What is Norethindrone?

Norethindrone: A First-Generation Progestin Used in Contraception

Norethindrone is a first-generation synthetic progestin that works primarily by thickening cervical mucus to prevent sperm penetration, suppressing ovulation in approximately half of users, and altering the endometrium to prevent implantation. 1

Pharmacology and Mechanism of Action

Norethindrone belongs to the estrane class of progestins and was among the earliest synthetic progestins developed for contraceptive use. After oral administration:

• It is rapidly absorbed with maximum plasma concentrations occurring within 1-2 hours
• Has an absolute bioavailability of approximately 65% due to first-pass metabolism
• Has a mean terminal elimination half-life of approximately 8 hours
• Is primarily excreted in urine and feces as metabolites 1

As a contraceptive, norethindrone works through multiple mechanisms:

• Suppresses ovulation in about 50% of users
• Thickens cervical mucus to inhibit sperm penetration
• Slows ovum movement through fallopian tubes
• Alters the endometrium to prevent implantation 1

Clinical Applications

Norethindrone is used in several formulations:

1. Progestin-only pills (POPs) - Contains 0.35 mg norethindrone with a typical-use failure rate of approximately 6% 2

   • Must be taken at the same time every day (within 3 hours) to maintain effectiveness
   • Suitable for women who cannot use estrogen-containing contraceptives

2. Combined oral contraceptives (COCs) - Paired with ethinyl estradiol

   • The FDA first approved COCs containing norethindrone in the early development of oral contraceptives 3
   • Used for both contraception and treatment of conditions like acne 3

3. Therapeutic uses beyond contraception:

   • Treatment of abnormal uterine bleeding
   • Management of endometriosis
   • Hormone replacement therapy 4

Safety Profile and Considerations

Norethindrone has several important safety considerations:

• Cardiovascular effects: As a first-generation progestin, norethindrone has some androgenic effects that may impact lipid profiles, though less significantly than danazol 3

• Metabolic impact: Can decrease high-density lipoprotein cholesterol and triglyceride levels 5

• Endocrine effects: May decrease estradiol, follicle-stimulating hormone, luteinizing hormone, and sex hormone-binding globulin levels 5

• Endometrial effects: Provides protection against endometrial hyperplasia when combined with estrogen 6

• Hypothalamic-pituitary effects: Can attenuate endogenous secretion of luteinizing hormone and follicle-stimulating hormone 7

Advantages and Disadvantages

Advantages:

• Safe for women with contraindications to estrogen (hypertension, history of venous thromboembolism, migraine with aura) 2
• Can be used during breastfeeding 2
• Fewer drug interactions than combined hormonal methods 2

Disadvantages:

• Requires strict adherence to timing (same time each day) 2
• Breakthrough bleeding is common, especially in first few months 2
• Lower effectiveness compared to long-acting reversible contraceptives
• May have androgenic side effects 4

Drug Interactions

Several medications can decrease the effectiveness of norethindrone:

• Rifampin
• Certain anticonvulsants (phenobarbital, phenytoin, carbamazepine)
• St. John's wort 3

Special Populations

Norethindrone is particularly suitable for:

• Women with hypertension (unlike estrogen-containing contraceptives which can raise blood pressure) 3
• Those with history of venous thromboembolism
• Women with migraine with aura
• Breastfeeding women 2

It's important to note that while norethindrone provides contraception, it does not protect against sexually transmitted infections, so condom use is recommended for those at risk 2.