Fertility Drugs

Fertility drugs treat ovulation disorders and support assisted reproduction. Common indications are anovulation from polycystic ovary syndrome, hypothalamic amenorrhoea, hyperprolactinaemia and unexplained infertility, and stimulation for intrauterine insemination and in vitro fertilisation. They need a diagnosis, a partner assessment, monitoring and counselling on multiple pregnancy.

Classification. Letrozole (aromatase inhibitor) and clomifene (selective oestrogen receptor modulator) for ovulation induction; gonadotropins (follicle stimulating hormone, human menopausal gonadotropin, human chorionic gonadotropin, luteinising hormone); gonadotropin-releasing hormone agonists and antagonists; dopamine agonists (cabergoline, bromocriptine); metformin; progesterone for luteal support.

Mechanism. Letrozole lowers oestrogen and raises follicle stimulating hormone. Clomifene blocks hypothalamic oestrogen receptors and raises follicle stimulating hormone. Gonadotropins stimulate the ovary directly. Human chorionic gonadotropin acts like luteinising hormone to trigger ovulation. Dopamine agonists lower prolactin.

Pharmacokinetics. Oral drugs are absorbed within hours; clomifene has a half-life of 5 to 7 days; letrozole about 2 days. Gonadotropins are injected subcutaneously or intramuscularly, with half-lives from hours to days.

Assisted reproduction. Controlled ovarian stimulation uses follicle stimulating hormone with a GnRH antagonist, a trigger with human chorionic gonadotropin or a GnRH agonist, and luteal support. Drug choice and doses are set by the fertility team.

Lifestyle. Weight loss in obesity, smoking cessation, folic acid 400 micrograms daily and treatment of thyroid disease improve success and safety.

• First-line. Letrozole for anovulatory infertility with polycystic ovary syndrome; lifestyle change; treat the cause (thyroid disease, hyperprolactinaemia).
• Alternative. Clomifene when letrozole is not available; metformin added in insulin resistance; ovarian drilling when drugs fail.
• Specialist. Gonadotropin ovulation induction, intrauterine insemination, in vitro fertilisation and intracytoplasmic sperm injection; male infertility therapy.
• Emergency. Ovarian hyperstimulation syndrome: fluids, thromboprophylaxis, paracentesis, and admission.

Selection. Assess ovulation, tubal patency and semen before treatment. Use the lowest effective dose, and monitor with ultrasound. Refer after 6 ovulatory cycles of oral treatment without pregnancy.

Contraindications. Pregnancy; undiagnosed vaginal bleeding; ovarian cyst unrelated to polycystic ovaries; hormone-dependent tumour; hypersensitivity; liver disease (clomifene); uncontrolled thyroid or adrenal disease; tubal occlusion or male factor not corrected.

Serious adverse effects.

• Multiple pregnancy (about 10% with clomifene, lower with letrozole, higher with gonadotropins).
• Ovarian hyperstimulation syndrome: abdominal distension, ascites, thrombosis, renal failure.
• Hot flushes, headache, nausea, visual disturbance (clomifene), mood change.
• Ectopic pregnancy risk; thrombosis with high oestradiol; cancer risk uncertain with prolonged use.

Major interactions. Clomifene and letrozole: few interactions; antipsychotics and metoclopramide raise prolactin and may blunt response; dopamine agonists with antipsychotics lose effect; gonadotropins have no major drug interactions.

Common prescribing errors.

• Starting without confirming ovulation disorder or checking tubal patency.
• Continuing clomifene beyond 6 cycles.
• Missing ultrasound monitoring and multiple pregnancy counselling.
• Ignoring thyroid and prolactin results.
• Not advising on folic acid.

Special groups.

• Pregnancy: stop the drug once pregnancy is confirmed; ongoing luteal progesterone is stopped by the fertility team.
• Breastfeeding: avoid cabergoline when lactation is wanted.
• Adolescents and children: not used except in pubertal induction by specialists.
• Older adults: age reduces response; refer early after 35.
• Kidney: caution with human chorionic gonadotropin in severe disease.
• Liver: avoid clomifene in liver disease.
• East Africa: tubal infertility from pelvic infection is a major cause, so ask about previous infection and test for tubal patency first; letrozole and clomifene are affordable first-line; assisted reproduction is concentrated in a few centres; counsel on multiple pregnancy risk where neonatal care is limited.

Monitoring. Follicle development by transvaginal ultrasound; mid-luteal progesterone to confirm ovulation; pregnancy test; ovarian hyperstimulation symptoms; body weight.

Referral and escalation. No pregnancy after 6 ovulatory cycles; age 35 or over after 6 months of trying; severe abdominal swelling, breathlessness or reduced urine (hyperstimulation); suspected tubal disease or male factor; pregnancy.

Comparison with alternative classes. Oral ovulation induction is cheap, simple and effective for anovulation. Gonadotropins and assisted reproduction have higher success rates but higher cost, multiple pregnancy and hyperstimulation risk.