Fertilization Terminology Infertility; it is failure to achieve pregnancy after 1 year of effort. It...
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Transcript of Fertilization Terminology Infertility; it is failure to achieve pregnancy after 1 year of effort. It...
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
rtil
ity
per
cen
t
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%