1. INFERTILITY

2. Fertilization

3. 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.

4. Statistics
80% of couples will conceive within 1 year of unprotected intercourse
~86% will conceive within 2 years

5. Etiologies Sperm disorders 30.6% Anovulation/oligo-ovulation 30%
Tubal disease 16%
Unexplained 13.4%
Cx factors 5.2%
Peritoneal factors 4.8%

6. Infertility increases with aging
Less ovulation
More LPD
Less uterine receptivity
Infertility per cent
years
Average incidence of infertility is 10%

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

8. Overview of Evaluation
Female
Ovary
Tube
Corpus
Cervix
Peritoneum
Male
Sperm count and function
Ejaculate characteristics, immunology
Anatomic anomalies

9. The Most Important Factor in the Evaluation of the Infertile Couple Is:

10. HISTORY

11. 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

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

13. History-Female Previous female pelvic surgery PID Appendicitis IUD use
Ectopic pregnancy history
DES (?relation to infertility)
Endometriosis

14. History-Female
Irregular menses, amenorrhea, detailed menstrual history
Vasomotor symptoms
Stress
Weight changes
Exercise
Cervical and uterine surgery

15. 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

16. Physical Exam-Male Size of testicles Testicular descent Varicocele
Outflow abnormalities (hypospadias, etc)

17. Physical Exam-Female Pelvic masses Uterosacral nodularity
Abdomino-pelvic tenderness
Uterine enlargement
Thyroid exam
Uterine mobility
Cervical abnormalities

18. Overall Guidelines for Work-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

20. Work-up by Organ Unit

21. Ovary

22. Ovarian 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

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

24. 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

25. Luteal 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

26. 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

27. 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

28. Fallopian Tubes

29. Tubal 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)

30. 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

31. Hysterosalpingography (HSG)
Can be uncomfortable
Pregnancy test is advisable
Can detect intrauterine and tubal disorders but not always definitive

32. 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

33. HyCoSy

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

35. Uterine Corpus

36. Corpus Asherman Syndrome Fibroids, Uterine Anomalies
Diagnosis by HSG or hysteroscopy
Associated with hypo/amenorrhea, recurrent miscarriage
Fibroids, Uterine Anomalies
Rarely associated with infertility
Work-up:
Ultrasound
Hysteroscopy
Laparoscopy

37. Cervix

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

39. 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)

40. Cervical 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 factors

41. 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

42. Peritoneum

43. 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

44. Male Factors

45. 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

47. Semen analysis Macleod criteria
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

48. Grading of sperm motility Macleod scale
0; immotile
Living immotile (Asthenospermia)
Dead immotile (Necrosprmia)
1; sluggish non-linear
2; sluggish linear
4; rapid linear (progressive)

49. Male Factors Serum T, FSH, PRL levels Semen analysis Testicular biopsy
Sperm penetration assay (SPA)

51. Treatment Options

52. Ovarian Disorders Anovulation PRL POF Clomiphene Citrate ± hCG hMG
Induction + IUI (often done but unjustified)
PRL
Bromocriptine
TSS if macroadenoma
POF
?high-dose hMG (not very effective)

53. Ovarian Disorders Central amenorrhea LPD CC first, then hMG
Pulsatile GnRH
LPD
Progesterone suppositories during luteal phase
CC ± hCG

54. Ovarian Matrix

55. 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

56. 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

57. 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

58. Fallopian Tubes
Tuboplasty
IVF
GIFT, ZIFT not options

59. Corpus Asherman syndrome Fibroids (rarely need treatment)
Hysteroscopic lysis of adhesions (scissor)
Postop Abx, E2
Fibroids (rarely need treatment)
Myomectomy(hysteroscopic, laparoscopic, open)
??UAE
Uterine anomalies (rarely need treatment)
metroplasty

60. Cervix 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

61. Peritoneum (Endometriosis)

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

63. Male Factor Idiopathic oligospermia No effective treatment ?IVF
donor insemination

64. 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

65. 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

67. 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

68. Non-infertility problems
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

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

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

71. 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.

72. Sonographic evaluation
Baseline assessment
Sonographic evaluation
Ovaries
Size
Position
Cysts
Uterus
Pathology
Endometrial thickness
Endocrine evaluation E2
4P
FSH LH
TVS alone does not eliminate the risk of plural pregnancy or OHS

73. GnRHa-HMG protocol Short 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
days of the cycle
Monitoring EOD
18 mm

74. Triggering ovulation hCG 10,000 IU IM shot Follicles Endometrium E2
Leading follicle 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

75. 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

76. Post transfer care Day 15 pregnancy test (B-hCG) Day 35 TVS
Luteal supplementation
Embry reduction

77. IVF success rate in relation to indication
Success of IVF
Endometriosis
Unexplained infertility
Cervical factor
Male factor
Immunologic factor
32%
31%
28%
15%
10%