Hormonal Contraception Pharmacology

Hormonal contraception uses synthetic or natural oestrogens and progestogens, alone or combined, to suppress ovulation and alter cervical mucus and endometrium. Their clinical effects, side effects, interaction risks and safety profile depend on the specific steroid, its dose, the route and the release pattern, so prescribing should rest on the agent, not the class.

Oestrogens in use.

• Ethinylestradiol: potent synthetic oestrogen; 20 to 35 micrograms in modern pills, 50 micrograms in older high-dose pills.

• Estradiol valerate and estradiol: natural oestradiol esters, used in some combined pills and combined injectables.

• Estetrol: natural foetal oestrogen with lower hepatic impact, combined with drospirenone in some newer pills.

Progestogens in use.

• Older 19-nortestosterone derivatives: norethisterone, levonorgestrel, norgestrel.

• Newer 19-nortestosterone derivatives: desogestrel (prodrug of etonogestrel), gestodene, norgestimate.

• Pregnane derivatives: medroxyprogesterone acetate, cyproterone acetate, chlormadinone acetate.

• Spironolactone derivative: drospirenone, with antimineralocorticoid and antiandrogenic activity.

• Other: dienogest, nomegestrol acetate.

Mechanism. Oestrogen suppresses FSH and stabilises the endometrium. Progestogen suppresses LH and the surge, thickens cervical mucus and thins the endometrium. Combined methods suppress ovulation reliably; progestogen-only methods vary in ovulation suppression by dose and agent.

Pharmacokinetics of key agents.

Hepatic effects of oral oestrogen. Ethinylestradiol raises SHBG, angiotensinogen, thyroxine-binding globulin, triglycerides and clotting factors (fibrinogen, factors VII, VIII, X), and lowers protein S and antithrombin activity. These changes underlie the VTE risk, rise in blood pressure, and higher thyroxine needs in treated hypothyroidism.

VTE risk. Baseline risk in non-users is about 2 in 10,000 women annually. With levonorgestrel, norethisterone or norgestimate combined pills it is about 5 to 7; with desogestrel, gestodene, drospirenone or cyproterone combined pills about 9 to 12; in pregnancy about 29 and postpartum several times higher. Progestogen-only pills, implants and IUDs do not appear to raise VTE risk; DMPA may carry a small increase.

Androgenicity. Levonorgestrel and norethisterone have more androgenic activity, relevant to acne and lipid changes. Desogestrel, gestodene, norgestimate, drospirenone, dienogest and cyproterone acetate have low or antiandrogenic activity and suit patients with acne or hirsutism.

Choosing a first combined pill. A monophasic pill with 30 micrograms ethinylestradiol and 150 micrograms levonorgestrel, or 35 micrograms ethinylestradiol with norethisterone or norgestimate, offers the lowest VTE risk with good cycle control.

Route and first pass. Nonoral routes (patch, ring, injection, implant, IUD) avoid first pass metabolism. The patch gives higher total oestrogen exposure than a 35 microgram pill. The levonorgestrel IUD gives very low systemic levels; its effects are largely local.

Drug interactions.

• Enzyme inducers (rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital, primidone, oxcarbazepine, eslicarbazepine, topiramate over 200 mg daily, efavirenz, nevirapine, ritonavir-boosted regimens, griseofulvin, St John's wort) lower levels of oral methods, patch, ring and implants. Use DMPA, an IUD or condoms during treatment and for 28 days after stopping.

• Lamotrigine levels fall with combined methods, risking seizures; levels rise in the pill-free interval, risking toxicity.

• Ulipristal acetate and progestogens antagonise each other at the progesterone receptor.

• Broad-spectrum antibiotics other than rifamycins do not reduce effectiveness.

• Dolutegravir-based antiretroviral therapy does not interact with hormonal methods.

Special groups. Hepatic impairment: avoid combined methods in severe decompensated cirrhosis, hepatocellular adenoma and hepatoma. Obesity: oral and implant methods keep effectiveness, though the patch is less effective at weight over 90 kg. Breastfeeding: progestogen-only methods do not reduce milk supply; combined methods may, especially in the first 6 weeks.

Common prescribing errors.

• Missing enzyme inducers in patients on tuberculosis or antiseizure treatment.

• Starting combined methods in women with migraine with aura, uncontrolled hypertension or recent VTE.

• Assuming all progestogen-only methods suppress ovulation.

• Using a drospirenone product with potassium-sparing drugs in kidney impairment without monitoring potassium.

Red flags requiring urgent assessment. Calf pain or swelling, chest pain, breathlessness, haemoptysis, sudden severe headache, new focal neurological signs, visual loss, jaundice or severe abdominal pain in a user of combined methods.

Referral and escalation. Stop the oestrogen-containing method and refer urgently for suspected VTE, stroke, myocardial infarction or acute liver disease; give a nonhormonal or progestogen-only interim method once stable.