lecture 14: conception, fertility, depo...

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


•• MiscarriageMiscarriage

•• birth defectsbirth defects

•• lower birth weightlower birth weight

•• earlier birthsearlier births

Infertility: AlcoholInfertility: Alcohol

•• AlcoholAlcohol


•• MiscarriageMiscarriage

•• birth defectsbirth defects


•• 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



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




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



•• 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


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


•• 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



•• 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



•• 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


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


•• 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


•• 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


•• 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

lecture 14: conception, fertility, depo...

Documents