Progesterone Preparations

Progesterone preparations include natural micronised progesterone and synthetic progestogens (dydrogesterone, medroxyprogesterone acetate, norethisterone, levonorgestrel). They support the luteal phase and early pregnancy, protect the endometrium from oestrogen, treat abnormal uterine bleeding, reduce preterm birth in selected women, and provide contraception.

Choice of agent, route and dose depends on the indication, and synthetic agents differ in androgenic, glucocorticoid and thrombotic effects.

Mechanism. Progestogens act on progesterone receptors to convert proliferative endometrium to secretory endometrium, reduce uterine contractility, thicken cervical mucus and suppress gonadotropins. Natural progesterone is metabolised to neurosteroids that cause drowsiness.

Pharmacokinetics. Oral micronised progesterone has low bioavailability and extensive first-pass metabolism, giving sedation. Vaginal gel or pessaries reach the uterus directly (first uterine pass). Intramuscular oil gives high levels but is painful.

Natural versus synthetic. Micronised progesterone and dydrogesterone have lower breast and venous thrombosis signals with oestrogen than medroxyprogesterone acetate. Do not use intramuscular 17-hydroxyprogesterone caproate for preterm birth prevention.

Counselling. Take oral micronised progesterone at bedtime because of drowsiness. Vaginal use may cause discharge.

• First-line. Luteal support in assisted reproduction; endometrial protection with menopausal oestrogen; norethisterone for acute abnormal uterine bleeding.
• Alternative. Dydrogesterone 10 mg twice daily for luteal support or recurrent loss; intrauterine system for endometrial protection and heavy bleeding.
• Specialist. Short cervix and prior preterm birth; threatened miscarriage with recurrent loss; endometrial hyperplasia and early endometrial cancer in fertility-sparing treatment (megestrol, medroxyprogesterone, specialist care).
• Emergency. Acute heavy uterine bleeding (norethisterone 5 mg three times daily, with tranexamic acid).

Selection. Do not use progesterone for the general prevention of miscarriage in women with no bleeding history. Use vaginal rather than oral routes when sedation is a problem.

Contraindications. Undiagnosed vaginal bleeding; breast or genital cancer (except in specific treatment); active venous thromboembolism; severe liver disease; missed or incomplete miscarriage; hypersensitivity; porphyria.

Serious adverse effects.

• Drowsiness, dizziness, bloating, breast tenderness, headache, mood change, acne.
• Irregular bleeding, weight gain, fluid retention.
• Venous thrombosis (higher with some synthetic agents), jaundice, depression.
• Intramuscular site pain, abscess; vaginal irritation.

Major interactions. Enzyme inducers (rifampicin, carbamazepine, phenytoin, St John’s wort) lower levels; ketoconazole raises levels; ciclosporin levels rise with progesterone; CNS depressants add sedation.

Common prescribing errors.

• Using norethisterone to delay periods as if it were contraception.
• Giving oral progesterone in the morning.
• Giving oestrogen to a woman with a uterus without a progestogen.
• Using intramuscular preparations when vaginal use would work.
• Continuing luteal support beyond the planned time without a reason.

Special groups.

• Pregnancy: used for specific indications only; natural progesterone is not teratogenic at these doses.
• Breastfeeding: compatible; may reduce milk supply if started too early.
• Adolescents: used for amenorrhoea and abnormal bleeding.
• Older adults: part of combined menopausal therapy for women with a uterus.
• Kidney: no adjustment.
• Liver: avoid in severe disease.
• East Africa: vaginal progesterone is costly outside assisted reproduction; norethisterone and medroxyprogesterone are widely available for abnormal bleeding; bleeding after menopause needs investigation, not empirical hormones.

Monitoring. Bleeding pattern, blood pressure, symptoms of thrombosis, endometrial thickness or biopsy in hyperplasia, cervical length where preventing preterm birth.

Referral and escalation. Postmenopausal bleeding; persistent bleeding despite treatment; suspected ectopic pregnancy; thrombosis; hyperplasia with atypia.

Comparison with alternative classes. Progestogens treat the endometrium and bleeding directly and are cheap, but oestrogen-containing therapy and tranexamic acid may act faster in bleeding. Natural progesterone has fewer metabolic effects than synthetic progestogens.