Aromatase Inhibitors in Fertility Treatment

Aromatase inhibitors block conversion of androgens to oestrogens. Letrozole is now the first-line oral drug for ovulation induction in women with polycystic ovary syndrome (PCOS), and it is also used in unexplained infertility, in intrauterine insemination cycles and in endometriosis-related infertility. Anastrozole works similarly but has less evidence.

Mechanism. Reduced oestradiol removes negative feedback on the hypothalamus and pituitary, so FSH rises and recruits follicles. Unlike clomifene, letrozole does not block oestrogen receptors, so cervical mucus and endometrial thickness are less affected. Intraovarian androgens rise, which may increase follicle sensitivity to FSH.

Pharmacokinetics. Letrozole is well absorbed orally with a half-life of about 2 days and clears from the body before implantation. It is metabolised by CYP3A4 and CYP2A6.

Letrozole regimen for ovulation induction.

• 2.5 mg orally once daily for 5 days, from cycle day 2 to 5 (after a spontaneous or progestogen-induced bleed).
• If there is no ovulation, increase by 2.5 mg each cycle to 5 mg and then 7.5 mg daily, up to a maximum of 7.5 mg (some units use 10 mg).
• Extended regimens (up to 10 days) are used in selected non-responders.
• Treat for up to 6 ovulatory cycles, and up to 9 in some units, before referral for other options.

Anastrozole. 1 mg daily for 5 days is an alternative with fewer data.

Combination. Letrozole with gonadotropin in intrauterine insemination raises ovulation and pregnancy rates; letrozole with metformin gives no extra benefit over letrozole alone in most studies. A single dose of letrozole 5 mg is used with the trigger for endometrial preparation in some frozen embryo cycles.

Comparison with clomifene. In PCOS, letrozole gives higher ovulation, pregnancy and live birth rates, thinner endometrium is less common, and multiple pregnancy is lower.

• First-line. Ovulation induction in PCOS with anovulation after lifestyle measures.
• Alternative. Clomifene when letrozole is unavailable or unaffordable; metformin as an adjunct in selected women.
• Specialist. Frozen embryo transfer preparation, controlled ovarian stimulation to prevent high oestradiol in breast cancer survivors, endometriosis, poor ovarian response.
• Emergency. None.

Selection. Confirm anovulation and exclude other causes (thyroid disease, hyperprolactinaemia, premature ovarian insufficiency). Check tubal patency and semen. Document that use for fertility is off-label in some regions.

Contraindications. Pregnancy and breastfeeding; hypersensitivity; severe liver impairment; undiagnosed vaginal bleeding.

Serious adverse effects.

• Hot flushes, fatigue, headache, dizziness, nausea, joint pain, back pain.
• Multiple pregnancy (about 3%) and rarely ovarian hyperstimulation.
• Bone density is not affected in short courses.
• No increase in major congenital anomalies compared with clomifene in current evidence.

Major interactions. CYP3A4 inhibitors and inducers may change levels; tamoxifen lowers letrozole concentrations; oestrogen-containing drugs oppose the effect.

Common prescribing errors.

• Starting without confirming anovulation.
• Prescribing in an unknown early pregnancy.
• Raising the dose without ultrasound review.
• Continuing indefinitely without referral.
• Skipping counselling on multiple pregnancy.

Special groups.

• Pregnancy: stop at confirmation; the short half-life leaves little drug by implantation.
• Breastfeeding: avoid.
• Children and adolescents: not used.
• Older adults: not applicable.
• Kidney: no adjustment.
• Liver: avoid in severe impairment.
• East Africa: letrozole is increasingly available and inexpensive; polycystic ovary syndrome is common, but pelvic infection and tubal disease are also major causes of infertility; do a pregnancy test and consider tubal assessment early.

Monitoring. Ultrasound for follicle growth when available (mid-cycle follicles of 18 mm or larger); mid-luteal progesterone on day 21 to confirm ovulation; pregnancy test if the period is late.

Referral and escalation. No ovulation at 7.5 mg; no pregnancy after 6 ovulatory cycles; age over 35; suspected tubal or male factor; pregnancy.

Comparison with alternative classes. Letrozole beats clomifene for live birth in PCOS and has a simpler monitoring need than gonadotropins, but is less effective than gonadotropins or IVF in other causes of infertility.