Infertility affects approximately 14-20% of couples in the US. Common causes include female ovulatory disorders (30-40%), male factor issues (30%), and tubal damage (16%). A thorough evaluation involves a detailed history and physical exam of both partners, as well as tests to evaluate ovarian function, tubal patency, uterine health, and male factors. Treatment options depend on the underlying cause, but may include ovulation induction, intrauterine insemination, surgery, and assisted reproductive technologies like in vitro fertilization. Infertility can have significant emotional impacts and its evaluation and treatment require a multi-disciplinary approach.

1. Infertility David Toub, M.D. Medical Director Newton Interactive

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. Work-up by Organ Unit

19. Ovary

20. 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

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

22. 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

23. 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

24. 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

25. 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

26. Fallopian Tubes

27. 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)

28. 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

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

30. 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

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

32. Uterine Corpus

33. 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

34. Cervix

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

36. 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)

37. 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

38. 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

39. Peritoneum

40. 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

41. Male Factors

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

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

44. Normal Semen Analysis

45. 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

46. Treatment Options

47. 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)

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

49. Ovarian Matrix

50. 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

51. 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

52. 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

53. Fallopian Tubes Tuboplasty IVF GIFT, ZIFT not options

54. 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

55. 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

56. 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

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

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

59. 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

60. 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

61. Thank you!