Gonadotropins

Gonadotropins are glycoprotein hormones that stimulate the ovary and testis. They include follicle stimulating hormone (FSH), luteinising hormone (LH), human menopausal gonadotropin (hMG, which contains FSH and LH activity) and human chorionic gonadotropin (hCG, which acts on the LH receptor).

They induce ovulation, drive multiple follicle growth in assisted reproduction, trigger final egg maturation and restore sperm production in hypogonadotropic hypogonadism. Treatment needs specialist monitoring.

Mechanism. FSH acts on granulosa cells to promote follicle growth and oestradiol production. LH and hCG act on theca cells and the corpus luteum, trigger ovulation and support progesterone production. In men, FSH supports spermatogenesis and hCG stimulates testosterone production.

Pharmacokinetics. Recombinant FSH (follitropin alfa, beta, delta) has a half-life of about 24 to 40 hours and is given subcutaneously. Corifollitropin alfa lasts a week. hCG has a half-life of about 30 hours. Urinary products (menotropin, urofollitropin) are cheaper alternatives.

Reducing risk. A GnRH agonist trigger (triptorelin 0.2 mg) instead of hCG lowers ovarian hyperstimulation syndrome (OHSS) in women at risk. Cabergoline 0.5 mg daily for 8 days after the trigger also reduces it. Freezing all embryos and transferring later avoids late OHSS.

Storage and administration. Follow the product label: many pens are kept at 2 to 8 degrees Celsius until first use, and some may be stored at room temperature for months. Train patients to inject subcutaneously in the abdomen at the same time each day.

• First-line. Controlled ovarian stimulation for IVF and intracytoplasmic sperm injection; hCG trigger of ovulation; hypogonadotropic hypogonadism in men.
• Alternative. Low-dose step-up FSH after failure of letrozole or clomifene in anovulation; hMG when LH is low.
• Specialist. Ovulation induction in women with hypogonadotropic hypogonadism (FSH plus LH); intrauterine insemination cycles; fertility preservation before cancer therapy.
• Emergency. OHSS (supportive care and admission).

Selection. Use the lowest dose that yields a good response. Choose urinary products where cost is limiting. Women with polycystic ovaries respond briskly and need low starting doses and close monitoring.

Contraindications. Pregnancy; ovarian, uterine or breast cancer; pituitary or hypothalamic tumour; undiagnosed vaginal bleeding; ovarian cyst not due to polycystic ovaries; primary ovarian or testicular failure; hypersensitivity; uncontrolled thyroid, adrenal or pituitary disease.

Serious adverse effects.

• OHSS: abdominal distension, ascites, pleural effusion, haemoconcentration, thrombosis, renal failure.
• Multiple pregnancy (up to 20 to 30% in unmonitored cycles) and preterm birth.
• Ovarian torsion, ectopic pregnancy, injection-site reactions, headache, mood change.
• Gynaecomastia and acne in men on hCG.

Major interactions. Few. GnRH agonists and antagonists are part of regimens. Dopamine antagonists may raise prolactin and blunt response.

Common prescribing errors.

• Starting doses too high in polycystic ovary syndrome.
• Skipping ultrasound and oestradiol monitoring.
• Giving hCG trigger when more than 3 large follicles are present.
• Not counselling on multiple pregnancy.
• Confusing units of hCG with micrograms of recombinant products.

Special groups.

• Pregnancy: stop once pregnancy is confirmed; luteal support continues under specialist care.
• Breastfeeding: not used.
• Children and adolescents: used in specialist units for delayed puberty (male) only.
• Older adults: not applicable; ovarian response falls with age.
• Kidney and liver: use with caution in severe disease.
• East Africa: treatment is concentrated in a few centres and is costly; make sure ultrasound monitoring is available before starting; counsel on multiple pregnancy where neonatal care is limited; pelvic infection is a common cause of tubal infertility, which gonadotropins cannot overcome.

Monitoring. Transvaginal ultrasound every 2 to 3 days; oestradiol where available; symptoms of OHSS for 2 weeks after trigger; serum testosterone and semen analysis in men.

Referral and escalation. Severe abdominal swelling, breathlessness, reduced urine, severe pain (OHSS or torsion); suspected ectopic pregnancy; more than 3 follicles over 14 mm in an ovulation induction cycle (cancel cycle).

Comparison with alternative classes. Gonadotropins give higher pregnancy rates than oral drugs but carry more OHSS and multiple pregnancy, and need injections and monitoring. Oral letrozole and clomifene are cheaper and simpler.