1. Infertility Petrenko N., M.D. PhD

2. Definitions • Infertility • Inability to conceive after one year of unprotected intercourse (6 months for women over 35?) • Fertility • Ability to conceive • Fecundity • Ability to carry to delivery

3. Statistics • 80% of couples will conceive within 1 year of unprotected intercourse • ~86% will conceive within 2 years • ~14-20% of US couples are infertile by definition (~3 million couples) • Origin: • Female factor ~40% • Male factor ~30% • Combined ~30%

4. Etiologies • Sperm disorders 30.6% • Anovulation/oligoovulation 30% • Tubal disease 16% • Unexplained 13.4% • Cx factors 5.2% • Peritoneal factors 4.8%

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

6. Emotional and Educational Needs • Disease of couples, not individuals • Feelings of guilt • Where to go for information? • Options • Feelings of frustration and anger • Support groups (e.g. Resolve)

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

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

9. HISTORY

10. 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

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

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

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

14. 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

15. Physical Exam-Male • Size of testicles • Testicular descent • Varicocoele • Outflow abnormalities (hypospadias, etc)

16. Physical Exam-Female • Pelvic masses • Uterosacral nodularity • Abdominopelvic tenderness • Uterine enlargement • Thyroid exam • Uterine mobility • Cervical abnormalities

17. 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

18. Ovarian Function • Document ovulation: • BBT • Luteal phase progesterone • LH surge • EMBx • If POF suspected, perform FSH • TSH, PRL, adrenal functions if indicated • The only convincing proof of ovulation is pregnancy

19. Ovarian Function • Three main types of dysfunction • Hypogonadotrophic, hypoestrogenic (central) • Normogonadotrophic, normoestrogenic (e.g. PCOS) • Hypergonadotrophic, hypoestrogenic (POF)

20. BBT • Cheap and easy, but… • Inconsistent results • Provides evidence after the fact (like the old story about the barn door and the horse) • May delay timely diagnosis and treatment • 98% of women will ovulate within 3 days of the nadir • Biphasic profiles can also be seen with LUF syndrome

21. 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

22. 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

23. 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

24. 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 • Falloposcopy (not widely available)

25. 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

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

27. 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

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

29. Corpus • Asherman Syndrome • Diagnosis by HSG or hysteroscopy • Usually s/p D+C, myomectomy, other intrauterine surgery • Associated with hypo/amenorrhea, recurrent miscarriage • Fibroids, Uterine Anomalies • Rarely associated with infertility • Work-up: • Ultrasound • Hysteroscopy • Laparoscopy

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

31. 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)

32. 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

33. 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

34. 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

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

36. Male Factors-Semen Analysis • Collected after 480 of abstinence • Evaluated within one hour of ejaculation • If abnormal parameters, repeat twice, 2 weeks apart

37. Normal Semen Analysis

38. Sperm Penetration Assay • aka “zona-free hamster ova assay” • Dynamic test of fertilization capacity of sperm • Failure to penetrate at least 10% of zona-free ova consistent with male factor • False positives and negatives exist

39. 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)

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

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

42. hMG (Pergonal) • LH +FSH (also FSH alone = Metrodin) • For patients with hypogonadotrophic hypoestrogenism or normal FSH and E2 levels • Close monitoring essential, including estradiol levels • 60-80% pregnancy rates overall, lower for PCOS patients • 10-15% multifetal pregnancy rate

43. 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 Risks

44. Fallopian Tubes • Tuboplasty • IVF • GIFT, ZIFT not options

45. 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

46. 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

47. Peritoneum (Endometriosis) • From a fertility standpoint, excision beats medical management • Lysis of adhesions • GnRH-a (not a cure and has side effects, expense) • Danazol (side effects, cost) • Continuous OCP’s (poor fertility rates) • Chances of pregnancy highest within 6 mos-1 year after treatment

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

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

50. 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