Difference Between Norethindrone and Norethindrone Acetate
Norethindrone acetate is a prodrug that is completely and rapidly converted to norethindrone after oral administration, making it twice as potent on a weight basis, but otherwise pharmacologically indistinguishable from norethindrone itself. 1
Pharmacological Relationship
Chemical Conversion and Bioequivalence:
- Norethindrone acetate is completely and rapidly deacetylated to norethindrone (NET) after oral administration 1
- The disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone once absorbed 1
- On a weight basis, norethindrone acetate is twice as potent as norethindrone, meaning 5 mg of norethindrone acetate delivers approximately the same effect as 10 mg of norethindrone 1
Clinical Dosing Implications
Dose Equivalency in Practice:
- When norethindrone acetate is used for endometriosis or abnormal uterine bleeding, typical doses are 2.5-5 mg daily 2, 3, 4
- Norethindrone for contraception is typically dosed at 0.35 mg daily as a progestin-only pill 5
- For hormone replacement therapy, norethindrone acetate doses as low as 0.1 mg combined with estradiol effectively prevent endometrial hyperplasia 6
Pharmacokinetic Profile
Absorption and Metabolism:
- Norethindrone acetate reaches maximum plasma concentration of norethindrone at approximately 2 hours post-dose 1
- The mean terminal elimination half-life is approximately 8-9 hours 1
- Both compounds undergo extensive biotransformation via reduction, followed by sulfate and glucuronide conjugation 1
- Norethindrone is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin 1
Unique Properties of Norethindrone Acetate
Hormonal Activity Profile:
- Norethindrone acetate possesses estrogenic, progestogenic, and androgenic properties 7
- Through its estrogenic activity, norethindrone acetate exerts beneficial effects on bone mineral density and vasomotor symptoms when used as add-back therapy with GnRH agonists 7
- It exhibits strong endometrial antiproliferative effects 7
- The androgenic activity may lower HDL cholesterol and cause progestogenic side effects 7
Clinical Applications
Therapeutic Uses:
- Norethindrone acetate is FDA-approved for treatment of secondary amenorrhea, endometriosis, and abnormal uterine bleeding 1
- Norethindrone is primarily used for contraception as a progestin-only pill 5
- In hormone replacement therapy, norethindrone acetate combined with estrogen is used to prevent endometrial hyperplasia 8, 6
- Norethindrone acetate (as part of ethinyl estradiol/norethindrone acetate/ferrous fumarate) is FDA-approved for acne treatment 8, 9
Safety Considerations
Cardiovascular Risk Profile:
- Norethindrone-containing pills carry the lowest thrombotic risk among combined oral contraceptives 10
- When used in hormone replacement therapy, norethindrone acetate combined with ethinyl estradiol showed worse cardiovascular profile (blood pressure, renal function, renin-angiotensin system activation) compared to transdermal 17β-estradiol with vaginal micronized progesterone 8
- Both compounds are contraindicated in pregnancy (Category X), active thromboembolic disease, liver disease, and known or suspected breast cancer 1
Practical Clinical Distinctions
Formulation and Prescribing:
- The key practical difference is dosing: clinicians must account for the 2:1 potency ratio when switching between formulations 1
- Both are well-tolerated in women with hereditary angioedema, unlike estrogen-containing contraceptives 8
- Norethindrone acetate controlled-release formulations help maintain constant drug levels and minimize side effects 2