Norethisterone Side Effects
Norethisterone causes irregular menstrual bleeding (most common), and carries dose-dependent risks including venous thromboembolism at therapeutic doses, breast cancer with long-term use, and adverse effects on lipid profiles, particularly HDL-cholesterol reduction. 1
Most Common Side Effects
Menstrual Irregularities (Most Frequent)
- Irregular bleeding is the predominant side effect across all formulations 1, 2
- Frequent and irregular bleeding patterns are common
- Amenorrhea and prolonged bleeding episodes occur less frequently
- Discontinuation rates reach 48.5%, with irregular bleeding accounting for 54.5% of discontinuations 2
Other Common Adverse Effects
According to FDA labeling, norethisterone commonly causes 1:
- Headache
- Breast tenderness and breast pain
- Nausea and vomiting
- Dizziness
- Fatigue and edema
- Abdominal pain
Androgenic Effects (Rare)
- Acne
- Hirsutism
- Weight gain These occur rarely due to norethisterone's androgenic activity 1
Serious Cardiovascular Risks
Venous Thromboembolism (VTE)
The VTE risk is dose-dependent and clinically significant:
- Contraceptive doses (0.35 mg): No increased risk 3
- Therapeutic doses (higher doses): Moderately increased VTE risk 4
- The risk appears related to norethisterone's partial conversion to ethinylestradiol (EE): 10-20 mg norethisterone converts to 20-30 µg EE 4
Arterial Events
- Combined with estrogen, norethisterone shows increased MI risk in smokers (OR: 2.7 for second-generation products containing norethisterone) 3
- Smoking dramatically amplifies cardiovascular risk - 70% of cardiovascular events occurred in smokers 3
Metabolic Side Effects
Lipid Profile Changes
Norethisterone adversely affects coronary heart disease risk factors 5:
- Significant reduction in HDL-cholesterol (protective factor decreases)
- Increase in LDL-cholesterol after one year of treatment
- Reduction in VLDL cholesterol and triglycerides
- These changes persist throughout treatment and represent unfavorable cardiovascular modifications 3, 5
Other Metabolic Effects
- Low-dose injectable formulations (20 mg monthly) show minimal metabolic disruption 6
- Peculiar tryptophan-niacin pathway aberration (increased kynurenic acid excretion) - correctable with multivitamin therapy 6
Hepatobiliary Effects
Norethisterone can cause liver injury, manifesting as 7:
- Hepatitis (hepatocellular pattern)
- Cholestatic injury
- Elevated liver enzymes (often asymptomatic)
- Jaundice
- Benign hepatic neoplasms and peliosis hepatis (rare)
Clinical pitfall: Liver enzyme elevation may be asymptomatic, requiring monitoring in high-risk patients 7
Psychiatric and Neurological Effects
- Depression and nervousness reported in clinical trials 1
- Widespread adverse mood and behavioral effects documented, including:
- Impaired concentration
- Behavioral changes
- Negative affect
- These effects are dose-related and resemble premenstrual syndrome symptoms 8
Reproductive System Effects
- Ectopic pregnancy risk: 5 per 1,000 woman-years; up to 10% of pregnancies in users are extrauterine 1
- Delayed follicular atresia/ovarian cysts - usually asymptomatic and resolve spontaneously 1
- Genital discharge
- Menorrhagia
- Suppressed lactation 1
Cancer Risks
Breast Cancer
- Small increased risk with long-term use, particularly in current users or those who stopped within the past 10 years 1
- Contraindicated in women with breast cancer 1
- Risk appears related to duration of use 1
Cervical Cancer
- Some studies suggest association with increased cervical intraepithelial neoplasia risk 1
Hypersensitivity Reactions
Key Clinical Considerations
Absolute contraindications:
- Active breast cancer
- Personal history of arterial events (MI, stroke) 3
- Current smoking (especially with cardiovascular risk factors) 9, 3
Relative contraindications requiring careful assessment:
- LDL-cholesterol >2.20 g/L (without other risk factors) 3
- Triglycerides >2.00 g/L 3
- Migraine with aura (due to EE conversion) 4
Important caveat: The partial conversion of norethisterone to ethinylestradiol (10-20 mg NET = 20-30 µg EE) means therapeutic doses carry estrogen-related risks that contraceptive doses do not 4. This distinction is critical when counseling patients and assessing contraindications.