achieve a pregnancywithin 12 months of unprotected intercourse. It is characterizedas primary if there is no previous conception, and as secondaryif at least one member of the couple has conceived previously.Infertility affects approximately 10–15% of couples [1,2], andabout half of all infertility cases are attributed to female factors[3]. OS, evidenced by an increase in ROS and decrease in anti-oxidant capacity, has been hypothesized to play a role in theetiology of infertility, including endometriosis, polycystic ovarysyndrome, idiopathic infertility and miscarriages. OS may alsocontribute to infertility in males.

Endometriosis

Endometriosis is a chronic disorder that is characterized bythe growth and implantation of endometrial cells and stromain areas of the body, outside of the uterus, most often on thepelvic peritoneum or ovaries. It is often associated with pelvicpain and infertility. Endometriosis affects 6–10% ofreproductive-aged women [18] and over 30% of infertilewomen [19]. It has been suggested that OS is involved in theetiopathology of the disease. Several studies have demon-strated an increased presence of biomarkers for OS in thewomen with endometriosis. Levels of SOD and GSH peroxi-dase in the peritoneal fluid were lowest among patients withendometriosis. Women with endometriosis also had higherconcentrations of lipid peroxidase [20]. Stromal cells fromwomen with endometriosis had increased superoxide andH2O2 production, as well increased SOD activity as com-pared with stromal cells from controls [21]. This suggests thatan increase in ROS production in the endometriotic cells iscompensated by a subsequent increase in antioxidant activity.Women with endometriosis also have higher serum levels ofthe heat shock protein HSP70b’, suggesting that the OS

associated with endometriosis is systemic, rather than con-fined to the peritoneal cavity [22].

Endometriosis is associated with decreased uterine receptiv-ity, tubal dysfunction due to adhesions or scarring and pooroocyte quality, which may lead to reduced implantation rates[23]. These factors may be the underlying causes of the infertil-ity in patients with endometriosis, and OS may be responsiblefor these negative effects. Ovarian cortex tissue surroundingendometriotic lesions contains higher levels of 8-hydroxy-2’-deoxyguanosine (8-OHdG) than ovarian tissue surroundingother benign ovarian cysts [24]. Infertile women with endome-triosis were found to have lower follicular fluid levels ofvitamin C, lower plasma levels of SOD and higher plasma lev-els of vitamin E [25]. However, this study did not account fordietary differences between women with and without endome-triosis. Since markers of the OS are present both in the ovariancortex where the follicles are located, and in the follicular fluiditself. This suggests that the OS associated with endometriosismay be responsible for the decrease in oocyte quality and sub-sequent decrease in implantation found in these patients.Changes in the endometrial epithelium in women with endo-metriosis may also decrease uterine receptivity and lead toreduced implantation rates. It has been hypothesized that freeradicals mediate these changes in the endometrium [26,27].Ota et al., in 2000 found that there are phase-dependentchanges in the expression of glutathione peroxidase (GPx), anenzyme that reduces ROS to water or alcohol, throughout themenstrual cycle in normal eutopic endometrial tissue. This var-iation in expression of GPx was not observed in the eutopicendometrium of women with endometriosis, suggesting thatthe endometrial tissue of women with endometriosis is moresusceptible to OS.

Lifestyle factors such as intake of specific fatty acids andmarkers such as adipokines have been investigated [28]. Thesefactors are known to affect inflammation and OS and influencerisk and behavior of endometriosis in humans and animalmodels.

OS has been identified in women with endometriosis, andthis underlies the cause of infertility among women withendometriosis. Majority of the study reports have investigatedcases of women with endometriosis where OS and relatedfactors have been measured post-diagnosis. The design ofthese studies temporally makes it impossible to tease theselevels from consequences of disease to imply a causal relation-ship. In the future, two types of studies are needed–onewhere OS is measured prior to symptom onset or at leastsoon after symptom onset but prior to diagnosis of endome-triosis, and another where it is evaluated if induced endome-triosis in animal models or ectopic endometrium in cellularmodels confers advancement of OS.

Polycystic ovary syndrome

PCOS is one of the most common hormonal disordersamong women of reproductive age, with a prevalence ofapproximately 4.6% [29]. PCOS is characterized by polycystic

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ovaries (enlarged ovaries containing multiple, small cystsaround the perimeter), hyperandrogenism and ovulatory dys-function [30]. Menstrual irregularities, such as amenorrhea ormenorrhagia, are also common in PCOS patients [30].Patients with PCOS also experience a higher rate of failedimplantation after inducing ovulation, as well as an increasedrisk of spontaneous abortion once pregnancy is achieved.This suggests that infertility associated with PCOS is due toovulatory dysfunction and an altered endometrial environ-ment [31]. The exact cause of PCOS remains unknown. How-ever, OS may play a role in its etiology.

Several studies have found increased biomarkers of OS inPCOS patients. Serum levels of malondialdehyde (MDA)-modified proteins, a maker of oxidative protein status, werehigher in patients with PCOS than in controls [32]. Kuscu et al.found that young, non-obese women with PCOS had signifi-cantly higher levels of MDA and SOD, and suggest thatPCOS is itself responsible for the presence of OS in thesepatients [33]. PCOS patients were also found to exhibit mito-chondrial dysfunction, manifested as a decrease in oxygen con-sumption by the mitochondria, an increase in ROS productionand a decrease in serum levels of GSH antioxidants. This char-acteristic augmentation of ROS and reduction in antioxidantstatus suggests that OS is present in women with PCOS [34].OS has also been linked to the development of insulin resist-ance and hyperandrogenism, by way of a proinflammatorystate, in women with this disorder [35]. Therefore, OS may playa role in the development of PCOS itself, as well as in thedevelopment of its associated symptoms. However, PCOS is acomplex disorder because many women with PCOS are alsooverweight or obese. Therefore it is difficult to tease apart if itis PCOS itself, or the comorbid obesity which contributesmost significantly to the infertility associated with the disorder.Additional research is greatly needed in order to elucidatethis relationship.

Sabuncu et al. compared PCOS patients (n = 27) with meanBMI 31.4 and mean age of 26.7 with BMI- and age-matchedcontrol group. They demonstrated that higher level of erythro-cyte MDA was seen in PCOS patients (mean value 70.9 mmol/mol Hb) compared to controls (p = 0.009) [36]. The signifi-cantly higher levels of MDA in PCOS patients than the controlwere also found by Palacio and colleagues [32]. Protein oxida-tion status was often assessed with a colorimetric assay thatmeasures protein carbonyl (PC) content, after reacting thepatient’s serum with dinitrophenylhydrazine. Fenkci et al.,demonstrated that the PC level was significantly higher inPCOS patients with normal BMI compared to the control(18.01 ± 0.80 vs 14.19 ± 0.40 nmol/l, p = 0.001) [37]. Thisobservation of higher protein oxidation suggested that free radi-cal damage proteins in PCOS patients. Furthermore, proteincarbonyls were shown to have a positive correlation with fastinginsulin. This suggested a strong association between insulinresistance and protein oxidation in PCOS.

This characteristic augmentation of ROS and reduction inantioxidant status suggests that OS is present in women with

PCOS. OS has also been linked to the development of insulinresistance and hyperandrogenism, by the way of a proinflam-matory state, in women with this disorder. The role of OS inthe pathogenesis of PCOS is not fully understood and the evi-dence is conflicting. The current evidence points toward anassociation between the oxidative microenvironment of theovarian tissue and ovarian steroidogenesis and follicular devel-opment. Whether the OS is the cause or the result of the meta-bolic disturbances encountered in PCOS, remains to beelucidated. However it is recognized that there is a strong rela-tionship between hyperinsulinemia, hyperlipedemia and OS.

Unexplained infertility

Idiopathic infertility affects 10–20% of infertile couples.Although the pathophysiology of unexplained infertility isunknown, OS may play a role in its development. Patientswith unexplained infertility have lower total antioxidant statusin peritoneal fluid than fertile women and those with tubalinfertility [38]. Higher levels of MDA, a biomarker of lipid per-oxidation, have been found in women with idiopathic infertility[39]. Significant higher levels of ROS were also present in theprocessed peritoneal fluid of patients with idiopathic infertility[8]. Women experiencing unexplained infertility have lower lev-els of antioxidants and higher levels of ROS, implicating OS asa possible mechanism for the development of this disorder.Although the administration of antioxidants such as N-acetylcysteine (NAC), an antioxidant and precursor to GSH, maycombat increases in ROS production and control systemic OS,NAC has not been demonstrated as an effective treatment forunexplained infertility [40]. Future well designed, with strict ran-domization of patients to intervention versus placebo andadequately powered randomized, controlled trials need to inves-tigate antioxidant supplementation and free-radical focused life-style modifications in cases of recurrent spontaneous abortion.

Recurrent pregnancy loss

Recurrent pregnancy loss affects 1–3% of women, and is char-acterized by a history of three or more consecutive pregnancylosses. In half of all recurrent pregnancy loss cases, there is noidentifiable cause. However, impaired antioxidant defenses andaugmented production of ROS have been associated with unex-plained recurrent spontaneous abortion [41]. Patients experienc-ing unexplained recurrent pregnancy loss had significantlylower blood concentrations of GSH and SOD, as well ashigher levels of MDA and nitric oxide (NO) than controls,reflecting an increase in OS [41]. This increase in OS may con-tribute to the pathogenesis of unexplained recurrent abortions.

Simsek et al., also demonstrated the involvement of OS inthe development of habitual abortion [42]. Women with habit-ual abortion were found to have lower blood levels of the anti-oxidants vitamin A, vitamin E, GSH and b-carotene, andhigher blood levels of lipid peroxidation and alkaline phospha-tase than healthy controls. It was also found that in womenwith recurrent abortion, an increase in serum lipid peroxidaselevels occurred in the time immediately preceding the



pregnancy loss, and a decrease in serum concentrations of lipidperoxidase occurred immediately following the abortion [43],suggesting that OS is the mechanism by which thissyndrome develops.

Augmented levels of TNF-a, an inflammatory cytokine,have also been linked to recurrent pregnancy loss [41]. NAC hasbeen shown to attenuate elevated levels of TNF-a in serumand amniotic fluid [44], suggesting that the control of OS withthe administration of antioxidants could be protective againstpregnancy loss in these women. Future is well designed, withstrict randomization of patients to intervention versus placeboand adequately powered randomized, controlled trials need toinvestigate antioxidant supplementation and free-radical focusedlifestyle modifications in cases of recurrent spontaneousabortion.

The link between lifestyle factors, oxidative stress &fertilityObesity

The NIH has reported that 35.5% of women in the USA areobese. Increased BMI is associated with a variety of healthcomplications, including those of the reproductive system.A pre-pregnancy BMI >24 is associated with a higher risk ofreproductive pathologies such as gestational diabetes mellitus,preeclampsia and pre-term labor [45]. Obesity is also associatedwith a longer time to conception, as well as decreased preg-nancy rates and increased risks of pregnancy loss. It has beensuggested that 25% of ovulatory infertility in the USA iscaused by overweight and obesity [46].

Ovarian function can be impaired in women with obesity.Insulin resistance is the mechanism by which ovarian dysfunc-tion can occur and which ultimately leads to infertility [47].Obesity is linked to insulin resistance, which stimulates theproduction of androgens from the ovaries and increases andro-gen aromatization to estrogens in the periphery. This mecha-nism can ultimately alter the development of the follicleswithin the ovaries in obese women [47]. Oocyte and embryoquality may also be compromised in women with obesity.Overweight and obese women have higher levels of insulin andtriglycerides in ovarian follicular fluid, as well as signs ofinflammation, which may negatively affect oocyte characteristicsthat are important for embryo development and implantation[48]. Fewer oocytes were retrieved, but embryo quality was notreduced [48].

Obesity is associated with decreased pregnancy rates andincreased risks of pregnancy loss. Van der Steeg et al. found alinear decline in spontaneous conception with BMI above29 kg/m2, with a 4% decrease in pregnancy rate with eachincreasing unit of BMI [49]. A recent systematic review alsoconcluded that the prevalence of recurrent early miscarriagewith spontaneous conception was significantly higher in obesewomen than in women with normal BMI values [50].A significant increase in euploid embryos was also found inoverweight women experiencing a spontaneous miscarriage, ascompared with healthy women who already had miscarriage

[51]. This suggests that obesity-associated miscarriage is inde-pendent of embryonic aneuploidy, and may instead result froman impaired uterine environment in these women. Therefore,obesity may also negatively affect the endometrium, potentiallyresulting in poor implantation rates and miscarriage.

OS, due to an increase in ROS, has been suggested as apotential mechanism responsible for the pathogenesis of obesity[52]. Several studies have demonstrated the association betweenobesity and increased OS. After the consumption of a high-fatmeal, blood levels of MDA were maintained and levels of xan-thine oxidase activity, H2O2 and triglycerides continued toincrease in obese women, while blood levels of these substancesdecreased in women who were not obese [52]. Increasing bodyweight was correlated with decreasing levels of SOD andincreasing levels of catalase and MDA in erythrocytes [53]. Thissimultaneous decrease in antioxidants and increase in peroxida-tion products suggests that OS is present in overweight women.Urinary creatinine-indexed levels of 8-epi-PGF2a, a marker forsystemic OS, were also positively associated with BMI as wellas with diabetes and smoking [54]. In addition to BMI, 8-epi-PGF2a was also positively correlated with waist circumference,peripheral DXA-derived regional fat mass accumulations andleptin levels [55]. This suggests that these parameters associatedwith obesity and central adiposity are important in the develop-ment of systemic OS in women. Increased OS may be themechanism by which fertility and pregnancy outcomes areimpaired in obese women. A study in mice demonstrated thatmaternal obesity was associated with increased rates of ROSproduction, decreased concentrations of GSH and mitochon-drial alterations in oocytes and zygotes as compared to leanfemale mice [56]. Blastocyst development was also significantlydecreased in obese mice, suggesting that OS impairs the mito-chondrial functioning in the oocytes and embryos of obesewomen which subsequently inhibiting blastocyst maturationand implantation [56]. Ultimately, the generation of OS as aresult of obesity and central adiposity seems to affect everyaspect of the female reproductive tract, suggesting OS may be apossible mechanism by which infertility develops among over-weight and obese women.

Underweight & eating disorders

The average lifetime prevalence rate for anorexia nervosa, a dis-order characterized by extreme thinness, or emaciation [201], is0.9% in adult women [57]. The disorder of infertility is one ofthe presentation of anorexia nervosa that may develop overtime. Women who are underweight or have an eating disorderhave a longer time to conception [58] and an increased risk ofspontaneous abortion [59]. In a sample of patients undergoingintrauterine insemination treatments at a fertility center, 20.7%of these infertile women had a past or current diagnosis of aneating disorder [60]. Since this statistic is five-times the nationalaverage lifetime prevalence rate in the USA, this suggests thatinfertility is a serious complication of eating disorders.

Menstrual abnormalities are a potential complication of dis-ordered eating and underweight. Stewart et al. reported that



58.3% infertile women with abnormal menstruation had beendiagnosed with an eating disorder [61]. Anorexia nervosa is asso-ciated with severe limitation of food intake and excessive exer-cise [201]. Reductions in metabolic fuel caused by caloricrestriction or increased energy expenditure can result in neuro-endocrine alterations that lead to amenorrhea and anovulation[62]. Women with anorexia nervosa had lower blood levels ofprolactin, estone, estradiol, progesterone, testosterone, androste-nedione and LH and a significantly higher FSH response toGnRH [63]. Women with anorexia nervosa, 73.5% of whomwere underweight and also had lower levels of estrogen, proges-terone and gonadotropins [64]. Lower levels of these hormonesare associated with a small, hypertropic uterus and small, amor-phous and inactive ovaries, which may contribute to menstrualand ovulatory dysfunction [65]. Rich-Edwards et al. estimatedthat 12% of ovulatory infertility is caused by being under-weight [46].

Maternal underweight may also be detrimental to fetalhealth. Underweight is associated with an increased risk of pre-term birth [66]. A recent systematic review and meta-analysis of78 studies reported that underweight women had an increasedrisk of pre-term birth, both spontaneous (adjusted relative risk[RR]: 1.32; 95% CI: 1.10–1.57) and induced (adjusted RR:1.21; 95% CI: 1.07–1.36), in addition to an increased risk fora low birth weight infant (adjusted RR: 1.64; 95% CI: 1.38–1.94) as compared to healthy controls [67]. Women with eatingdisorders also had a higher rate of intrauterine growth restric-tion and significantly higher rates of low birth weight infantsand cesarean sections than healthy mothers [68]. This correlationbetween underweight and poor fetal and infant health could becaused directly, by a lack of nutrients leading to insufficientfetal growth, or indirectly, by other factors that are associatedwith maternal underweight, such as smoking, susceptibility toillness or generalized debility.

Similarly to obesity, low BMI is also associated withincreased levels of OS. Patients with low BMI (<18.5 kg/m2)had higher plasma concentrations of 8-OHdG and higherserum concentrations of MDA-modified low-density lipopro-tein–both markers of OS–than did patients within a normalweight range [69]. A study of the antioxidant status in femaleadolescents with anorexia nervosa found that erythrocytetocopherol concentration and SOD activity were significantlydecreased (p < .02 and p < .001, respectively) in women withanorexia, as compared with controls [70]. This finding sug-gests that oxidative damage is occurring in anorexia nervosa,due to insufficient intake of micronutrients and OS as aresult of low antioxidant capacity [70]. The oxidative damagepresent in women who are underweight or who have beendiagnosed with an eating disorder could negatively affect thereproductive system and may be a mechanism by whichinfertility develops.

Exercise

The overall health benefits of exercise often outweigh the risks.Exercise has been shown to have protective effects on infertility

in some populations, such as in women who are overweight orobese. However, excessive physical activity is associated withmenstrual and ovulatory disturbance and impaired follicledevelopment, which may result in decreased fertility in womenwho participate in vigorous exercise or in female athletes.

Menstrual abnormalities are often seen both in female ath-letes and in women who participate in intense physical activity.Ovarian function is especially vulnerable to chronic low energybalance and extremely low amounts of body fat [64]. The femaleathlete triad refers to the relationship between energy balance,menstrual function and bone density, and may manifest itselfas functional hypothalamic amenorrhea [71]. Women with ahigh drive for thinness had significantly lower daily dietaryenergy intakes than controls. 73.9% of the women with highdrive for thinness had severe menstrual disturbances, such asamenorrhea and oligomenorrhea, as opposed to 38% of con-trols with menstrual abnormalities [72]. Russell et al. found thatwomen undergoing strenuous exercise and experiencing oligo-menorrhea had lower serum levels of LH, prolactin and estra-diol-17 b[73]. These hormonal imbalances are often due todisturbances of hypothalamic-pituitary-ovarian axis, causing asuppression of pulsatile gonadotropin-releasing hormone(GnRH) secretions, which controls the secretion of LH andFSH and ultimately resulting in hypoestrogenism and anovula-tion [74].

Several studies suggest that there is a positive correlationbetween amount of exercise and risk of infertility. Increases inthe frequency, intensity and duration of physical activity werealso correlated with increased subfertility in women. Womenwho exercised to exhaustion had 2.3-times the odds of infertil-ity as compared to women who participated in mild physicalactivity [75]. However, some researchers have reported a lowerrisk of ovulatory infertility with increasingly vigorous exercise[46,76]. Ultimately, hormonal disturbance and low energy avail-ability are few of the likely causes of infertility related toexcessive exercise.

Moderate amounts of physical activity have been shown todecrease levels of OS, as it decreases systemic oxidation andincreases the expression of antioxidants. However, strenuousexercise may have a deleterious effect. Intense exercise increasesoxygen consumption, thereby upsetting the balance betweenpro-oxidants and antioxidants within cells [77]. A large body ofliterature has reported an increase in lipid peroxidation prod-ucts following exercise, indicating that oxidative damage isoccurring. Blood levels of protein carbonyls, lipid hydroperox-ides and total antioxidants significantly increase (p < 0.05) afterboth exhaustive aerobic and nonaerobic isometric types of exer-cise [78]. Exercising in a warm environment (33˚C) was alsoassociated with an OS response, evidenced by significant eleva-tions (p < 0.001) in blood levels of lipid hydroperoxides, aswell as in antioxidant capacity [79]. Animal studies have foundthat total plasma thiols (TPT) significantly decreased(p = 0.022) and plasma xanthine oxidase (XOD) activity signif-icantly increased (p = 0.039) following exhaustive swimmingexercise in guinea pigs, indicating that exhaustive exercise



generates OS, and that XOD is a significant source of theseROS [80]. Additionally, plasma antioxidant levels were dimin-ished following exhaustive exercise, although the finding wasnot significant (0.755) [80]. Nutritional supplements and exoge-nous antioxidants, including L-carnitine [81], coenzyme Q10(CoQ10) [82] and dark chocolate [83], are protective against theOS induced by excessive exercise.

Cigarette smoke

Approximately 30% of reproductive-aged women in the USAare smokers [84]. Cigarette smoke is composed of over4000 chemicals. Smoking is associated with a number ofpotential health complications in women, including infertility.Female smokers have a significantly increased frequency ofinfertility as compared to women who are non-smokers [85].The negative effects of smoking on fertility involve almostevery aspect of the female reproductive system [86].

Cigarette smoke can be detrimental to ovarian function aswell as oocyte and embryo quality. Benzo(a)pyrene (BaP) is achemical component of cigarette smoke that has well-documented effects on fertility, including premature ovarianfailure and a longer time to achieve pregnancy.Sobinoff et al. found that, in ovaries exposed to BaP, therewas an increase in primordial follicle activation, in additionto atresia of the developing follicles [87]. Oocytes retrievedfrom these women displayed a decrease in sperm-egg fusionand an increased concentration of mitochondrial ROS andlipid peroxidation [87]. These results implicate OS as a poten-tial mechanism by which cigarette smoke affects folliculardevelopment within the ovary and results in subfertility. Cig-arette smoke is also associated with a diminished ovarianreserve, which may be another factor contributing to infertil-ity in women who smoke [88]. Mice exposed to cigarettesmoke or cigarette smoke condensate (CSC) for 4 weeks werefound to exhibit reduced development of blastocysts in vitro,as a result of increased egg fragmentation and delayed fertil-ization. Additionally, the rate of abnormal embryos signifi-cantly increased in the mice exposed to cigarette smoke orcondensate, and there was a dose-dependent relationshipbetween exposure time and embryo apoptosis [89]. A declinein embryo quality could affect implantation, leading toimpaired conception in women who smoke. It is alsohypothesized that cigarette smoke alters uterine receptivity,which may lead to infertility. Oocyte donation is a modelmost often used to ascertain the role of uterine factors inreproductive outcome. A retrospective study by Soares et al.,in which embryo quality was controlled, found that, amongwomen receiving donor oocytes, non-smokers had a signifi-cantly higher pregnancy rate (52.2%) than women whosmoked 10 or more cigarettes per day (34.1%) [90]. Theseresults suggest that cigarette smoke may negatively affect theuterine tissue, resulting in lower pregnancy rates in womenwho smoke.

Impaired functioning of the fallopian tube could also con-tribute to infertility problems among women who smoke [91].

The oviduct has an important role in transportation of ovu-lated oocytes as well as in fertilization. A study in rats foundthat when they were exposed to either mainstream or side-stream smoke, 70–75% of embryos were retained in the ovi-duct, as compared to 35% retention rates in controls [92]. Thecontraction rate of muscles in the oviducts significantly slowedwithin 15 min of exposure to smoke, suggesting that cigarettesmoke retards transport of embryos within the fallopian tubeby slowing contractions of the muscle [92]. As evidenced, theadverse effects of cigarette smoke on ovarian, uterine and fallo-pian tube functioning, as well as on embryo quality are likelyresponsible for the decreased fertility, observed in womenwho smoke.

Cigarette smoking is associated with increases in OS andthus an increased risk of many health complications. Exposureto cigarette smoke extract is associated with the generation ofthe hydroxyl radical, leading to plasma membrane damage, aswell as the production of H2O2 and O2, which results in cellapoptosis [93]. Smokers have been found to have lower bloodserum concentrations of vitamin C, carotenoids and selenium,as well as lower erythrocyte GSH peroxidase activity andincreased erythrocyte CuZn-SOD activity, as compared to non-smokers [94]. As cigarette smoke has been demonstrated to bothincrease ROS and decrease antioxidant capacity, OS maydevelop in people who smoke.

Additionally, several studies have linked cigarette smoke-induced OS specifically to deficits in reproductive health.Paszkowski et al. found that as exposure to cigarette smokeincreased, follicular fluid levels of final peroxidation productsincreased significantly (p < 0.001), and follicular fluid levels ofcotinine, a biomarker for exposure to tobacco, were signifi-cantly correlated with these values (r = 0.471; p < 0.001) [95].Furthermore, as cotinine concentrations increased, follicularfluid total antioxidant potential significantly decreased(p = 0.004) [95]. The impaired folliculogenesis observed infemale smokers may be a result of the OS induced by thisshifted balance between pro-oxidants and antioxidants in thefollicular fluid. A study using a mouse model found that theeggs of mice have been exposed to cigarette smoke or CSC,had an increased level of fragmentation, and that the frag-mented eggs exhibited an increase in ROS [89]. Cigarette smok-ing also leads to the development of the tar adducts in theoocytes and potentially impaired oocyte and embryo quality.Some of this damage can be repaired by the oocyte itself andthe repairing capacity of the oocyte is critical for carrying outdamage control [96].

Alcohol

The CDC reports that 43% of adult women in the USA areregular drinkers, defined as having consumed 12 or more alco-holic drinks within 1 year (CDC, 2012). Alcohol consumptionmay be a predictor for and cause of infertility problems inwomen. Many early studies concluded that alcohol had a nega-tive impact on female fertility. Infertile women in Finland con-sumed significantly more alcohol and reported experiencing



more hangovers during a period of 12 months than did fertilecontrols [97]. Tolstrup et al. also found that alcohol intake wassignificantly correlated with the incidence of infertility prob-lems among Danish women aged 30 or older, although it didnot predict infertility among younger women [98]. The oddsratio (OR) of conception also decreased as a woman’s alcoholconsumption increased from one to five drinks per week (OR:0.61; 95% CI: 0.40–0.93) to more than 10 drinks each week(OR: 0.34; 95% CI: 0.22–0.52; p = 0.03), as compared withwomen who did not consume alcohol [99]. Moderate and heavyalcohol intake has been correlated with increased infertilityassociated with both ovulatory factor and endometriosis [100],although this result has been inconsistent. More recent litera-ture suggests that there may be no significant relationshipbetween alcohol and infertility risk. For instance, Chavarro andcolleagues found that the incidence of ovulatory infertility wasunrelated to alcohol consumption (RR: 1.11; 95% CI: 0.76–1.64; p = 0.78) [101].

Maternal alcohol use may also be associated with spontane-ous abortion. In a case-controlled study by Rasch in 2003, itwas found that women who consumed five or more units ofalcohol each week had a risk of spontaneous abortion five-timesgreater than that seen among women who did not drink alco-hol [102]. However, Tolstrup et al., found no associationbetween maternal alcohol consumption and increased risk ofmiscarriage [103]. Furthermore, moderate and high levels ofalcohol consumption were not found to correlate with adelayed time to conception, as compared with women who didnot drink alcohol [104]. In fact, women who did not consumealcohol experienced a longer time to conception than womenwho did drink (OR: 1.2; 95% CI: 1.1–1.3). Although somestudies conclude that any amount of alcohol consumption isdetrimental to fertility in women, the evidence is largelyinconclusive.

The regular consumption of substances of abuse, includingalcohol, has been linked to the generation of OS within thebody. Although a smaller percentage of adult women than menreported using alcohol within the past month (49.4 and62.3%, respectively), women may be more susceptible thanmen to alcohol-related problems at lower levels of the sub-stance, due to differences in genetic and biological factors [202].A recent study in rats found that the livers and esophagi of ani-mals fed with a high concentration of ethanol and an irregular,vitamin-deprived diet contained higher levels of 8-oxoguanine,a common DNA lesion resulting from oxidative damage, thandid rats fed with a low level of ethanol and a regular diet [105].Chronic red wine consumption is also associated with a signifi-cant increase in urinary levels of 8-iso-PGF(2a), a marker ofoxidative lipid damage, as compared with the consumption ofde-alcoholized red wine (p = 0.006) [106]. Furthermore, anyamount of maternal alcohol use during pregnancy caused a sig-nificant decrease in plasma GSH concentrations post-partum(p < 0.05), while alcohol consumption greater than three drinksper occasion was also associated with significant oxidation ofthe plasma GSH redox potential (p < 0.05) [107].

Caffeine

Caffeine is the most widely consumed psychotropic drug in theworld. Caffeine consumption is suspected to have negativeeffects on conception and pregnancy. Several studies have dem-onstrated the relationship between caffeine, infertility and mis-carriage. Wilcox et al., found that women who consumed morecaffeine than the equivalent of one cup of coffee, had half thefecundability as compared to women drinking less caffeine [108].There was also a dose-dependent relationship between caffeineconsumption and pregnancy rates in these women. High levelsof caffeine intake may also delay the time to conception.Women consuming >500 mg of caffeine per day had a signifi-cantly increased risk for subfecundity in their first pregnancy,and had an 11% increase in time to conception [109].

Not only the time to conception is affected by caffeine, butspontaneous abortion is also associated with caffeine [110].Women aged between 20–29 years who consumed 75–900 mgof caffeine per day had an increased risk of spontaneous abor-tion compared to women whose pre-pregnancy caffeine intakewas below 75 mg/day [103]. One study examining fetal karyo-types determined that women who consumed caffeine weremore likely to abort a fetus with a normal karyotype in the firsttrimester than those women who were taking in little or no caf-feine [110]. Several studies report negative outcomes associatedwith caffeine consumption during the first trimester such asincreased chance of stillbirth and miscarriage [111]. One studyconducted by Wisborg et al., in 2003 reported that womenwho drank four to seven cups of coffee a day had almost an80% increased chance of stillbirth, and that for women whodrank at least eight cups a day had almost a 300% increasedchance of stillbirth [112]. However, a meta-analysis of 15 epide-miological studies concluded that, despite the fact that manyresearchers have reported positive correlations between caffeineconsumption and spontaneous abortion, this evidence is equiv-ocal at best, given that biases are likely present in the data thatmay lead to overestimation of any associations [113]. Further-more, the current evidence is limited by confounding variablessuch as smoking and by measurement error, and thus thehypothesis that caffeine consumption negatively impacts fertilityis not supported [114].

There is little agreement among researchers on the relation-ship between caffeine and OS. Caffeine is actually thought toexhibit antioxidant-like properties. Several recent studies haveconcluded that, by attenuating OS, caffeine may be protectiveagainst pathologies including alcoholic liver injury [115], galac-tose cataracts [116] and the neurodegeneration associated withAlzheimer’s [117]. Other research, however, provides evidencethat caffeine may in fact induce OS. Azam et al., demonstratedthat, in addition to its ability to suppress the production ofhydroxyl radicals, caffeine and its catabolic products induce oxi-dative DNA damage when in the presence of copper ions [118].Therefore, caffeine may possess both antioxidant and pro-oxidant capabilities. However, based on the current literature itseems unlikely that the effect caffeine may have on fertility isdue to an oxidative mechanism.



Recreational drug use

Between the years 2007 and 2009, 11.4% of adult womenreported using an illicit drug [202]. However, research on theeffects of illegal drug use on fertility is limited, due to ethicalconcerns and constraints that prevent randomized controlledhuman trials. Studies therefore are limited to epidemiologic orretrospective research. A potential confounding factor in thesestudies, however, is the reporting and confirmation of drug useby the individuals being studied. Nevertheless, there is a bodyof evidence that suggests that recreational drug use is detrimen-tal to fertility and reproductive success.

Marijuana is the most used illegal drug among women ofreproductive age. The use of cannabis and cannabinoid deriva-tives can have a negative impact on fertility and pregnancy out-come. The cannabinoid receptor CB1, which responds to themajor psychoactive component of marijuana, D9-tetrahydrocan-nabinol (THC), has been localized in the female reproductivetract–specifically, in the ovary and uterine endometrium [119].These cannabinoid receptors have been postulated to play a sig-nificant role in the maintenance and regulation of early preg-nancy; thus, any disruptions to the functioning of theCB1 receptor could have a negative impact on reproduction.Marijuana smoke can also act on estrogen receptors [120], andTHC has been shown to shorten the menstrual cycle [119],potentially disrupting fertility. Cannabis use has been associatedwith increased risks of infertility among women. A study byMueller et al., in 1990 found that women who smoked mari-juana had a slightly elevated risk of ovulatory abnormality-induced infertility (RR: 1.7; 95% CI: 1.0–3.0) as compared topair-matched controls, and that risk was greatest among womenwho smoked marijuana in the year preceding pregnancy (RR:2.1; 95% CI: 1.1–4.0) [121]. Among the women with ovulatoryabnormalities, 33% and 16% were oligo- and amenorrhic,respectively, and 34% had a luteal phase defect [121]. Marijuanause can also directly affect fetal health. Maternal cannabis useduring pregnancy was associated with decreased fetal growthand lower birth weight [122]. In fact, fetuses exposed to cannabisin utero exhibited a reduction in growth of -14.44 g/week ascompared to controls, and this growth restriction was morepronounced than that associated with tobacco exposure [122].

Marijuana is associated with the induction of OS. Endothelialcells exposed to marijuana smoke containing 3.95% THC had80% increase in levels of ROS, as well as an 81% decrease in GSHlevels as compared with controls [123]. Acute exposure to marijuanasmoke containing any level of THC also induced necrotic celldeath in the endothelial cells [123]. However, more recent studieshave found that cannabinoids have antioxidant properties, andmay in fact reduce the OS caused by other illicit drugs, such as3,4-methylendioxymethamphetmaine (MDMA) [124].

Cocaine is another recreational drug associated with infertil-ity and the generation of ROS. Cocaine use has been found tosignificantly increase a woman’s risk of developing tubal factorinfertility (RR: 11.1; 95% CI: 1.7–70.8) [121]. Furthermore, astudy by Thyer et al., in nonhuman primates found thatcocaine administration led to a decrease in ovarian

responsiveness to exogenous gonadotropins, suggesting thatcocaine has a direct effect on the ovary and transiently disruptsovulatory function [125]. Increased levels of ROS were found inboth the frontal cortex and striatum of rats treated with eitheran acute injection or chronic injections of 20 m mg/kg ofcocaine over a period of 10 days; this increase in ROS wasaccompanied by an increase in SOD and GPx [126]. Cocaine-induced oxidative damage has also been reported in heart, liverand kidney tissues [127]. Impaired mitochondrial function, per-oxidation of phospholipid membranes and depletion of antioxi-dant defenses are the proposed mechanisms by which cocaine-induced OS may lead to cell damage and apoptosis [127,128].Although the current evidence is suggestive of a negativeimpact on fertility due to cocaine use, further research isrequired for better understanding of its effects.

Psychological stress

The relationship between stress and infertility is complex andcyclical. Infertility problems may themselves cause significantlevels of stress [129]. Although stress from social and job-relatedsources may lead to subfertility in women, the personal distresscaused by infertility itself may perpetuate this cycle. Womenare more likely to report fertility-related, personal and socialstress than men [129], suggesting that stress may have a moresignificant effect on females. Domar et al., reported thatapproximately 37% of infertile women show depressive symp-toms [130].

Cortisol, a hormone associated with stress, is suspected tosuppress the secretion of gonadotropins, leading to impairmentsin the development of follicles and in ovulation. This isexpected to contribute to the subfertility associated with psy-chological stress. A study in sheep determined that the infusionof concentrations of cortisol comparable to those generated inconditions of stress, attenuated or blocked expected increases inserum estradiol as well as the LH surge [131]. This suggests thatcortisol is responsible for a delay in follicular maturation andovulation. Salivary a-amylase levels were also negatively associ-ated with probability of conception in women between the ageof 18 and 40 years, suggesting that stress may contribute tofemale subfertility [132].

Job-related stress is another potential risk factor for infertilityproblems in women. An Italian study found that female trafficpolice officers exposed to urban psycho-social stressors hadincreased plasma concentrations of LH in both the follicularand lutheal phases of the ovarian cycle, which could lead toreproductive health disorders [133]. Furthermore, women whowork 32 or more hours/per week have a significantly longertime to pregnancy than women who work between 16 and32 h per week [134].

The role of emotional stress and anxiety in pathology is notwell understood or thoroughly researched. However, a smallbody of evidence suggests that the induction of OS may be themechanism by which psychological stressors affect overallhealth. In men, increased levels of mental stress are associatedwith higher seminal plasma levels of the SOD as compared to



periods of non-stress, which suggests that antioxidant defensesincrease during stressful conditions in order to counterbalancean increase in the production of ROS [135]. Furthermore,researchers found significantly higher levels of 8-OHdG in livernuclear DNA of rats as compared to controls following therats’ second, third and fourth exposures to psychologicallystressful stimuli (p < 0.01), suggesting that psychological stressmay be responsible for oxidative DNA damage [136].

A potential limitation of the current research regarding stressis the difficulty of accurately measuring levels of stress. Studieson stress may implement a number of different techniques forquantifying stress levels, including self-report, concentrations ofbiomarkers such as cortisol or salivary amylase or stimulationresponse, limiting the generalizability and reproducibility of theresults. Future research should focus on developing a standar-dized protocol for quantifying levels of stress, in order toenhance the current understanding of the relationship betweenstress and health. There is also a difficulty of quantifying stressthrough self-report, biologic marker or stimulation response,limiting the reproducibility and generalizability of much of thisfield and requiring future developments in methods to enhanceunderstanding of these relationships.

Environmental & occupational exposures

Chlorinated organic compounds such as polychlorinatedbiphenyls (PCBs), hexachlorobenzene (HCB), dichlorodiphe-nyltrichloroethane (DDT) and dichlorodiphenyldichloroethy-lene (DDE) are environmental contaminants that have adverseeffects on fertility. Many chemicals and pesticides are endocrinedisrupting agents. High blood concentrations of organochlorinecompounds have been found to cause menstrual abnormalities,spontaneous abortions and longer times to conception inwomen [137]. Prenatal exposure to organochlorines can have sev-eral negative effects on fetal development and neonatal health.A study by Herrero-Mercado et al., found that concentrationsof organochlroine pesticides increased from maternal adiposetissue, to maternal blood serum, to umblicial cord bloodserum, suggesting that maternal adipose tissue releases organo-chlorine pesticides into the blood, and that these pesticides aretransferred to the fetus via the umbilical cord blood [138]. Neo-nates that were exposed to organochlorine compounds, such asDDT and PCBs, in utero had reduced birth size parameters,including decreased birth weights, lengths and head circumfer-ences [139]. Furthermore, many cosmetics and personal careproducts for women contain endocrine-disrupting chemicalssuch as phthalates and bisphenol A (BPA). Parlett, Calafat andSwan found that women who used perfume had a 2.92-timeshigher urinary concentration of monoethyl phthalate than inother women (95% CI: 2.20–3.89) [140]. In a study of 56 cou-ples experiencing infertility, infertile women had significantlyhigher urinary concentrations of mono-ethylphtalate(p < 0.001) than in a control group of women who had previ-ously given birth [141]. Despite a growing body of evidence,conclusions regarding the effects of pesticides and organochlor-ine compounds on female fertility and fetal health remain

controversial, as many studies have been unable to show signifi-cant dose-response relationships and results are often inconsis-tent with previous observations [142].

Exposures to organochlorine compounds such as PCBs,HCB, DDT and DDE, as well as to pesticides and other envi-ronmental pollutants, are associated with increased levels ofROS and oxidative damage. PCBs and PCB metabolites havebeen hypothesized to increase OS, which may result in cytotox-icity and increase susceptibility to disease. Workers in electricalfactories in China exposed to high levels of PCBs had signifi-cantly increased urine concentrations of 8-OHdG in samplescollected post-work (24.55 +/- 5.96 mmol/mol creatinine), ascompared with samples collected before work (6.40 +/-1.64 mmol/mol creatinine; p < 0.05) [143]. Studies in MCF-10Ahuman breast and RWPE-1 human prostate epithelial cellshave demonstrated that continuous exposure to 3 mmol/molPCBs induces apoptosis, as well as increases intracellular con-centrations of both superoxide and H2O2; treatment with theantioxidant N-acetylcysteine up to 1 h after exposure mayattenuate these effects [144]. A recent study by Pathak et al.,determined that pre-term delivery was associated with signifi-cantly increased markers of OS, including increased levels ofMDA and protein carbonyls and decreased GSH activity, aswell as increased concentrations of organochlorine pesticide(OCP) residues in both maternal and cord blood, and thatthere was a significant positive correlation between OS andOCP residue levels [145]. Pesticides such as organophosphatesare also associated with markers of OS. Agricultural workersexposed to organophosphate pesticides were found to havelower levels of SOD and GSH reductase activity as comparedto controls [146]. Urban air pollution has also been linked tothe induction of OS, as evidenced by increased levels of 8-iso-prostane [147] and MDA [148].

Methylparaben is present in almost all cosmetics. This sub-stance acts as a strong xeno-estrogen and considered as anendocrine disruptor. It is important to highlight the adverseimpact of this substance, which is also present in surface watersand in refined natural fibers, such as cotton and silk used inready-made clothes. Studies have reported that there is dimin-ished ovarian reserve associated with exposure to the paraben[149].

Impact of lifestyle on assisted reproductive techniquesThe outcome of IVF and intracytoplasmic sperm injection(ICSI) treatments may be negatively affected by several of thelifestyle factors previously discussed. Obesity has one of themost severe effects on IVF treatment. Within a single cycle ofIVF, the pregnancy rate for obese women has been shown tobe half of that for women within a normal weight range [150].In a retrospective study of 6500 IVF-ICSI cycles, obese womenhad significantly lower embryo implantation rates, lower preg-nancy rates and live birth rates than women with a normalweight. In fact, there was a significant decrease in pregnancyrate (OR: 0.984; 95% CI: 0.972–0.997; p = .016) and livebirth rate (OR: 0.981; 95% CI: 0.967–0.995; p = .009) with



each increasing unit of BMI [151]. Increases in pregnancy com-plications after conception with assisted reproductive techniques(ART) were also associated with maternal overweight and obe-sity [152]. Overweight and obese women also had increased risksof early pregnancy loss in IVF and ICSI [153], and very earlypreterm birth in IVF treatments [154]. Using data from the soci-ety for assisted reproductive technology clinic online reportingsystem (SART CORS), Luke et al., evaluated a total of45,163 ART embryo transfers. They found that increasing obe-sity was significantly correlated with failure to achieve a preg-nancy using autologous oocytes (p < 0.0001), as was failure toachieve a live birth, although there was no significant correla-tion when donor oocytes were used [155]. Furthermore, Styne-Gross et al., found no difference in implantation or pregnancyrate between obese and healthy women who were usingdonated oocytes, suggesting that endometrial receptivity is notimpaired in obese women [156]. In a sample of 1721 womenundergoing IVF, women with BMIs >35 were also found tohave fewer normally fertilized autologous oocytes than womenof a normal weight (p < .03), even when adjusting for age [157].Although weight loss may seem to be a logical treatmentoption to consider before undergoing ART, weight loss maynot confer any significant benefit to ART outcome.Chavarro et al. reported in a sample of 170 women, althoughshort-term weight loss was associated with a higher number ofmetaphase II oocytes retrieved, it was unrelated to successfulpregnancy and live birth rates [158].

Underweight and low energy balances caused by excessiveexercise have been shown to have a slight, but significant negativeimpact on ART outcome. Underweight women in China had alower rate of clinical pregnancy with IVF or ICSI treatment(31.1%) as compared to healthy weight controls (37.1%),although there were no differences in the amount of ovarianstimulation required between these groups [159]. Of women whowere able to conceive within a cycle of IVF-ICSI, underweightwomen had an increased risk of miscarrying, and this risk waseven greater if hormonally substituted frozen-thawed embryocycles were utilized [160]. Underweight women also had fewerdeveloped embryos available in each IVF or ICSI cycle [161]. Exer-cising for 4 or more hours per week was associated with a 40%decrease in live birth rate, a threefold increase in cancellation ofcycles and a twofold increase in implantation failure and preg-nancy loss with the first cycle of IVF, as compared to womenundergoing IVF who did not exercise [162]. These results demon-strate that maternal weight is an important factor influencing theoutcome of assisted reproductive techniques.

Cigarette smoking among infertile women seeking ART canalso be detrimental to the outcome of IVF and ICSI proce-dures. A meta-analysis with nine selected studies found thatamong women undergoing IVF treatments, there was a signifi-cant reduction in fertility in smokers (OR: 0.66; 95% CI:0.49–0.88) [85]. Another recent meta-analysis of 21 studiesfound that women who smoked had significantly lower odds ofboth live birth (OR: 0.54; 95% CI: 0.30–0.99) and clinicalpregnancy (OR: 0.56; 95% CI: 0.43–0.73) per cycle. These

women also had significantly higher odds of both spontaneousmiscarriage (OR: 2.65; 95% CI: 1.33–5.30) and ectopic preg-nancy (OR: 15.69; 95% CI: 2.87–85.76) with each cycle ofART [163].

Substances of abuse such as alcohol, recreational drugs andcaffeine have been demonstrated to negatively impact IVF.Women who consumed four or more alcoholic drinks perweek had a 16% decrease in live birth rate with IVF, as com-pared to women who consumed fewer than four drinks eachweek [164]. Drug abuse, such as with marijuana and cocaine,can be potentially detrimental to ART outcomes. Women whohad smoked marijuana within the year preceding IVF or gam-ete intrafallopian transfer (GIFT) treatment had 25% feweroocytes retrieved, as well as smaller infants at birth [165]. Asstated previously, research in this area is limited, and no infor-mation regarding the effects on cocaine on ART have beenpublished to date. Caffeine may also be harmful to assistedreproductive processes. Overall caffeine consumption was nega-tively correlated with the number of oocytes retrieved for IVFtreatments, while coffee intake was associated with pregnancyloss and tea intake was associated with a decrease in embryoquality [166]. Despite these correlations, no association betweencaffeine consumption and pregnancy rate with IVF was found[166]. Although evidence that substance abuse affects ART out-come is limited, these findings suggest that alcohol, illicit drugsand caffeine may have a negative impact on assistedconception.

Several studies have demonstrated that psychological stresshas a significant, if only slight, impact on conception withIVF and ICSI. The IVF and ICSI treatments are often thesources of stress themselves. The incidence of depressive oranxious symptoms was 18.5% in infertile women undergoingIVF treatment [167]. Baseline levels of psychological stress arenegatively associated with clinical pregnancy rate in womenundergoing IVF [168]. Both infertility-specific stress, includingsocial, sexual and relationship concern, need for parenthoodand rejection of a childless lifestyle; and nonspecific anxiety,including feelings of tension, nervousness, worry and percep-tion of the environment as threatening, were negatively asso-ciated with IVF outcome [169]. An et al. in 2011 also foundthat in women undergoing IVF or ICSI, State Anxiety Inven-tory scores were positively correlated with norepinephrineand cortisol concentrations in serum and follicular fluid, andthat elevated norepinephrine and cortisol concentration wereassociated with failure to become pregnant [170]. This findingwas supported by Li et al., who found that an increased levelof norepinephrine in follicular fluid was associated with adecrease in the percentage of good quality embryos [168].A recent meta-analysis of 31 prospective studies also found aslight but significant correlation between stress, defined asperceived stress, job-related stress or minor life events; dis-tress, defined as the presence of anxiety or depression; andclinical pregnancy rate in women undergoing ART proce-dures [171]. These studies suggest that psychological stress,whether it originates as a result of IVF and ICSI treatments



or from another source, can have a negative impact on theoutcome of assisted reproduction.

Environmental exposures can negatively affect conceptionand pregnancy with ART, and over 50% of women attendingIVF clinics have detectable levels of organic chemicals in theirsera and follicular fluids [172]. Chlorinated organic compoundssuch as PCBs, HCB, DDT and DDE are environmental con-taminants that can have adverse effects on IVF and ICSI out-comes. A prospective study by Meeker et al., found thatmaternal blood serum levels of PCBs were significantly anddose-dependently correlated with elevated odds of implantationfailure and decreased odds of live birth among 720 womenundergoing IVF-ICSI [173]. Serum concentrations of HCB werealso demonstrated to be significantly, dose-dependently corre-lated with decreased implantation rates among women under-going IVF, although no significant associations were foundbetween DDT and implantation rate [174]. Serum and follicularfluid levels of DDE were negatively correlated with fertilizationrate [172].

ConclusionsThere are cumulative evidence in the literature that lifestyle fac-tors such as weight, exercise, cigarette smoking, alcohol and caf-feine consumption, recreational drug use, stress andenvironmental exposures are detrimental to both natural andassisted fertility in women, and that these factors likely mediatetheir effects, at least in part, through an oxidative mechanism.Therefore, lifestyle modification may be the most effective wayto counteract these negative effects, to improve fertility poten-tial and to maximize a woman’s chances for a healthy and suc-cessful pregnancy. Women experiencing infertility may turn toassisted reproductive techniques in order to better their chancesof achieving a pregnancy and having a child. However, thevery causes of infertility in these women can also potentially bedetrimental to ART procedure outcome. Therefore, it may beoptimal to implement lifestyle changes before proceeding withassisted reproductive techniques, in order to attenuate the nega-tive effects and maximize the potential for a positive outcome.However, the underlying cause of infertility can be treated andnatural fertility potential can be improved, ART proceduresmay no longer even be necessary for these women. However,for many women experiencing infertility that turn to ART, agemay be the most critical factor to address. In these cases, itmay be best to proceed with ART, rather than to delay theseprocedures in order to first implement lifestyle changes.

Several studies have demonstrated the benefits that lifestylemodification, especially in regards to weight loss, may have inregards to female fertility. Dei et al. found that a greater changebetween current and premorbid BMI was a predictor of theresumption of menses in women with amenorrhea associatedwith low BMI [175]. A prospective study, which followed agroup of obese (average BMI 38.7 ± 6.8), infertile and anovula-tory women as they underwent a diet and exercise program,found that after a significant average weight loss of 6.3 ±4.2 kg, 12 of the 13 subjects resumed ovulation and 11 were

able to achieve pregnancy [176]. More extreme weight-loss pro-cedures, such as bariatric surgery, may be detrimental to fertil-ity in women. Although current research suggests that weightloss from bariatric surgery may improve ovulation, and thusspontaneous pregnancy rates in obese women, pregnancies inwomen who have undergone these procedures are often consid-ered high risk [177]. Further research into the effects that otherlifestyle modifications, such as smoking cessation, reduced alco-hol and caffeine consumption and decreasing stress levels mayhave on fertility is greatly needed, as these fields remainrelatively unexplored.

Another potential therapy for infertility caused by oxidativedamage is antioxidants. Administration of antioxidants may sig-nificantly improve the imbalance between ROS and antioxidantdefenses observed in infertile women [178]. A clinical trial of theneutraceutical Improve, which contains the antioxidantsCoQ10, astaxanthin and anthocyanidines, essential omega-3fatty acids, zinc and folic acid, in combination with fish oil forwomen found that the probability of conception and successfulpregnancy was improved with supplementation of the neutra-ceutical in infertile women conceiving naturally or using ART[178]. It is recommended that treatment begin at least 6 weeksbefore the ART procedure and be continued for 2 weeks fol-lowing IUI or IVF.

Current evidence is limited and lacking in well conductedRCT for assessing the impact of antioxidants in subfertility.There is a need for future well-designed randomized trialswith adequate power to provide conclusive evidence. Thetrials need to follow strict randomization of patients tointervention or placebo and describe their allocation con-cealment methods. This will ensure that the future trialswill be of the highest quality and has definite clinicalimplications.

Expert commentaryLifestyle modification should be considered as a therapeuticoption for women experiencing infertility. Radical surgical pro-cedures, which may in fact be detrimental to fertility, shouldbe avoided or considered only if attempts at lifestyle modifica-tion are unsuccessful. Antioxidants may be another alternativeor complementary therapeutic approach. However, in somecases, such as when the age of the woman is of greatest con-cern, it may be best not to delay ART procedures to firstimplement lifestyle changes. Ultimately, although lifestyle mod-ification appears to be potentially protective of fertility and apossible avenue for the treatment of infertility, future researchmust elucidate the duration of the benefits these lifestyle modi-fications may confer, as well as the time it may take from theimplementation of modification to the recovery of reproductivefunction.

Five-year viewMore research is needed into the potential benefits of life-style modification for the treatment of infertility in women.Although it seems evident that weight loss greatly improves



fertility potential among obese women, it remains to be seenif the negative reproductive effects caused by smoking,alcohol, caffeine, recreational drugs, stress and the environ-ment are reversible and are able to be attenuated by ceasingor reducing the frequency of these behaviors and aspectsof life. Furthermore, with our increasingly active society,and as everyday life stress, chronic depression and anxietydisorders become more prevalent, it is necessary for researchto focus on determining the long-term implications that psy-chological factors may have on health, including fertility.

The potential for antioxidants and nutritional supplementsto have significant benefits in the attenuation of OS and theimprovement of fertility and pregnancy outcome must befully explored.

Financial & competing interests disclosure

The authors have no relevant affliations or financial involvement with

any organization or entity with a financial interest in or financial conflict

with the subject matter or materials discussed in the manuscript.

No writing assistance was utilized in the production of this manuscript.

Key issues

• A number of conditions affecting fertility in women, including endometriosis, polycystic ovary syndrome, recurrent pregnancy loss and

unexplained infertility are associated with a systemic increase in reactive oxygen species (ROS) or oxidative stress (OS).

• Obesity is linked to ovarian dysfunction, compromised oocyte and embryo quality and longer times to conception. Positive correlations

have been found between increasing BMI and ROS, as well as negative correlations between BMI and antioxidants.

• Being underweight can be a risk factor for infertility. Women who have eating disorders do not take enough micronutrients and

therefore have lower antioxidant levels. Women who are underweight tend to have higher levels of OS markers.

• Excessive exercise can negatively impact fertility by increasing oxygen consumption, and thereby increasing the ROS released by cells.

Nutritional supplements and antioxidants may be protective against exercise-induced OS.

• Impaired ovarian function and decreased oocyte and embryo quality are often associated with women who smoke cigarettes. Smoking

has been associated with a decrease in serum antioxidant levels as well as increases in ROS.

• Maternal alcohol consumption is associated with a longer time to pregnancy and elevated risk for spontaneous abortion, as well as with

increased levels of markers of oxidative damage.

• Women who use recreational drugs and consume caffeine are more likely to develop infertility associated with a tubal factor or an

ovulatory-abnormality, and have increased risks of spontaneous abortion and still birth, respectively. The substances have been found to

possess both pro-oxidant and antioxidant capabilities.

• Psychological stress may be responsible for subfertility, potentially by disrupting the production of key hormones. Although to date there

is little conclusive evidence, there may be a causal link between stress and an increase in oxidative DNA damage.

• Environmental and occupational exposure to chemicals is associated with menstrual abnormalities, spontaneous abortion and pre-term

delivery. Levels of polychlorinated biphenyls, pesticides and urban air pollutants are correlated with markers of OS.

• The outcomes of IVF and intracytoplasmic sperm injection procedures may also be negatively affected by the oxidative damage

associated with lifestyle factors such as weight, exercise, recreational and illicit substances, stress and environmental exposures.

• Lifestyle modification should be the first course of treatment to improve fertility potential. Antioxidants and other supplements may

confer additional benefits by further combating ROS. Assisted reproductive technology should be considered only if less extreme, mini-

mally invasive methods are unsuccessful.

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Websites

201 Eating Disorders.www.nimh.nih.gov/health/publications/

eating-disorders/complete-index.shtml

(Accessed 20 January 2013)

202 U.S. Department of Health and Human

Services, Health Resources and Services

Administration, Maternal and Child Health

Bureau. Women’s Health USA2011 Rockville, Maryland: U.S. Departmentof Health and Human Services, 2011. www.mchb.hrsa.gov/whusa11/hstat/hshb/pages/

200hshb.html





















































































www.nimh.nih.gov/health/publications/eating-disorders/complete-index.shtml

www.nimh.nih.gov/health/publications/eating-disorders/complete-index.shtml

www.mchb.hrsa.gov/whusa11/hstat/hshb/pages/200hshb.html



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