Gonadal system - infertility
Description
- Failure to conceive after 12 months of regular unprotected intercourse
- 6 months if the woman is >=35, or immediately if there is an obvious cause (amenorrhoea, known tubal disease, azoospermia, prior chemotherapy)
- Primary (never conceived) vs secondary (previous conception)
Where the cause sits
| Share | |
|---|---|
| Male factor | ~30% (sole), contributory in ~50% |
| Ovulatory dysfunction | ~25% |
| Tubal/pelvic | ~20% |
| Uterine/cervical | ~10% |
| Unexplained | ~15-25% |
- *Investigate both partners from the start* - a male factor is present in half of couples and a semen analysis is cheap and fast
Epidemiology
- Affects ~1 in 6 couples
- ~1 in 18 Australian babies is born after assisted reproductive technology
- Female age is the dominant variable: monthly fecundability ~20-25% at 20-30y, falling steeply after 35, and markedly after 40
- Male fertility declines more gradually; paternal age >45 raises miscarriage and de novo mutation risk
- PCOS is the commonest cause of anovulatory infertility
Aetiopathogenesis
Female
Ovulatory (WHO groups)
- Group I - hypogonadotrophic hypogonadism (low FSH/LH, low oestradiol): functional hypothalamic amenorrhoea (low BMI, excessive exercise, stress), Kallmann, pituitary disease, hyperprolactinaemia
- Group II - normogonadotrophic (~85%): PCOS
- Group III - hypergonadotrophic (high FSH, low oestradiol): premature ovarian insufficiency, Turner syndrome, FMR1 premutation, autoimmune, prior chemotherapy/radiotherapy
Tubal/pelvic
- PID/chlamydia (the leading preventable cause), prior ectopic, appendicitis, pelvic surgery, endometriosis, adhesions
Uterine
- Submucosal fibroid, polyp, Asherman syndrome (intrauterine adhesions after instrumentation), congenital anomaly, adenomyosis
Male
- Pre-testicular - hypogonadotrophic hypogonadism, hyperprolactinaemia, exogenous anabolic steroids or testosterone (suppresses spermatogenesis - a common and reversible cause that must be asked about), opioids
- Testicular - varicocele, cryptorchidism, mumps orchitis, torsion, trauma, Klinefelter (47,XXY), Y-chromosome microdeletion (AZFa/b/c), chemotherapy/radiotherapy, heat, alcohol, cannabis
- Post-testicular - CBAVD in CFTR mutation carriers, vasectomy, ejaculatory duct obstruction, retrograde ejaculation (diabetes, alpha blockers, spinal injury), erectile/ejaculatory dysfunction
Gonadotoxic chemotherapy - the risk hierarchy
- *Alkylating agents (cyclophosphamide, ifosfamide, busulfan, procarbazine, melphalan) carry the highest gonadotoxicity* - dose-dependent, cumulative
- Platinum agents intermediate
- Vincristine, methotrexate, bleomycin, 5-FU: comparatively low risk
- Total body irradiation and pelvic/cranial radiotherapy add substantially
Diagnosis
Confirm ovulation
- Regular cycles (21-35 days) with molimina are strong evidence of ovulation
- Mid-luteal progesterone (day 21 of a 28-day cycle, i.e. 7 days before the expected period) >30 nmol/L confirms it
- If anovulatory: FSH, LH, oestradiol, prolactin, TSH, testosterone/SHBG/free androgen index, 17-OHP if virilised
Ovarian reserve - prognosis, not diagnosis
- AMH - produced by granulosa cells of pre-antral and small antral follicles; physiological role is restraining early follicular recruitment
- Cycle-independent, so can be taken any day
- Low AMH = reduced ovarian reserve and predicts oocyte yield at IVF; it does NOT predict natural conception and must not be used to tell a woman she cannot conceive
- *Paradoxically high in PCOS* (many small antral follicles)
- Uses: prior to IVF, after gonadotoxic chemotherapy, suspected POI
- Antral follicle count on transvaginal ultrasound - equivalent information
- Day 2-5 FSH - cruder, cycle-dependent
Tubal patency
- Hysterosalpingogram or HyCoSy (contrast sonography) first line
- HSG has a small therapeutic flushing effect on subsequent conception rates
- Laparoscopy and dye if endometriosis or adhesions suspected, or HSG abnormal
- Chlamydia serology/NAAT before any uterine instrumentation
Uterine
- Transvaginal ultrasound; saline infusion sonohysterography or hysteroscopy for suspected polyp, submucosal fibroid or adhesions
Male
- Semen analysis - the single most informative male test; repeat after >=6 weeks if abnormal (spermatogenesis takes ~74 days)
- Volume, concentration, total count, progressive motility, morphology (WHO reference limits)
- Azoospermia -> FSH, LH, testosterone, karyotype, Y-chromosome microdeletion, CFTR if vasa are absent
- High FSH + small testes = primary testicular failure (non-obstructive)
- Normal FSH + normal testes + absent sperm = obstructive - sperm retrievable
- Examination: testicular volume (orchidometer), varicocele, vasa deferentia, secondary sexual characteristics
- Scrotal ultrasound; transrectal ultrasound for ejaculatory duct obstruction
Both partners
- Rubella and varicella immunity, blood group, FBE, ferritin, vitamin D, cervical screening, BMI, smoking, alcohol, drug use
- Genetic carrier screening (cystic fibrosis, spinal muscular atrophy, fragile X - Medicare-funded in Australia)
Management
A. Before anything else - modifiable factors
- Preconception folic acid 0.5 mg daily (5 mg if BMI >30, diabetes, epilepsy on valproate, or prior NTD), iodine 150 microg
- Weight: BMI 20-25 optimises spontaneous and assisted conception; even 5-10% loss restores ovulation in PCOS
- Stop smoking, cannabis, anabolic steroids; limit alcohol and caffeine
- Timed intercourse every 2-3 days across the cycle - not restricted to a predicted ovulation day
- Optimise thyroid function, glycaemia, prolactin
B. Ovulatory dysfunction
- PCOS/WHO group II
- Letrozole is first-line ovulation induction (higher live birth rate than clomiphene in PCOS)
- Clomiphene; metformin as an adjunct
- Gonadotrophins or laparoscopic ovarian drilling if resistant
- Multiple pregnancy is the main risk - monitor with ultrasound
- WHO group I - restore weight/energy availability; pulsatile GnRH or gonadotrophins
- Hyperprolactinaemia - cabergoline/bromocriptine
- WHO group III / POI - oocyte donation is the realistic route to pregnancy
C. Tubal and pelvic
- Tubal surgery in selected young women with distal disease; salpingectomy for hydrosalpinx before IVF (a hydrosalpinx halves IVF success)
- Laparoscopic excision/ablation of endometriosis improves fecundity in minimal-mild disease
D. Male factor
- Treat reversible causes: stop exogenous androgens, treat hyperprolactinaemia, gonadotrophins for hypogonadotrophic hypogonadism
- *Never give testosterone to a man wanting to conceive* - it suppresses spermatogenesis
- Varicocele repair in selected men with clinical varicocele and abnormal parameters
- ICSI for severe oligo/asthenozoospermia; surgical sperm retrieval (TESE/micro-TESE) for azoospermia
- Donor sperm if retrieval fails
E. Assisted reproduction
- IUI - unexplained, mild male factor, cervical factor, donor sperm
- IVF - tubal disease, severe male factor, failed ovulation induction, endometriosis, unexplained after 12-24 months, advanced maternal age
- ICSI - severe male factor, prior fertilisation failure
- PGT-M / PGT-A for known monogenic disease or recurrent loss
- Complications: OHSS (largely preventable with GnRH-antagonist protocols, agonist trigger and freeze-all), multiple pregnancy (single embryo transfer is standard in Australia), procedural risk
F. Fertility preservation - act BEFORE gonadotoxic therapy
- *Refer at diagnosis, before the first cycle of chemotherapy - this is a time-critical referral*
- Female: oocyte or embryo cryopreservation (needs ~2 weeks of stimulation); ovarian tissue cryopreservation if treatment cannot wait or pre-pubertal; GnRH agonist during chemotherapy offers partial ovarian protection but is not a substitute
- Male: sperm cryopreservation before the first dose - simple, cheap, and frequently forgotten
- Post-treatment: AMH to assess residual reserve and counsel about a shortened reproductive window
Associations
- PCOS - anovulation, insulin resistance, high AMH
- Endometriosis - dysmenorrhoea, dyspareunia, subfertility
- Turner syndrome, FMR1 premutation, autoimmune POI
- Klinefelter (47,XXY), Y-microdeletion, CFTR mutation with congenital absence of the vasa
- Kallmann syndrome (anosmia + hypogonadotrophic hypogonadism)
- Coeliac disease, thyroid disease, hyperprolactinaemia
- Chlamydia/PID; prior appendicectomy or pelvic surgery
- Cancer therapy - alkylating agents and pelvic/total body irradiation
- Obesity, smoking, anabolic steroid use, opioid use
Natural history & complications
- ~85% of couples conceive within 12 months, ~92% within 24 with no intervention
- Cumulative live birth rate per IVF cycle is strongly age-dependent: ~40-45% per initiated cycle under 35, ~5% or less over 42 using her own oocytes
- Unexplained infertility has a meaningful spontaneous conception rate - expectant management for 6-12 months is legitimate in younger women
- Untreated hydrosalpinx, submucosal fibroid and severe male factor do not improve with time
- Ovarian reserve declines irreversibly; the counselling that changes outcomes is about age, delivered early
- Psychological burden is high - depression, anxiety, relationship strain; counselling should be offered routinely, not on request
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