Key Facts

Infertility is a common condition with significant psychological impact. A systematic approach to investigation of both partners is essential, as male and female factors contribute equally.

Epidemiology

• Affects approximately 1 in 7 couples (3.5 million people in the UK)
• 84% of couples conceive within 1 year; 92% within 2 years of regular unprotected intercourse
• Prevalence increasing due to delayed childbearing, rising obesity, and declining sperm quality

Aetiology

• Male factor (30%): oligospermia, azoospermia, abnormal morphology/motility, varicocele, undescended testes, genetic (Klinefelter, Y-microdeletions)
• Ovulatory dysfunction (25%): PCOS (most common), hypothalamic amenorrhoea, hyperprolactinaemia, thyroid disease, POI
• Tubal factor (20%): PID (Chlamydia), previous ectopic, endometriosis, previous surgery
• Unexplained (25%): no identifiable cause after standard investigations
• Other: endometriosis, uterine factors (fibroids, Asherman syndrome), cervical factors

Pathophysiology

• Varies by cause: ovulatory dysfunction impairs oocyte release, tubal damage prevents sperm-egg interaction, male factor reduces sperm quantity/quality, endometriosis creates hostile peritoneal environment

History Taking

• Duration of trying to conceive
• Menstrual history: cycle regularity, length, associated symptoms
• Sexual history: frequency and timing of intercourse, erectile dysfunction
• Previous pregnancies (either partner)
• Medical history: PID, endometriosis, PCOS, thyroid disease, undescended testes
• Surgical history: pelvic surgery, appendicectomy
• Drug history: NSAIDs, chemotherapy, sulfasalazine, testosterone
• Lifestyle: smoking, alcohol, BMI, recreational drugs, occupation

Red Flags

• Age >35 (female) or >45 (male)
• Amenorrhoea or very irregular cycles
• Known tubal damage or previous ectopic
• Known azoospermia or severe oligospermia
• Previous chemotherapy or pelvic radiotherapy

Bedside

• BMI (both partners)
• Blood pressure
• Examination: thyroid, breast (galactorrhoea), pelvic examination (tenderness, masses)
• Testicular examination (size, varicocele)

Bloods

• Female: Day 2-5 FSH, LH, oestradiol (ovarian reserve); day 21 progesterone (ovulation confirmation); AMH (ovarian reserve); TFTs; prolactin; rubella immunity
• Male: testosterone, FSH, LH (if abnormal semen analysis)
• Chlamydia screening (both partners)

Imaging

• Hysterosalpingography (HSG) or HyCoSy: assess tubal patency (first-line per NICE CG156 if no risk of tubal disease)
• Pelvic USS: assess uterine and ovarian morphology, antral follicle count

Special Tests

• Semen analysis (×2 if first abnormal, 3 months apart): WHO criteria
• Laparoscopy + dye test: gold standard for tubal assessment; also diagnoses endometriosis
• Karyotype: if azoospermia (exclude Klinefelter 47XXY) or POI
• Y-microdeletion testing: if severe oligospermia (<5 million/mL)
• Genetic counselling: for known genetic conditions before ART

Non-pharmacological

• Lifestyle optimisation: BMI 19-30 for both partners, stop smoking, limit alcohol (≤1 unit/day), reduce caffeine
• Regular intercourse every 2-3 days (timing with ovulation not essential per NICE CG156)
• Folic acid supplementation 400mcg OD (5mg if risk factors for NTD)
• Psychological support

Pharmacological

• Ovulation induction (for anovulatory infertility):
  • Letrozole 2.5mg OD days 2-6 (aromatase inhibitor; increasingly used as first-line)
  • Clomifene 50-150mg OD days 2-6 (anti-oestrogen; max 6 cycles per NICE)
  • Gonadotrophins (FSH injections): second-line; low-dose step-up protocol; requires USS monitoring
  • Metformin: adjunct in PCOS (off-label)
• Male factor: treat underlying endocrine cause; surgical sperm retrieval for obstructive azoospermia

Surgical/Interventional

• IUI (intrauterine insemination): with or without ovarian stimulation; 10-15% per cycle success rate; not recommended for unexplained infertility by NICE CG156
• IVF (in vitro fertilisation): offered after 2 years of unexplained infertility or failed ovulation induction; NICE recommends up to 3 full cycles if <40, 1 cycle if 40-42
• ICSI (intracytoplasmic sperm injection): for severe male factor; single sperm injected into oocyte
• Laparoscopic surgery: tubal surgery, endometriosis excision, ovarian drilling (PCOS)
• Donor gametes: for POI, azoospermia refractory to treatment
• Surrogacy: for women unable to carry a pregnancy

Referral Criteria

• Refer after 12 months of trying if <35 years; earlier if >35 or known risk factors (NICE CG156)
• Known anovulation: refer immediately for ovulation induction
• Known azoospermia: refer immediately to reproductive medicine
• Tubal factor: reproductive medicine referral
• Recurrent pregnancy loss: specialist recurrent miscarriage clinic

• 84% of couples conceive within 1 year; 92% within 2 years of unprotected intercourse
• Clomifene/letrozole ovulation induction: 70-80% ovulation rate; 20-25% live birth rate per treatment cycle
• IVF live birth rate per cycle: 25-30% average (varies by age: 32% at <35 years, 21% at 38-39, 11% at 40-42, 4% at >42)
• Cumulative live birth rate with 3 IVF cycles: approximately 45-65% (age-dependent)
• Unexplained infertility: 50% conceive spontaneously within 3 years
• Male factor: ICSI success rates comparable to standard IVF for non-male factor

WHO Semen Analysis Reference Values (6th Edition, 2021)

NICE CG156 Key Recommendations