•C 2018 EDIZIONIMil\1lRVAMED!CA PanmincrvaMcdica 2019 March:61{1):58-67 Online version at http:/!\,.\,.\,·.111111ervi1med1ca.1t DOI 10.21716/SOOl l-OROR.18.01490-0
REVIEW HOT TOPICS IN FEMALE INFERTILITY
Impact of Body Mass Index on female fertility and ART outcomes
Majdi IMTERAT 1, Ashok AGARWAL 2, Sandro C. ESTEVES\ Jenna MEYER 4, Avi HARLEY 1, 2 *
JDepanmenL of Obstetrics and Gynecology. Soroka University Medical Center, Ben-Gurion University of the Negev. Beer-Sheva, Israel; 2American Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, CSA; 3Andrology and Human Reproduction Clinic, Al\-nROFERT. Referral CenLer for :Viale Reproduction, Campinas. Brazil; 4f'aculty of Health Sciences, Ben-Gurion University of Lhe Negev, Beer-Sheva, Israel �conesponding author: Avi Harlev, Depa1tment of Obstetricsand Gynecolq,,y, Soroka University rv!edical Center, l 5 l l7ak H.ager Ave. Heer-Sheva 84101, Israel. E-mail: harlev(fi;b1,'l1ac. il
ABSTRACT As the global mean Body l\fass Index (B!l:fI) is on the rise, the importance of understanding exactly how female fertility is impacted by once outlier BMl values, becomes ever more important. Studies have 1mphcatcd abnormal BMl on the female reproductive system by contributing to anovulatio11, irregular menses, adverse oocyte quality, endometrial alterations,and hormonal imbalances. These well ultimately result in female infertility, which could complicate natural conception efforts and request considcrmg assisted reproductrve technology ( ART) in such couples. vVitl1 an increase in the demand for ART, it is crucial to understand what factors can be alteredby the female BMI in order to maximize tl1e op porn1nityfor successfulpregmmcy. The current manuscnpt aimed to review the information about the effectof Bl\:11 on the female fertilityand ART out.rnmes. The cmnplex nature orthe remale repruduct.ive sysle111 leaves space for multiple ractors lo adversely affectits processes. Tmbal ances in tl1e hypothalamus-pituitary-ovarian a,"is can impede efforts for couples to conceive. Leptin and estrogen are two hormones tliat have been implicated in regulatingBMl as well as reproductive physiology. Lifestyle modificationspnor to. and dmmg ART have shown promise in enhancing fecundity. The intricacies in female reproductive system leaves much to tl1e unknown, and often witl1 conflicting results. Furtl1er research is rcqmrcd to fully elucidate what aspectsof femalefertility arc mfluencedby B!Vll, and how the healthcare provider can facilitatesuc cessful outcomes. The current review will enable a better consultation and treatment.
(Ote this arflcle a�: lmterat rvl, Agarwal A. Esteves SC, t>.foyerJ. Harlev A. Impact of Body Mass Index on female fettility and Alff outcomes. Pan minc1va Med 2019;61:58-67. DOl: 10.23736/S0031-0808.18.03490-0) KEY WORDS: Fertility - Infertility - Body Mass Index - Estrogens - Insulin - Life style.
ody Mass Index (BMI) has long been known to af result from impaired follicular recmitment, impedance of Bfect various aspects of human health. An abnormal oocyte development, and reduced fertilization rates. This BMI alters the ability for the body to function normally; lack of accord on pathophysiology and impactof an abnor whether above or below a healthy range, lhcsc extremes mal B:rvII,compl icates the caregiver 's ability to adequately hinder regular physiology. The cffccls of BMT on female address and counteract the effects abnomial BMT on lhc fertility have been detailed lo a degree. There has not been reproductive syslcm function in general and fertility in a consensus on how exactly BMI impacts the reproduc particular. tive system, and even less agreement on the effects BMI The goal of this review is to provide a comprehensive has had on assisted reproductive technology (ART) out accumulation of the literature regarding the various effects comes. Thus, conflicting reports on how exactly BMI af of BMI and associated molecular pathways on ART, as fects femalefert ility are abundant in the literature. It has ,vell as to assess any modifications necessary when treat been suggested that reproductive system malfunctionmay ing individuals outside the normal BMI range.
58 PANMJNl-:RVA_v llilJlCJ\ l\.hlrdt2lll9 It.IPA.CTOF BM! ON FEIVIALE FERTILITYAND ART OUTCOMES IMTERAT
Overview of BMI BMT required forregular menscs.1 0, 11 Below this level, the body's available energy to use towards cellular processes, E11idemiology growth, and reproduction is diminished. A study conduct ed by Loucks et al.,10 defined energy availability as the BMT is a simple calculation using a person's height and energy intake minus the energy expendihire. In women weight in order to qmmtify an individual's amount of tis sufferingfrom anorexia who reduce the energy intake, less sue mass. BMl>25.0kg/m2 is considered ovenveight, and is available for health maintenance, including reproduc < l 8.5kg/m2 is undenveight. An individual with a BMI Livc processcs.1 o greater than 30.0kg/m2 is obese, and those over 40.0kg/m2, or are 35.0kg/m2 and su.ITer from obesity related hyperten Pathways associating BMI and the rcprnductivc system sion or diabetes, are defined as morbidly obese.1 Though this measurement does not consider distribution of weight Numerous pathv,;ays were suggested Lo associate an ab in Lcm1s of muscle or fat, iL has long been used as a stan normal BMl and the reproductive system. Two major ones dardized measurement of hcallh.1 will be described. Increased BMI ,md obesity has plagued the modem world and has become an international public health con Leptin cem.2 Over the past three decades, the average BMI rose ln lnunans, leptin has been shown to have a direct asso dramatically in 200 countries worldwidc.3 Data collected ciationwith adipose density.12 Since leptin is produced by from 1980 and 2000, showed the BMI lo have increased adipose tissue, circulating serum levels of leptin correlates at an annual rate of 0.4 kg/m2 per decade formen and 0.5 1 2 Yvith the amount of adipose tissue present in the body. 3 kg/m forwomen. In 2008, the prevalence of overweight ln order to regulate energy expenditure and appetite ho adults reached alanning 1.47 billion people across the meostasis, leptin acts on the arcuate nucleus in the hypo globe.' Another assessment of 1698 population-based data thalamus via a single lransmcmbranc Lypc T cytokinc rc sets that involved more than 19 million adults, sho\ved ccptor.12 Additionally, lcptin helps lo control the levels of global age-standardized mean BMI to have increased from insulin, insulin-likegrowth factor, and growth hormone.14 21. 7 kg/m2 in 1975 to 24.2 kg/m2 in 2014 in men, and from In this w , leptin plays an integral role in monitoring 2 2 4 ay 22.1 kg/m in 1975 Lo 24.4 kg/111 in 2014 in womcn. For the pathogenesis of obesity and other eating disorders. In women of reproductive age in particular, the prevalence of obese women, there is an increased resistance to leptin, obesity has markedly increased within the past decade. A disrupting their ability to control energy intake, 13 while in 2 review by Jungheim et al., reported that 35.8 percent of undern'eight women low energy availability dysregulates menstruating,,,omen had a higher than normal BMI, with the diurnal leptin sccrclion.15 a mean BMT of28.7 kg/m2. Beyond its substantial central effectson the hypothalam On the other end of the spectrum, low BMI (such as an ic-pih1itacy axis, leptin has significant regulatoryresponsi orexia nervosa) is an important factor affecting fertility in bilities in peripheral physiology as well. Leptin deficiency women of reproductiveage. This disorder is characterized may lead to obesity, bone mincrali:r.alionissues, and repro by a tremendously low BML due to intense fear of gain ductive cycle changes.13 Ovulatory cycles in females are ing weight, and body image issues. Although its reported connected to energy stores, thatas aforementioned,are rep prevalence is between 0.9% and 4.3% in women, this val resented by leptin levels.12 A study conducted in hypogo ue does not reflectthe trueseverity of this disorder. 5 In sur nadolropic hypogonadism leplin-dcficicnl transgenic mice, veys completed by university aged women, 26% of them showed that administration of leptin corrected the amenor were reported to have abnonnal altitudes about ealing.h rhea and restored reproductivestatus. 16 This study conclud Though recently there has been an increase in anorexia di ed that lcplin helps Lo regulate honnonc axis contributing lo agnoses in young women, it is unclear as to whether this is reproductive capabilities when in BMT extremes. a trueupward trendin the disorder, or whether the medical ln healthy individuals, leptin was shown to have an ef practice is clumging to recognize this devastating mental fecton luteinizing hormone (LH) and estradiol levels, sug illness more readily. 7, s Contrastingly, some large reviews gesting that lepLin may have a distinct regulatory effect conducted at mulliplc institutions failed lo show any sig on hormones involved in reproductive processes. 16 Thus, nificantincrease in the prevalence of this disorder. h, 9 leptin has an integral role in maintaining normal homeo Yet what is known is that there is indeed a minimum stasis and body physiology beyond that of hunger.
Vul.61-Nu. l P:\Mv!INbRVA MEO JC:\ 59 IMTERAT Th1PACT OF BM! ON FE:VIALEFERTILITY AND ART OUTCOJ\,1ES
Estrogen talivc hypotheses implicate the negative impact BMT has on embryo quality and endometrial function. Estrogen is the primary hormone of nonnal female repro A studv conducted bv Gaskins et al. found that in fe ductive physiology. Estrogen is responsible for inducing males of 18 years of age: both a BMT>25, and a BMT
PANMJNl:RVA_v llilJlCJ\ M,Hdt2lll9 It.IPA.CTOF BM! ON FEIVIALE FERTILITYAND ART OUTCOMES IMTER.AT women (BMT 20-24 ). Another study of unique design also of reactive oxygen species. This induces mitochondrial concluded that increased BMl and the associated insulin and endoplasmic reticulum stress that ultimately activates resistance in particular, have detrimental effects on the the apoptotic pathways in these cells. Furthennore, the oocylc qualily. 29 Hmvcvcr, despite the abundant research chronic lmv-gradc inllammalory stale and high levels of efforts dedicated to elucidating these pathways, the details circulating senun leptin in obese women have detrimental of cellular mechanisms and the exact nature of the oocyte effectson thefollicle fluid milieu-37 quality impainnent in abnormalBMI humans remains un clear. Tn animal models, oocylcs from obese mice demon f;ndomelrium receplivily strated delayed oocy1e maturation and higher rates of an euploidy_3o This was due to the lipotoxic effects on oocy1e There is no paucity of literature on the hypothesis that ex cess body weight adversely impacts the endometriwn and maturation, which severely impaired mitochondrial and its environment. Yet, exactly how obesity influences endo endoplasmic reticulum function, and increased apoplosis mclrial rcccplivily to the embryois not well understood.TI1c in the cumulus oocyte complex_31 negative effects ofobesity maybe manifested in changes in Additionally, diabetes mellitus is a common comorbid endometrialthickness, through metabolic and honnonal dis ity in obese women. Such patients suffer from insulin re sistance, which causes a slate of chronic hyperglycemia turbances,and by the embryo-uterine dialogue, the complex along with hyperinsulinemia. "cross-talk'' thal occurs as part of the im pl anlat ion process. 38 Obesity may affect trophoblast cell invasion and endome Insulin has long been implicated in the regulation of cndomclrial dcvclopmcnl, metabolism, and rcccptivily.'2 trial receptivity through hormonal alterations, leading to increased spontaneous abortion rates in the first trimester.19 Hence, insulin resistance, commonly exhibited by obese women, may have a negative influence on implantation, Moreover,gene expression analyses during theimplantation window have revealed endometrial dysregulation in obese further complication hopes of subsequent pregnancy. Be 40 yond insulin, the production of reactive oxygen species women, especially in women also sufferingfrom PCOS. and decreased efficiency of antioxidants, also known as Genetic mechanisms lhal may contribute Lo cndomc oxidative stress, is a key mechanism behind infertility in trial function arc also being studied to dctcm1inc whether there are genetic predispositions to suboptimal fecw1dity. diabetic vvomen. Oxidative stress leads to mitochondrial 41 damage and serves as a trigger for many alterations in Comstock el al. observed that obesity appeared to be as sexual function. Furthermore, the excess of radical oxygen sociated ,vith significant allcrations in cndomclrial gene species production may also disturb oocy1e maturation, expression during the optimal window of implantation, es pecially in patients with w1derlying metabolic syndrome. oocyte fertilization, emb ogenesis, and pregnancy. 33 ry As BMI increased, exponentialvariations in gene expres Impact on ovulation sion were found along with an increased incidence of a nonreceptive endometrium. This endometrial gene dysreg Multiple processes of ovarian physiology are altered in ulation could contribute to the increased risk of infertility, obese women, including the hypothalamic-pituitary-ovari adverse pregnancy events, and poor in vitro fertilization an axis.34 Obesity is associated with greater adipose tissue (TVF) outcomes seen in obese womcn.41 levels in the body, thereby affecting the gonad hormonal Another study conducted by Souter et al. reported a balance. This leads to increased plasma insulin levels, ul positive association between endometrial thickness and 42 timately resulting in hyperandrogenism and anovulation. both B:rvII and pregnancy. Perhaps the most effective The elevated adipose tissue aromatizcs androgens lo es study model forthese correlations is ovum donation. How trogens at high rates in the periphery, leading to negative ever, while Bellvet et al. did report poorer ongoing preg feedback on the hypothalamic-pituitary-ovarian axis and nancy rates per oocyte donation cycle in women with high dmvnrcgulaling gonadotropin produclion.35 This impaired BMT, they were unable to show a significant dilTcrcncc in pulsalile secretion of pituilary gonadolrophins leads to im the thickness of the cndomctrium and implantation rate paired folliculogenesis_36 among the differentBMl groups_43 As aforementioned, the lipotoxicity, also known as adi Other reports have shown an increased risk of sponta posily, associated with obesity serves as ycl anothcr polcn neous abortion an10ng obese women after TVF with au tial mechanism causing oocy1e organelle damage. Obese tologous or donated oocyies. Luke et al. conducted a ret women have higher levels of circulating free fatty acids rospective analysis on 45,163 embryo transfers performed that damage non-adipose cells by increasing the formation in 345 clinics in tl1e USA They described a statistically
Vul.61-Nu. l P:\Mv!INbll.VA MEO JC:\ 61 IMTERAT Th1PACT OF BM! ON FE:VIALEFERTILITY AND ART OUTCOJ\,1ES significanl reduction in clinical inlraulcrinc gcslalion and increased risks of several adverse pregnancy complica live-birth ralcs in obese women using aulologous oocylcs, lions, such as prclcnn birth before 37 weeks, leading lo but nol when donated oocylcs were considered. This fmd signifkanl neonatal morbidily andmorlalily. Furlhcr, arc ing suggested an impaired embryo quality but not reduced ccnl meta-analysis suggcslcd lhal even modcsl increases endometrial receptivity in obese women.44 The compli in maternal BMI arc associated ,vith an increased risk of calcd nature of how obesity impacls the cndomclrium and fclal death (95% CT: 1.09-1.35), stillbirth (95% CT: 1.18- successful oocyte implantation is complex, often yielding 1.30) and infantdcalh (95% CT: l .09-1.28).·50 contrasting results. LowBMI ART Low BMI is a well-recognized risk factor for infertility Background and adverse pregnancy outcomes. Lov, body ,vcighl, ex TnfcrLilily is defined as one or more years of unprolcclcd ercise andpsychogenic stress arc the leading reasons for intercourse without pregnancy.s1 An analysis from 2007 functional hypothalamic failure, potentially causing a suggested Lhal approximalcly 72.4 million women arc in shortened lulcal phase, or anovulalory menstrual cycles, fertile, with 40.5 million of them seeking lrcalmcnL.4 Rc and in the severe cases even amenorrhea.45 Another known porls explaining lhc need for infertility lrcalmcnls showed mechanism contributing lo reproductive system malfunc these values lo be equal across less developed and more tion is that the decreased amow1t of adipose tissue in un developed countries. However, the means by which to pay derweight Yvomcn causes estrogen lo be mclabolizcd inlo for these services is lacking in resource poor areas. ART in a less polcnl fonn, lhc calcchol cslrogcn.20, 46 Furthcm10rc, cludes special techniques used Lo help infertilecouples con low BMI may indicate inadequate energy intake and sta ceive andmainly refers Lo NF and inlracyloplasmic spcm1 tus. thereby impacting gonadotropin concentration, fol injection (TCST).51 These lrcalmcnl modalities arc the mosl licle growth, and oocy1e quality.47 advanced fertility treatment available and usually include Leptin. a molecule secreted in response to adipose tis controlled ovarian simulation prior to ovum pickup. sue mass, influences munerous neuro-endocrine systems including those involved with fertility.As previously men Indications for treatment tioned, leptin playsa critical role in the regulation of hy pothalamic hormonal axes and oocyte implantation time. Consideration forART is not a decision to be made lightly. Specifically, low expression of leptin in the endometrium Indications for treatment are strict in order to maximize die has been associated ,vith higher implantation failure rates. potential for successful conception. Aside from physical Decreased leptin mRNAexpression (0.76 folddovm) was stress on the female. die mental and emotional tolls taken reported to lead to infertility.48 The reduced leptin levels vvhile undergoing ART are significant and cannot be ig observed in underweightwomen could thereforebe further nored. As aforementioned, a couple must have difficulty implicated as a factor contributing to reduced fecundity. getting pregnant for 12 months to be defined as infertile. s2 Similarly, Cai et al.47 found a significant increased inci This could be due to hormonal (anovulation) abnormali dence of miscarriage in undcrwcighl women (BT'vfl PANMJNl:RVA_v llilJlCJ\ M,Hdt2lll9 It.IPA.CTOF BM! ON FEIVIALE FERTILITYAND ART OUTCOMES IMTER.AT lhc most common medical complication of pregnancy, and low and high BMT arc associalcd with reduced fecundity dramatically affects female fertility.ss Over 371 million in women receiving ARTs (OR 0.81 for lmv and 0.5-0.81 people have been diagnosed wilh diabclcs worldwide, wilh for high BMl, respectively). Kawwass et af.,Gs postulated many more unaware of their potential diagnosis.ss Type I that pre-pregnancy BMl affects pregnancy and obstetric diabetes results froman autoimmune mediated destruction outcomes. Underweight status may have a limited impact of insulin secreting beta-cells in lhc pancreas. Insulin re on pregnancy and live-birth rates but is associated with in ceptors arc abundant throughout the ovary on Lhccal cells, creased preterm and low-birth-weight delivery. Dokras et granulosa cells, and stromal components, alike, as ,veil as al. 66 reported that obese \Vomen undergoing IVF treatment in the utcrus.55 As such, impaired insulin signaling can dra demonstrated higher rates of second and the third trimes malically affccl nonnal reproductive processes and fcrlil ter risk factorsincluding hypertension and pre-eclampsia. ily. In 1954, iL was documcnlcd thal JO Vul.61-Nu. l P:\Mv!INbll. VA MEO JC:\ 63 IMTERAT Th1PACTOF BM! ON FE:VIALE FERTILITYAND ART OUTCOJ\,1ES componcnl is the dominanl cliology for infertility in the fatroge n receptor - Lipotox1c effecton oocytes inlemclions · Reduced oocyte qua llty TCST group compared to the NF group.�9 · Altered/delayed oocyte Contrary to fairly robust data regarding the impact of IIUILUrily high BMl on ART success rates, the effect of low BMl on ART outcome is conflicting and not well established. \ / Reports by Veleva et al.80 and Cai et al.4: demonstrated - Hypcrkptincmia - Reduced endomctrial a positive association between w1derweight women and - Lcptinresistance ___. Anovulation� receptivity - Central effect(axis) subfertili lv• - Endo mernaI dysregu lat,on miscarriage in ART-induced pregnancies, suggesting that - Peripheral effect{UT) - EndomernalThickness women \vith low B:rvtJ are less likely to achieve live birth. \Reduced ART success: · btcreased duration of Do lifestyle modificationsaffect ART outcome? ovil rian sti 111uln11011 - T11.5uli11 resistance I · Higher lotal dose of go1u1dolrophilLS Study evidence suggests that physical activitymay decrease - Jiyper111�uline111ic1 · Lower ovarian response - Less sex lwnnone binding · Reduced oocyte retrieval systemic inflammatorymediators and contributeto improve globulin · Poorer embtyo quality ment in forlility.81 Losing weight prior to ART initiation cor - :Vforcfree testosterone · Lower fcnilizationrates relates with a higher yield of methaphase oocytes, particular Figure 1.�Mechanisms by which increased B1\His associaled with sub ly among women who were overweight or obese at baseline. ferLiliLy and fertility trealmenl oulcome. Although short-term ,,,eight change was not consistent with clinical outcomes among women who undenventARTJO it and complex effects of abnormal BMI of the female re has been demonstrated that a 5% weight loss can improve productive system. \Ve can conclude that there are vari menstrualcyclicity and reproductive outcomes.82 ous modes by which lhis occurs (Figure I). Leplin has The British Fertility Society recommends withholding been shown Lo be an integral regulalory component in the TVF Lrcatmcnl for women with BMTs>35 and advises a processes controlling BMl as well as reproduction. Be weight loss program for BMis>30.81 However, literature cause leptin correlates with adipose density, it has been dclailing the effect or barialric surgery on reproduclivc used as a marker for the energy balances, and therefore health outcomes is limited. Clark et al.84 have shown lhal imbalances, within the human body. Energy homeostasis weight loss in ovenveight women is associated ,vith return is crucial fornormal reproductive processes to occur, and of spontaneous ovulation. They compared the pregnancy as such, slates or elevated BMT or low BMT can unfavor rates belween obese ,vomen who undenvenl a lifeslyle ably affect lhe female reproduclive environment. Estro modificalion program wilh women who failed Lo complete gen is well documenled to be the mosl important control the course. Among the women who were unable to con for female reproduction. Its roles in female reproductive ceive naturally during the program and went on to receive pathophysiology and its well elucidated roles in modulat infertility treatment, 26 of the 4 7 women who completed ing BMI make it an important considerationwhen consult the program and underwent lVF became pregnant com ing couples diagnosed with infertility. These factorshave pared to none of the 35 women who dropped out of the all been shown to affccl nomrnl ovulalion and endomelrial program and undern'ent IVF. receplivily, components that must be accounted for when Moran el al.K5 completed a pilot randomized trial of consulting for ART States of insulin imbalance leading weight loss among obese women undergoing ART, yet Lo diabeles mcllilus or lhyroid hom10ne discrepancies can showed there were no differences in pregnancy or live also impact female fertilityand thereforeART outcomes. births between ,vomen randomized lo lifestyle intcrvcn Yet despite this, there is no consensus on ,:vhether lifestyle lion and women randomized Lo conlrol. Clearly, the data modifications in efforts to change BMI have any benefits available lo dale do nol clarify Yvhclhcr losing weighl be towards increasing the chances forsuccessful conceplion fore iniliating A RT has any slalislically significant benefi naturally or via ART. Fulurc studies should hope to far cial effects on clinical outcomes. ther elucidate how couples can adjust behavior or lifoslylc to enhance the chances for successful conception. Other Conclusions research should also look into the intricacies of the path ways controlling fertility, in the hopes of further elucidat The objective of this review was to offer an inclusive ac ing just hov,' well these are able to be changed to increase crual of the published literature concerningthe numerous fecundity. PANMJNl:RVA _VllilJlCJ\ M,Hdt2lll9 It.IPA.CTOF BM! ON FEIVIALE FERTILITYAND ART OUTCOMES IMTER.AT References 22. Hakimi 0, Cameron LC. Effe-:lof Exercise 011 Ovulalio11: A System atic Review. Sports Med 2017:47:1555-67. 1. Must A. l\:lckcown NM. The Disease Burden Associated with Over 23. Rich-Edwards JW. Goldman tvlB. Willett WC, Hunter DJ. Stampfcr weight and Obesily. Tn: De Grool LJ, Chrousos G, Dungan K, fieingold MJ, Colditz GA, et al. 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Implementation of the NICE guideline - recom lot study: short-term weight loss improves pregnancy rates in over mendations from the British f ertiltty Society fornational criteria forNHS we1ght,'obese women undertakmg 1 VF. Aust N Z J Obstet Gynaecol fundmgof assisted conception. Hum Fcrtil (Camb) 2006;\J:181-\J. 2011;51:455-\J. Confiictrnfmterest.-Theauthors cettifythat.there is no conflict of interestwith any firnncialorgani7ation regardingthe material discussed in the manusctipt Attielc firstpublished onlinc: June 28. 2018. - Mannsc1ipt accepted: Jtmc 20, 2018. - Manuscript received: May 31. 2018. Vul.61-Nu. l P:\Mv!INbRVA MEO JC:\ 67