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Infertility - Comprehensive Review

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1. Definition of Infertility

• ~85% of couples achieve pregnancy within 12 months
• ~95% achieve pregnancy within 24 months
• If the female partner is >35 years - evaluation is initiated after 6 months
• If the female partner is >40 years - evaluation starts immediately
• Harrison's Principles of Internal Medicine 22E, p. 3193

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2. Primary vs. Secondary Infertility

• Harrison's Principles of Internal Medicine 22E, p. 3193

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3. Male and Female Infertility

Causes (Distribution)

• Female factors alone: 30-40% of couples
• Male factors alone: 40-50% of couples
• Both male and female factors: 20-30% of couples
• Unexplained infertility: up to 30% of couples

Female Causes

1. Tubal factors - PID, endometriosis, prior pelvic surgery, salpingitis isthmica nodosa
2. Uterine factors - fibroids, congenital malformations (Mullerian anomalies), uterine scarring (Asherman's syndrome)
3. Ovulatory dysfunction - PCOS, diminished ovarian reserve, premature ovarian insufficiency (POI)
4. Endocrine dysfunction - hypothyroidism, hyperprolactinemia
5. Age-related decline - chromosomal abnormalities in oocytes during meiosis; fecundability is reduced by 14% at age 34-35, 19% at 36-37, 53% at 40-41, and 59% at 42-44 years

Male Causes

1. Anatomic - vasectomy, infection, absence of vas deferens
2. Endocrine - hypogonadotropic hypogonadism, hypothyroidism, hyperprolactinemia, morbid obesity, certain medications
3. Sexual dysfunction - erectile/ejaculatory dysfunction, decreased libido
4. Genetic - Klinefelter's syndrome, Y chromosome microdeletions causing defects in spermatogenesis

• Harrison's Principles of Internal Medicine 22E, p. 3193

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4. WHO Parameters of Semen Analysis (2010 Lower Reference Limits - 5th centile)

Terminology

• Berek & Novak's Gynecology, p. 2027-2031

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5. Assisted Reproductive Technology (ART)

Definition

Indications

Standard ART Protocol (4 Steps)

• Exogenous hMG/FSH stimulates multiple follicle development (10-20 follicles vs. normal single follicle)
• Monitored by transvaginal ultrasound + serial serum estradiol
• When follicles reach ≥18 mm + adequate estradiol, hCG bolus is given (as surrogate LH surge)

• Performed ~34-36 hours after hCG (12 hours before expected ovulation)
• Transvaginal ultrasound-guided follicle aspiration

• Conventional IVF: Each oocyte mixed with sperm; fertilization check at 24 hours (two polar nuclei = fertilized)
• ICSI (Intracytoplasmic Sperm Injection): Single sperm injected directly into oocyte - used for severe male factor, failed conventional IVF

• Zygote incubated to morula/blastocyst stage (Day 5)
• Either transferred fresh or cryopreserved for later frozen embryo transfer (FET)

Other ART Procedures

• GIFT (Gamete Intrafallopian Transfer) - rarely practiced
• ZIFT (Zygote Intrafallopian Transfer) - rarely practiced
• Tubal Embryo Transfer

Laboratory Monitoring During ART

• Post-retrieval: Estradiol drops, then rebounds as corpus luteum forms
• Luteal phase support: exogenous progesterone (oral, vaginal, or IM)
• Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 750

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6. Ovulation Induction Drugs - Dose and MOA

A. Clomiphene Citrate (SERM)

B. Letrozole (Aromatase Inhibitor) - NOW PREFERRED FIRST-LINE for PCOS

C. Gonadotropins (Injectable)

D. GnRH Pulsatile Therapy

• MOA: Pulsatile IV or SC GnRH via programmable pump → physiological pulsatile stimulation of pituitary → normal FSH/LH release
• Indication: Hypogonadotropic hypogonadism (low estrogen + low gonadotropins); requires functional ovary and pituitary
• Advantage: Low risk of OHSS and multiple births; endogenous LH surge triggered naturally
• Disadvantage: Pump maintenance, injection site problems, unavailable in some countries

E. Metformin (Insulin Sensitizer - adjunct)

• MOA: Inhibits hepatic gluconeogenesis, increases peripheral glucose uptake → reduces insulin resistance → improves LH/FSH ratio in PCOS → promotes spontaneous ovulation
• Dose: 500 mg TID, 850 mg BD, or 1,000 mg BD (start low, increase gradually)
• Role: Adjunct in PCOS; combination with clomiphene may help obese patients
• Berek & Novak's Gynecology, pp. 1895-1897 and 2051-2053

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7. Ovarian Hyperstimulation Syndrome (OHSS)

Definition

Pathogenesis

Clinical Features

• Abdominal bloating and pain
• Nausea and vomiting
• Peripheral edema
• Oliguria
• Breathlessness and orthopnea
• Venous thromboembolism (VTE) risk
• Lab: elevated hematocrit, reduced serum osmolality, hyponatremia

Classification (Golan)

Management

• Self-limiting: ~7 days in non-pregnant women; 10-20 days in pregnant women
• Moderate-severe: Hospital admission
  • IV crystalloids (first-line)
  • Correct electrolytes (especially hyperkalemia)
  • Analgesia, nutrition
  • Prophylactic anticoagulation (VTE risk)
  • Paracentesis if needed (+ human albumin as plasma volume expander)
  • Respiratory support

Prevention

• GnRH antagonist protocols have lower OHSS incidence vs. GnRH agonist protocols
• Cancel cycle if too many follicles recruited or estradiol too high (withhold hCG trigger)
• Convert to IVF with freeze-all strategy (FET in a subsequent cycle rather than fresh transfer)
• Incidence is higher when conception occurs (endogenous hCG prolongs course)
• Comprehensive Clinical Nephrology 7th Ed., p. 438; Berek & Novak's Gynecology

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8. Detection of Ovulation - Tests

A. Urinary LH Surge (OPK - Ovulation Predictor Kit)

• Detects the LH surge in urine ~24-36 hours before ovulation
• Most practical home method
• With clomiphene/letrozole (days 5-9), LH surge typically occurs on cycle days 16-17
• LH kits typically started when largest follicle reaches 14 mm on ultrasound

B. Midluteal Serum Progesterone

• Measured 7 days after expected ovulation (typically Day 21 in a 28-day cycle)
• A level >3 ng/mL (or >10 nmol/L) confirms ovulation
• Most reliable biochemical marker

C. Basal Body Temperature (BBT)

• Temperature rises 0.2-0.5°C in luteal phase due to progesterone thermogenic effect
• A biphasic pattern confirms ovulation retrospectively
• Less reliable than LH testing or progesterone measurement

D. Transvaginal Ultrasound (Follicle Tracking)

• Serial ultrasound monitoring of follicular growth
• Pre-ovulatory follicle: 19-25 mm diameter (sometimes up to 30 mm)
• Evidence of ovulation: follicle collapse, free fluid in pouch of Douglas
• Also documents corpus luteum formation

E. Serum FSH + Estradiol (Day 2-3) + AMH + Antral Follicle Count (AFC)

• Assess ovarian reserve, not ovulation per se
• AMH and AFC predict response to stimulation and guide gonadotropin dosing

F. Endometrial Biopsy

• Historically used (now less common) to document secretory endometrial changes consistent with progesterone effect post-ovulation
• Harrison's 22E, p. 3195; Berek & Novak's Gynecology, p. 2053; Textbook of Family Medicine 9e

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9. Tubal Patency Tests

A. Hysterosalpingography (HSG) - First Choice

• What: Radiopaque water- or oil-based contrast injected through cervix; X-ray imaging shows uterine cavity and tubal fill/spill
• Timing: Follicular phase (after menstruation, before ovulation)
• Sensitivity/Specificity for tubal patency: 65% / 83% vs. laparoscopy
• Additional findings: Uterine polyps, submucosal fibroids, adhesions (Asherman's), tubal architecture
• Therapeutic effect: Pregnancy rates are higher after HSG - likely due to tubal flushing of mucus plugs; oil-based contrast superior to water-based
• Risks:
  • PID risk: 0.3-3.1% overall; >10% if hydrosalpinges present (avoid HSG if hydrosalpinges known)
  • Oil embolism (theoretical with oil-based contrast, not observed in large studies)
  • Vasovagal reactions, uterine perforation, cervical laceration
  • Antibiotic prophylaxis: doxycycline 100 mg BD (day before + 3-5 days after) in high-risk patients
• Contraindications: Known hydrosalpinges, active/suspected PID, iodine allergy (pretreat with glucocorticoids)

B. Sonohysterography (HyCoSy - Hystero-Contrast Sonography)

• Agitated saline (air-saline) or ultrasound contrast media injected transcervically
• Tubal patency demonstrated by saline passage or accumulation in cul-de-sac on ultrasound
• Advantages: No ionizing radiation, can be done in clinic
• Disadvantage: Standard 2D - cannot define tubal architecture as well as HSG; contrast agents not available in all countries
• Better negative predictive value; superior for intrauterine pathology (polyps, scars)

C. Laparoscopy with Chromopertubation - Gold Standard

• Direct visualization of all pelvic organs
• Chromopertubation: Transcervical installation of dye (indigo carmine or methylene blue) → direct visualization of dye spill from fimbriae
• Detects and treats: subserosal fibroids, peritubal/periovarian adhesions, endometriosis
• False positive rate for proximal tubal occlusion: ~11%
• Laparoscopy is the gold standard for tubal and peritoneal disease

D. Falloposcopy

• Used with hysteroscopy; direct fiberoptic visualization of tubal ostia and intratubal architecture
• Identifies tubal ostial spasm, abnormal mucosal patterns, intraluminal debris
• Less widely available; risk of tubal perforation

E. Chlamydia Serology

• Chlamydia antibody testing has comparable sensitivity/specificity to HSG
• Does not localize pathology and has no therapeutic benefit
• Positive serology with normal HSG: laparoscopy should still be considered (rule out peritubal adhesions)

F. Hysteroscopy

• Direct visualization of uterine cavity
• Diagnoses and treats intrauterine adhesions, polyps, septa
• Combined with tubal cannulation for proximal tubal occlusion

• Berek & Novak's Gynecology, pp. 2059-2060; Harrison's 22E, p. 3195; Textbook of Family Medicine 9e