Infertility

David Toub, M.D. Medical Director Newton Interactive

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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

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%

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

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

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)

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

Male

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

HISTORY

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

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

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

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

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

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

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

Overall Guidelines for Workup

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

Work-up by Organ Unit

Ovary

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

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

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

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

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

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

Fallopian Tubes

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 Falloposcopy (not widely available)

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

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

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

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

Uterine Corpus

Corpus
Asherman Syndrome Fibroids, Uterine Anomalies
Ultrasound Hysteroscopy Laparoscopy

Diagnosis by HSG or hysteroscopy Usually s/p D+C, myomectomy, other intrauterine surgery Associated with hypo/amenorrhea, recurrent miscarriage Rarely associated with infertility Work-up:

Cervix

Cervical Function
Infection
Ureaplasma suspected

Stenosis
S/P LEEP, Cryosurgery, Cone biopsy (probably overstated)

Immunologic Factors
Sperm-mucus interaction

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)

Cervical Function
PK, continued (normal values in yellow)
Quantity (very subjective) Quality (spinnbarkeit) (>8 cm) Clarity (clear) Ferning (branched) Viscosity (thin) WBCs (~0)

# progressively motile sperm/hpf (5-10/hpf) Gross sperm morphology (WNL)

Male factors

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

Peritoneum

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

Male Factors

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

Male Factors-Semen Analysis

Collected after 480 of abstinence Evaluated within one hour of ejaculation If abnormal parameters, repeat twice, 2 weeks apart

Normal Semen Analysis

Quality Volume Concentration Normal Value >1 cc >2 x 10 /cc
6

Initial Forward >50% Motility Normal Morphology >60%

Sperm Penetration Assay

aka zona-free hamster ova assay Dynamic test of fertilization capacity of sperm Failure to penetrate at least 10% of zonafree ova consistent with male factor False positives and negatives exist

Treatment Options

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)

Ovarian Disorders
Central amenorrhea
CC first, then hMG Pulsatile GnRH

LPD
Progesterone suppositories during luteal phase CC hCG

Ovarian Matrix
Gonadotropins E2 High WNL Low Treatment

Low ??high-dose hMG, r/o autoimmune diseases WNL CC hCG Low CC first, then hMG

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

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

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

Fallopian Tubes
Tuboplasty IVF GIFT, ZIFT not options

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

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

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 OCPs (poor fertility rates) Chances of pregnancy highest within 6 mos-1 year after treatment

Male Factor
Hypogonadotrophism
hMG GnRH CC, hCG results poor

Varicocoele
Ligation? (no definitive data yet)

Retrograde ejaculation
Ephedrine, imipramine AIH with recovered sperm

Male Factor
Idiopathic oligospermia
No effective treatment ?IVF donor insemination

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

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

Thank you!