norethisterone

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norethisterone clinical pharmacology

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Norethisterone

Classification & Chemistry

Norethisterone (also called norethindrone in the US) is a synthetic progestogen belonging to the oestrane (19-nortestosterone) group of progestogens. The oestranes include norethisterone, norethisterone acetate, lynestrenol, ethynodiol diacetate, and norethynodrel - all of which are metabolized to norethisterone before becoming pharmacologically active. It is structurally derived from testosterone by removal of the 19-methyl group, which gives it both progestogenic and weak androgenic activity.

Progestogens are broadly classified into three structural groups:

Pregnanes - megestrol, chlormadinone, medroxyprogesterone acetate
Oestranes (19-nortestosterones) - norethisterone and its congeners
Gonanes - levonorgestrel, desogestrel, gestodene

Mechanism of Action

Norethisterone acts primarily through progesterone receptors. Its contraceptive effects involve multiple mechanisms:

Suppression of LH secretion - inhibits the LH surge, thereby preventing ovulation; it decreases the frequency of GnRH pulses
Thickening of cervical mucus - impairs sperm penetration
Altered endometrial receptivity - makes the endometrium hostile to implantation
Impaired tubal motility - reduces sperm transport

In combined oral contraceptives, the estrogen component suppresses FSH (preventing follicular development), while the progestin (norethisterone) suppresses LH and maintains these additional barriers. - Harrison's Principles of Internal Medicine 22E, p. 1524

Because of its 19-nortestosterone structure, norethisterone also has weak androgenic activity, which distinguishes it from the newer gonane progestogens.

Formulations & Dosages

Preparation	Route	Dose	Interval
Norethisterone tablet	Oral (POP "minipill")	350 µg (0.35 mg)	Daily
+ Ethinylestradiol 35 µg	Oral (combined pill)	1 mg	Daily (21/28 days)
Norethisterone acetate (NETA)	Oral	5 mg / 10 mg	Varies by indication
NET-EN (norethisterone enantate)	IM injection	200 mg	Every 60 days

NET-EN has been used as an injectable contraceptive since 1966. It is less widely used than DMPA (depot-medroxyprogesterone acetate). Its failure rate (0.4 pregnancies/100 women-years) is slightly higher than DMPA. - Park's Textbook of Preventive and Social Medicine

Clinical Uses

Oral contraception
- As the progestogen component in combined oral contraceptive pills (COCPs) with ethinylestradiol
- As a progestogen-only pill (POP) / "minipill" - indicated when estrogen is contraindicated (e.g., breastfeeding women, cardiovascular risk factors, migraine with aura, DVT history)
Injectable contraception (NET-EN)
- IM 200 mg every 60 days; acts via ovulation inhibition and cervical mucus thickening
Menstrual disorders
- Dysmenorrhea, menorrhagia, irregular periods
- Postponement of menstruation (short-term)
- Endometriosis management (norethisterone acetate ± letrozole)
Hormone replacement therapy (HRT)
- In combination with estrogen for postmenopausal women
Premenstrual syndrome (PMS)

Pharmacokinetics

Oral bioavailability: ~65% (first-pass metabolism)
Protein binding: Bound to albumin and SHBG
Metabolism: Hepatic; prodrugs (lynestrenol, ethynodiol diacetate) are converted to norethisterone in vivo
Elimination: Urine and feces (as conjugates)

Adverse Effects

Menstrual irregularities - breakthrough bleeding, amenorrhea, especially with POP
Androgenic effects - acne, oily skin, mild hirsutism (due to 19-nortestosterone structure)
Nausea, breast tenderness, bloating
Mild increase in blood pressure (monitor at follow-up)
Teratogenic risk - in female embryos, has caused virilization (enlarged clitoris, labioscrotal fusion) if used during pregnancy, due to androgenic activity. - Langman's Medical Embryology
Lipid effects - may lower HDL cholesterol (some concern)
DVT risk - lower than with estrogen-containing pills, but third- and fourth-generation progestins carry some association; norethisterone (1st/2nd generation) has relatively lower DVT risk

Contraindications / Cautions

Known or suspected pregnancy
Active or past DVT/thromboembolism (relative)
Severe hepatic disease
Undiagnosed genital bleeding
Hormone-sensitive malignancies (e.g., breast cancer)
Women with history of androgenic adverse effects may prefer a less androgenic progestogen

Key Comparisons

Feature	Norethisterone	Levonorgestrel	Desogestrel
Class	Oestrane	Gonane	Gonane
Androgenicity	Moderate	High	Low
Antiestrogenic	Moderate	High	Low
Metabolically active	Yes (active itself + from prodrugs)	Yes	Yes (via etonogestrel)

Recent Evidence

A 2025 systematic review (PMID 39987087) examined the impact of progestogens (including norethisterone) on the renin-angiotensin-aldosterone system (RAAS), relevant to blood pressure effects of different progestins.

Sources: Park's Textbook of Preventive and Social Medicine | Harrison's Principles of Internal Medicine 22E | Goodman & Gilman's Pharmacological Basis of Therapeutics | Langman's Medical Embryology

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