Stress and Reproduction - Colorado State Universitycsu-cvmbs.colostate.edu/Documents/640-stressrepro-slides-meyers.pdf · Extremes in climate alter energy transfer with ... High protein

Stress and ReproductionMindy Meyers, BS and Joy Altermatt, BS, DVM

svarner

Stamp

What is stress as it relates to What is stress as it relates to reproduction?reproduction?

►► Imbalance of homeostasis in the struggle of the Imbalance of homeostasis in the struggle of the individual between maintaining itself within its individual between maintaining itself within its environment and perpetuating its geneticsenvironment and perpetuating its genetics

Classic indicators of stressClassic indicators of stress

►►Elevated blood plasma levelsElevated blood plasma levelsACTHACTHCortisolCortisolAdrenalinesAdrenalines

Clinically… Clinically… NeutrophiliaNeutrophiliaLymphopeniaLymphopeniaHyperglycemiaHyperglycemia

How and to whom does it manifest? How and to whom does it manifest?

►►Many molecular mechanisms and Many molecular mechanisms and pathways (HPA/HPG, pathways (HPA/HPG, immune, oxidativeimmune, oxidative))

►►Both sexes at all reproductive stages of Both sexes at all reproductive stages of lifelife

Qualifiers of stress responseQualifiers of stress response►►Previous experience Previous experience (adaptation to stimuli)(adaptation to stimuli)

►►Genetics Genetics ((BosBos indicusindicus vs. vs. BosBos taurustaurus))

►►Species Species (human complexity)(human complexity)

►►Age Age (last ditch effort)(last ditch effort)

Lower levels of Lower levels of glucocorticoidsglucocorticoids released in released in response to handling stress decreases with age response to handling stress decreases with age in nesting ternsin nesting terns ((HeidlingerHeidlinger 2006)2006)

Qualifiers of stress responseQualifiers of stress response

►►Physiologic status Physiologic status (i.e negative energy balance)(i.e negative energy balance)

►►Gender Gender sex hormone “sex hormone “neuroactiveneuroactive steroid” influences on steroid” influences on pain response pain response ►►Higher Higher glucocorticoidglucocorticoid levels in females than males after HPA levels in females than males after HPA

axis stimulation axis stimulation ((AloisiAloisi 2006)*2006)*

►►Timing, type, and duration of stress Timing, type, and duration of stress stimulus stimulus

Different Different stimuliistimulii result in different physiologic responses i.e. Blood result in different physiologic responses i.e. Blood cortisolcortisol, fatty acids, and glucose blood levels (, fatty acids, and glucose blood levels (OdioOdio 1985)1985)►► Example: Example: cortisolcortisol levels are higher for immobilization than levels are higher for immobilization than footshockfootshock in ratsin rats

WHAT WHAT is stress? is stress? Broad categories of stressBroad categories of stress

►►1) Environmental 1) Environmental i.e. thermal ?oxidative?i.e. thermal ?oxidative?

►►2) Physiologic 2) Physiologic i.e. nutritional deficiencyi.e. nutritional deficiency

►►3) Psychological/psychosocial 3) Psychological/psychosocial i.e. overcrowdingi.e. overcrowding

HOW HOW : Stress pathways (HPA): Stress pathways (HPA)

►►HypothalamusHypothalamus(PVN)(PVN)

CRH, AVP

Adrenal glandcortisol

Ant. pituitary

ACTH, β endorphins

catecholamines

release of neurotransmitters (i.e. NE, cholecystokinin, serotonin)

Stress event

+-

Stress pathways (HPG/HPA integration)Stress pathways (HPG/HPA integration)

►►HypthalamusHypthalamus(PVN)(PVN)

GnRH

cortisol

Ant. pituitary

LH FSHcatecholamines

Gonads

E2testosterone

adrenalCRH

ACTH- ?

- ?

- ?

-

-

Repro tracts abundant in receptors for CRH and cortisol

Complicated by…Complicated by…►► GlucocorticoidsGlucocorticoids negative feedback at each level of HPA axisnegative feedback at each level of HPA axis

Multiple receptor types: have both genomic and nonMultiple receptor types: have both genomic and non--genomic genomic effectseffects

►► ACTH can suppress pit. responsiveness to ACTH can suppress pit. responsiveness to GnRHGnRH in ovary intact ewesin ovary intact ewes

►► ββ endorphins can directly affect endorphins can directly affect GnRHGnRH neuronal activity in some studies neuronal activity in some studies but actual role undeterminedbut actual role undetermined

►► CatecholaminesCatecholamines also involved but to what extentalso involved but to what extent

►► HPG affects HPA? Estrogens bind to receptors on the CRH gene, HPG affects HPA? Estrogens bind to receptors on the CRH gene, increasing CRH activity (increasing CRH activity (AloisisAloisis 2005)2005)

►► CRH CRH direct roles in inhibiting direct roles in inhibiting GnRHGnRH release not well definedrelease not well defineddecreases testosterone synthesis in rat decreases testosterone synthesis in rat leydigleydig cells cells receptors present in many tissues, incl. placenta and gonadsreceptors present in many tissues, incl. placenta and gonadsactions at local levels unknown?actions at local levels unknown?Breen 2006

Relevant findingsRelevant findings

►► Suppression of LH pulse freq with Suppression of LH pulse freq with cortisolcortisoltreatment in womentreatment in women

►► CortisolCortisol inhibits inhibits pulsatilepulsatile LH secretion in LH secretion in ovariectomizedovariectomized ewes ewes (w/in 0.5(w/in 0.5--2h)2h)

Without reducing Without reducing GnRHGnRH secretionsecretion

► Women with chronic anovulation and lower implantation rates have higher serum cortisoland CRH concentrations than healthy controls

(Breen 2006, (Breen 2006, GallinelliGallinelli 2001)2001)

Campagne 2006

WHEN WHEN ::Stress effects at multiple stagesStress effects at multiple stages

►► PrePre--fertilizationfertilizationCopulatoryCopulatory behaviorbehaviorGamete maturation (females more crucial?)Gamete maturation (females more crucial?)

►► Gestational Gestational PrePre--implantationimplantationPlacentationPlacentation and beyondand beyondorganogenesisorganogenesis

►► PostPost--partum behaviorpartum behavioroffspringoffspringmaternalmaternal

Stress at preStress at pre--fertilizationfertilization

►►CopulatoryCopulatory behaviorbehavior

depression, anxiety and chronic stress may depression, anxiety and chronic stress may interfere with central and peripheral pathways interfere with central and peripheral pathways of the sexual response (decreased sex drive)of the sexual response (decreased sex drive)►►zoo animals decreased reproductive capacity zoo animals decreased reproductive capacity

associated with captivityassociated with captivity►►Classically, decreased estrus in heat stressed cattleClassically, decreased estrus in heat stressed cattle


►►Effect on testosteroneEffect on testosteroneAcute treatment of ACTH inhibits testosterone Acute treatment of ACTH inhibits testosterone by bovine, ovine and primate testisby bovine, ovine and primate testisIn contrast single injection ACTH stimulates In contrast single injection ACTH stimulates testosterone from boar, rabbit testistestosterone from boar, rabbit testisGlucocorticiodGlucocorticiod receptor present in receptor present in LeydigLeydig cellscells►►CortisolCortisol can lower LH receptor numbercan lower LH receptor number►►Resulting decreased androgen synthesisResulting decreased androgen synthesis


►►Heat stress dampens estrus behavior in Heat stress dampens estrus behavior in cattlecattle

►►Effect Effect GlucocorticoidGlucocorticoid treatment decreases treatment decreases gonadotropingonadotropin secretion and induction of secretion and induction of aromatasearomatase activityactivityEstrogen decreaseEstrogen decreaseProtective mechanisms Protective mechanisms ((cortisolcortisol--metabolizing metabolizing enzymes in repro tissues)enzymes in repro tissues)


►► Gamete maturation via HPA/HPG interferenceGamete maturation via HPA/HPG interference

Males: disturbance of spermatogenesis, decreased Males: disturbance of spermatogenesis, decreased sperm fertility parameters sperm fertility parameters

Females: disturbance of Females: disturbance of folliculogenesisfolliculogenesis►► Inhibits LH pulses, subsequent E2 and thus, LH/FSH surge Inhibits LH pulses, subsequent E2 and thus, LH/FSH surge ►►Also may inhibit Also may inhibit gonadotropicgonadotropic responsiveness in responsiveness in granulosagranulosa cells, cells,

given given glucocorticoidglucocorticoid receptor presence (Breen 2006)receptor presence (Breen 2006)

Stress effects in gestationStress effects in gestation

►► PrePre--implantation stagesimplantation stagesEarly embryonic loss in livestock and miceEarly embryonic loss in livestock and mice

►► PlacentationPlacentation and beyondand beyondPlacenta: abundant receptors for corticosteroids and Placenta: abundant receptors for corticosteroids and catecholaminescatecholaminesHumans: Humans: ►► increased incidence of spontaneous abortion, preterm delivery anincreased incidence of spontaneous abortion, preterm delivery and low birth d low birth

weightweight►► increased uterine a. resistance with high anxiety scores (increased uterine a. resistance with high anxiety scores (MulderMulder 2002)2002)

Cattle, sheep in heat stress last 2/3 Cattle, sheep in heat stress last 2/3 gestgest..►► exhibit reduced exhibit reduced utineutine and umbilical blood flows, resulting reduced fetal and umbilical blood flows, resulting reduced fetal

oxygen, nutrients and fetal size (VEGF and oxygen, nutrients and fetal size (VEGF and RmRNASRmRNAS) ) (Reynolds 2005)(Reynolds 2005)

►► OrganogenesisOrganogenesisadrenaladrenal

Stress effects postStress effects post--partumpartum

►►Maternal behaviorMaternal behavior

Stress during gestation alters postpartum Stress during gestation alters postpartum maternal care and the development of the maternal care and the development of the offspring in a rodent model offspring in a rodent model ►►Possible mechanism: Possible mechanism: cortisolcortisol alters alters oxytocinoxytocin receptor expressionreceptor expression

(Champagne 2006)(Champagne 2006)

Stress effects postStress effects post--partumpartum

►►Behavior of offspringBehavior of offspring

prenatal stress induces developmental and prenatal stress induces developmental and behavioral disordersbehavioral disorders►►Female progeny bad mothers too Female progeny bad mothers too ((MulderMulder 2002)2002)

prenatal stress had a longprenatal stress had a long--term negative effect term negative effect on sexual behavior in rats on sexual behavior in rats ((GerardinGerardin 2005)2005)

Stress Stress ≠≠ infertilityinfertility

►► CortisolCortisol required for normal parturitionrequired for normal parturitionInductionInductionPTSD: low profile PTSD: low profile cortisolcortisol, more complications , more complications ((SengSeng2005)2005)

►► Certain oxidative stress necessary for disulfide Certain oxidative stress necessary for disulfide bond formation and ovulationbond formation and ovulation

►► Acute stress causes increase in LH/testosterone Acute stress causes increase in LH/testosterone in monkey and boarin monkey and boar

1) Environmental stress1) Environmental stress

►►HeatHeat

►►Oxidative Oxidative In close connection with heat stress and In close connection with heat stress and metabolic stressmetabolic stress

►►ToxicantsToxicants

Environmental stress: Environmental stress: heatheat

►► MALESMALESSpermatogenesisSpermatogenesis

►► FEMALESFEMALESReproductive lossReproductive loss►►Widely known in cattleWidely known in cattle

Reduced Reduced intesityintesity and duration of estrusand duration of estrusReduced Reduced oocyteoocyte quality (Rocha 1998)quality (Rocha 1998)Reduced pregnancy rates from AI or natural service during periodReduced pregnancy rates from AI or natural service during periods s of hot weatherof hot weather

►►heat stress reduces the developmental ability of embryos heat stress reduces the developmental ability of embryos (mice: (mice: Ozawa 2002; sheep and cattle: Ozawa 2002; sheep and cattle: Rutledge 2001 ))

►► cattle, sheep models subjected to chronic heat stress result in cattle, sheep models subjected to chronic heat stress result in decreased uterine, umbilical blood flow decreased uterine, umbilical blood flow (Reynolds 2005)(Reynolds 2005)

Rutledge 2001, Hansen 2001, Collier 2006

Environmental stressEnvironmental stress

►►What about What about coldcold??Extremes in climate alter energy transfer with Extremes in climate alter energy transfer with deleterious effects on reproductiondeleterious effects on reproduction►►possibly through possibly through cortisolcortisol mediation and increased mediation and increased

caloric needcaloric need

►►cold as stress inducer in mice studiescold as stress inducer in mice studies

►►Most obvious in calf scrotal frostbite, Most obvious in calf scrotal frostbite, may result in infertilitymay result in infertility

repeated cold stress (rapid freq. temp. repeated cold stress (rapid freq. temp. changes) in rats changes) in rats prenatallyprenatally produced produced offspring with higher startle responsesoffspring with higher startle responses ((TazumiTazumi2005)2005)

COLD and maternal stress

Environmental stress: oxidativeEnvironmental stress: oxidative►► Involves production of ROS (OInvolves production of ROS (O2--*, H*, H2OO2, OH*) , OH*)

►► Not all badNot all badRequired for many processes (sperm DNA condensation, ovulation) Required for many processes (sperm DNA condensation, ovulation)

►► Increased ROS implicated in heat stress Increased ROS implicated in heat stress in vivo and in vitroin vivo and in vitro

►► Lipid, protein, DNA damage Lipid, protein, DNA damage Leads to cellular injuryLeads to cellular injuryImpedes, inhibits embryonic development (Impedes, inhibits embryonic development (Rutledge 2001)

Ozawa 2002, FAO,

Presence of ROS (i.e. from heat)

Lack of adequate ROS reduction, scavagingsystem

NORMAL DEGENERATING

Maternally heat stressed embryos Maternally heat stressed embryos

Ozawa 2002

Environmental stress: oxidativeEnvironmental stress: oxidative►►More detrimental More detrimental in vitroin vitro than than in vivo*in vivo*

►►Major concern in ARTMajor concern in ARTsuperoxidesuperoxide dismutasedismutase (SOD), (SOD), catalasecatalase, vitamins , vitamins (A, C and E), (A, C and E), glutathione and and pyruvate pyruvate ►►Inhibition of glutathione reduces Inhibition of glutathione reduces thermotolerancethermotolerance

[increase ROS] of embryos (interference with [increase ROS] of embryos (interference with genome activation?)genome activation?)

►►Female SOD knockouts infertile Female SOD knockouts infertile ((FujiiFujii 2005)2005)

Ozawa 2002

2) Physiological stress2) Physiological stress

►► MetabolicMetabolic

►► InflammatoryInflammatory

Physiological StressPhysiological Stress

►Nutritional and metabolic stress Impact the reproductive system

Undernutrition results in a compromised reproductive function

Metabolic signals play a critical role in response to stress

Nutritional StressNutritional Stress

►► Nutritional stress factors:Nutritional stress factors:Altered body fat ratioAltered body fat ratioWeight LossWeight LossNutrient deficiencyNutrient deficiencyEating disordersEating disorders

Models:Models:►► Postpartum Dairy CowsPostpartum Dairy Cows►► Rats, Pigs, and SheepRats, Pigs, and Sheep► Undernourished Women

Nutritional and Metabolic SignalsNutritional and Metabolic Signals

►Glucose is main energy source

► If glucose is not available, body shifts to maintain homeostasis

► Body attempts to produce glucose through alternate forms of metabolism

►Mechanisms impaired during times of stress

Metabolic StressMetabolic Stress

► Neuro-hormonal axis works to maintain energy balance

► Serum glucose and insulin provide feedback to the brain regarding fuel availability

► Adiponectin and leptin are hormones produced by adipocytes that help regulate fuel storage

► Thyroid axis is responsible for adjusting basal metabolic rate

(Basanta-Henry 2006)

Metabolic Factors on Ovarian Function

Webb et al. 2004

Metabolic - Stress► The GnRH pulse is very sensitive to stress and metabolic

factors

► GnRH pulse is highly sensitive to insultsWeight loss Decreased energy availabilityAltered body fat ratio

► Stress disrupts pulsatile GnRH secretion

► GnRH secretion affects pituitary secretionLH and FSHOvarian stimulation Estrogen production

(Lucy 2000, Basanta-Henry 2006)

Postpartum Dairy CowsPostpartum Dairy Cows

Regaining Homeostasis:Regaining Homeostasis:

11stst) Energy in milk production) Energy in milk production

22ndnd) Body Condition) Body Condition

33rdrd) Reproductive Process) Reproductive Process

(Beam 1997, Butler 2000, Webb 2004)(Beam 1997, Butler 2000, Webb 2004)


►► Shifting metabolic statusShifting metabolic statusIGFIGF--1 1 -- LiverLiverInsulin Insulin -- PancreasPancreasLeptin Leptin -- Adipose tissueAdipose tissue

**These signals act on hypothalamus to convey These signals act on hypothalamus to convey information to ovary to release/inhibit FSH information to ovary to release/inhibit FSH and LHand LH

(Lucy 2000)


►► Lactating cowsLactating cows

IGFIGF--1 1 –– gradually increasesgradually increases(can remain low)(can remain low)

Insulin Insulin –– gradually increasegradually increase

Leptin Leptin –– remains lowremains low

(Lucy 2000)(Lucy 2000)


►► Time to 1Time to 1stst ovulation is increasedovulation is increasedDependent upon LH reDependent upon LH re--establishmentestablishment

►► Smaller CLsSmaller CLs

►► Decrease of ProgesteroneDecrease of Progesterone

►► Less estrogenic dominant folliclesLess estrogenic dominant follicles(Beam 1997, Butler 2000, Webb 2004)(Beam 1997, Butler 2000, Webb 2004)

PostpartumPostpartum

►► Increase in LH Increase in LH appropriate body massappropriate body mass

►► Increase LH stimulates dominant Increase LH stimulates dominant follicle maturationfollicle maturation


What does this mean?What does this mean?

►►Selecting for increased milk productionSelecting for increased milk productionIncreasing stress on system Increasing stress on system Decreasing nutrientsDecreasing nutrientsDecreasing reproductionDecreasing reproduction

►►Nutritional needs shift from regaining body Nutritional needs shift from regaining body condition to milk productioncondition to milk production



►► Time to 1Time to 1stst ovulation is increasedovulation is increasedDependent upon LH reDependent upon LH re--establishmentestablishment

►► Smaller CLsSmaller CLs

►► Decrease of ProgesteroneDecrease of Progesterone

►► Less estrogenic dominant folliclesLess estrogenic dominant follicles(Beam 1997, Butler 2000, Webb 2004)(Beam 1997, Butler 2000, Webb 2004)


►► High protein diet or adding lipids to diet?High protein diet or adding lipids to diet?

►► Adding LipidsAdding LipidsLipid supplementation during 1Lipid supplementation during 1stst follicular wavefollicular wavecows unaffectedcows unaffected

►► High protein diet supports milk production High protein diet supports milk production Does not reactivate ovulation Does not reactivate ovulation Can increase uterine pHCan increase uterine pHIncrease blood concentrations of ammonia and ureaIncrease blood concentrations of ammonia and ureaIncreased plasma urea nitrogen = decreased fertilityIncreased plasma urea nitrogen = decreased fertility

* Increased milk production leads to cows with less adipose tiss* Increased milk production leads to cows with less adipose tissue ue and greater infertilityand greater infertility

(Butler 2000)(Butler 2000)

Nutritional Imbalance Nutritional Imbalance -- Rat ModelRat Model

►► Restricted protein 2wks prior to mating Restricted protein 2wks prior to mating throughout gestationthroughout gestation

Modest restriction (9% vs. 18% protein)Modest restriction (9% vs. 18% protein)

►► Upregulation of glycolysis Upregulation of glycolysis stress response, 9.5stress response, 9.5--10.5 days post fertilization10.5 days post fertilization

►► Increased offspring insulin resistance Increased offspring insulin resistance

►► Increased offspring blood pressureIncreased offspring blood pressure

(Lesse 2002)(Lesse 2002)

Feed Restriction on Cyclic GiltsFeed Restriction on Cyclic Gilts

►► Moderate Feed Restriction Moderate Feed Restriction 11st st or 2or 2ndnd week of estrusweek of estrus

►► Lower embryonic survivalLower embryonic survival

►► Unaltered IGFUnaltered IGF--1, T3, or Insulin1, T3, or Insulin

►► Lowered ProgesteroneLowered Progesterone

►► Improvement with insulin injections ??Improvement with insulin injections ??(Almeida 2000,2001)(Almeida 2000,2001)

Cyclic GiltsCyclic Gilts

►► Insulin to counteract feed restrictionInsulin to counteract feed restrictionFeed restricted 2Feed restricted 2ndnd wk/plus insulinwk/plus insulinInsulin (0.4IU/kg body weight 2x’s/day)Insulin (0.4IU/kg body weight 2x’s/day)Influences steroid oogenic activity?Influences steroid oogenic activity?Affected follicular maturationAffected follicular maturationGreater development of oocytesGreater development of oocytesDecreased detrimental affects (hyperinsulinemia)Decreased detrimental affects (hyperinsulinemia)

►► Progesterone shotsProgesterone shotsEarly pregnancyEarly pregnancyCounteracted nutritional induced embryonic lossCounteracted nutritional induced embryonic loss

(Almedia 2000,2001)(Almedia 2000,2001)

Lactating SowsLactating Sows►► Feed restriction lateFeed restriction late--lactationlactation

Decrease embryonic survivalDecrease embryonic survivalDevelopment of sex ratio skewingDevelopment of sex ratio skewingTreatment sows had ½ the control sow’s feed (n=17/group)Treatment sows had ½ the control sow’s feed (n=17/group)

►► Decreased litter growthDecreased litter growth

►► Decreased sow fertilityDecreased sow fertility

►► Decreased embryonic survivalDecreased embryonic survival

►► Trend towards male based littersTrend towards male based littersnot desirable in pigs (61% males vs. 54% in controls)not desirable in pigs (61% males vs. 54% in controls)

►► Improper methylation of genes on X chromoImproper methylation of genes on X chromofeed restriction decreases female embryosfeed restriction decreases female embryos

►► Uterine and embryonic environment skew in favor of malesUterine and embryonic environment skew in favor of males(Vinsky 2006)(Vinsky 2006)

Sheep ModelSheep Model►► Decreased late gestational nutritionDecreased late gestational nutrition

120hrs. Complete fasting120hrs. Complete fastingFasting between days 130Fasting between days 130--135 of gestation135 of gestation

►► InsulinInsulin--signaling pathway most responsive to stress?signaling pathway most responsive to stress?

►► Glucose decreased 50%Glucose decreased 50%

►► Intrauterine growth restrictionIntrauterine growth restriction

►► Postnatal insulin resistance Postnatal insulin resistance –– nutritional stressnutritional stress

►► Decreases sensitivity to steroid hormonesDecreases sensitivity to steroid hormones

(Shen 2005)(Shen 2005)

Sheep ModelSheep Model

►► UndernutritionUndernutrition½ feed at day 28 pregnancy½ feed at day 28 pregnancy

►► Oxidative base damages to DNA of fetal Oxidative base damages to DNA of fetal oogoniaoogonia

►► Decreased number of follicles Decreased number of follicles ►► Tumor suppressor protein p53 Tumor suppressor protein p53

Arrests oogonia Arrests oogonia Allowing for repair and proofAllowing for repair and proof--reading of DNAreading of DNA

►► p53 found on ovaries of restricted ewesp53 found on ovaries of restricted ewes

(Murdoch 2003)(Murdoch 2003)

WomenWomen

►► Energy investment Energy investment Poor condition Poor condition –– investment unwiseinvestment unwise

►► Extreme stress Extreme stress Early parturitionEarly parturitionGrowth restrictionGrowth restrictionIncreased morbidity and mortalityIncreased morbidity and mortality

(Wiley(Wiley--Less 2005)Less 2005)

Functional Hypothalamic Amenorrhea (FHA)

► Stress Induced Amenorrhea

► Exercise Induced Amenorrhea

► Eating disorders cause a range of menstrual disorders/infertility

► Amenorrhea due to chronic low energy intake

► Metabolic factors mediate reproductive adaptations

(Andrico 2002, Basanta-Henry 2006)

FHA Women

►No significant change in serum glucose levels

Elevated cortisol caused other energy sources to be converted into glucose

► Low Insulin levels Chronic undernutrition results in depletion of pancreatic glucose storesElevated cortisol levels


FHA Women

►Reduced secretion of:GnRHLHFSH

►Increased secretion of:CortisolIGFBP-1 (limits activity of IGF-1)GH


FHA Women

► Energy imbalance major mechanism

► Inadequate leptin productionStimulate the release of ACTH & endogenous opiods

► Increased cortisol

► Low estrogen

► HPA axis displays altered feedback inhibitionincreased cortisol does not alter CRH level

► HPT axis displays low levels of T3 and T4w/o compensatory rises in TSH


FHA Women

►Chronic hypoinsulinemia decreased insulin sensitivitymay affect the leptin and adiponectin production

►Leptin and adiponectin provide feedback to hypothalamus

Decreases GnRH


Gambia Rural Women StudyGambia Rural Women Study

►► 40yr study40yr study►► Poor nutritionPoor nutrition►► Low birth weightLow birth weight►► Low blood pressureLow blood pressure►► Low cardiovascular diseaseLow cardiovascular disease

•• Women in unnourished environmentsWomen in unnourished environmentsSmaller individualsSmaller individualsProduced smaller babiesProduced smaller babies

**Adaptation to stressful environment****Adaptation to stressful environment**(Wiley(Wiley--Less 2005)Less 2005)

Physiological stress: Physiological stress: inflammatoryinflammatory

►►Immune mediators of stressImmune mediators of stressInterleukin receptors at all levels of HPA and Interleukin receptors at all levels of HPA and HPG axes, affecting hormonal release HPG axes, affecting hormonal release ((gonadotropinsgonadotropins directly) directly) ((Breen 2006)

Early pregnancy loss attributed to a stressEarly pregnancy loss attributed to a stress--induced TNFinduced TNF--αα pathway pathway Bacterial Bacterial endotoxinsendotoxins block or delay LH surge block or delay LH surge (rat, cow, sheep, monkey)(rat, cow, sheep, monkey)

And reduce And reduce lutealluteal phase progesterone secretionphase progesterone secretion(sheep, monkey)(sheep, monkey)

Psychological/psychosocial stressPsychological/psychosocial stress

►► Human studies Human studies conflicting resultsconflicting results►►Some find no effects of psycho stress on IVF success rate Some find no effects of psycho stress on IVF success rate

(markers inadequate?)(markers inadequate?)►►Recent studies suggest links (cause or effect?)Recent studies suggest links (cause or effect?)

High anticipatory High anticipatory cortisolcortisol levels prior to OR and ET result in levels prior to OR and ET result in lower pregnancy rateslower pregnancy rates

►►Behavioral treatment shown effective (to what degree?)Behavioral treatment shown effective (to what degree?)

mental stress negatively affected semen qualitymental stress negatively affected semen quality ((Eskiocak 2005)

• decreased levels of glutathione, insufficent SOD (ROS overcomes)

• inhibition of the conversion of androstenedioneinto testosterone in Leydig cells on account of higher adrenocorticotrophichormone (ACTH) and cortisol levels

Campagne 2006

Campagne2006

Investigating further…Investigating further…

►► NeuroendocrineNeuroendocrine sites, cell types and better characterize sites, cell types and better characterize mechanisms of mechanisms of cortisolcortisol effect on decreased pituitary effect on decreased pituitary responsivenessresponsiveness

►► Chronic vs. acute effects (diet/schedules vs. counseling)Chronic vs. acute effects (diet/schedules vs. counseling)►► Methods of stress management and control Methods of stress management and control ►► Appropriate modelsAppropriate models

overcrowdingovercrowdingisolationisolationtransportationtransportationrestraint/captivityrestraint/captivityForced swimming Forced swimming shockshockcold/heat stresscold/heat stress

Stress managementStress management

►►Managerially (livestock)Managerially (livestock)Diet, housing, temperature controlDiet, housing, temperature control

►►PharmacologicallyPharmacologicallyWork in progress (i.e. antiWork in progress (i.e. anti--oxidants in oxidative stress)oxidants in oxidative stress)

►►Psychiatrically (human ART)Psychiatrically (human ART)Stress levels/test responses as predictors of IVF Stress levels/test responses as predictors of IVF outcomesoutcomes

Addressing StressAddressing Stress

►►Circumventing heat stress in cattleCircumventing heat stress in cattleFixedFixed--time insemination synchronization and time insemination synchronization and embryo transfer embryo transfer FanFan--misting at hottest periods of daymisting at hottest periods of dayTimed breeding season and gestation around Timed breeding season and gestation around heatheatGenetic influenceGenetic influence