Infertility

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INFERTILITY
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Fertilization
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Terminology

• 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.

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Statistics

• 80 of couples will conceive within 1 year of
  unprotected intercourse
• 86 will conceive within 2 years

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Etiologies

• Sperm disorders 30.6
• Anovulation/oligo-ovulation 30
• Tubal disease 16
• Unexplained 13.4
• Cx factors 5.2
• Peritoneal factors 4.8

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Infertility increases with aging

• Aging
• Less ovulation
• More LPD
• Less uterine receptivity

5 10 15 20 25 30
Infertility per cent
25-29 30-34 35-39 40-44 years
Average incidence of infertility is 10
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Associated Factors

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

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Overview of Evaluation

• Female
• Ovary
• Tube
• Corpus
• Cervix
• Peritoneum
• Male
• Sperm count and function
• Ejaculate characteristics, immunology
• Anatomic anomalies

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The Most Important Factor in the Evaluation of
the Infertile Couple Is
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HISTORY
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History-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

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History-Male

• History of pelvic infection
• Radiation, toxic exposures (include drugs)
• Mumps
• Testicular surgery/injury
• Excessive heat exposure (spermicidal)

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History-Female

• Previous female pelvic surgery
• PID
• Appendicitis
• IUD use
• Ectopic pregnancy history
• DES (?relation to infertility)
• Endometriosis

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History-Female

• Irregular menses, amenorrhea, detailed menstrual
  history
• Vasomotor symptoms
• Stress
• Weight changes
• Exercise
• Cervical and uterine surgery

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When Not to Pursue an Infertility 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

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Physical Exam-Male

• Size of testicles
• Testicular descent
• Varicocele
• Outflow abnormalities (hypospadias, etc)

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Physical Exam-Female

• Pelvic masses
• Uterosacral nodularity
• Abdomino-pelvic tenderness
• Uterine enlargement
• Thyroid exam
• Uterine mobility
• Cervical abnormalities

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Overall Guidelines for Work-up

• Timeliness of testing-w/u can usually be
  accomplished in 1-2 cycles
• Timing of tests
• Dont over test
• Cut to the chase, i.e. proceed with laparoscopy
  if adhesive disease is likely

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Work-up by Organ Unit
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Ovary
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Ovarian Function

• Document ovulation
• BBT
• Luteal phase progesterone
• LH surge
• Endometrial secretory phase biopsy
• If Premature Ovarian Failure suspected, perform
  FSH
• FSH, LH, Testosterone Androstenedionegtgt pco
• TSH, PRL, adrenal functions if indicated
• Karyotyping if suspected
• The only convincing proof of ovulation is
  pregnancy

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Ovarian Function

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

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BBT

• 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

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Luteal Phase Progesterone

• Pulsatile release, thus single level may not be
  useful unless elevated
• Performed 7 days after presumptive ovulation
• Done properly, gt15 ng/ml consistent with
  ovulation

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Urinary 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

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Endometrial Biopsy

• Invasive, but the only reliable way to diagnose
  LPD
• ??Is LPD a genuine disorder???
• Pregnancy loss rate lt1
• Perform around 2 days before expected
  menstruation ( day 28 by definition)
• Lag of gt2 days is consistent with LPD
• Must be done in two different cycles to confirm
  diagnosis of LPD

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Fallopian Tubes
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Tubal Function

• Evaluate tubal patency whenever there is a
  history of PID, endometriosis or other
  adhesiogenic condition
• Kartageners syndrome can be associated with
  decreased tubal motility
• Tests
• HSG
• Laparoscopy
• HyCoSy
• Falloposcopy (not widely available)

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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

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Hysterosalpingography (HSG)

• Can be uncomfortable
• Pregnancy test is advisable
• Can detect intrauterine and tubal disorders but
  not always definitive

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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

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HyCoSy
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Falloposcopy

• Hysteroscopic procedure with cannulation of the
  Fallopian tubes
• Can be useful for diagnosis of intraluminal
  pathology
• Promising technique but not yet widespread

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Uterine Corpus
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Corpus

• 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

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Cervix
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Cervical Function

• Infection
• Ureaplasma suspected
• Stenosis
• S/P LEEP, Cryosurgery, Cone biopsy (probably
  overstated)
• Immunologic Factors
• Sperm-mucus interaction

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Cervical 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)

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Cervical Function

• PK, continued (normal values in yellow)
• Quantity (very subjective)
• Quality (spinnbarkeit) (gt8 cm)
• Clarity (clear)
• Ferning (branched)
• Viscosity (thin)
• WBCs (0)
• progressively motile sperm/hpf (5-10/hpf)
• Gross sperm morphology (WNL)

Male factors
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Problems 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

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Peritoneum
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Peritoneal 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

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Male Factors
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Male 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

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Semen analysisMacleod criteria

• Volume 2-4 ml
• Count gt 20 million/ml
• Motility gt 50 progressive
• Morphology gt 30 normal
• Oval head
• Acrosomal cap
• Single tail
• Pus cells lt 1 million/ml
• FSH, PRL, karyotype

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Grading of sperm motilityMacleod scale

• 0 immotile
• Living immotile (Asthenospermia)
• Dead immotile (Necrosprmia)
• 1 sluggish non-linear
• 2 sluggish linear
• 4 rapid linear (progressive)

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Male Factors

• Serum T, FSH, PRL levels
• Semen analysis
• Testicular biopsy
• Sperm penetration assay (SPA)

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Treatment Options
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Ovarian Disorders

• Anovulation
• Clomiphene Citrate hCG
• hMG
• Induction IUI (often done but unjustified)
• PRL
• Bromocriptine
• TSS if macroadenoma
• POF
• ?high-dose hMG (not very effective)

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Ovarian Disorders

• Central amenorrhea
• CC first, then hMG
• Pulsatile GnRH
• LPD
• Progesterone suppositories during luteal phase
• CC hCG

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Ovarian Matrix
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Ovulation 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

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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

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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

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Fallopian Tubes

• Tuboplasty
• IVF
• GIFT, ZIFT not options

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Corpus

• 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

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Cervix

• Repeat PK test to rule out inaccurate timing of
  test
• If cervicitis Abx
• If scant mucus low-dose estrogen
• Sperm motility issues (? Antisperm ABs)
• Steroids?
• IUI

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Peritoneum (Endometriosis)
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Male Factor

• Hypogonadotrophism
• hMG
• GnRH
• CC, hCG results poor
• Varicocoele
• Ligation? (no definitive data yet)
• Retrograde ejaculation
• Ephedrine, imipramine
• AIH with recovered sperm

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Male Factor

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

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Unexplained 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

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Summary

• 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

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ART

• 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

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Indication 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

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ART program

• Macro-manipulation
• IVF-ET
• GIFT
• ZIFT
• Micro-manipulation
• ZD (Zona drilling)
• PZD (Partial zona dissection)
• AZP (Artificial zona pellucida)

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ART program

• Insemination
• IUI
• SUZI (Subzonal few sperms)
• ICSI (Cytoplasmic one sperm)
• Preimplantation manipulation
• Blastomere biopsy
• Gene therapy and cloning
• Assisted embryo hatching

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Ovarian stimulation

• Un-stimulated cycles
• CC-stimulated cycles
• HMG-stimulated cycles
• GnRHa-HMG stimulated cycles

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

• Sonographic 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
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GnRHa-HMG protocolShort down regulation
E2 400 pg/ml/large follicle
hCG Shot
Day-8 evaluation
PR/cycle 18
HMG ampoules
36 hr
48 hr
Lupron 1 mg sc every day
OPU
ET
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
16 days of the cycle
Monitoring EOD
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Triggering ovulation

• hCG 10,000 IU IM shot
• Follicles
• Leading follicle 18-20 mm
• Endometrium
• Thickness gt 7 mm
• Trilaminar halo appearance
• E2
• 400 pg/ml/follicle gt 18 mm

OPU 36 hr after shot ET After 48 hr later
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Trans-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

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Post transfer care

• Day 15 pregnancy test (B-hCG)
• Day 35 TVS
• Luteal supplementation
• Embry reduction

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IVF success ratein relation to indication
Indication Success of IVF
Endometriosis Unexplained infertility Cervical factor Male factor Immunologic factor 32 31 28 15 10
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