Fertilization

TerminologyTerminology• Infertility; it is failure to achieve pregnancy

after 1 year of effort. It can be primary or

secondary. The period in definition may be

extended to 2 years in young patient and

shortened to 6 months in older one.

• Sterility; it is absolute infertility.

• Fecundity rate; monthly pregnancy rate.

• Cumulative pregnancy rate; ratio of pregnant

women to all treated women.

StatisticsStatistics

• 80% of couples will conceive within 1 year of unprotected intercourse

• ~86% will conceive within 2 years

EtiologiesEtiologies

• Sperm disorders 30.6%

• Anovulation/oligo-ovulation 30%

• Tubal disease 16%

• Unexplained 13.4%

• Cx factors 5.2%

• Peritoneal factors 4.8%

Infertility increases with agingInfertility increases with aging

25-29 30-34 35-39 40-44 years

5

10

1

5

20

25

30

Average incidence of infertility is 10%

Aging

•Less ovulation

•More LPD

•Less uterine receptivity

Infe

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per

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Associated FactorsAssociated Factors• PID• Endometriosis • Ovarian aging• Spermatic varicocele• Toxins • Previous abdominal surgery (adhesions)• Cervical/uterine abnormalities• Cervical/uterine surgery• Fibroids

Overview of EvaluationOverview of Evaluation• Female

– Ovary– Tube – Corpus– Cervix– Peritoneum

• Male– Sperm count and function– Ejaculate characteristics, immunology– Anatomic anomalies

The Most Important Factor in The Most Important Factor in the Evaluation of the Infertile the Evaluation of the Infertile

Couple Is:Couple Is:

HISTORYHISTORY

History-GeneralHistory-General

• Both couples should be present• Age• Previous pregnancies by each partner• Length of time without pregnancy• Sexual history

– Frequency and timing of intercourse– Use of lubricants– Impotence, anorgasmia, dyspareunia– Contraceptive history

History-MaleHistory-Male

• History of pelvic infection

• Radiation, toxic exposures (include drugs)

• Mumps

• Testicular surgery/injury

• Excessive heat exposure (spermicidal)

History-FemaleHistory-Female

• Previous female pelvic surgery

• PID

• Appendicitis

• IUD use

• Ectopic pregnancy history

• DES (?relation to infertility)

• Endometriosis

History-FemaleHistory-Female

• Irregular menses, amenorrhea, detailed menstrual history

• Vasomotor symptoms • Stress• Weight changes• Exercise• Cervical and uterine surgery

When Not to Pursue an When Not to Pursue an Infertility EvaluationInfertility Evaluation

• Patient not sexually-active

• Patient not in long-term relationship?

• Patient declines treatment at this time

• Couple does not meet the definition of an infertile couple

Physical Exam-MalePhysical Exam-Male

• Size of testicles

• Testicular descent

• Varicocele

• Outflow abnormalities (hypospadias, etc)

Physical Exam-FemalePhysical Exam-Female

• Pelvic masses

• Uterosacral nodularity

• Abdomino-pelvic tenderness

• Uterine enlargement

• Thyroid exam

• Uterine mobility

• Cervical abnormalities

Overall Guidelines for Work-Overall Guidelines for Work-up up

• Timeliness of testing-w/u can usually be accomplished in 1-2 cycles

• Timing of tests

• Don’t over test

• Cut to the chase, i.e. proceed with laparoscopy if adhesive disease is likely

Work-up by Organ UnitWork-up by Organ Unit

OvaryOvary

Ovarian FunctionOvarian Function

• Document ovulation:– BBT– Luteal phase progesterone – LH surge– Endometrial secretory phase biopsy

• If Premature Ovarian Failure suspected, perform FSH• FSH, LH, Testosterone & Androstenedione>> pco• TSH, PRL, adrenal functions if indicated• Karyotyping if suspected • The only convincing proof of ovulation is pregnancy

Ovarian FunctionOvarian Function

• Three main types of dysfunction– Hypogonadotropic, hypoestrogenic (central)– Normogonadotrophic, normoestrogenic (e.g.

PCOS)– Hypergonadotropic, hypoestrogenic (POF)

BBTBBT

• Cheap and easy, but…– Inconsistent results– May delay timely diagnosis and treatment– 98% of women will ovulate within 3 days of

the nadir– No correlation with increased pregnancy rate

Luteal Phase ProgesteroneLuteal Phase Progesterone

• Pulsatile release, thus single level may not be useful unless elevated

• Performed 7 days after presumptive ovulation

• Done properly, >15 ng/ml consistent with ovulation

Urinary LH KitsUrinary LH Kits

• Very sensitive and accurate

• Positive test precedes ovulation by ~24 hours, so useful for timing intercourse

• Downside: price, obsession with timing of intercourse

Endometrial Biopsy Endometrial Biopsy • Invasive, but the only reliable way to diagnose LPD• ??Is LPD a genuine disorder???• Pregnancy loss rate <1%• Perform around 2 days before expected

menstruation (= day 28 by definition)• Lag of >2 days is consistent with LPD• Must be done in two different cycles to confirm

diagnosis of LPD

Fallopian TubesFallopian Tubes

Tubal FunctionTubal Function

• Evaluate tubal patency whenever there is a history of PID, endometriosis or other adhesiogenic condition

• Kartagener’s syndrome can be associated with decreased tubal motility

• Tests– HSG– Laparoscopy – HyCoSy– Falloposcopy (not widely available)

Hysterosalpingography (HSG)Hysterosalpingography (HSG)

• Radiologic procedure requiring contrast• Performed optimally in early proliferative phase

(avoids pregnancy)• Low risk of PID except if previous history of PID

(give prophylactic doxycycline or consider laparoscopy)

• Oil-based contrast– Higher risk of anaphylaxis than H2O-based– May be associated with fertility rates

Hysterosalpingography (HSG)Hysterosalpingography (HSG)

• Can be uncomfortable• Pregnancy test is

advisable• Can detect intrauterine

and tubal disorders but not always definitive

Laparoscopy Laparoscopy • Invasive; requires OR or

office setting

• Can offer diagnosis and treatment in one sitting

• Not necessary in all patients

• Uses (examples):– Lysis of adhesions– Diagnosis and excision of

endometriosis– Myomectomy – Tubal reconstructive surgery

HyCoSy

FalloposcopyFalloposcopy

• Hysteroscopic procedure with cannulation of the Fallopian tubes

• Can be useful for diagnosis of intraluminal pathology

• Promising technique but not yet widespread

Uterine CorpusUterine Corpus

CorpusCorpus

• Asherman Syndrome– Diagnosis by HSG or hysteroscopy– Associated with hypo/amenorrhea, recurrent

miscarriage• Fibroids, Uterine Anomalies

– Rarely associated with infertility– Work-up:

• Ultrasound • Hysteroscopy• Laparoscopy

CervixCervix

Cervical FunctionCervical Function

• Infection– Ureaplasma suspected

• Stenosis– S/P LEEP, Cryosurgery, Cone biopsy (probably

overstated)

• Immunologic Factors– Sperm-mucus interaction

Cervical FunctionCervical Function

• Tests:– Culture for suspected pathogens – Postcoital test (PK tests)

• Scheduled around 1-2d before ovulation (increased estrogen effect)

• 480 of male abstinence before test• No lubricants• Evaluate 8-12h after coitus (overnight is ok!)• Remove mucus from cervix (forceps, syringe)

Cervical FunctionCervical Function

• PK, continued (normal values in yellow)– Quantity (very subjective)– Quality (spinnbarkeit) (>8 cm)– Clarity (clear)– Ferning (branched)– Viscosity (thin)– WBC’s (~0)

– # progressively motile sperm/hpf (5-10/hpf)– Gross sperm morphology (WNL)

Male factorsMale factors

Problems with the PK testProblems with the PK test

• Subjective

• Timing varies; may need to be repeated

• In some studies, “infertile” couples with an abnormal PK conceived successfully during that same cycle

PeritoneumPeritoneum

Peritoneal FactorsPeritoneal Factors

• Endometriosis – 2x relative risk of infertility– Diagnosis (and best treatment) by laparoscopy – Can be familial; can occur in adolescents– Etiology unknown but likely multiple ones

• Retrograde menstruation• Immunologic factors• Genetics• Bad karma

– Medical options remain suboptimal

Male FactorsMale Factors

Male Factors-Semen AnalysisMale Factors-Semen Analysis

• Sample collected after 3-days abstinence• Sample should be produced manually, no

lubricants

• Sample should not be chilled on transport

• Rapid delivery of sample to the lab.

• Two semen analysis 3-months apart

• Do not say azoo without centrifugation

• Volume; 2-4 ml

• Count; > 20 million/ml

• Motility; > 50% progressive

• Morphology; > 30% normal – Oval head

– Acrosomal cap

– Single tail

• Pus cells; < 1 million/ml

• FSH, PRL, karyotype

Semen analysisMacleod criteria

Grading of sperm motilityGrading of sperm motilityMacleod scaleMacleod scale

• 0; immotile – Living immotile (Asthenospermia)

– Dead immotile (Necrosprmia)

• 1; sluggish non-linear

• 2; sluggish linear

• 4; rapid linear (progressive)

Male FactorsMale Factors

• Serum T, FSH, PRL levels

• Semen analysis

• Testicular biopsy

• Sperm penetration assay (SPA)

Treatment OptionsTreatment Options

Ovarian DisordersOvarian Disorders

• Anovulation– Clomiphene Citrate ± hCG– hMG– Induction + IUI (often done but unjustified)

• PRL– Bromocriptine– TSS if macroadenoma

• POF– ?high-dose hMG (not very effective)

Ovarian DisordersOvarian Disorders

• Central amenorrhea– CC first, then hMG– Pulsatile GnRH

• LPD– Progesterone suppositories during luteal phase– CC ± hCG

Ovarian MatrixOvarian Matrix

Gonadotropins E2 Treatment

High Low ??high-dose hMG, r/oautoimmune diseases

WNL WNL CC ± hCG

Low Low CC first, then hMG

Ovulation InductionOvulation Induction

• CC– 70% induction rate, ~40% pregnancy rate– Patients should typically be normoestrogenic– Induce menses and start on day 2– With dosages, antiestrogen effects dominate– Multifetal rates 5-10%– Monitor effects with PK, pelvic exam

hMG (Pergonal)hMG (Pergonal)

• LH +FSH (also FSH alone = Metrodin)• For patients with Hypogonadotropic

hypoestrogenic or normal FSH and E2 levels• Close monitoring essential, including

estradiol levels,folliculo-metry by uss• 60-80% pregnancy rates overall, lower for

PCOS patients • 20-30% multifetal pregnancy rate

Risks Risks

CC• Vasomotor symptoms • H/A• Ovarian enlargement• Multiple gestation• NO risk of SAb or

malformations

hMG• Multiple gestation• OHSS (~1%)

– Can often be managed as outpatient

– Diuresis

– Severe cases fatal if untreated in ICU setting

Fallopian TubesFallopian Tubes

• Tuboplasty

• IVF

• GIFT, ZIFT not options

CorpusCorpus

• Asherman syndrome– Hysteroscopic lysis of adhesions (scissor)

– Postop Abx, E2

• Fibroids (rarely need treatment)– Myomectomy(hysteroscopic, laparoscopic, open)– ??UAE

• Uterine anomalies (rarely need treatment)– metroplasty

CervixCervix

• Repeat PK test to rule out inaccurate timing of test

• If cervicitis Abx

• If scant mucus low-dose estrogen

• Sperm motility issues (? Antisperm AB’s)– Steroids?– IUI

Peritoneum (Endometriosis)Peritoneum (Endometriosis)

Male FactorMale Factor

• Hypogonadotrophism– hMG– GnRH– CC, hCG results poor

• Varicocoele– Ligation? (no definitive data yet)

• Retrograde ejaculation– Ephedrine, imipramine– AIH with recovered sperm

Male FactorMale Factor

• Idiopathic oligospermia– No effective treatment – ?IVF– donor insemination

Unexplained InfertilityUnexplained Infertility• 5-10% of couples• Consider PRL, laparoscopy, other hormonal tests,

cultures, ASA testing, SPA if not done• Review previous tests for validity• Empiric treatment:

– Ovulation induction– Abx– IUI– Consider IVF and its variants

• Adoption

SummarySummary• Infertility is a common problem• Infertility is a disease of couples• Society places huge pressure on early conception• Evaluation must be thorough, but individualized• Treatment is available, including IVF, but can be

expensive, invasive, and of limited efficacy in some cases

• Psychological support is important• Consultation with a BC/BE reproductive

endocrinologist is advisable

ARTART• It is the art of getting the gametes together or gamete manipulation.

• This in vitro imitation of natural reproduction resulted in the first

test tube baby Louise Brown (Edward and Steptoe 1978).

• The art is ever expanding and the scope now covers infertility,

gene therapy, cloning and sex selection.

• ART and embryo cryopreservation are real advances in the

medical history

Indication for ARTIndication for ART

Infertility problems• Male factor• Tubal factor• Unexplained infertility

– Cervical factor

– Immunologic factor

– Endometriosis

Non-infertility problems

• RSA– Genetic basis

• Hostile gestation– Rh sensitization

• Gene therapy– SCD, Tay-Sachs, CF

• Sex selection– XLD

• Cloning

ART programART program• Macro-manipulation

– IVF-ET– GIFT– ZIFT

• Micro-manipulation– ZD (Zona drilling)– PZD (Partial zona dissection)– AZP (Artificial zona pellucida)

ART programART program• Insemination

– IUI– SUZI (Subzonal few sperms)– ICSI (Cytoplasmic one sperm)

• Preimplantation manipulation– Blastomere biopsy– Gene therapy and cloning– Assisted embryo hatching

• Un-stimulated cycles

• CC-stimulated cycles

• HMG-stimulated cycles

• GnRHa-HMG stimulated cycles

Ovarian stimulationOvarian stimulation

The addition of GnRH agonist in ovulation induction decreased cancellation rate, increased oocyte yields and pregnancy rates but increased the expenses.

Baseline assessmentBaseline assessmentSonographic evaluation

• Ovaries– Size– Position– Cysts

• Uterus– Size– Pathology– Endometrial thickness

Endocrine evaluation• E2 4P• FSH• LH

TVS alone does not eliminate the risk of plural pregnancy or OHS

GnRHa-HMG protocolGnRHa-HMG protocolShort down regulationShort down regulation

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 days of the cycle

Lupron 1 mg sc every day

HMG ampoules

E2 400 pg/ml/large follicle

hCG

Shot

36 hr 48 hr

OPU ET

Day-8 evaluation

Monitoring EOD

18 mm

PR/cycle 18%

Triggering ovulationTriggering ovulation• hCG 10,000 IU IM shot

• Follicles– Leading follicle 18-20 mm

• Endometrium– Thickness > 7 mm

– Trilaminar halo appearance

• E2 – 400 pg/ml/follicle > 18 mm

OPU

36 hr after shot

ET

After 48 hr later

Trans-cervical ETTrans-cervical ET• Tetracycline to clear cervical mucus

• The best stage is blactocyst

• Knee-chest position

• Monach catheter carrying the embryo

• Push 0.2 ml air

• Rotate the catheter at withdrawal

• Keep the patient prone for 4 hours

• Corticosteroid to cover replacement

Post transfer carePost transfer care• Day 15 pregnancy test (B-hCG)

• Day 35 TVS

• Luteal supplementation

• Embry reduction

IVF success rateIVF success ratein relation to indicationin relation to indication

Indication Success of IVF

Endometriosis

Unexplained infertility

Cervical factor

Male factor

Immunologic factor

32%

31%

28%

15%

10%