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Case 24.4 – Infertility

Category: Medicine | Discipline: Obstetrics & Gynaecology | Setting: GP Surgery

Case

Mrs. Claire Johnson, a 33-year-old teacher, and her husband Mark (aged 35) present to their GP requesting help with conceiving. They have been trying for a baby for 18 months without success. They have regular unprotected intercourse 2-3 times per week throughout the month.

Claire has regular menstrual cycles (28-30 days) with moderate flow lasting 5 days. She denies dysmenorrhoea, intermenstrual bleeding, or pelvic pain. She has never been pregnant previously. Her last cervical smear 2 years ago was normal. She stopped taking the combined oral contraceptive pill 2 years ago after using it for 10 years.

Mark works as an IT consultant. He has no significant medical history and takes no regular medications. He denies any previous children from other relationships. He drinks 10-15 units of alcohol per week and is a non-smoker.

Claire denies any history of pelvic inflammatory disease, sexually transmitted infections, or abdominal/pelvic surgery. She had an appendicectomy aged 16. She is otherwise fit and well with no chronic medical conditions. Both partners are non-smokers. Claire's BMI is 24.

On Examination (Claire):

Investigations

Female Partner (Claire): Male Partner (Mark) - Semen Analysis: Repeat Semen Analysis (3 months later): Tubal Patency (Claire) - Hysterosalpingogram (HSG):

Questions

Question 1: What is the definition and classification of infertility, and what are the key causes?

Definition of Infertility:

  • Infertility: Failure to conceive after 12 months of regular unprotected intercourse
  • Primary infertility: Never conceived previously
  • Secondary infertility: Previously conceived (regardless of outcome) but unable to conceive again

Epidemiology:

  • Affects 1 in 7 couples (15%) in the UK
  • 84% of couples conceive within 1 year, 92% within 2 years (with regular intercourse)
  • Fertility declines with age, especially female age >35 years

When to Investigate:

  • After 12 months of trying (if female aged <35)
  • After 6 months of trying (if female aged ≥35, or known risk factors)
  • Immediately if: Amenorrhoea, known tubal disease, known male factor, age >40

Causes of Infertility (Percentage Breakdown):

1. Male Factor (30%):

  • Oligozoospermia: Low sperm count (\<15 million/mL)
  • Asthenozoospermia: Poor sperm motility (\<32% progressive motility)
  • Teratozoospermia: Abnormal sperm morphology (\<4% normal forms)
  • Azoospermia: No sperm in ejaculate
    • Obstructive: Blockage (vas deferens obstruction, vasectomy, congenital bilateral absence of vas deferens in CF carriers)
    • Non-obstructive: Testicular failure (Klinefelter syndrome 47,XXY, cryptorchidism, mumps orchitis, chemotherapy)
  • Erectile/ejaculatory dysfunction
  • Risk factors: Varicocele, testicular trauma, smoking, alcohol, obesity, heat exposure (saunas, tight underwear), anabolic steroids

2. Ovulatory Disorders (25%):

  • PCOS (80% of anovulatory infertility) - oligomenorrhoea, hyperandrogenism
  • Hypothalamic amenorrhoea: Stress, weight loss, excessive exercise
  • Hyperprolactinaemia: Prolactinoma, medications
  • Premature ovarian insufficiency (POI): Menopause <40 years
  • Thyroid disorders: Hypo/hyperthyroidism

3. Tubal Factor (20%):

  • Pelvic inflammatory disease (PID): Chlamydia, gonorrhoea → tubal damage/blockage
  • Endometriosis: Adhesions, distorted pelvic anatomy
  • Previous ectopic pregnancy (may damage/remove tube)
  • Tubal surgery, sterilisation
  • Appendicitis/peritonitis causing adhesions

4. Uterine/Cervical (10%):

  • Fibroids (especially submucosal - distort cavity)
  • Endometrial polyps
  • Asherman syndrome (intrauterine adhesions)
  • Congenital uterine anomalies: Bicornuate uterus, septate uterus
  • Cervical mucus problems: Hostile mucus (rare)

5. Unexplained Infertility (25%):

  • All investigations normal but couple not conceiving
  • May represent undiagnosed subtle ovulatory/sperm/tubal issues
  • Prognosis better than other causes - many conceive spontaneously

6. Combined Male and Female Factors (10%):

This couple's findings:

  • Primary infertility: 18 months of trying, no previous conception
  • Female factors: Normal (ovulating, normal ovarian reserve, patent tubes, normal uterus)
  • Male factor identified: Oligozoospermia (sperm count 8-10 million/mL, normal ≥15 million/mL)
  • Diagnosis: Male factor infertility (oligozoospermia)
Question 2: What investigations are required for infertility, and what are the treatment options?

Infertility Investigations:

Initial Assessment (GP/Fertility Clinic):

Both Partners:

  • History:
    • Duration of infertility, frequency of intercourse, previous pregnancies/children
    • Menstrual history (regularity suggests ovulation)
    • Medical history: Pelvic surgery, PID, STIs, testicular trauma, chronic illness
    • Medications, smoking, alcohol, recreational drugs
    • Occupational exposures (heat, chemicals)
  • Lifestyle advice: BMI 19-25 optimal, smoking cessation, reduce alcohol (\<14 units/week), folic acid 400mcg daily (female), avoid saunas/hot baths (male)

Female Investigations:

  • 1. Confirm ovulation:
    • Mid-luteal progesterone (Day 21 of 28-day cycle): >30 nmol/L confirms ovulation
      • Time 7 days before expected next period (not always day 21 if irregular cycles)
      • If <30 nmol/L → repeat, consider ovulatory dysfunction
  • 2. Assess ovarian reserve (especially if age ≥35):
    • AMH (Anti-Müllerian Hormone): Can be done any day of cycle
      • >15 pmol/L = normal reserve
      • 5-15 pmol/L = low reserve
      • <5 pmol/L = very low reserve
    • Day 2-5 FSH: <10 IU/L normal, >15 IU/L suggests low reserve
  • 3. Screen for ovulatory disorders:
    • Day 2-5: FSH, LH, oestradiol, prolactin, TSH, testosterone (if PCOS suspected)
  • 4. Assess tubal patency:
    • Hysterosalpingogram (HSG): X-ray with contrast dye to check tubal patency
      • Outpatient procedure, done days 5-12 of cycle (before ovulation)
      • Shows tubal blockage, uterine abnormalities, filling defects
    • HyCoSy (Hysterosalpingo-contrast sonography): Ultrasound alternative to HSG
    • Laparoscopy + dye test: Gold standard (also treats endometriosis/adhesions), but invasive
  • 5. Infection screening:
    • Chlamydia screen (endocervical swab or urine NAAT)
    • Rubella immunity (vaccinate if non-immune, avoid pregnancy 1 month post-vaccine)

Male Investigations:

  • Semen analysis (ESSENTIAL first test):
    • 2-5 days abstinence before sample
    • Assess: Volume, concentration, motility, morphology
    • WHO 2010 reference values (lower limits of normal):
      • Volume ≥1.5 mL
      • Concentration ≥15 million/mL
      • Total count ≥39 million
      • Progressive motility ≥32%
      • Normal forms ≥4%
    • If abnormal: Repeat after 3 months (spermatogenesis cycle = 3 months)
  • If azoospermia:
    • FSH, LH, testosterone
    • Genetic testing (karyotype for Klinefelter 47,XXY, cystic fibrosis gene if CBAVD)
    • Testicular biopsy (distinguish obstructive vs non-obstructive)

Management of Infertility:

General Measures (All Couples):

  • Lifestyle optimization:
    • Achieve healthy BMI (19-25)
    • Stop smoking (both partners)
    • Reduce alcohol (\<14 units/week women, <21 units/week men)
    • Folic acid 400mcg daily (female, preconception + first 12 weeks pregnancy)
    • Regular intercourse (every 2-3 days) throughout cycle (no need to time exactly)
  • Address reversible factors: Treat infections, optimize medications, avoid occupational exposures

Specific Treatments:

1. Ovulatory Disorders (Female):

  • PCOS: Weight loss, clomifene citrate, letrozole, metformin, ovarian drilling
  • Hyperprolactinaemia: Dopamine agonists (cabergoline)
  • Hypothalamic amenorrhoea: Weight gain, reduce exercise, pulsatile GnRH or gonadotropins

2. Tubal Factor (Female):

  • Mild tubal damage/adhesions: Laparoscopic adhesiolysis, tubal surgery
  • Severe tubal damage/blockage: IVF (bypasses tubes)
  • Hydrosalpinx: Salpingectomy before IVF (toxic fluid reduces IVF success)

3. Male Factor:

  • Mild oligozoospermia:
    • Lifestyle: Stop smoking, reduce alcohol, lose weight, avoid heat
    • Treat varicocele if present (surgical ligation)
    • Intrauterine insemination (IUI) with prepared sperm
    • IVF with ICSI if IUI fails
  • Severe oligozoospermia/azoospermia:
    • IVF with ICSI (intracytoplasmic sperm injection): Single sperm injected directly into egg
    • If obstructive azoospermia: Surgical sperm retrieval (PESA, TESA) + ICSI
    • If non-obstructive azoospermia: Donor sperm

4. Unexplained Infertility:

  • Expectant management: Continue trying naturally (up to 2 years) - many conceive spontaneously
  • Ovulation induction + IUI: Modest improvement (if female age <35)
  • IVF: Higher success rates (especially if age >35 or trying >2 years)

Assisted Reproduction Techniques (ART):

A) Intrauterine Insemination (IUI):

  • Indications: Mild male factor, unexplained infertility, same-sex couples, single women (donor sperm)
  • Procedure:
    • Sperm sample prepared (washed, concentrated)
    • Inseminated into uterus around ovulation (natural or stimulated cycle with clomifene/FSH)
  • Success: 10-15% per cycle (cumulative 30-40% after 6 cycles)
  • Max 6 cycles - if unsuccessful, move to IVF

B) In Vitro Fertilisation (IVF):

  • Indications: Tubal factor, endometriosis, failed IUI, severe male factor (with ICSI), unexplained infertility
  • Procedure:
    1. Ovarian stimulation: Daily FSH injections (10-14 days) to produce multiple eggs
    2. Egg retrieval: Transvaginal ultrasound-guided aspiration under sedation
    3. Fertilisation: Eggs + sperm mixed in lab (or ICSI if severe male factor)
    4. Embryo culture: 3-5 days (blastocyst stage)
    5. Embryo transfer: 1-2 embryos transferred to uterus via catheter
    6. Luteal support: Progesterone pessaries
    7. Pregnancy test: 2 weeks after transfer
  • Success rates (per cycle):
    • Age <35: 30-35%
    • Age 35-37: 25-30%
    • Age 38-40: 15-20%
    • Age >40: \<10%
  • Risks: Ovarian hyperstimulation syndrome (OHSS), multiple pregnancy (twins 10-15%), ectopic pregnancy

C) ICSI (Intracytoplasmic Sperm Injection):

  • Single sperm injected directly into egg (part of IVF cycle)
  • Indications: Severe oligozoospermia, previous IVF fertilisation failure, obstructive azoospermia

NHS Funding for IVF (England - 2024):

  • Eligibility (NICE guidelines):
    • Female aged <40 (some CCGs up to 42)
    • Tried to conceive for 2 years (or 6 cycles IUI if donor sperm/same-sex couple)
    • No previous children (either partner) - varies by CCG
  • NHS offers: 1 full cycle (some CCGs offer 3 cycles if <40)
  • Private IVF: £5,000-8,000 per cycle

This couple's management plan:

  1. Diagnosis: Male factor infertility (oligozoospermia 8-10 million/mL)
  2. Male partner (Mark):
    • Lifestyle: Reduce alcohol (\<21 units/week), avoid hot baths/saunas, lose weight if overweight
    • Scrotal ultrasound to exclude varicocele
    • Repeat semen analysis in 3 months
  3. Fertility treatment options:
    • Option 1: IUI (3-6 cycles): Prepared sperm inseminated at ovulation - success 10-15% per cycle
    • Option 2: IVF with ICSI: If IUI fails or couple prefer - success 30% per cycle (Claire aged 33)
  4. Referral to fertility clinic for specialist assessment and treatment planning
  5. Female partner (Claire): Continue folic acid 400mcg daily, optimize health
  6. Prognosis: Good - Claire is young (33) with normal ovarian reserve and patent tubes. IVF with ICSI has 30-35% success per cycle.

Key Learning Points