Female infertility

Infertility is the failure to conceive after 12 months of regular unprotected intercourse (every 2 to 3 days) in a woman under 35, or after 6 months in a woman aged 35 or over. Assessment starts earlier when there is a known cause (amenorrhoea, oligomenorrhoea, tubal disease, previous cancer treatment, endometriosis, known male factor) or the woman is over 40.

The main clinical point is to evaluate both partners together, to identify ovulatory, tubal, uterine and male factors in the first visits, and to treat or refer by age, ovarian reserve and cause.

Clinical relevance. About 85% of couples conceive within 1 year and about 92% within 2 years, with fecundity falling steeply with the woman's age from the mid thirties. A male factor contributes to roughly one third of cases, so both partners need assessment.

Physiology. Conception needs ovulation of a mature oocyte, patent fallopian tubes, a receptive endometrium and a normal uterine cavity, adequate sperm in number, motility and morphology, and intercourse timed within the fertile window (the 6 days ending on the day of ovulation).

Classification. Primary (never conceived) or secondary (previous pregnancy). By cause: ovulatory (anovulation, diminished ovarian reserve), tubal and peritoneal, uterine and cervical, male factor, combined, and unexplained (normal assessment in both partners).

Key distinctions. Regular cycles every 21 to 35 days almost always indicate ovulation. Amenorrhoea or oligomenorrhoea points to ovulatory failure. A history of pelvic infection, ectopic pregnancy or pelvic surgery points to tubal disease. Dysmenorrhoea and deep dyspareunia suggest endometriosis.

A history of testicular problems, drugs or abnormal semen indicates male factor.

History (both partners where possible)

• Duration of trying, frequency and timing of intercourse, coital difficulties (dyspareunia, vaginismus, erectile and ejaculatory problems), use of lubricants.
• Previous pregnancies and outcomes (miscarriage, ectopic pregnancy, termination, live birth), contraception history, time to prior conception, and previous fertility treatment.
• Menstrual history: age at menarche, cycle length and regularity, flow, intermenstrual or postcoital bleeding, premenstrual symptoms, dysmenorrhoea.
• Pelvic and sexual history: pelvic inflammatory disease, sexually transmitted infection, endometriosis symptoms (dysmenorrhoea, deep dyspareunia, dyschezia), cervical procedures, pelvic or abdominal surgery (appendicectomy, ovarian cystectomy, myomectomy, caesarean section), tuberculosis.
• Medical: thyroid disease, diabetes, coeliac disease, autoimmune disease, hyperprolactinaemia symptoms (galactorrhoea), hirsutism, acne, weight change, eating disorder, cancer treatment (chemotherapy, radiotherapy), chronic illness.
• Drugs: NSAIDs (may inhibit ovulation), antipsychotics, antiepileptics, chemotherapy, anabolic steroids, opioids, recreational drugs; for the male partner testosterone, sulphasalazine, anabolic steroids, nitrofurantoin, chemotherapy.
• Lifestyle: smoking, alcohol, caffeine, recreational drugs, exercise, BMI (best fertility between 19 and 30), diet, occupational exposure to heat, solvents, pesticides.
• Family history of early menopause, congenital anomalies, genetic disorders (cystic fibrosis, haemoglobinopathy, fragile X).
• Male partner: previous paternity, cryptorchidism, testicular torsion or trauma, mumps orchitis, hernia repair, genital infection, varicocele, erectile and ejaculatory function, cystic fibrosis symptoms, tight underwear and hot baths.
• Psychological: stress, depression, relationship strain, sexual dysfunction.
• Cervical screening, rubella immunity, vaccination, folic acid use.

Examination

• Woman: BMI, blood pressure, thyroid, breasts and galactorrhoea, hirsutism (modified Ferriman Gallwey score of 8 or more), acne, acanthosis nigricans, striae, signs of androgen excess, visual fields.
• Abdominal and pelvic examination: uterine size and mobility, fixed retroverted uterus, tender nodularity of uterosacral ligaments or posterior fornix (endometriosis), adnexal mass or tenderness, vaginal septum or stenosis, cervical abnormality, vaginal discharge.
• Man: genital examination (testicular volume, consistency, epididymis, vas deferens, varicocele, hypospadias, penile abnormality), body habit, gynaecomastia, hair distribution.

Red flags

• Amenorrhoea, galactorrhoea, headache or visual disturbance (hyperprolactinaemia, pituitary tumour).
• Age 40 or over, or amenorrhoea under age 40 with hot flushes (premature ovarian insufficiency).
• Previous cancer treatment, pelvic radiotherapy or ovarian surgery.
• Known tubal disease, previous ectopic pregnancy, pelvic inflammatory disease or tuberculosis.
• Severe endometriosis, pelvic mass, or abnormal bleeding (cancer).
• Severe oligozoospermia or azoospermia, small testes, or signs of hypogonadism in the man.
• Abnormal cervical screening.
• Rapid virilisation or testosterone over 5 nmol/L (androgen secreting tumour).
• Positive pregnancy test with pain (ectopic pregnancy risk is higher after tubal disease or fertility treatment).

Special groups. Women over 35: earlier investigation and referral. Same sex couples and single women: assessment after failure of donor insemination (usually after 6 cycles) or earlier with known factors. Transgender and non binary people: individual counselling. Women with HIV: viral suppression before conception. Cancer survivors: fertility preservation counselling before treatment.

Organised by factor. Each cause is common unless marked serious or uncommon. Ovulatory disorders

• Polycystic ovary syndrome (the commonest cause of anovulation).
• Functional hypothalamic amenorrhoea (low weight, excessive exercise, stress, eating disorder).
• Hyperprolactinaemia (prolactinoma, drugs, hypothyroidism).
• Thyroid disease (hypothyroidism, hyperthyroidism).
• Premature ovarian insufficiency and diminished ovarian reserve (age related, genetic, autoimmune, chemotherapy, radiotherapy, surgery).
• Turner syndrome and mosaics, fragile X premutation, gonadal dysgenesis.
• Obesity and underweight.
• Hypogonadotropic hypogonadism (Kallmann syndrome, pituitary disease, Sheehan syndrome, cranial irradiation).
• Non classic congenital adrenal hyperplasia, Cushing syndrome, androgen secreting tumours.
• Chronic illness (kidney disease, inflammatory bowel disease, coeliac disease, diabetes, sickle cell disease).
• Luteal phase defect (diagnosis and treatment are contested).
• Serious: pituitary tumour, ovarian tumour.

Tubal and peritoneal factors

• Pelvic inflammatory disease (chlamydia, gonorrhoea, Mycoplasma genitalium), hydrosalpinx.
• Previous ectopic pregnancy or tubal surgery, tubal ligation.
• Endometriosis (peritoneal, ovarian, deep).
• Pelvic adhesions after surgery, ruptured appendix or inflammatory bowel disease.
• Genital tuberculosis (endemic regions) and genital schistosomiasis.
• Septic abortion.

Uterine and cervical factors

• Submucous or distorting intramural fibroids.
• Endometrial polyps.
• Adenomyosis.
• Intrauterine adhesions (Asherman syndrome).
• Congenital uterine anomalies (septate, bicornuate, unicornuate, didelphys).
• Chronic endometritis.
• Caesarean scar defect (niche).
• Cervical stenosis after cervical surgery, cervical infection, abnormal mucus.
• Serious: endometrial hyperplasia or cancer in a woman with prolonged anovulation.

Male factor

• Idiopathic oligoasthenoteratozoospermia.
• Varicocele.
• Obstructive azoospermia (congenital absence of the vas deferens in cystic fibrosis gene carriers, vasectomy, infection, surgery).
• Non obstructive azoospermia (Klinefelter syndrome, Y chromosome microdeletion, cryptorchidism, testicular failure, chemotherapy, radiation).
• Hypogonadotropic hypogonadism and hyperprolactinaemia.
• Drugs (testosterone, anabolic steroids, sulphasalazine, chemotherapy), heat exposure, smoking, alcohol, obesity.
• Ejaculatory disorders (retrograde ejaculation, anejaculation, erectile dysfunction).
• Serious: testicular tumour.
• Genital infection (epididymo orchitis, mumps orchitis).

Coital and other factors

• Sexual dysfunction (vaginismus, erectile dysfunction), poor timing of intercourse.
• Antisperm antibodies (contested significance).
• Immunological and thrombophilic disorders (not proven causes of infertility).
• Unexplained infertility (normal ovulation, tubes, uterus and semen; commonly about one quarter to one third of couples).

Stepwise reasoning

1. Assess both partners at the same visit with history, examination and baseline tests.
2. Confirm ovulation, check ovarian reserve and look for endocrine disease.
3. Assess tubal patency and uterine cavity once ovulation and semen are known.
4. Perform semen analysis early.
5. Plan treatment by cause and age, with earlier referral at age 36 or over.

First line tests in the woman

• Ovulation:
  • Regular cycles of 21 to 35 days are enough.
  • Mid luteal serum progesterone (day 21 of a 28 day cycle, or 7 days before the expected period): over 30 nmol/L indicates ovulation; 16 to 30 nmol/L repeat; under 16 nmol/L suggests anovulation.
  • Basal body temperature charts are not used.
  • Urinary luteinising hormone kits can time intercourse (test daily from day 10; intercourse on the day of the surge and the next 2 days).
• Ovarian reserve:
  • Anti Müllerian hormone: under about 5 pmol/L, 0.7 ng/mL, suggests a low response to stimulation; over about 25 pmol/L, 3.5 ng/mL, a high response with a risk of hyperstimulation.
  • Antral follicle count on transvaginal ultrasound: 4 or fewer predicts a low response; 16 or more a high response.
  • Follicle stimulating hormone on days 2 to 5: over 8.9 IU/L predicts a low response.
• These predict response to ovarian stimulation, not natural fertility.
• Hormone tests:
  • Thyroid stimulating hormone.
  • Prolactin (if irregular cycles or galactorrhoea).
  • Total testosterone, sex hormone binding globulin and free androgen index (if PCOS suspected).
  • Luteinising hormone, follicle stimulating hormone and oestradiol on days 2 to 5 for amenorrhoea or oligomenorrhoea (follicle stimulating hormone over 25 IU/L on two samples at least 4 weeks apart suggests premature ovarian insufficiency).
• Early morning follicular phase 17 hydroxyprogesterone (over 6 nmol/L needs a synacthen test for non classic congenital adrenal hyperplasia).
• Rubella immunity, HIV, hepatitis B and C, and syphilis serology; nucleic acid amplification test for chlamydia and gonorrhoea (treat before uterine instrumentation); HbA1c; full blood count; ferritin; haemoglobinopathy screening; coeliac serology when suggested.
• Karyotype for primary amenorrhoea, premature ovarian insufficiency or recurrent pregnancy loss.
• Cervical screening if due.

Tests for the male partner

• Semen analysis after 2 to 7 days of abstinence, delivered to the laboratory within 1 hour, repeated after 3 months if abnormal (earlier for azoospermia or severe oligozoospermia). Lower reference limits: volume 1.4 mL, concentration 16 million/mL, total sperm number 39 million in the ejaculate, total motility 42%, progressive motility 30%, vitality 54%, normal forms 4%.
• Further male tests:
  • Testosterone, luteinising hormone, follicle stimulating hormone and prolactin if semen is abnormal.
  • Karyotype and Y chromosome microdeletion testing if the sperm concentration is under 5 million/mL.
  • Cystic fibrosis gene testing in congenital absence of the vas deferens.
  • Scrotal ultrasound for suspected varicocele, tumour or obstruction.
  • Post ejaculation urine for retrograde ejaculation.

Assessment of the tubes and uterus

• Hysterosalpingography (X ray with contrast; moderate sensitivity and specificity for tubal occlusion, with false occlusion from tubal spasm) or hysterosalpingo contrast sonography for women without comorbidity.
• Give azithromycin 1 g orally as a single dose, or doxycycline 100 mg orally twice daily for 5 days, as prophylaxis before the test when there is a history of pelvic infection or dilated tubes.
• Avoid in pregnancy; do within the first 10 days of the cycle.
• Laparoscopy with dye test (chromopertubation) and hysteroscopy for women with pelvic inflammatory disease, previous ectopic pregnancy, endometriosis or pelvic pain.
• Transvaginal ultrasound for uterine size, fibroids, polyps, adenomyosis, hydrosalpinx, ovarian cysts and polycystic ovarian morphology (20 or more follicles in an ovary or ovarian volume 10 mL or more; not used within 8 years of menarche).
• Saline infusion sonography or three dimensional ultrasound for cavity and anomalies.
• Hysteroscopy for suspected polyp, septum, adhesions or submucous fibroid.
• MRI pelvis for complex anomalies, adenomyosis and deep endometriosis.
• Endometrial biopsy only for abnormal bleeding or suspected endometritis or hyperplasia (tuberculosis culture and nucleic acid test in endemic regions).

Limitations. Ovarian reserve tests do not predict spontaneous conception in the general population. Hysterosalpingography has radiation exposure and may miss peritoneal factors. Semen parameters vary between samples. Unexplained infertility is a diagnosis of exclusion. Occult causes such as sperm DNA damage and endometrial receptivity cannot be tested reliably.

Immediate steps. Treat any acute condition (ectopic pregnancy, pelvic infection). Explain that infertility is common, that both partners are assessed, and that outcomes depend on age and cause.

Start preconception care for every couple.

Preconception care

• Folic acid 400 microgram orally daily from before conception until 12 weeks of pregnancy; 5 mg daily for women with BMI over 30, diabetes, a previous neural tube defect, sickle cell disease, thalassaemia or antiepileptic use.
• Vitamin D 10 microgram daily.
• Intercourse every 2 to 3 days across the cycle; timed intercourse is not required.
• Stop smoking, avoid alcohol, limit caffeine to under 200 mg daily, and avoid recreational drugs; maintain BMI between 19 and 30 (weight loss of 5 to 10% restores ovulation in many overweight women with PCOS).
• Rubella vaccination if non immune, avoiding conception for 1 month afterwards; cervical screening; review drugs for teratogenicity (warfarin, isotretinoin, methotrexate, valproate, ACE inhibitors, mycophenolate).
• Optimise diabetes, thyroid disease, hypertension and epilepsy.
• Genetic carrier screening where indicated (cystic fibrosis, haemoglobinopathy).

Ovulation induction in polycystic ovary syndrome

• Letrozole 2.5 mg orally once daily on days 3 to 7 of the cycle (after spontaneous or progestogen induced bleeding), increased by 2.5 mg each cycle to a maximum of 7.5 mg daily if no ovulation; first line (use is off label in many countries). Confirm ovulation with mid luteal progesterone. Continue for up to 6 ovulatory cycles.
• Clomifene citrate 50 mg orally once daily for 5 days starting on days 2 to 5 of the cycle, increased to 100 mg and then 150 mg daily in later cycles if there is no ovulation (maximum 150 mg daily).
• Usual course up to 6 ovulatory cycles.
• Warn about hot flushes, visual disturbance (stop the drug), ovarian cysts, multiple pregnancy, and mood change.
• Ultrasound monitoring during the first cycle, avoiding clomifene when there is liver disease, ovarian cyst, undiagnosed abnormal bleeding or hormone dependent cancer.
• Metformin 500 mg orally once daily with food, increased by 500 mg each week to 1500 to 2000 mg daily in divided doses, as an adjunct to clomifene or letrozole in obese women or those with insulin resistance.
• It is unlicensed for infertility; maximum 3 g daily.
• Avoid if eGFR is under 30 mL/min/1.73 m2, reduce if under 45; monitor vitamin B12.
• Gonadotropins (follitropin alfa 37.5 to 50 IU subcutaneously daily, with a low dose step up regimen, dose increased after 7 to 14 days by about 50% when no response) for failure of oral agents; specialist ultrasound monitoring; risk of multiple pregnancy and ovarian hyperstimulation.
• Laparoscopic ovarian drilling for clomifene resistant women who need laparoscopy.
• In vitro fertilisation for failure of these measures or additional factors.

Other ovulatory causes

• Hyperprolactinaemia: cabergoline 0.25 mg orally twice weekly, increased in steps of 0.25 mg twice weekly every 4 weeks to normalise prolactin; usual maximum 1 mg twice weekly; take with food.
• Monitor for nausea, postural hypotension and impulse control disorder.
• Contraindicated with cardiac valvulopathy and pulmonary, retroperitoneal or pericardial fibrosis.
• Stop at diagnosis of pregnancy in microadenoma.
• Hypothyroidism: levothyroxine 1.6 microgram/kg orally daily on an empty stomach, aiming for thyroid stimulating hormone under 2.5 mIU/L before conception; increase the dose by about 30% at confirmation of pregnancy. Hyperthyroidism: carbimazole 15 to 40 mg daily initially, or propylthiouracil in the first trimester, with specialist care.
• Hypothalamic amenorrhoea: restore weight and reduce exercise; if ovulation does not return, pulsatile gonadotropin releasing hormone (gonadorelin 5 to 20 microgram subcutaneously every 90 minutes by pump) or gonadotropins with luteinising hormone activity under specialist care.
• Premature ovarian insufficiency and diminished ovarian reserve: counselling, oocyte donation or in vitro fertilisation with donor oocytes.
• Hormone replacement for bone and cardiovascular health: transdermal oestradiol 50 to 100 microgram patch twice weekly with micronised progesterone 200 mg orally at night for 12 to 14 days each month, until about age 51.
• Spontaneous pregnancy occurs in about 5 to 10%.
• Obesity and underweight: dietary support, exercise programme and psychological care.

Tubal and peritoneal factors

• Mild tubal disease or distal occlusion: tubal surgery in selected women, but in vitro fertilisation is usual practice for moderate or severe disease.
• Hydrosalpinx: salpingectomy or proximal tubal occlusion before in vitro fertilisation to improve implantation.
• Endometriosis: laparoscopic excision or ablation of minimal to mild disease increases pregnancy rate; ovarian endometrioma excision when large or painful (with ovarian reserve counselling); medical suppression does not improve fertility; in vitro fertilisation for moderate to severe disease or failure.
• Pelvic inflammatory disease: ceftriaxone 1 g intramuscularly once, doxycycline 100 mg orally twice daily for 14 days and metronidazole 400 mg orally twice daily for 14 days; treat partners.
• Genital tuberculosis: isoniazid 5 mg/kg (maximum 300 mg) daily, rifampicin 10 mg/kg (maximum 600 mg) daily, pyrazinamide 25 mg/kg daily and ethambutol 15 mg/kg daily for 2 months, then isoniazid and rifampicin daily for 4 months; add pyridoxine 10 mg daily; specialist care.

Uterine and cervical factors

• Hysteroscopic resection of polyps and submucous fibroids.
• Hysteroscopic division of a septum (benefit for pregnancy rate is uncertain; used for recurrent miscarriage).
• Adhesiolysis for Asherman syndrome, followed by oestradiol 2 mg orally daily for 4 weeks with a progestogen in the last 10 days.
• Treatment of chronic endometritis: doxycycline 100 mg orally twice daily for 14 days.
• Myomectomy for large intramural fibroids that distort the cavity (evidence of benefit for fertility is limited).
• Adenomyosis: evidence is limited; in vitro fertilisation with pre treatment by gonadotropin releasing hormone agonist for 3 to 6 months is used.

Male factor

• Treat the cause: stop causative drugs, lose weight, stop smoking and reduce heat exposure; treat infection; stop testosterone.
• Replace hypogonadotropic deficiency with gonadotropins: human chorionic gonadotropin 1500 to 2000 IU subcutaneously twice weekly with follicle stimulating hormone 75 to 150 IU three times weekly, adjusted to semen.
• Varicocele repair for large, palpable varicocele with abnormal semen and a female partner with a normal reserve (evidence is limited).
• Intrauterine insemination for mild male factor or coital dysfunction; in vitro fertilisation with intracytoplasmic sperm injection for severe male factor; surgical sperm retrieval for azoospermia; donor sperm.
• Antioxidants have uncertain benefit.

Unexplained infertility. Expectant management for up to 2 years from the start of trying is reasonable for women under 36 with a good prognosis; then in vitro fertilisation. Intrauterine insemination with ovarian stimulation gives modest gains over expectant management and is used where in vitro fertilisation is not available. Offer in vitro fertilisation earlier for women aged 36 or over or with low ovarian reserve.

Assisted reproduction

• Indications: tubal disease, severe male factor (with intracytoplasmic sperm injection), endometriosis, failure of ovulation induction and intrauterine insemination, unexplained infertility after 2 years, diminished ovarian reserve at an older age, and donor gamete use.
• Live birth rates fall with age: they are highest under 35 and decline markedly after 38 and 40.
• Single embryo transfer reduces multiple pregnancy. Preimplantation genetic testing for known genetic disease.
• Complications:
  • Ovarian hyperstimulation syndrome: abdominal distension, ascites, haemoconcentration with haematocrit over 45%, white cell count over 15 x 10^9/L, oliguria, thromboembolism, hyponatraemia with sodium under 135 mmol/L. Manage with fluids, analgesia, enoxaparin 40 mg subcutaneously daily, drainage of ascites and specialist admission.
  • Ectopic and heterotopic pregnancy.
  • Multiple pregnancy.
  • Bleeding and infection after egg retrieval.
• Counsel about emotional strain, financial cost, and the possibility of unsuccessful treatment; offer counselling and peer support.

Fertility preservation. Offer oocyte, embryo or ovarian tissue cryopreservation before chemotherapy, radiotherapy or gonadotoxic surgery. Gonadotropin releasing hormone agonist cover during chemotherapy has uncertain benefit.

Special groups. Women over 35: refer after 6 months; over 40: refer immediately. Same sex couples: intrauterine insemination with donor sperm, in vitro fertilisation after 6 unsuccessful cycles. Women with HIV: viral suppression, and sperm washing or pre exposure prophylaxis for serodiscordant couples. Cancer survivors: oncology and fertility specialist joint care.

Monitoring.

• After ovulation induction: confirm ovulation with mid luteal progesterone.
• Use ultrasound monitoring in the first cycle of clomifene and during gonadotropin therapy (number of follicles of 16 mm or more, endometrial thickness), and stop if more than 2 follicles of 16 mm or more develop to avoid multiple pregnancy.
• Pregnancy test 2 weeks after missed period, and early ultrasound at 6 to 7 weeks after fertility treatment to exclude ectopic pregnancy.
• Review the plan every 3 to 6 cycles of treatment.

Referral and escalation. Refer to a fertility specialist when 12 months (or 6 months at age 36 or over) have passed without conception, immediately for known cause or age 40 or over, and for any red flag. Refer to endocrinology for pituitary disease, premature ovarian insufficiency or complex endocrine disease; to urology or andrology for abnormal semen; to gynaecology for surgery; to oncology for cancer survivors; to genetics for chromosomal abnormalities.

Admission criteria. Suspected ectopic pregnancy, severe ovarian hyperstimulation syndrome, pelvic sepsis, torsion of enlarged ovaries, and haemorrhage after retrieval.

Discharge and follow up. Outpatient care with a named clinician. Provide written instructions on timing of intercourse, folic acid, lifestyle and when to seek help, and a review date.

Safety netting. Return for severe abdominal pain, shoulder tip pain, fainting, heavy bleeding, fever, rapid weight gain, abdominal swelling, reduced urine output, breathlessness or leg swelling.