11
Lecture 14: Conception, Fertility, Lecture 14: Conception, Fertility,
Early Fetal Loss Early Fetal Loss
•• Birth Birth Control Control (cont.)(cont.)
•• ConceptionConception
•• What Influences Probability of What Influences Probability of Conception?Conception?
•• Early Fetal LossEarly Fetal Loss
•• InfertilityInfertility
•• Fertility EnhancementFertility Enhancement
•• Assisted reproductionAssisted reproduction
Behavioral Biology of Women-2007
DepoDepo--proveraprovera
•• Injectable Injectable contraceptive contraceptive ---- ProgestinProgestin
•• Shot every 3 months Shot every 3 months
•• First year failure rate of 0.3%First year failure rate of 0.3%
•• Can delay fertility for 6 months Can delay fertility for 6 months -- 1 yr after 1 yr after
discontinuediscontinue
•• Used by 30 million womenUsed by 30 million women
NorplantNorplant
•• 6 sticks under skin6 sticks under skin
•• Synthetic progestinSynthetic progestin
•• Lasts up to 5 yearsLasts up to 5 years
•• First year failure rate of 0.05%, 3.7% over 5 First year failure rate of 0.05%, 3.7% over 5 yearsyears
•• Inhibits ovulation, thickens and decreases Inhibits ovulation, thickens and decreases cervical mucous, thins endometrial liningcervical mucous, thins endometrial lining
•• Progestin 4Progestin 4--5x lower than birth control pills5x lower than birth control pills
•• Used by 3 million women Used by 3 million women
ImplanonImplanon
•• New birth control similar to Norplant but New birth control similar to Norplant but just 6 stick under skinjust 6 stick under skin
•• Not yet readily availableNot yet readily available
The PatchThe Patch
••Works similar to the pillWorks similar to the pill
•• Contains progestin and estrogenContains progestin and estrogen
•• Delivered through skinDelivered through skin
•• Put a new patch on once a Put a new patch on once a weekweek
•• ReversibleReversible
Nuva Nuva RingRing
•• Works similar to the pill, butWorks similar to the pill, but delivers hormones delivers hormones vaginallyvaginally
•• Contains progestin and estrogenContains progestin and estrogen
•• Ring inserted in vaginaRing inserted in vagina
•• Leave in for 3 weeks Leave in for 3 weeks -- take out take out for 1for 1
•• ReversibleReversible
•• Should be more effective than Should be more effective than bill < 1% failure ratebill < 1% failure rate
22
Homunculus in SpermHomunculus in Sperm ConceptionConception
The Ovum
33
The OvumThe Ovum
•• Shed into peritoneal cavityShed into peritoneal cavity
•• Rising estradiol causes fimbria to sweep Rising estradiol causes fimbria to sweep
ovum in to fallopian tubeovum in to fallopian tube
•• Cilia is activated in ampullaCilia is activated in ampulla
•• Ovum moves into fallopian tube and into Ovum moves into fallopian tube and into
ampullaampulla
•• Ovum continues to Ovum continues to ‘‘ripenripen’’ in ampullain ampulla
The SpermThe Sperm
44
How do sperm get into Cervix?
•• Opening of cervix has cilia to Opening of cervix has cilia to waft sperm throughwaft sperm through
•• Components of seminal fluid Components of seminal fluid --maybe maybe prostaglandings prostaglandings --stimulate contractions in upper stimulate contractions in upper vagina to propel sperm into vagina to propel sperm into cervixcervix
55
CapacitationCapacitation
•• Change to Change to
hyperactivated hyperactivated
motility pattern motility pattern --
whipwhip--like beats of like beats of
tailtail
•• Change in surface Change in surface
membrane membrane ----
responsive to responsive to
signals from oocytesignals from oocyte
The SpermThe Sperm
•• Seminal fluid causes contractions of upper Seminal fluid causes contractions of upper vaginavagina
•• Cervical mucous changesCervical mucous changes
•• Cilia propel sperm into ampulla where Cilia propel sperm into ampulla where fertilization takes placefertilization takes place
•• Chemicals surrounding egg may attract Chemicals surrounding egg may attract spermsperm
•• In ampulla goes through In ampulla goes through ‘‘capacitationcapacitation’’
66
FertilizationFertilization
77
Acrosome ReactionAcrosome Reaction Acrosome Reaction
Binds to OocyteBinds to Oocyte
Perivetelline Space
• Fusion with oocyte
• Zona pellucida hardens (Zona
reaction)
• Final division of meiosis in oocyte
88
Male and Female Pronuclei formMale and Female Pronuclei form
Polar BodiesPolar Bodies Pronuclei of Male and Female FusePronuclei of Male and Female Fuse
99
FertilizationFertilization
•• Progesterone from granulosa cells causes Progesterone from granulosa cells causes
enzymes in acrosome to leak out and enzymes in acrosome to leak out and
dissolve matrix around eggdissolve matrix around egg
•• One Sperm binds to zona pellucidaOne Sperm binds to zona pellucida
•• Acrosome reactionAcrosome reaction
•• Microvilli of egg engulf spermMicrovilli of egg engulf sperm
•• Egg enzymes harden zona pellucidaEgg enzymes harden zona pellucida
•• Final division of oocyte occursFinal division of oocyte occurs
ImplantationImplantation
YOU YOU -- Day 1!Day 1!
Morula
8 Cell Stage
1010
100 Cell Stage
Trophoblast
Inner Cell Mass
Blastocyte
Day 5: “Hatching” from Zona Pellucida Day 8-10: Implantation
Day 11
1111
ImplantationImplantation ImplantationImplantation
• First forms a morula after initial cell division
• At 8-cell stage differentiates tissues• Forms blastocyte
• Trophoplast
• Inner Cell Mass
• Trophoblast “hatches” out of zona pellucida for implantation
How does the Embryo signal itHow does the Embryo signal it’’s s
presence to the motherpresence to the mother
HCG (Human Chorionic HCG (Human Chorionic
Gonadotropin) RescueGonadotropin) Rescue
•• Embryo produces HCG to signal the motherEmbryo produces HCG to signal the mother
•• Mimics LHMimics LH
•• Maintains the corpus luteumMaintains the corpus luteum
What Influences the Probability What Influences the Probability
of Conception?of Conception?
(Lipson & Ellison, 1996)
1212
(Lipson & Ellison, 1996)
Behavior and Behavior and
ConceptionConception
Causes of SubfertilityCauses of Subfertility
EnglandEngland
0
5
10
15
20
25
30
Fre
quen
cy (%
)
Endometriosis Tubal
Damage
Ovulatory
Problems
Sperm Defects Unexplained
Johnson & Everitt 2000
Infertility: CaffeineInfertility: Caffeine
•• CaffeineCaffeine
•• InfertilityInfertility
•• MiscarriageMiscarriage
•• birth defectsbirth defects
•• lower birth weightlower birth weight
•• earlier birthsearlier births
Infertility: AlcoholInfertility: Alcohol
•• AlcoholAlcohol
•• InfertilityInfertility
•• MiscarriageMiscarriage
•• birth defectsbirth defects
•• lower birth weightlower birth weight
•• earlier birthsearlier births
Alcohol and ConceptionAlcohol and Conception
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Fec
undability R
atio
No Alcohol 1-5
Drinks/week
>10
Drinks/week
(Jensen, et al., 1998)
1313
Alcohol and Caffeine Alcohol and Caffeine
ConsumptionConsumption
0
5
10
15
20
25
30
Pre
gnanci
es/1
00 C
ycl
es
No Alcohol + < 1 cup
coffee/day
Alcohol + >1 cup
coffee/day
(Hakim et al., 1998)
Alcohol and Caffeine Alcohol and Caffeine
ConsumptionConsumption
•• >50% reduction in >50% reduction in
probability of probability of
conception during conception during
a menstrual cycle a menstrual cycle
where alcohol was where alcohol was
consumedconsumed
•• Caffeine enhanced Caffeine enhanced
negative effect of negative effect of
alcohol (no alcohol (no
independent effect)independent effect)
0
5
10
15
20
25
30
Pre
gnanci
es/1
00 C
ycl
es
No Alcohol + < 1 cup
coffee/day
Alcohol + >1 cup
coffee/day
(Hakim et al., 1998)
Infertility: SmokingInfertility: Smoking
•• SmokingSmoking
•• InfertilityInfertility
•• lower birth weightlower birth weight
Smoking and ConceptionSmoking and Conception
0.82
0.84
0.86
0.88
0.9
0.92
0.94
0.96
0.98
1
Fec
undability R
atio
Nonsmokers Female Smokers Male Smokers
(Curtis et al., 1997)
Smoking and Caffeine Smoking and Caffeine
Consumption Consumption
•• Nonsmokers had Nonsmokers had
a dose response a dose response
relationship with relationship with
caffeinecaffeine
•• No doseNo dose--
response with response with
caffeine in caffeine in
smokerssmokers0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.91
Fec
undability R
atio
Nonsmoker <
300 mg/d
Nonsmokers
300-700 mg/d
Nonsmokers
> 700 mg/d
Smokers with
>300 mg/d
Caffeine Consumption
(Jensen et al., 1998)
Male InfertilityMale Infertility
•• Sperm counts Sperm counts
decrease during decrease during
IVF treatmentIVF treatment
1414
Timing of Intercourse?Timing of Intercourse?
Lovers by Paolo Fiammingo
Timing of Intercourse and Timing of Intercourse and
ConceptionConception
Dunson et al., 1999
Early Fetal LossEarly Fetal Loss
(Wilcox et al., 1988)
HCG Concentrations in 5 women
with early Pregnancy Loss
Wilcox et al. 1988
Wilcox StudyWilcox Study
•• 25% chance of conceiving with each cycle25% chance of conceiving with each cycle
Wilcox et al. 1988
•• 31% pregnancies ended in miscarriage31% pregnancies ended in miscarriage
•• No increased loss if conceived in next cycle No increased loss if conceived in next cycle
after miscarriageafter miscarriage
•• Risk didnRisk didn’’t increase if had just 1 t increase if had just 1
miscarriagemiscarriage
•• DoesnDoesn’’t include loss before HCG secretion t include loss before HCG secretion
detected or if HCG too lowdetected or if HCG too low
•• Higher rate of miscarriage in women who Higher rate of miscarriage in women who
eventually conceivedeventually conceived
Early Fetal loss in BangladeshEarly Fetal loss in Bangladesh
1515
Holman StudyHolman Study
•• Observed early pregnancy loss was 34%Observed early pregnancy loss was 34%
•• No difference between this and the western No difference between this and the western
samplesample
Holman StudyHolman Study
•• Observed early pregnancy loss was 34%Observed early pregnancy loss was 34%
•• Extend findings back to period between Extend findings back to period between
conception and HCG detectionconception and HCG detection
•• 1818--yearyear--olds olds -- 64% loss64% loss
•• 2828--yearyear--olds olds -- 85% loss85% loss
•• 3838--yearyear--olds olds -- 96% loss96% loss
•• 4848--yearyear--olds olds -- 99% loss99% loss
Criticisms:Criticisms:
•• Problems with mathematical modelProblems with mathematical model
•• Fecundability Fecundability must be almost 100% for this must be almost 100% for this
rate of lossrate of loss
Age and ConceptionAge and Conception
•• Fecundity decreases with ageFecundity decreases with age
Chromosomal Abnormalities & Age Chromosomal Abnormalities & Age
•• Increased chromosomal abnormalitiesIncreased chromosomal abnormalities
1616
Age and DownAge and Down’’s Syndrome Risks Syndrome Risk
0
1
2
3
4
5
6
7
8
9
Per
cent R
isk
20 25 30 35 40 45 49
Age
(Scher and Dix, 1990)
Conception Conception
and Age and Age
•• Increased Increased
chromosomal chromosomal
abnormalitiesabnormalities
•• Zona pellucida Zona pellucida
too dense too dense ---- no no
implantationimplantation
Oral Consumption
Consumption of Dill Rome, 1st Century
Wild Rue 11 century Middle East
Wormwood 11 century Middle East
"Hot" Foods (fish, eggs, brown sugar Modern Afghanistanalmonds, dates, ginger, garlic, raisins)
Ginger Jivaro of PeruIntravaginal
Alum Greco-Roman
Linseed Oil Greco-Roman
Frankincense & Wormwood 13th century Middle East
Mechanical
Application of Greco-Roman, modern Afghanistanvacuumed containers
Wearing of fresh skins Central Asia
Massage to move navel Afghanistan
Magico-Religious
Traditional Methods Traditional Methods -- FertilityFertility EnhancementEnhancement
Assisted ReproductionAssisted Reproduction
•• ClomidClomid
•• PerganolPerganol
•• in vitroin vitro FertilizationFertilization
•• IntraIntra--Uterine InseminationUterine Insemination
•• Sex SelectionSex Selection
•• GIFTGIFT
•• ZIFTZIFT
1717
Fertility Drug: ClomidFertility Drug: Clomid
•• Fertility drug given to women to promoteFertility drug given to women to promoteovulationovulation
•• Ring structure similar to estradiolRing structure similar to estradiol
•• Binds to receptors for estrogenBinds to receptors for estrogen
•• Hypothalamus Hypothalamus ““thinksthinks”” estrogen is low and pumps estrogen is low and pumps out FSH to make more estrogenout FSH to make more estrogen
•• So causes woman to produce estrogen on her ownSo causes woman to produce estrogen on her own
•• Multiple birthsMultiple births
•• Possibly associated with ovarian cancer (concern for Possibly associated with ovarian cancer (concern for women who donate eggs)women who donate eggs)
Fertility Drug: PerganolFertility Drug: Perganol
(Human Menopausal (Human Menopausal
Gonadotropin)Gonadotropin)
•• LH and FSH combined (distilled from LH and FSH combined (distilled from
menopausal urine)menopausal urine)
•• Stimulates follicular growth and estrogen Stimulates follicular growth and estrogen
productionproduction
•• MidMid--cycle dose of HCG to stimulate cycle dose of HCG to stimulate
ovulation (mimicking action of LH)ovulation (mimicking action of LH)
•• Multiple gestation risk (higher than clomid)Multiple gestation risk (higher than clomid)
Fertility Treatment:Fertility Treatment: in vitroin vitro
Fertilization (IVF)Fertilization (IVF)•• Take fertility drugs to get several eggs to matureTake fertility drugs to get several eggs to mature
•• Ultrasound to watch follicular developmentUltrasound to watch follicular development
•• When follicle mature get dose of HCG (as an LH When follicle mature get dose of HCG (as an LH
mimic mimic -- to encourage follicular development)to encourage follicular development)
•• After 36 hours (just before ovulation would occur After 36 hours (just before ovulation would occur
naturally) surgically remove 4naturally) surgically remove 4--12 eggs12 eggs
•• Fertilization outside (in petri dish) of bodyFertilization outside (in petri dish) of body
•• Grow 4Grow 4--10 cells10 cells
•• Put back 2Put back 2--5 in hopes 1 will implant5 in hopes 1 will implant
•• Tubal blockage, as a result of infectionTubal blockage, as a result of infection
•• Low sperm count (select Low sperm count (select ““bestbest”” sperm)sperm)
Fertility Treatment:Fertility Treatment: IntraIntra--Uterine Uterine
Insemination (IUI)Insemination (IUI)
•• Take fertility drugs to get several eggs to Take fertility drugs to get several eggs to
maturemature
•• Ultrasound to watch follicular developmentUltrasound to watch follicular development
•• When follicle mature get dose of HCG (high When follicle mature get dose of HCG (high
enough to cause ovulationenough to cause ovulation
•• Inseminate with partnerInseminate with partner’’s sperm in the uteruss sperm in the uterus
GIFTGIFT
•• Gamete Intrafallopian Gamete Intrafallopian
TransferTransfer
•• Mix egg and sperm and Mix egg and sperm and
put back in fallopian put back in fallopian
tube before fertilizationtube before fertilization
ZIFTZIFT
•• Zygote Intrafallopian Zygote Intrafallopian
TransferTransfer
•• Put zygote in fallopian Put zygote in fallopian
tube (instead of tube (instead of
uterus)uterus)
1818
Sex SelectionSex Selection
•• YY--sperm lighter can sperm lighter can
separate out separate out
•• CentrifugeCentrifuge
•• Avoid sexAvoid sex--linked linked
recessive diseasesrecessive diseases
Assisted Reproduction ImplicationsAssisted Reproduction Implications
•• Higher rate of multiple birthsHigher rate of multiple births
Assisted Reproduction ImplicationsAssisted Reproduction Implications
•• Higher rate of multiple birthsHigher rate of multiple births
•• Lower birth weight of singletons AND Lower birth weight of singletons AND
multiplesmultiples
Percentage with Low Birth WeightPercentage with Low Birth Weight
0
2
4
6
8
10
12
14
General Population
Singletons
Assisted
Reproduction
Singletons
Schieve et al., 2002
Percent Risk of Low Birth Weight & Percent Risk of Low Birth Weight &
Procedure TypeProcedure Type
13.6
10.5
14
11.8
8.7
6.6
0
2
4
6
8
10
12
14
Fresh
Em
bryo,
nondonor
oocyte
Frozen
Em
bryo,
nondonor
oocyte
Fresh
em
bryo,
donor o
ocyte
Frozen
Em
bryo, D
onor
Oocyte
Gest
ational
Carrie
r
No A
ssis
tance
Schieve et al., 2002
Possible Causes of Low Birth Weight Possible Causes of Low Birth Weight
with Assisted Reproductionwith Assisted Reproduction
•• Increased levels of endometrial proteinsIncreased levels of endometrial proteins
Schieve et al., 2002
•• Increased rates of structural abnormalities Increased rates of structural abnormalities of the placentaof the placenta
•• Human Menopausal gonadotropin (Perganol) Human Menopausal gonadotropin (Perganol) increases insulinincreases insulin--like growth factorlike growth factor--binding binding protein protein -- intrauterine growth restrictsintrauterine growth restricts
•• PregnancyPregnancy--induced hypertensioninduced hypertension
•• Elective cesarean section Elective cesarean section -- earlier deliveryearlier delivery
1919
Assisted Reproduction ImplicationsAssisted Reproduction Implications
•• Higher rate of multiple birthsHigher rate of multiple births
•• Lower birth weight of singleton AND Lower birth weight of singleton AND
multiplesmultiples
•• Greater risk of short and long term Greater risk of short and long term
disabilities and death with low birth weightdisabilities and death with low birth weight
Assisted Reproduction ImplicationsAssisted Reproduction Implications
•• Higher rate of multiple birthsHigher rate of multiple births
•• Lower birth weight of singletons AND Lower birth weight of singletons AND
multiplesmultiples
•• Greater risk of short and long term Greater risk of short and long term
disabilities and death with low birth weightdisabilities and death with low birth weight
•• Higher rates of birth defectsHigher rates of birth defects
Assisted Reproduction & Birth DefectsAssisted Reproduction & Birth Defects
4.20%
9.70% 9.50%
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
Natural
Conception
Intracytoplasmic
Sperm Injection
In Vitro
Fertilization
Hansen et al. , 2002
Assisted Reproduction & Birth DefectsAssisted Reproduction & Birth Defects
Singleton BirthsSingleton Births
1.6%1.3%
0.6%
2.7%2.7%
1.3%
2.7%
3.8%
1.1%
0%
1%
1%
2%
2%
3%
3%
4%
4%
Cardiovascular Urogenital Musculoskeltal
Intracytoplasmic Sperm Injection In Vitro Fertilization Natural
Hansen et al. , 2002
Possible Causes of Increased Birth Possible Causes of Increased Birth
Defects with Assisted ReproductionDefects with Assisted Reproduction
•• Freezing and thawing of embryosFreezing and thawing of embryos
Hansen et al. , 2002
•• Medications to induce ovulationMedications to induce ovulation
•• Underlying cause of their infertilityUnderlying cause of their infertility
•• Medications to maintain pregnancy early onMedications to maintain pregnancy early on
•• Potential for polyspermic fertilizationPotential for polyspermic fertilization
•• Delayed fertilization of oocyteDelayed fertilization of oocyte
Assisted ReproductionAssisted Reproduction
•• 23% success rate23% success rate
•• 2.6 times risk of low birth weight2.6 times risk of low birth weight
•• Twice the risk of major birth defectsTwice the risk of major birth defects
Mitchell 2002
2020
Assisted ReproductionAssisted Reproduction
•• 23% success rate23% success rate
•• 2.6 times risk of low birth weight2.6 times risk of low birth weight
•• Twice the risk of major birth defectsTwice the risk of major birth defects
However However ……
94% will be of normal birth weight94% will be of normal birth weight
91% free of major birth defects91% free of major birth defects
Mitchell 2002
Next Time Next Time ……
•• Views of PregnancyViews of Pregnancy
•• Gestational DevelopmentGestational Development
•• The Physiology of PregnancyThe Physiology of Pregnancy
•• Pica eatingPica eating
•• Pregnancy SicknessPregnancy Sickness
•• Energetics of PregnancyEnergetics of Pregnancy
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