INFERTILITY

Fertilization

Terminology Infertility; it is failure to achieve pregnancy after 1 year of effort. It can be primary or secondary. The period in definition may be extended to 2 years in young patient and shortened to 6 months in older one. Sterility; it is absolute infertility. Fecundity rate; monthly pregnancy rate. Cumulative pregnancy rate; ratio of pregnant women to all treated women.

Statistics 80% of couples will conceive within 1 year of unprotected intercourse ~86% will conceive within 2 years

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

Infertility increases with aging Less ovulation More LPD Less uterine receptivity 5 10 15 20 25 30 Infertility per cent 25-29 30-34 35-39 40-44 years Average incidence of infertility is 10%

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

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

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 Varicocele Outflow abnormalities (hypospadias, etc)

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

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

Work-up by Organ Unit

Ovary

Ovarian Function Document ovulation: BBT Luteal phase progesterone LH surge Endometrial secretory phase biopsy If Premature Ovarian Failure suspected, perform FSH FSH, LH, Testosterone & Androstenedione>> pco TSH, PRL, adrenal functions if indicated Karyotyping if suspected The only convincing proof of ovulation is pregnancy

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

BBT Cheap and easy, but… Inconsistent results May delay timely diagnosis and treatment 98% of women will ovulate within 3 days of the nadir No correlation with increased pregnancy rate

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 Kartagener’s syndrome can be associated with decreased tubal motility Tests HSG Laparoscopy HyCoSy 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

HyCoSy

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 Diagnosis by HSG or hysteroscopy Associated with hypo/amenorrhea, recurrent miscarriage Fibroids, Uterine Anomalies Rarely associated with infertility Work-up: Ultrasound Hysteroscopy Laparoscopy

Cervix

Cervical Function Infection Stenosis Immunologic Factors 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) WBC’s (~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-Semen Analysis Sample collected after 3-days abstinence Sample should be produced manually, no lubricants Sample should not be chilled on transport Rapid delivery of sample to the lab. Two semen analysis 3-months apart Do not say azoo without centrifugation

Semen analysis Macleod criteria Volume; 2-4 ml Count; > 20 million/ml Motility; > 50% progressive Morphology; > 30% normal Oval head Acrosomal cap Single tail Pus cells; < 1 million/ml FSH, PRL, karyotype

Grading of sperm motility Macleod scale 0; immotile Living immotile (Asthenospermia) Dead immotile (Necrosprmia) 1; sluggish non-linear 2; sluggish linear 4; rapid linear (progressive)

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

Treatment Options

Ovarian Disorders Anovulation PRL POF 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 LPD CC first, then hMG Pulsatile GnRH LPD Progesterone suppositories during luteal phase CC ± hCG

Ovarian Matrix

Ovulation Induction CC 70% induction rate, ~40% pregnancy rate Patients should typically be normoestrogenic Induce menses and start on day 2 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 Hypogonadotropic hypoestrogenic or normal FSH and E2 levels Close monitoring essential, including estradiol levels,folliculo-metry by uss 60-80% pregnancy rates overall, lower for PCOS patients 20-30% 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 Fibroids (rarely need treatment) 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 mucus low-dose estrogen Sperm motility issues (? Antisperm AB’s) Steroids? IUI

Peritoneum (Endometriosis)

Male Factor Hypogonadotrophism Varicocoele Retrograde ejaculation 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 Society places huge pressure on early conception Evaluation must be thorough, but individualized Treatment is available, including IVF, but can be expensive, invasive, and of limited efficacy in some cases Psychological support is important Consultation with a BC/BE reproductive endocrinologist is advisable

ART It is the art of getting the gametes together or gamete manipulation. This in vitro imitation of natural reproduction resulted in the first test tube baby Louise Brown (Edward and Steptoe 1978). The art is ever expanding and the scope now covers infertility, gene therapy, cloning and sex selection. ART and embryo cryopreservation are real advances in the medical history

Non-infertility problems Indication for ART Infertility problems Male factor Tubal factor Unexplained infertility Cervical factor Immunologic factor Endometriosis Non-infertility problems RSA Genetic basis Hostile gestation Rh sensitization Gene therapy SCD, Tay-Sachs, CF Sex selection XLD Cloning

ART program Macro-manipulation Micro-manipulation IVF-ET GIFT ZIFT ZD (Zona drilling) PZD (Partial zona dissection) AZP (Artificial zona pellucida)

ART program Insemination Preimplantation manipulation IUI SUZI (Subzonal few sperms) ICSI (Cytoplasmic one sperm) Preimplantation manipulation Blastomere biopsy Gene therapy and cloning Assisted embryo hatching

Ovarian stimulation Un-stimulated cycles CC-stimulated cycles HMG-stimulated cycles GnRHa-HMG stimulated cycles The addition of GnRH agonist in ovulation induction decreased cancellation rate, increased oocyte yields and pregnancy rates but increased the expenses.

Sonographic evaluation Baseline assessment Sonographic evaluation Ovaries Size Position Cysts Uterus Pathology Endometrial thickness Endocrine evaluation E2 4P FSH LH TVS alone does not eliminate the risk of plural pregnancy or OHS

GnRHa-HMG protocol Short down regulation E2 400 pg/ml/large follicle hCG Shot Day-8 evaluation PR/cycle 18% HMG ampoules 36 hr 48 hr Lupron 1 mg sc every day OPU ET 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 days of the cycle Monitoring EOD 18 mm

Triggering ovulation hCG 10,000 IU IM shot Follicles Endometrium E2 Leading follicle 18-20 mm Endometrium Thickness > 7 mm Trilaminar halo appearance E2 400 pg/ml/follicle > 18 mm OPU 36 hr after shot ET After 48 hr later

Trans-cervical ET Tetracycline to clear cervical mucus The best stage is blactocyst Knee-chest position Monach catheter carrying the embryo Push 0.2 ml air Rotate the catheter at withdrawal Keep the patient prone for 4 hours Corticosteroid to cover replacement

Post transfer care Day 15 pregnancy test (B-hCG) Day 35 TVS Luteal supplementation Embry reduction

IVF success rate in relation to indication Success of IVF Endometriosis Unexplained infertility Cervical factor Male factor Immunologic factor 32% 31% 28% 15% 10%