Infertility

Infertility is failure to achieve a clinical pregnancy after 12 months of regular unprotected intercourse (6 months if the woman is 35 or older), or an impairment of a person's capacity to reproduce either as an individual or with a partner. It affects about 10 to 15% of couples. Primary infertility is no prior pregnancy, and secondary infertility is difficulty after a previous conception.

Contributions:

• Female factors about 35%, male factors about 30%, both about 20%, and unexplained about 10 to 15% of couples.

Fecundability: a healthy couple has about 20 to 25% chance per month of conception, with cumulative rates of 85% at 1 year and 92% at 2 years. Female fertility declines from the early 30s, and sharply after 35, because of falling oocyte quantity and quality (aneuploidy).

Female causes

• Ovulatory disorders (25 to 30%): polycystic ovary syndrome (the commonest), hypothalamic amenorrhoea, premature ovarian insufficiency, hyperprolactinaemia, thyroid disease, and diminished ovarian reserve.
• Tubal and peritoneal (about 25%): pelvic inflammatory disease (chlamydia, gonorrhoea), endometriosis, adhesions from surgery, ectopic pregnancy, and hydrosalpinx.
• Uterine and cervical: fibroids (submucosal), polyps, intrauterine adhesions (Asherman syndrome), congenital anomalies (septate uterus), adenomyosis, and cervical stenosis.
• Age-related decline in ovarian reserve.

Male causes

• Pre-testicular: hypogonadotropic hypogonadism, hyperprolactinaemia, anabolic steroids.
• Testicular (about 60 to 80% of male factor): idiopathic, varicocele (15% of men, 40% of infertile men), cryptorchidism, genetic (Klinefelter syndrome, Y chromosome microdeletions AZFa, b, c), orchitis, torsion, gonadotoxins (chemotherapy, radiotherapy), and heat.
• Post-testicular: obstruction (congenital bilateral absence of vas deferens associated with CFTR mutations, vasectomy, infection), ejaculatory dysfunction (retrograde ejaculation, spinal cord injury, diabetes), and antisperm antibodies.
• Lifestyle and environmental: smoking, heavy alcohol, obesity, cannabis, opioid or testosterone use, and certain drugs (sulfasalazine, chemotherapy).

Unexplained infertility: normal ovulation, tubes, semen analysis and uterine cavity. Cause is likely subtle gamete, fertilisation or implantation defects.

History (both partners):

• Duration of infertility, previous pregnancies, coital frequency and timing, sexual dysfunction.
• Female: menstrual pattern (regular 24 to 35 day cycles suggest ovulation), dysmenorrhoea, dyspareunia, pelvic pain, galactorrhoea, hirsutism, weight change, surgeries, pelvic infections, STIs, cervical screening, contraceptive use, smoking, alcohol, caffeine, medications, chronic disease, and family history of early menopause.
• Male: childhood illnesses (mumps, cryptorchidism, hernia repair), testicular trauma or torsion, infections, previous surgery, medications, radiation or chemotherapy, occupational heat or chemical exposure, anabolic steroid use, smoking, alcohol, and sexual function.

Examination:

• Female: BMI, blood pressure, thyroid, signs of hyperandrogenism (acne, hirsutism, acanthosis nigricans), galactorrhoea, pelvic examination (tenderness, adnexal mass, uterosacral nodules, fixed retroverted uterus), and speculum assessment.
• Male: BMI, secondary sexual characteristics, gynaecomastia, penile abnormalities (hypospadias), testicular size (orchidometer, normal volume above 15 mL, small below 12 mL), consistency, palpable vasa, epididymal thickening, varicocele (Valsalva, standing), and rectal examination.

Red flags that expedite investigation: age 35 or older, amenorrhoea or oligomenorrhoea, known tubal or uterine disease, endometriosis, history of pelvic infection, previous cancer treatment, azoospermia, severe oligospermia, abnormal genital examination, or patient preference.

Counselling: modifiable factors (weight, smoking, alcohol, drugs), timing of intercourse (every 2 to 3 days across the cycle or in the 6-day fertile window ending on ovulation), and lubricants (avoid spermicidal products).

Evaluate both partners simultaneously and early.

Female

• Ovulation: regular cycles are sufficient evidence. Confirm with mid-luteal progesterone (about 7 days before expected menses, above 30 nmol/L or about 10 ng/mL), or serial ultrasound, or urinary LH kits.
• Hormones: TSH, prolactin, FSH and oestradiol (day 2 to 5), AMH and antral follicle count (ovarian reserve), androgens when hyperandrogenism, and HbA1c.
• Tubal patency: hysterosalpingography (HSG) with water-soluble contrast, hysterosalpingo-contrast sonography (HyCoSy), or laparoscopy with dye (chromopertubation) for suspected endometriosis or adhesions. Screen for chlamydia before instrumentation, and give prophylactic doxycycline when risk factors.
• Uterine cavity: pelvic ultrasound (transvaginal), saline infusion sonography, hysteroscopy for polyps, fibroids and septa, and MRI for complex anomalies and adenomyosis.
• Other: rubella immunity, cervical screening, HIV, hepatitis B and C, syphilis, and chlamydia testing. Genetic testing (karyotype, FMR1 premutation) in premature ovarian insufficiency.

Male

• Semen analysis (after 2 to 7 days abstinence, two samples at least 2 to 4 weeks apart if abnormal), WHO 6th edition lower reference limits: volume 1.4 mL, concentration 16 million/mL, total count 39 million, total motility 42%, progressive motility 30%, vitality 54%, normal morphology (strict) 4%. Azoospermia is no sperm on centrifuged sample, and oligospermia a low count.
• Hormones: FSH, LH, testosterone, prolactin. Raised FSH suggests testicular failure, low FSH and LH central disease.
• Genetic: karyotype and Y chromosome microdeletion testing in azoospermia or severe oligospermia (under 5 million/mL), and CFTR testing in obstructive azoospermia.
• Imaging: scrotal ultrasound for varicocele, testicular lesions and obstruction, and transrectal ultrasound for ejaculatory duct obstruction.
• Advanced: DNA fragmentation index in recurrent loss or unexplained infertility, post-ejaculatory urinalysis for retrograde ejaculation, and testicular biopsy.

General measures (both partners)

• Folic acid 400 micrograms daily (5 mg with risk factors) from preconception, weight optimisation (BMI 19 to 30), smoking and recreational drug cessation, alcohol limited, regular exercise, and stress reduction. Review and change teratogenic or gonadotoxic drugs. Vaccination (rubella). Treat chronic illness.
• Psychological support and counselling, as infertility causes marked distress.

Ovulatory disorders

• PCOS: weight loss, letrozole 2.5 mg daily on days 3 to 7, increasing to 5 mg then 7.5 mg in following cycles (first line, higher live birth than clomiphene), clomiphene citrate 50 to 150 mg daily for 5 days (6 cycles at most), metformin 500 mg up to 1000 to 1500 mg twice daily adjunct in insulin resistance, gonadotropins (low-dose step-up FSH 37.5 to 50 units daily) with ultrasound monitoring, laparoscopic ovarian drilling, and IVF if these fail. Cycle monitoring to prevent multiple pregnancy and ovarian hyperstimulation.
• Hypogonadotropic hypogonadism: pulsatile GnRH or gonadotropins (FSH and LH or hMG).
• Hyperprolactinaemia: cabergoline 0.25 to 0.5 mg twice weekly. Hypothyroidism: levothyroxine to TSH below 2.5 mIU/L.
• Premature ovarian insufficiency: oocyte donation.

Tubal disease and endometriosis

• Hydrosalpinx: salpingectomy or tubal occlusion before IVF. Tubal surgery (adhesiolysis, salpingostomy) in mild disease. Endometriosis: laparoscopic ablation or excision improves natural pregnancy in minimal-mild disease, and IVF is used for advanced disease. Avoid medical suppression for fertility alone.

Uterine factors

• Hysteroscopic resection of submucosal fibroids, polyps, septum and adhesions.

Male factor

• Treat reversible causes: stop gonadotoxins, treat infection, correct endocrine disorders (hypogonadotropic hypogonadism responds to hCG 1500 to 5000 units 2 to 3 times weekly with FSH 75 to 150 units 3 times weekly for 6 to 24 months).
• Antioxidants and empiric clomiphene/anastrozole have uncertain benefit.
• Varicocele repair (microsurgical subinguinal varicocelectomy) for palpable varicocele with abnormal semen parameters, and in couples where female factors are excluded.
• Retrograde ejaculation: pseudoephedrine 60 mg or imipramine 25 mg, and sperm retrieval from post-ejaculate urine (alkalinised).
• Obstructive azoospermia: surgical reconstruction (vasovasostomy, vasoepididymostomy) or surgical sperm retrieval (percutaneous or microsurgical epididymal sperm aspiration, testicular sperm extraction) with ICSI. Non-obstructive azoospermia: micro-TESE (sperm recovery 40 to 60% overall, lower in Sertoli-cell-only and AZFa/b deletions).

Assisted reproduction

• Intrauterine insemination (IUI): with or without mild stimulation (letrozole or gonadotropins) for mild male factor, unexplained infertility, cervical factor, or ejaculatory dysfunction (pregnancy rate 10 to 15% per cycle in stimulated cycles, 3 to 6 cycles).
• In vitro fertilisation (IVF) and ICSI: indicated for tubal disease, severe male factor, endometriosis, unexplained infertility after failed IUI, advanced maternal age, and diminished ovarian reserve.
• Ovarian stimulation: FSH 150 to 300 units daily from cycle day 2 to 3 for 8 to 12 days, with GnRH antagonist (cetrorelix 0.25 mg daily) to prevent premature LH surge, trigger with hCG 5000 to 10,000 units or GnRH agonist (triptorelin 0.2 mg) in high responders, oocyte retrieval at 34 to 36 hours, fertilisation, culture to blastocyst, single embryo transfer, luteal phase support (vaginal progesterone 200 mg three times daily or 400 mg twice daily, or IM progesterone 50 mg daily).
• Live birth per cycle declines with age: about 40 to 50% under 35, 30% at 35 to 37, 20% at 38 to 40, 10% at 41 to 42, under 5% over 43 (fresh autologous).
• Freeze-all and frozen embryo transfer reduces ovarian hyperstimulation syndrome. Preimplantation genetic testing (PGT-A, PGT-M) in selected patients.
• Complications: ovarian hyperstimulation syndrome (1 to 5% moderate to severe, managed with fluids, cabergoline 0.5 mg daily, paracentesis, and thromboprophylaxis), multiple pregnancy (minimise with single embryo transfer), bleeding, infection, ectopic pregnancy, and egg retrieval risks.
• Donor gametes, surrogacy and adoption where appropriate.

Unexplained infertility: expectant management for up to 2 years in younger couples with good prognosis, then IUI with stimulation or IVF.

Fertility preservation

• Oocyte, embryo, ovarian tissue and sperm cryopreservation before gonadotoxic treatment. GnRH agonist (goserelin 3.6 mg monthly) during chemotherapy may reduce ovarian failure.

Follow-up and referral

• Refer after 12 months (6 months if age 35 or over, immediately for known pathology). Offer a limit of 3 full IVF cycles in funded programmes. Provide counselling, support for pregnancy loss, and antenatal care that treats these pregnancies as higher risk.