18/10/2010

1

Fertility OptionsFertility OptionsFertility OptionsFertility Options

Mark Perloe, M.D.

Georgia Reproductive

Specialists

www.medigogy.com

www.medigogy.comOct 18, 2010

Objectives

• Discuss general fertility factors

• Describe basic evaluation and treatment

• Describe Assisted Reproductive

Technology (ART) at GRS

• Understand fertility preservation options

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Fertility Preservation

• Indications

– Chemotherapy, radiation therapy, surgery

– On-hold for career

– Haven’t found partner

• Criteria: Age, Antral follicle count, AMH

• Success: 2-5% chance for each stored oocyte

• Cost:

– Cryopreservation cycles: ~$9-$21,000 (1-3x)

– Thaw, culture & transfer: $5,000www.medigogy.com

Infertility….

• Inability to conceive after an interval of

unprotected intercourse• One year for women under 35

• Six months for women over 35

• Medical history and physical findings may

dictate earlier evaluation and treatment

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Scope

• At any given time, 10% of reproductive

age couples seeking conception are

unable to do so

�7.5 million women and their partners

• 15% of all reproductive age women have

an infertility-related office visit each year

• Half of couples experiencing fertility

problems never seek treatment

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Fertility Factors

• Ovulation factors 25%

• Male factor 40%

• Tubal/anatomic factors 35%

• Endometriosis 35% or more

• Multiple factors 25%

• Unexplained 30%

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0

20

40

60

80

100

1 3 5 7 9 11Months

% women pregnant

Cumulative frequency of

pregnancy in couples

trying to conceive

Let’s look

first at how easy, or difficult, it

is to get pregnant…

Fecundity

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Oocyte

Membrana granulosa

Theca interna

Basement membrane

Graafian follicle

Antrum

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-50 -4 +10-9 +1-180

Time (days)

0

Very little

atresia

Ovulation

Corpus

luteum

Large

antral

50 - 80% atresia

Primordial Small

Antral

Pre-ovulatory

Possible time of action of nutrition on folliculogenesis

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2

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The cleavage divisions produce cells called blastomeres.

Embryo Cleavage

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Blastomeres undergo compaction and form morula.

Gap junctions and tight junctions will form placenta.

The cells gain distinct polarity (i.e. have inside and outside faces) and flatten against each other.

Embryo growth

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Hatching from zona

The zona pellucida must be

lost before the embryo can contact the uterine epithelium.

Observations in vitro suggests that the blastocyst squeezes

out of fractures in the zona (“hatches”).

Identical twins may be produced if the embryo

breaks into two during this process.

Empty zona

Zona free blastocystswww.medigogy.com

Fertilization occurs in the ampulla of the oviduct,

implantation in the uterus.

Motile systems are important: cilia and smooth muscle.

The Fallopian tube produces

secretions which control and

provide a vehicle for transport.

Control over embryo transport

may also operate at the ampullary isthmic junction and

at the utero-tubal junction.

Implantation at

the blastocyst

stage

Fertilization

Embryo enters uterus

after about 4-5 days

Embryo transport

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Apposition

Attachment

Invasion

Uterine responses

In humans, the maternal epithelium and stroma in invaded by the embryo…

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The syncytiotrophoblast proliferates and invades the extracellular matrix of the stroma.

Cytotrophoblast cells migrate between the syncytia, followed by fetal stroma -leading to placental villi.

Implantation

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Ovulation Factors

• Insulin resistance– PCOS, hyperandrogenism

• Hypothalamic dysfunction– Exercise induced, eating

disorders, stress

• Pituitary disorders– hyperprolactinemia

• Ovarian Failure– Chemotherapy, Age, Surgery

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Polycystic Ovary Syndrome

• Low glycemic diet

• Metformin, TZD, GLP-1

• Exercise

• Ovarian drilling

• Clomiphene/letrozole

• Injectable gonadotropins

– OHSS risk

– High multiple birth rate

• IVF

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PCOS Ovarian Drilling

65-85% success

not effective in smokers

1/3 require ovulation meds

requires surgery

adhesion formation

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Endometriosis

• Presence of uterine lining in locations outside the uterus

• 35-55% of infertile women demonstrate endometriosis at laparoscopy

• Not all women with endometriosis have infertility

• Surgical treatment and Lupron do not enhance success rates

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Age related infertility

Reduced pregnancy

rates

Increased miscarriage rates

Increased risk fetal anomalies

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Pregnancy, Live Birth, and Singleton Live

Birth by Age,* 2001

0

10

20

30

40

50

22 24 26 28 30 32 34 36 38 40 42 44 46

Age (years)

Pe

rce

nta

ge

Pregnancy rate Live birth rate Singleton live birth rate

*For consistency, all rates are based on cycles started.*For consistency, all rates are based on cycles started.www.medigogy.com

Miscarriage Rates by Age, 2001

0

10

20

30

40

50

60

<24 24 26 28 30 32 34 36 38 40 42 44+

Age (years)

Pe

rce

nta

ge

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Male Factor Infertility

• Causes– varicocele– infection

– undescended testicle– smoking– genetic

– cancer, radiation, chemorx

– hot tub– bicycle riding, trauma

– Medications, steroids

• Testing– Semen analysis– DNA fragmentation

– HBA

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Sperm Chromatin Structure Assay

SCSA®/SDFA test

is a good predictor,relative to other sperm measures,

for the clinical diagnosis of male infertility

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DNA Fragmentation Study Results

• 998 cycles from 637

patients

• Unexplained infertility, with sufficient sperm count did IUI

• Female factor

infertility did IVF

• <500,000 sperm after gradient did ICSI

Bungum, Human Reprod, 2007

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P34H Testing

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P34H Testing

Sullivan, Fertil & Steril, 2006www.medigogy.com

SDD

• Study A– Retrospective study of

58 patients receiving IUI or IVF (w/o ICSI)

• None with abnormal SDD had live birth

• Those with normal SDD had a 28% success rate

• Study B– Prospective ICSI only

study..50 patients• 20 with abnormal SDD

• 30 with normal SDD

– ICSI success rates were not statistically different

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Advanced Sperm Testing Panel

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Uterine Evaluation

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Uterine Fibroids

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5. Analyze ResultsReal-time continuous monitoring with 3D dose accumulation and thermometry determines whether treatment can proceed as planned or has to be changed.

This interactive process continues until the entire region of treatment has been ablated.

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Congenital Uterine Anomalies

Bicornuate

Vs

Septate

Uterus

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Hydrosalpinx

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Abnormal Hysterosalpingogram

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Pelvic Adhesions

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Hydrosalpinx

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What do we know about pregnancy losses??

6 20 40

Weeks gestation

100

50

%

Pregnancies can easily be

recognized clinically by 6 wks.

Ovulation rates are high!

So probably are fertilization rates!

Early human embryos may

show a high incidence of

developmental abnormalities.

10-15% of of all

clinically recognised pregnancies are lost in

the 1st trimester; 2-3% are lost later.

50% of these losses

have cytogenetic abnormalities.

1/3 of all

pregnancies are lost soon

after implantation -

before they are clinically

recognised. www.medigogy.com

Unexplained InfertilityUnexplained Infertility

Letrozole or Clomid/IUI

Letrozole/HMG/IUI

IVF

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Injectable Gonadotropins

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Assisted Reproductive

Technology (ART)

• In vivo = inside the body

• In vitro = in glass = outside the body

• IVF = in vitro fertilization

• ART involves both the sperm and the egg in the laboratory

• Fertilization and early embryo development usually achieved in vivoaccomplished in vitro

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In vitro fertilization

Screening

Optimize reproductive health [nutrition, acupuncture]

Psychological counseling

Financial counseling

Nursing education

Ovarian hyperstimulation

Egg retrieval

Embryo culture

Embryo transfer

Cryopreservation

The wait!

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Lifestyle

• Smoking

– Up to 13% of infertility problems may be attributable to smoking

– Conception delay

– Egg depletion and diminished quality

– Higher miscarriage rates, ectopic pregnancies

– Passive smoking equivalent to active smoking

– Possibly lower IVF delivery rates

– Male smoking may pose greater riskwww.medigogy.com

Emotional Support

• Psychological counseling requirement prior to cycle initiation; continued referral as necessary

• Patient support groups, AFA, INCIID, RESOLVE

• “Mind, Body…Baby” Program– Acupuncture

– Massage

– Nutrition, Exercise, Yoga

– Supportwww.medigogy.com

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Financial Support

• Assisted Reproductive Technology Financial Options– “Making IVF Affordable Plan”

• Includes all Frozen Embryo Transfers

• No “Hidden Fees” for extra visits or ICSI

• FREE second IVF treatment cycle

– Shared Risk Program Refund IVF

– Global Fee IVF

– Global Frozen Embryo Transfer

– IVF PLUS

– Advanced Reproductive Care (ARC) financing

• 60% of patients have some degree of insurance coverage www.medigogy.com

IVF Overview

• Stimulation phase ~ 8-12 days

– Over-ride usual ovulation status

– Intentionally hyperstimulate ovaries with injectable hormones

– Monitor closely with vaginal ultrasound and blood hormone levels

– Anticipate 4-6 clinic visits

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IVF Overview

• Retrieval ~ 20 minutes

– Outpatient minor surgery under IV sedation

– Vaginal ultrasound guided oocyte retrieval

– All visible follicles entered and aspirated

– Recovery ~ 1 hour in clinic, remainder of day at home

– Goal: multiple eggs to work with in the laboratory

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IVF Overview

• Laboratory ~ 3-5 days

– Provide semen specimen

– Combine sperm and eggs at appropriate intervals

– Inject sperm into eggs as required

– Incubate and allow to grow for 3-5 days

– Embryologists update patients regarding progress

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IVF Overview

• Transfer

– Plan transfer for Day 3 or 5 after retrieval

– Abdominal ultrasound visualization requires a FULL bladder; Valium available

– Transfer catheter containing embryos threaded though cervix

– Embryos gently injected into uterus

– Normal activity after transfer

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IVF Overview

• Number of embryos transferred based on

patient age and embryo quality

– General for Day 3:

• < 35 years: 2 embryos

• 35-37: 2-3 embryos

• 38-40: 3-4 embryos

• >40: 4 embryos

– Blastocysts (Day 5): 2 embryos up to age 40

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Embryos

• Day 3 • Day 5

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IVF Overview

• 14 days after retrieval…

– Check pregnancy test

• Progesterone supplementation from just

after retrieval until outcome known

– Progesterone vaginal inserts or gel

– Continues through the 8th week of pregnancy

after IVF and 10th week after FET

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Special Issues

• Intracytoplasmic sperm injection (ICSI)– Individual sperm injected into each egg

– Important for profound male factor

• Pre-implantation genetic diagnosis (PGD/PGS)– Prevention of genetic disease

– Recurrent pregnancy loss

• Egg donation– anonymous vs. known donor

• Fertility preservationwww.medigogy.com

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Special Issues

• ICSI • PGD

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Reasons to Consider Embryo BiopsyReasons to Consider Embryo BiopsyReasons to Consider Embryo BiopsyReasons to Consider Embryo Biopsy

�� Recurrent MiscarriageRecurrent Miscarriage

��Unsuccessful IVF CyclesUnsuccessful IVF Cycles

��Unexplained InfertilityUnexplained Infertility

��Advanced Maternal AgeAdvanced Maternal Age

��Severe Male Factor InfertilitySevere Male Factor Infertility

��Single Gene Disorders/Translocations*Single Gene Disorders/Translocations*

2008 GRS IVF Statistics

Age <35 35-37 38-40 >40 Donor

# cycles 137 74 41 14 29

birth/cycle 40.1% 37.8% 34.1% 1/14 44.8%

Avg # ET

%Twins

%FET del

2.2

30.3

29.4

2.8

28.1

3 of 19

2.9

3 of 17

30.4

3.9

-

-

2.1

-

1 of 19www.medigogy.com

Success Rates: What do they mean?

32.8

27.0

31.433.4

20.2 21.4

0

10

20

30

40

50

Pe

rce

nta

ge

PregnanciesPregnancies

per cycleper cycleLive birthsLive births

per retrievalper retrieval

Live birthsLive births

per cycleper cycle

Live birthsLive births

per transferper transfer

Singleton Singleton

live births live births

per transferper transfer

Singleton Singleton

live births live births

per cycleper cycle

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Live Birth Rates by Diagnosis, 2001

27.530.6

13.9

30.8

25.0

32.0

25.728.5

22.624.8

0

10

20

30

40

50

Tubal factorO

vulat ory dysfunct ion

Dim

inished ovarian rese rve

Endom

et rios isU

terine factorM

ale factorO

ther c auseU

nexpla ined causeM

ult iple fac tors-f emale only

Multiple fac tors-f em

ale + male

Diagnosis

Liv

e b

irth

s p

er

cy

cle

(p

erc

en

t)

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CB1

Live Birth Rates by Woman’s Age and

Previous Live Births, 2001

34.0

27.1

18.7

9.9

4.1

40.3

31.8

21.4

11.4

5.0

0

10

20

30

40

50

<35 35-37 38-40 41-42 >42

Age (years)

Liv

e b

irth

s p

er

cy

cle

(p

erc

en

t)

No previous live births 1 or more previous live births

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Live Birth Rates by Age and History of Miscarriage, with No Prior Births,* 2001

34.1

26.6

18.4

8.94.4

33.7

27.4

19.3

10.7

4.2

0

10

20

30

40

50

<35 35-37 38-40 41-42 >42

Age (years)

Liv

e b

irth

s p

er

cy

cle

(p

erc

en

t)

No previous pregnancies 1 or more previous miscarriages

*Women reporting only previous ectopic pregnancies or pregnancies that ended in *Women reporting only previous ectopic pregnancies or pregnancies that ended in induced abortion were not included in the above statistics. induced abortion were not included in the above statistics. www.medigogy.com

Live Birth Rates by Woman’s Age and History

of Previous ART Cycles, 2001

36.2

28.4

20.0

10.2

4.8

30.325.5

17.5

9.6

3.6

0

10

20

30

40

50

<35 35-37 38-40 41-42 >42

Age (years)

Liv

e b

irth

s p

er

cy

cle

(p

erc

en

t)

No previous ART 1 or more previous ART cycles

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Live Births per Transfer and % Multiple Births in Women <35 by Number of Embryos Transferred, 2001

0

10

20

30

40

50

60

1 2 3 4 5 +

Number of embryos transferred

Liv

e b

irth

s p

er

tra

ns

fer

(pe

rce

nt)

Singletons Twins Triplets or more

(100.0)*(100.0)* (59.3)*(59.3)*

(39.6)*(39.6)*

(53.4)*(53.4)*

(38.8)*(38.8)*

(7.8)*(7.8)*

(49.1)*(49.1)*

(41.3)*(41.3)*

(9.6)*(9.6)*

(43.3)*(43.3)*

(46.8)*(46.8)*

(9.9)*(9.9)*

*Percentages of live births that were singletons, twins, and triplets or more are in parentheses. *Percentages of live births that were singletons, twins, and triplets or more are in parentheses. Note: In rare cases a single embryo may divide and thus produce twins. For this reason a smallNote: In rare cases a single embryo may divide and thus produce twins. For this reason a smallpercentage of triplets resulted when two embryos were transferred.percentage of triplets resulted when two embryos were transferred.

30.030.0

51.751.746.946.9

42.942.9 43.143.1

(1.2)*(1.2)*

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Slide 59

CB1 need to bring back bottom labes and take out small green boxes beside numbersConnie Butler, 14/10/2003

18/10/2010

8

Frozen Embryos vs. Fresh Embryos, 2001

22.7 23.4

17.2

33.4

21.4

0

10

20

30

40

50

Live births

per thaw

Live births

per transfer

Singleton live

births per

transfer

Live births

per transfer

Singleton live

births per

transfer

Pe

rce

nta

ge

Frozen embryos Fresh embryos

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Live Births per Transfer Using

Fresh Embryos From Own and Donor Eggs, by ART Patient’s Age, 2001

0.0

10.0

20.0

30.0

40.0

50.0

60.0

25 27 29 31 33 35 37 39 41 43 45

Age (years)

Pe

rce

nta

ge

Live births per transfer (Donor Eggs)

Live births per transfer (Own Eggs)

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Success Rates vs. Multiple Births

Type of ARTType of ARTwww.medigogy.com

AneuploidyAneuploidy--10 Probe FISH10 Probe FISHAneuploidyAneuploidy

--10 Probe FISH10 Probe FISH

Until recently…Until recently…

•• test for 10 chromosomestest for 10 chromosomes

•• 13, 14, 15, 16, 17, 18, 21, 22, X and Y13, 14, 15, 16, 17, 18, 21, 22, X and Y

–– 2 rounds of hybridizations 2 rounds of hybridizations

•• PrePre--implantation Genetic Screening (PGS) by fluorescence implantation Genetic Screening (PGS) by fluorescence in in situsitu hybridization (FISH): limit to technology for Aneuploidy hybridization (FISH): limit to technology for Aneuploidy Screening to improve IVF outcomes in ‘at risk’ couplesScreening to improve IVF outcomes in ‘at risk’ couples

CGHCGH--based DNA Microarray (aCGH)based DNA Microarray (aCGH)

Test

DNA

Normal

DNA

2700 probes

Same band resolution as karyotype

Cycles Maternal PriorCycles Maternal Prior EmbryosEmbryos Implant PregnantImplant PregnantAgeAge Failed Transfered Failed Transfered (+ fhb)(+ fhb)

CyclesCycles

CGH : CGH : 4545 37.737.7 2.4 2.4 2.02.0 67%67% 79% 79%

Control : Control : 113113 37.137.1 1.2 1.2 2.72.7 28%28% 60% 60%

p=0.0003p=0.0003

-- Schoolcraft et al (2010 Schoolcraft et al (2010 -- in press)in press)

CGH on CGH on blastocystblastocyst biopsies:biopsies:

Preliminary clinical resultsPreliminary clinical results

Embryo Evaluation “omics”• GENomics

– FISH

– CGH

– SNPs

• TRANSCIPTomics– Gene transcription

• PROTEomics– Proteins

– Secretomics

• METABOLomics– Metabolites

– Amino Acids

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Multiple Births rates are NOT

1996, 2000 and 2001

38.4

27.0

41.6

26.2

35.3

26.829.1

40.6

25.828.4

41.7

35.8

0

5

10

15

20

25

30

35

40

45

50

Fresh Nondonor Frozen Nondonor Fresh Donor Frozen Donor

Type of ART

Mu

ltip

le b

irth

s p

er

liv

e-b

irth

de

liv

ery

(p

erc

en

t)

1996

2000

2001

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18/10/2010

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GRS

• Meridian Mark

– Drs. Perloe, Kaplan and Singleton

• Alpharetta

– Dr. Conway

• DeKalb Medical Center

– Dr. Kaplan

Please join us for a complimentary 20 minute visit….Please join us for a complimentary 20 minute visit….

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