Which is more effective and has fewer side effects (SE), norethindrone or desogestrel?

Comparison of Norethindrone and Desogestrel: Effectiveness and Side Effects

Desogestrel is more effective with fewer androgenic side effects compared to norethindrone, though it carries a slightly higher risk of venous thromboembolism. 1, 2

Progestin Classification and Properties

• Norethindrone is a first-generation progestin (estrane) with mild androgenic activity 1
• Desogestrel is a third-generation progestin (gonane) with very low androgenic properties and potent antiovulatory effects 1, 2
• Desogestrel is a prodrug that must be metabolized into its biologically active form (3-keto-desogestrel) 3, 4

Effectiveness

• Both progestins are effective for contraception when combined with ethinyl estradiol 1
• Desogestrel provides effective pregnancy prevention at lower doses than older progestins like norethindrone 3, 2
• A 2012 Cochrane meta-analysis of 31 trials (12,579 women) found that all combined oral contraceptives (COCs) effectively reduce acne, with no consistent differences between formulations 1

Side Effect Profile Comparison

Androgenic Effects

• Desogestrel has significantly lower androgenic properties compared to norethindrone 2, 5
• Desogestrel may be more beneficial for women with hyperandrogenic symptoms (acne, hirsutism) 2, 5
• Norethindrone, being mildly androgenic, may worsen acne in some women 1

Bleeding Patterns

• Desogestrel provides better cycle control with lower incidence of intermenstrual bleeding compared to older progestins 3
• Norethindrone-containing pills may have poorer gynecologic tolerance with breakthrough bleeding, pelvic discomfort, and mastalgia 1

Cardiovascular Risk

• All COCs increase the risk of venous thromboembolism (VTE) compared to non-users 1
• Desogestrel carries approximately 50-80% higher VTE risk compared to levonorgestrel-containing COCs 1
• The absolute risk remains low: non-users (1-5/10,000 woman-years), COC users (3-9/10,000 woman-years), desogestrel-containing COC users (approximately 10/10,000 woman-years) 1

Metabolic Effects

• Desogestrel has favorable effects on lipid profiles, potentially improving the ratio of LDL to HDL cholesterol 3, 5
• Desogestrel shows reduced impact on carbohydrate metabolism compared to older formulations 3

Special Considerations

• For women with hereditary angioedema, progestin-only pills containing norethindrone are well-tolerated in about two-thirds of patients 1
• Etonogestrel (active metabolite of desogestrel) implants have been well-tolerated by some patients with hereditary angioedema 1
• Women with risk factors for VTE should consider norethindrone over desogestrel due to the lower thrombotic risk 1
• Risk factors include age ≥35 years, smoking, history of VTE, thrombophilia, obesity, and hypertension 1

Common Side Effects for Both

• Menstrual irregularities (may be more common with norethindrone) 1
• Headache, nausea, and breast tenderness (reported to be lower with newer progestins like desogestrel) 3
• Weight changes (less common with newer progestins) 3

Drug Interactions

• Both progestins may have reduced effectiveness when combined with medications that induce hepatic enzymes (rifampin, griseofulvin, some anticonvulsants) 1, 4
• Desogestrel, like other newer progestins, is bound to sex hormone binding globulin (SHBG), which can cause plasma concentrations to increase with time 4

In conclusion, desogestrel generally offers advantages over norethindrone in terms of effectiveness at lower doses, reduced androgenic side effects, better cycle control, and favorable metabolic profile. However, the slightly increased risk of VTE with desogestrel should be considered, particularly in women with existing risk factors for thromboembolism 1, 2.