InfertilityInfertility

Petrenko N., M.D. PhD

DefinitionsDefinitions

• 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

StatisticsStatistics• 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%

EtiologiesEtiologies

• Sperm disorders 30.6%

• Anovulation/oligoovulation 30%

• Tubal disease 16%

• Unexplained 13.4%

• Cx factors 5.2%

• Peritoneal factors 4.8%

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

Emotional and Educational Emotional and Educational NeedsNeeds

• 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 EvaluationOverview of Evaluation• Female

– Ovary– Tube – Corpus– Cervix– Peritoneum

• Male– Sperm count and function– Ejaculate characteristics, immunology– Anatomic anomalies

The Most Important Factor in The Most Important Factor in the Evaluation of the Infertile the Evaluation of the Infertile

Couple Is:Couple Is:

HISTORYHISTORY

History-GeneralHistory-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-MaleHistory-Male

• History of pelvic infection

• Radiation, toxic exposures (include drugs)

• Mumps

• Testicular surgery/injury

• Excessive heat exposure (spermicidal)

History-FemaleHistory-Female

• Previous female pelvic surgery

• PID

• Appendicitis

• IUD use

• Ectopic pregnancy history

• DES (?relation to infertility)

• Endometriosis

History-FemaleHistory-Female

• Irregular menses, amenorrhea, detailed menstrual history

• Vasomotor symptoms • Stress• Weight changes• Exercise• Cervical and uterine surgery

When Not to Pursue an When Not to Pursue an Infertility EvaluationInfertility 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-MalePhysical Exam-Male

• Size of testicles

• Testicular descent

• Varicocoele

• Outflow abnormalities (hypospadias, etc)

Physical Exam-FemalePhysical Exam-Female

• Pelvic masses

• Uterosacral nodularity

• Abdominopelvic tenderness

• Uterine enlargement

• Thyroid exam

• Uterine mobility

• Cervical abnormalities

Overall Guidelines for Work-Overall Guidelines for Work-up 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

Ovarian FunctionOvarian 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 FunctionOvarian Function

• Three main types of dysfunction– Hypogonadotrophic, hypoestrogenic (central)– Normogonadotrophic, normoestrogenic (e.g.

PCOS)– Hypergonadotrophic, hypoestrogenic (POF)

BBTBBT

• 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 ProgesteroneLuteal 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 KitsUrinary 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 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

Tubal FunctionTubal 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)

Hysterosalpingography (HSG)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)Hysterosalpingography (HSG)

• Can be uncomfortable

• Pregnancy test is advisable

• Can detect intrauterine and tubal disorders but not always definitive

Laparoscopy 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

FalloposcopyFalloposcopy

• Hysteroscopic procedure with cannulation of the Fallopian tubes

• Can be useful for diagnosis of intraluminal pathology

• Promising technique but not yet widespread

CorpusCorpus• 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

Cervical FunctionCervical Function

• Infection– Ureaplasma suspected

• Stenosis– S/P LEEP, Cryosurgery, Cone biopsy (probably

overstated)

• Immunologic Factors– Sperm-mucus interaction

Cervical FunctionCervical 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 FunctionCervical 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 factorsMale factors

Problems with the PK testProblems 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

Peritoneal FactorsPeritoneal 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 FactorsMale Factors

• Serum T, FSH, PRL levels

• Semen analysis

• Testicular biopsy

• Sperm penetration assay (SPA)

Male Factors-Semen AnalysisMale Factors-Semen Analysis

• Collected after 480 of abstinence

• Evaluated within one hour of ejaculation

• If abnormal parameters, repeat twice, 2 weeks apart

Normal Semen AnalysisNormal Semen Analysis

Quality Normal Value

Volume >1 cc

Concentration >2 x 106/cc

Initial ForwardMotility

>50%

Normal Morphology >60%

Sperm Penetration AssaySperm 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

Ovarian DisordersOvarian 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 DisordersOvarian Disorders

• Central amenorrhea– CC first, then hMG– Pulsatile GnRH

• LPD– Progesterone suppositories during luteal phase– CC ± hCG

Ovulation InductionOvulation 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)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 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 TubesFallopian Tubes

• Tuboplasty

• IVF

• GIFT, ZIFT not options

CorpusCorpus

• 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

CervixCervix

• 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

Peritoneum (Endometriosis)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

Male FactorMale Factor

• Hypogonadotrophism– hMG– GnRH– CC, hCG results poor

• Varicocoele– Ligation? (no definitive data yet)

• Retrograde ejaculation– Ephedrine, imipramine– AIH with recovered sperm

Male FactorMale Factor

• Idiopathic oligospermia– No effective treatment – ?IVF– donor insemination

Unexplained InfertilityUnexplained 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

SummarySummary

• 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!