The Diagnosis and Treatment of Infertility

Ashim Kumar, M.D.Ashim Kumar, M.D.Reproductive Endocrinology and InfertilityReproductive Endocrinology and Infertility

Clinical Assistant Professor, Clinical Assistant Professor, UCLA School of MedicineUCLA School of Medicine

Fertility & Surgical Associates of California,

Encino & Thousand Oaks, CA

InfertilityInfertility 1 in 8 couples affected1 in 8 couples affected

Definition: FDefinition: Failure to conceive after ure to conceive after 1 year1 year of regular, unprotected intercourseof regular, unprotected intercourse

Earlier evaluation is recommended if:Earlier evaluation is recommended if: Women >35 years old Irregular menses History of Pelvic Inflammatory Disease Endometriosis Men with risk factors (e.g. testicular

surgery, abnormal semen analysis)

Female Genital TractFemale Genital Tract

The Menstrual Cycle

Follicular Phase Luteal Phase

Fertilization & ImplantationFertilization & Implantation

Causes of InfertilityCauses of Infertility

Speroff and Fritz –Clinical Gynecologic

Endocrinology and Infertility 2005

5%

35%

15%

35%

10%

MaleMale

?? UnusualUnusual

Tubal &Tubal &PelvicPelvic

OvulatoryOvulatory

Critical Factors Affecting FertilityCritical Factors Affecting Fertility

OocytesOocytes SpermSperm UterusUterus Fallopian TubesFallopian Tubes

Critical Factors Affecting FertilityCritical Factors Affecting Fertility Oocytes – FSH / EstradiolOocytes – FSH / Estradiol

Ovarian ReserveOvarian Reserve Age – QualityAge – Quality FSH – QuantityFSH – Quantity

Ovulatory DysfunctionOvulatory Dysfunction Midluteal Progesterone – OvulationMidluteal Progesterone – Ovulation TSH & Prolactin TSH & Prolactin

SpermSperm UterusUterus Fallopian TubesFallopian Tubes

Evaluation of OvulationEvaluation of Ovulation Basal BodyTemperature – Poor Sensitivity

Urinary LH kits start 2-3 days before surge is expected ovulation is 24-48 hrs later

Midluteal Progesterone > 3 ng/ml shows evidence of ovulation > 10 ng/ml shows evidence of “good”

ovulation 1 wk before menses is best

Oocyte AttritionOocyte Attrition

20 weeks in utero – 6 to 7 million 20 weeks in utero – 6 to 7 million Birth – 1 millionBirth – 1 million Menarche – 300,000 to 400,000Menarche – 300,000 to 400,000 37yr – 25,00037yr – 25,000 Menopause – 1,000 Menopause – 1,000

Ovarian ReserveOvarian Reserve

is the number and quality of eggs in is the number and quality of eggs in the ovariesthe ovaries

Quantification of Ovarian ReserveQuantification of Ovarian Reserve

AgeAge FSHFSH Inhibin B, AMHInhibin B, AMH Basal antral follicle count Basal antral follicle count Ovarian volumeOvarian volume Clomid challenge testClomid challenge test FSH stimulation testFSH stimulation test

SerumSerum

U/SU/S

Response to Response to StimulationStimulation

Age and Female FertilityAge and Female Fertility

Age & Female Fertility

0

5

10

15

20

25

30

Age (Years)

Ch

an

ce

of

Co

nc

ep

tio

n

(per

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Pregnancy rates, Pregnancy rates, Live births rates and Singleton Live births rates and Singleton

birth rates for ART-Fresh embryosbirth rates for ART-Fresh embryos

CDC Data, 2003CDC Data, 2003

Age and Miscarriage RiskAge and Miscarriage Risk

Risk of Chromosomal AbnormalityRisk of Chromosomal Abnormalityin Newborns by Maternal Agein Newborns by Maternal Age

Maternal Age (years)

Risk for Down Syndrome

Total Risk for Chromosomal Abnormalities

20 1/1,667 1/52625 1/1,250 1/47630 1/952 1/38535 1/378 1/19240 1/106 1/6641 1/82 1/5342 1/63 1/4243 1/49 1/3344 1/38 1/2645 1/30 1/2146 1/23 1/1647 1/18 1/1348 1/14 1/1049 1/11 1/8

Maternal Fetal Medicine: Practice and Principles. Maternal Fetal Medicine: Practice and Principles.

Creasey and Resnick 1994Creasey and Resnick 1994

0.0000

0.0200

0.0400

0.0600

0.0800

0.1000

0.1200

0.1400

Maternal Age

Inci

denc

e

Meiotic NondisjunctionMeiotic Nondisjunction

Preimplantation Genetic DiagnosisPreimplantation Genetic Diagnosis

Preimplantation Genetic DiagnosisPreimplantation Genetic Diagnosis

Preimplantation Genetic DiagnosisPreimplantation Genetic Diagnosis

Critical Factors Affecting FertilityCritical Factors Affecting Fertility Oocytes Oocytes Sperm – Semen AnalysisSperm – Semen Analysis

Volume Volume ConcentrationConcentration MotilityMotility MorphologyMorphology

UterusUterus Fallopian TubesFallopian Tubes

Semen AnalysisSemen Analysis

The gross examinationThe gross examinationThe gross examinationThe gross examination Microscopic evaluationMicroscopic evaluationMicroscopic evaluationMicroscopic evaluation

• Appearance (opaque)Appearance (opaque)

• Volume (2-6 mL)Volume (2-6 mL)

• Viscosity (liquefaction, Viscosity (liquefaction, 1 hr) 1 hr)

• pH value (7-8)pH value (7-8)

• Count (Count ( 20 million/mL) 20 million/mL)

• Motility (>50%)Motility (>50%)

• Morphology (Morphology ( 30 % normal) 30 % normal)(World Health Organization Criteria)(World Health Organization Criteria)

Other TestsOther Tests• • Sperm Chromatin Structure Assay / TUNELSperm Chromatin Structure Assay / TUNEL

• • Sperm DNA DecondensationSperm DNA Decondensation

• • Sperm Penetration TestsSperm Penetration Tests

• • Postcoital TestPostcoital Test

Semen AnalysisSemen Analysis

• Should be ordered in any couple who presents for infertility

• Repeat if abnormal

• Ideally there should be more than 10 million Normal Motile Sperm

• 5-20 million – insemination indicated

• <1 million – ICSI indicated

Sperm Attrition Sperm Attrition

Additional Male EvaluationAdditional Male Evaluation

FSH, LHFSH, LH TestosteroneTestosterone Prolactin, TSHProlactin, TSH KaryotypeKaryotype Y Chromosome MicrodeletionY Chromosome Microdeletion Urology referral – evaluation for Urology referral – evaluation for

varicocele (ultrasound)varicocele (ultrasound) Freeze viable sperm if undergoing Freeze viable sperm if undergoing

a diagnostic biopsya diagnostic biopsy

Critical Factors Affecting FertilityCritical Factors Affecting Fertility OocytesOocytes SpermSperm Uterus – HSG or SHGUterus – HSG or SHG

FibroidsFibroids PolypsPolyps

SynechiaeSynechiae Fallopian TubesFallopian Tubes

Uterine EvaluationUterine Evaluation

UltrasoundUltrasound Sonohysterogram (saline ultrasound)Sonohysterogram (saline ultrasound) HysterosalpingogramHysterosalpingogram MRIMRI HysteroscopyHysteroscopy

UltrasoundUltrasound Evaluates uterus, adnexa and occasionally Evaluates uterus, adnexa and occasionally

the fallopian tubesthe fallopian tubes May be helpful in diagnosing uterine May be helpful in diagnosing uterine

abnormalitiesabnormalities

Sonohystogram (SHG)Sonohystogram (SHG) Concurrent saline distention of the uterine Concurrent saline distention of the uterine

cavity and vaginal ultrasonographycavity and vaginal ultrasonography

Hysterosalpingogram (HSG)Hysterosalpingogram (HSG)

HysteroscopyHysteroscopy Allows direct evaluation the uterine cavity Concurrently diagnose and treat

Critical Factors Affecting FertilityCritical Factors Affecting Fertility OocytesOocytes SpermSperm UterusUterus Fallopian Tubes – HSGFallopian Tubes – HSG

Patent vs. Occluded Patent vs. Occluded Proximal vs. Distal OcclusionProximal vs. Distal Occlusion Potential therapeutic effectPotential therapeutic effect

Hysterosalpingogram (HSG)Hysterosalpingogram (HSG)

MRIMRI

In Lieu of Surgery In Lieu of Surgery Non-surgically evaluate the uterus to Non-surgically evaluate the uterus to

differentiate between various forms of differentiate between various forms of congenital anomaliescongenital anomalies

In Preparation for SurgeryIn Preparation for Surgery To map fibroids prior to surgery To map fibroids prior to surgery Help diagnose adenomyosisHelp diagnose adenomyosis

LaparoscopyLaparoscopy Allows direct visualization of the pelvic Allows direct visualization of the pelvic

anatomy.anatomy. Can evaluate endometriosis, adhesions, Can evaluate endometriosis, adhesions,

uterine abnormalities or ovarian massesuterine abnormalities or ovarian masses ChromotubationChromotubation

use of a dilute solution of blue dye instilled use of a dilute solution of blue dye instilled through the cervixthrough the cervix

can demonstrate tubal patency or distal tubal can demonstrate tubal patency or distal tubal occlusive disease.occlusive disease.

Surgically correct the disease processSurgically correct the disease process

LaparoscopyLaparoscopy

LaparoscopyLaparoscopy

Peritubal AdhesionsPeritubal Adhesions

Lysis of Adhesions Lysis of Adhesions and Chromotubationand Chromotubation

LaparoscopyLaparoscopy

Resection of HydrosalpinxResection of Hydrosalpinx

Treatment - OocytesTreatment - Oocytes

Ovulation InductionOvulation Induction ClomidClomid hMG or FSHhMG or FSH Clomid + FSHClomid + FSH

Controlled Ovarian Controlled Ovarian HyperstimulationHyperstimulation Long ProtocolLong Protocol AntagonistAntagonist Microdose FlareMicrodose Flare

Treatment - SpermTreatment - Sperm

Intrauterine Insemination (IUI) – place the Intrauterine Insemination (IUI) – place the washed sperm at the top of the uterus near washed sperm at the top of the uterus near the opening of the fallopian tubesthe opening of the fallopian tubes

Intracytoplasmic Sperm Injection (ICSI) – Intracytoplasmic Sperm Injection (ICSI) – directly inject each sperm into each eggdirectly inject each sperm into each egg

Treatment - UterusTreatment - Uterus

Hormonal – estrogen supplementation Hormonal – estrogen supplementation to increase endometrial thicknessto increase endometrial thickness

Surgical – remove polyps, fibroids, Surgical – remove polyps, fibroids, scar tissue, septum, etc. scar tissue, septum, etc.

Treatment – Fallopian TubesTreatment – Fallopian Tubes

Surgical – correct tubal disease, Surgical – correct tubal disease, endometriosis, scar tissueendometriosis, scar tissue

OI & IUI – if unilateral tubal OI & IUI – if unilateral tubal obstructionobstruction

IVF – for bilateral tubal diseaseIVF – for bilateral tubal disease

Unexplained InfertilityUnexplained Infertility

Normal Semen analysis, evidence of ovulation, normal uterus, tubes are open

Surgery-Laparoscopy-to exclude endometriosis/adhesions Consider the addition of hysteroscopy

Stepwise empiric treatment of OI & IUI and IVF

When to Use Assisted When to Use Assisted Reproductive Technology (ART)Reproductive Technology (ART)

• Neither fallopian tube is patent

• Severe endometriosis

• Severe male factor infertility

• Unexplained infertility

• After medical treatment has failed

• For genetic indications-PGD

Intracytoplasmic Sperm Injection Intracytoplasmic Sperm Injection (ICSI)(ICSI)

Embryo Development Embryo Development In VitroIn Vitro

Zygote First Division Second Division 8-cell stage

Morula Blastocysts Hatching Blastocyst

Embryo transferEmbryo transfer

Embryos are inserted into the uterusEmbryos are inserted into the uterus

EmbryoEmbryo

Preimplantation GeneticPreimplantation Genetic Diagnosis Diagnosis

a procedure that allows embryos to be a procedure that allows embryos to be tested for genetic disorders before they tested for genetic disorders before they enter the uterus and before pregnancy has enter the uterus and before pregnancy has begunbegun

Thornhill et al, JMD 2002Thornhill et al, JMD 2002

Donor OocytesDonor Oocytes

10% of ivf cycles10% of ivf cycles IndicationsIndications

Live Births Rates from Own vs. Donor EggsLive Births Rates from Own vs. Donor Eggs

CDC Data, 2003CDC Data, 2003

22ndnd Opinion Opinion