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

3. 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

4. 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%

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

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

7. 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)

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 Varicocoele Outflow abnormalities (hypospadias, etc)

17. Physical Exam-Female Pelvic masses Uterosacral nodularity Abdominopelvic 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

19. 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

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

21. 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

22. 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

23. 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

24. 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

25. 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)

26. 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 H 2 O-based –May be associated with fertility rates

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

28. 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

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

30. 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

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

32. Cervical Function Tests: –Culture for suspected pathogens –Postcoital test (PK tests) Scheduled around 1-2d before ovulation (increased estrogen effect) 48 0 of male abstinence before test No lubricants Evaluate 8-12h after coitus (overnight is ok!) Remove mucus from cervix (forceps, syringe)

33. 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

34. 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

35. 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

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

37. Male Factors-Semen Analysis Collected after 48 0 of abstinence Evaluated within one hour of ejaculation If abnormal parameters, repeat twice, 2 weeks apart

38. Normal Semen Analysis

39. 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

40. 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)

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

42. 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

43. hMG (Pergonal) LH +FSH (also FSH alone = Metrodin) For patients with hypogonadotrophic hypoestrogenism or normal FSH and E 2 levels Close monitoring essential, including estradiol levels 60-80% pregnancy rates overall, lower for PCOS patients 10-15% multifetal pregnancy rate

44. 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

45. Fallopian Tubes Tuboplasty IVF GIFT, ZIFT not options

46. Corpus Asherman syndrome –Hysteroscopic lysis of adhesions (scissor) –Postop Abx, E 2 Fibroids (rarely need treatment) –Myomectomy(hysteroscopic, laparoscopic, open) –??UAE Uterine anomalies (rarely need treatment) –metroplasty

47. Cervix Repeat PK test to rule out inaccurate timing of test If cervicitisAbx If scant mucuslow-dose estrogen Sperm motility issues (? Antisperm AB’s) –Steroids? –IUI

48. 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

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

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

51. 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

52. Summary Infertility is a common problem Infertility is a disease of couples Evaluation must be thorough, but individualized Treatment is available, including IVF, but can be expensive, invasive, and of limited efficacy in some cases Consultation with a BC/BE reproductive endocrinologist is advisable

53. Thank you!