Integrative Approaches toInfertility for Women

Increasing Difficulty in ObtainingPregnancy

The more you learn about whatgoes into conception, the moreamazing it seems that anyone getspregnant. The process of conceptionstarts with the transformation ofgerm cells into gametes (egg andsperm) and ends with the complexsignaling processes that allow aembryo to properly implant into theendometrium, altering a woman'snormal hormonal cycle and creatingan environment to nourish andmaintain that pregnancy. From aphysiological perspective, pregnancydepends on proper functioning ofnearly every underlying process thatintegrative practitioners consider:balanced inflammatory pathways,angiogenesis, oxidative stress,hormonal balance, detoxification,proper nutrient status, and the listgoes on. And so, it's not necessarilysurprising that we have seen a declinein fertility over the last few decadesalong with the declining healthreported overall in Americans.

According to the CDC reportFertility, Family Planning, andReproductive hiealth of US Women:Data from the 2002 National Surveyof Family Crowth, more and morewomen in every age group have hada more difficult time getting pregnant.Between 1982 and 2002, rates ofreported impaired fecundity (inabilityto carry a pregnancy to term) haverisen as high as 157o for womenaged 35 to 44, or 1 in 8 couples.Even among women with the highestfertility, aged 15 to 24, impaired

by Jaclyn Chasse, NDfecundity rates have nearly doubledfrom 47o to 77o over the 20-yearspan.̂

Fertility has been declining inmen as well. A review of 61 paperspublished between 1940 and 1990reported trends in semen analysisresults for 14,947 men. Over thehalf-century, the participants' averagesperm concentration decreased from113 million/mL to 66 million/mL. Inaddition, the average seminal volumeper ejaculation decreased from 3.4 to2.74 mL.2 This means that the averagesperm count (per ejaculation) haddropped from 384.2 million to 181.5million, a 52.87o decrease.

We are aware of several factors thatnegatively affect fertility, includingnutrient deficiency, environmentalexposures, and stress. Thankfully,there may be opportunities topositively affect fertility of couplesby decreasing exposure to harmfulsubstances and supporting a healthfulenvironment for both mother andfather.

A study conducted by theForsight Group, a UK-basednonprofit dedicated to promotingpreconception care, followed 367couples ranging in age from 22 to59. Many couples in the study hada previous history of infertility (377oof couples), miscarriage (387o),therapeutic abortion (117o), stillbirth (37o), low-birth-weight babies(157o), malformations (27o), andSIDS (17o). All couples receivedbasic preconception care includingnutritional counseling and a prenatalmultivitamin for both partners. After

2 years, 897o of the couples hadachieved live births. Of those withpreviously diagnosed infertility, 817oachieved live births, suggesting thatlifestyle modification may positivelyaffect fertility. Also of note is thatwithin this treatment group, therewere no reported miscarriages,perinatal deaths, or malformations,and that most children were born fullterm and of a healthful weight.^

Starting at the BeginningSeveral lifestyle factors have been

identified that can promote optimalfertility, including dietary behaviors,stress management, and maintenanceof a healthful weight. In addition,adequate nutrient status can influencenot only the ability to get pregnant,but the health of the egg and sperm,and thus the health of the childborn to those parents. The followinginterventions can greatly influencefertility, and it is recommendedthat all couples trying to conceiveconsider these interventions, whetherthey have trouble with fertility or not.

Addressing ObesityObesity poses a significant threat

to fertility as well as for the offspringborn to obese parents. In obesemen, there is increased aromataseactivity, which irreversibly convertstestosterone to estradiol, resulting indecreased testosterone and increasedestrogen levels.'' It is likely that thisplays a role in the lower spermcounts, lower sperm concentration,and poor sperm morphology seen inmen with increased BMI and central

52 TOWNSEND LETTER - APRIL 2013

adiposity. Obese men also have fewermotile sperm and lower testosteronelevels, as mentioned above. '̂''

It's not only men who experiencedecreased fertility as their weightcreeps up; women are also affected.Obese women have lower pregnancyrates (20.8% versus 28.3% successfulcycles, p = 0.04) when they undergovitro fertilization (IVF) and obesewomen are more likely to experiencepreterm births after IVF.^ '̂ Althoughthis study represents womenundergoing IVF, similar fertility trendsexist in women trying to conceivenaturally."^ Together, obese couplesexperience higher rates of miscarriagein both spontaneous conception andassisted reproduction." In addition tothe hormonal changes noted for men,this decreased fertility may be dueto increased levels of inflammationwhich affect ovarian response and theuterine/endometrial environment.

Obesity poses such a hindranceto fecundity that many fertility clinicsplace a BMI limit for candidacy forthe procedure. Addressing obesityfor patients is essential to support ahealthy conception and pregnancy,and maintenance of a healthfulweight should be a first goal forcouples wishing to get pregnant. If aweight-loss plan is implemented, it isstrongly recommended that cliniciansencourage a modified Mediterraneandiet, as this diet also has fertility-promoting effects.

Mediterranean DietThe Mediterranean diet is a

recommendation based on thetraditional dietary patterns of Creteand the rest of Greece, southernItaly, and southern France.'̂ Itemphasizes an abundance ofplant foods, especially fruits andvegetables, and a low intake of redmeat. Generally, fat makes up 257o to357o of total calories, with low intakeof saturated fats and high intake ofmonounsaturated fats such as thosein olive oil and omega-3 fats such asin fish. The primary fat consumed inthis diet comes from fish, poultry, andolive oil. The diet is high in legumesand whole grains and suggests low

to moderate consumption of dairyproducts and red wine.

The Mediterranean diet has, ofcourse, been studied for its positiveeffects on cardiovascular diseaseand overall mortality.'^ It has beenresearched for its effects on diabetes,depression, cognitive function,cancer, weight loss, and muchmore.'" Of note for this article is thediet's effect on fertility. Observationof 2154 Spanish women aged 20 to45 years showed that those womenwith the greatest adherence to aMediterranean diet pattern (versusWestern diet) showed the lowestdifficulty of getting pregnant.'=Additionally, a 2010 study of 161Dutch couples undergoing IVF or IVFwith intracytoplasmic sperm injection(ICSI) found that Mediterranean dietadherence increased the probabilityof pregnancy (odds ratio 1.4).""Mediterranean diet adherence wasalso associated with higher folate andvitamin B6 levels in red blood cellsand in follicular fluid in the samestudy.

Stress ManagementStress has a documented impact

on fertility. Studies have confirmedthat stress inhibits the hypothalamic-pituitary-gonadal (HPG) axis.'^ Thestress hormones cortisol, epinephrine,and norepinephrine and thehypothalamic-pituitary-adrenal (HPA)axis directly interact with severalother hormones, including hormonesthat regulate the menstrual cycle andgamete maturation (Table 1). Stresscan directly modify levels of FSH(follicle stimulating hormone) and LH(luteinizing hormone), which directlyaffect synthesis of estrogen andprogesterone, and dictate follicularmaturation and ovulation in womenand spermatogenesis and testosteroneproduction in men. Elevated cortisoland ACTH in men can also inhibitthe conversion of androstenedioneinto testosterone in Leydig cells.'"Higher follicular cortisol/cortisoneratios are associated with higher ratesof infertility in women." It has beennoted that men with increased stresshave a decrease in glutathione and

free sulfhydryl content of semen,both compounds important tocombat oxidative stress and toxic

Table 1 : Hormones Directly Affected bythe HPA Axis

Gonadotropin reieasing hormone (GnRH)ProiactinLuteinizing hormone (LH)Foiiicie stimuiating hormone (FSH)CortisolEndogenous opioldsMeiatonin

Interestingly, the link betweenstress and female fertility goes beyondan increase in stress hormone levelsand their downstream effects. HansSelye observed ovarian atrophyin response to stress in rats." It isimportant to acknowledge that stressmediators can be protective, not justdamaging, but high levels can leadto allosteric overload, where thereis a high likelihood of changes tothe physiological systems that affectfertility."

It seems as though various methodsof stress management and counselingmay be successful for couples tryingto conceive. A group mind/bodyintervention increased IVF pregnancyrates from 437o to 527o in womenunder age 40 about to start their firstIVF cycle at a Massachusetts fertilityclinic.^'' Additionally, "letting go"counseling, focused around releasingcontrol of the process of conception,has also shown benefit. This type ofcounseling nearly doubled pregnancyrates in the treatment group." Manyother interventions have showedbenefit for both men and women,including standard psychotherapy.

It is essential for practitioners towork with patients to develop a stress-management protocol that will workfor each couple, and to be sensitiveto the fact that a robust treatment planmay create an increased focus oninfertility and therefore, an increasedstress in and of itself.

Basic PreconceptionSupplementation

In this author's opinion, everycouple trying to conceive shouldbe put on a basic preconception

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regimen. Specific nutrients, suchas folie acid, have been shown notonly to be beneficial to preventserious birth (defects such as spinabifida, but also to negate deleteriousepigenetic effects to the offspring oftoxic exposures, poor nutrition, andelevated stress levels in the parents.̂ ^No couple lives in a perfect world,and these extra precautions nnaynot only promote fertility but alsosignificantly affect the offspring'sadult health status. The most simplepreconception program wouldinclude a good multivitamin and fishoil for both partners.

A prenatal multivitamin provideskey nutrients necessary for bothmother and baby throughout fetaldevelopment. These include iron,calcium, folate, and zinc. Studieshave demonstrated significantlyimproved pregnancy rates inwomen on multiple micronutrientsupplements compared with folieacid alone (66.7% versus 39.3%achieved conception after 3 menstrualcycles, 60% versus 25% ongoingpregnancy rate)." Consumption ofa prenatal multivitamin has alsobeen associated with significantlyimproved birth outcomes comparedwith consumption of folie acidand iron alone, including morehealthful birth weight of babies,and decreased rate of stillbirth andmiscarriage. A nonsignificant trendof decrease in neonatal deaths hasalso been observed.^" The same studyalso reported, not surprisingly, thatmothers who took a prenatal vitaminhad better micronutrient statuspostpartum.

Fish oil is another key supplementto include in a preconception protocolfor every couple who is contemplatingpregnancy in the next 6 months.It has been observed that fertilemen tend to have higher blood andspermatozoan levels of omega-3 fattyacids as well as lower serum ratiosof omega-6 to omega-3 comparedwith infertile men.^' For men with

oligoasthenoteratospermia (OAT),the worst semen parameters possible,supplementation with omega-3s significantly improved semenparameters including increasingsperm count from 38.7 to 61.7 millionand increasing sperm concentrationfrom 15.6 to 28.7 million/mL.^« It isclinically useful to understand that asperm concentration greater than 20million/mL is associated with a muchhigher rate of clinical pregnancythan below 20 million/mL, wherethe likelihood of natural conceptionis considered to be approximatelyzero.̂ ^ This fact further emphasizesthe benefit of fish oil supplementation.Fish oil supplementation has alsobeen correlated with increasedSuperoxide dismutase (SOD)-likeand catalase-like activity, which bothdemonstrate an increased ability towithstand oxidative stress, as well aspositive nonsignificant improvementsin sperm motility and morphology.^^

While there are not as manystudies to validate the benefit ofomega-3 supplementation in women,it is fair to assume that the significantbenefits to gamete production inmen would have some correlation tothe analogous structure in a woman,the egg. Increased dietary intakeof omega-3 fatty acids in women,especially alpha-linolenic anddocosahexaenoic acids (DHA), havebeen correlated with an improvementin embryo morphology in couplesundergoing IVF with ICSI.̂ ^

Improving Female FertilityBefore we discuss the interventions

researched to enhance fertility inwomen, it is interesting to note that farmore research exists on interventionsfor men. This is likely due to thecomparative ease of a study in men,where semen can be analyzed beforeand after an intervention to determineany effect on sperm parameters.For women, analysis is far morechallenging, since egg retrieval is afar more invasive process. While thequantity of direct research on femalefertility is relatively scant, there aresome clinical gems worthy of noting.The remainder of this article will focus

on interventions for women, as that isthe topic of interest for this issue.

The process of conception isvery complex, and while a man'scontribution is significant, themother's role has more breadth, andtherefore there are more areas thatcould be dysfunctional in a womantrying to conceive. It's essential toidentify where a fertility problem lies,and a proper work-up followed by anaccurate diagnosis is the first step toeffective treatment of infertility. It isnecessary to confirm that a womanis ovulating, and that intercourse istimed appropriately around ovulation.As a woman tries to have childrenlater in life, it also has becomeincreasingly important to confirmthat her eggs are good enough qualityto conceive and to develop into ahealthy child. Lastly, a woman'suterine environment must beappropriate to allow for implantation.Inadequate uterine lining thickness,excess inflammation, and many othercauses can contribute to an inabilityofthe embryo to implant properly andcreate the tether to sustain its life.

One of the most common causesof anovulation or irregular mensesis polycystic ovarian syndrome(PCOS). PCOS affects 10% ofwomen of reproductive age andis characterized by anovulation orinfrequent menses, cysts on theovaries, blood sugar dysregulation,and hormone imbalances such asincreased testosterone or an increasedLH/FSH ratio. Women with PCOSmay experience difficulty maintaininga healthful weight, hirsutism, andfrequently, infertility. The currentstandard of care for women withPCOS is insulin sensitizing agentssuch as metformin, but metformin isnot effective in inducing ovulation inmany patients. ^̂

Because the phosphoglycan thatmediates insulin action containsD-ch/ro-inositol, and because thisphosphoglycan is deficient in womenwith PCOS, it was postulated thatrestoration of adequate inositollevels may play an important role inrestoring proper hormonal functionin women with PCOS." Studies

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have demonstrated the significantlysuperior effect of inositol insensitizing cells to insulin, comparedwith metformin, in PCOS patients aswell as restoring ovulation, whichis particularly important for womenwith PCOS trying to conceive.^''Administration of both D-chiro- and/or myo-inositol, typically at a doseof 4 grams daily, has been shown toimprove insulin sensitivity, improveovulatory function, decrease serumandrogens, decrease elevated bloodpressure, decrease elevated plasmatriglycérides, and improve oocytequality in women with PCOS.̂ -̂̂ ''Myo-inositol is the preferred form todose, as it seems to perform betterthan the more expensive D-chiro-inositol.^'

In women with PCOS who areundergoing Clomid-supported cycles,coadministration of N-acetylcysteineat a dose of 1200 mg daily fromcycle day 3 through 8 signif̂ icantlyimproved ovulation rates from 17.97oin the control group to 52.17o inthe treatment group. In additionto an increased ovulation rate,women in the treatment group alsoproduced more mature follicles,had greater endometrial thickness,higher follicular estradiol levels, andincreased luteal phase progesteronelevels."" These are all signs ofimproved hormone balance andenhanced fertility.

A thin uterine lining can preventproper embryo implantation.Unfortunately, a thin uterine liningis a common side effect of "fertility-promoting" medications such asClomid, or clomiphene citrate.Clomiphene citrate acts as an estrogenblocker to decrease the negativefeedback signals that estrogenprovides to the hypothalamus andpituitary glands. This communicationblock can result in enhancedproduction of GnRH and FSH, whichprovides additional stimulation tothe ovaries to enhance follicularproduction. One downside of thismedication is that with the blockingof estrogen comes the side effects of adecrease in endometrial developmentand cervical mucus production, both

of which are enhanced by estrogen.For some women, clomipheneuse may simply move their fertilityproblem from one of ovulationdifficulty to implantation difficulty.Two small studies demonstrate thepromise that black cohosh may havein protecting women who chooseto take clomiphene citrate againstthese negative effects. In a 2009study by Shahin et al., 134 womenwere randomized to receive blackcohosh extract 120 mg daily orethinyl estradiol from cycle day 1through 12. The women receivingblack cohosh extract needed fewerdays for follicular maturation, hada thicker endometrium, and hadhigher estrogen levels (p < 0.001).Also, their luteal-phase progesteronelevels were higher, which canindicate an improved quality ofthe corpus luteum that develops inthe follicular phase of a women'smenstrual cycle. Clinical pregnancyrates were also significantly higherin the black cohosh group versus theethinyl estradiol group (36.77o versus13.67o)."i"2 Black cohosh appearsto provide a safe and viable optionfor women who experience negativeside effects of clomiphene citratestimulation.

Improving Ovarian ReserveForwomen over 35, ovarian reserve

can be one of the most challengingareas of fertility to overcome. Ovarianreserve describes the quantity andquality of eggs produced in responseto natural or drug-stimulated folliculardevelopment. It is unknown whetherpoor ovarian reserve is caused by anabnormally rapid loss of a normal-sized follicular pool, or by a normalrate of degradation of an abnormallysmall follicular pool. Either way,conventional medical options arelimited, and women diagnosed witha low ovarian reserve are typicallyrecommended egg donation as theironly option.

Just as oxidative stress plays asignificant decrease in quality ofsperm in men, it is also believed toplay a major role in the reductionof egg quality in women. For

Infertility

women with decreased egg quality,additional antioxidant support shouldbe considered over and above thatprovided through a standard prenatalvitamin.

An Italian study published in 2010has suggested that melatonin may bea useful antioxidant to support eggquality. 65 women undergoing IVFwere randomized to receive myo-inositol and folate or an identicalpreparation of the same combinationplus melatonin. The melatoningroup experienced a significantincrease in the number of matureoocytes and decrease in the numberof immature oocytes produced afterGnRH stimulation. There was nodifference in total oocytes produced,but the melatonin group had asignificant increase in quality andmaturity."3 A similar study showedpositive trends in clinical pregnancyrates and implantation rates in themelatonin group, although the resultswere not statistically significant.""In another study by Tamura etal., 115 women with a history offailed IVF and low fertilizationrate of their oocytes (<507o) inprevious cycles were randomizedto receive melatonin 3 mg daily atbedtime or placebo. Fertilizationrate improved significantly in themelatonin group only after 8 weeks ofsupplementation."^'"'

DHEA is commonly prescribed towomen with poor ovarian reserve.In fact, it is used by over one-thirdof all IVF centers worldwide."^DHEA is thought to improve ovarianfunction and ovarian reserve bypromoting preantral follicle growthand reducing follicular atresia. Severalstudies have looked at the effect ofDHEA supplementation in womenundergoing IVF with decreasedovarian reserve, and generally,supplemented women have higherpregnancy rates and lower miscarriagerates (by reducing aneuploidy),especially among women over age35."^ One such study supplemented

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women with 25 mg of DHEAthree times daily. Supplementationsignificantly increased women'slevels of anti-Müllerian hormone(AMH; p = 0.002), a hormoneproduced by developing folliclesthat is currently considered the bestindication of good egg quality andquantity. Improvement of AMH wasapproximately 60% (p < 0.0002),and longer use (up to 120 days)showed the greatest improvement.In addition to improvement in testsfor egg quality, treated women alsoexperienced a significant increasein the number of fertilized oocytes(p < 0.001), normal looking day 3embryos (p = 0.001), transferredembryos (p = 0.005), and improvedtotal embryo scores (p < 0.00)).'*'''^° Itis interesting to note that in the studiesof DHEA supplementation, there arefew reported side effects; however,supplementation of DHEA at 25 mgthree times daily is a high dose inthis author's opinion, and should bedone only under the supervision of anexperienced clinician.

ConclusionInfertility has become a widespread

problem in the US. Amazingly,the rate of infertility is the same asthe rate of breast cancer in the US.Although the suffering incurred withinfertility is not comparable to that ofbreast cancer, couples experiencinginfertility do incur amazingly high

stress levels, and increased rates ofdivorce, depression, and anxiety.Furthermore, those suffering withinfertility often do so in isolation, asthey feel a social stigma around notbeing able to easily conceive. Whilerates of fertility are on the rise, so arethe rates of the use of technologicalmedical approaches to overcomeinfertility. While procedures such aslUl and IVF are not without merit,there is little focus on correcting anyunderlying dysfunction, deficiency,and imbalance leading to troubleconceiving. Integrative practitionersserve an essential bridge to bring thesehealth-promoting practices into thefield of reproductive endocrinology,and should take a leadership role inbringing preconception practices toevery couple wanting to have a child.

Notes1. us Center for Disease Control. Fertility, Family

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5. Sermondade N, Faure C, Fezeu L, et al. Obesityand increased risk for oligozoospermia andazoospermia. Arch Intern Med. 2012;172(5):440-442.

6. Hakonsen LB, Thulstrup AM, Aggerholm AS, etal. Does weight loss improve semen quality andreproductive hormones? Results from a cohortstudy of severely obese men. Reprod hiealth.2011 Aug17;8-24.

7. Pinborg A, Gaarsiey C, Hougaard CO, et al.Influence of female bodyweight on IVF outcome:a longitudinal multicentre cohort study of 467

infertile couples. Reprod Biomed Online. 2011Oct;23(4):490-499.

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9. Dickey RP, Xiong X, Gee RE, et al. Effect ofmaternal height and weight on risk of pretermbirth in singleton and twin births resulting from invitro fertilization: a respective cohort study usingthe Society for Assisted Reproductive TechnologyClinic Outcome Reporting System. Fértil Steril.2012;97(2):349-54.

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16. Vujkovic M, de Vries JH, Lindemans J, et al. Thepreconception Mediterranean dietary patternin coupies undergoing in vitro fertilization/intracytoplasmic sperm injection treatmentincreases the chance of pregnancy. Fértil Steril.2010 Nov;94(6):2096-2101.

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Dr. Jaclyn Chasse, ND, is a practicing naturopathic doctor in New Hampshire, and medical directorat Emerson Ecologie. She also holds an adjunct faculty position at Bastyr University, teachingcourses on reproductive endocrinology. Dr. Chasse's clinical practice focuses on women's health,especially infertility, and pediatrics (a natural extension of treating Infertility!). In 2012, Dr. Chassewas honored to be named Leading Physician in Alternative Medicine by NH Magazine. Dr. Chassehas been very involved throughout her professional career in improving health care access andeducation. As a medical student, she cofounded the Naturopathic Medical Student Association, nowan affiliate branch of AMSA. She is the immediate past-president of the New Hampshire Associationof Naturopathic Doctors and currently serves on the AANP board of directors.

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LEARN FROMTHE BEST AT CLIMB

Renowned herbalist andCLIMB instructor KP Khalsa PCC's CLIMB for Health Professionals offers

programs to help you prepare for a new career orupdate your skills in the alternative health field.

• Herbalism - courses available online• Nutritional Therapy - courses available

online or on weekends in our downtownPortland facility

Expert instructors like KP Khalsa bring yearsof experience and practical application tothe classroom.

For more information, visit:www.pcc.edu/herbalism3 (Herbalism)www.pcc.edu/nutrition3 (Nutritional Therapy)Or email climbhealth@pcc.edu

/ ^ l I | l i | D Center for\ # I L i I I w l P AdvancementContinuous Learning for Individuals, Management & Business

PortlandCommunityCollege

TOWNSEND LETTER - APRIL 201357

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