Can norethindrone (a progestin) cause hypertension in women, particularly those with a history of hypertension or cardiovascular disease?

Does Norethindrone Raise Blood Pressure?

Norethindrone as a progestin-only pill is considered a safer contraceptive option for women with hypertension compared to combined oral contraceptives, though its cardiovascular effects remain insufficiently studied. 1

Evidence for Blood Pressure Effects

Progestin-Only Formulations

• Progestin-only pills containing norethindrone have minimal to no significant impact on blood pressure in most women, making them an appropriate contraceptive choice for those with existing hypertension 1

• The European Society of Hypertension/Cardiology guidelines specifically identify the progestogen-only pill as a contraceptive option for women with high blood pressure, though they acknowledge the influence on cardiovascular outcomes has been insufficiently investigated 1

Combined Formulations with Norethindrone

When norethindrone is combined with estrogen (combined oral contraceptives), the blood pressure effects differ:

• Monophasic norethindrone combinations (with ethinyl estradiol) showed no significant blood pressure elevation compared to non-users in a large study of 1,189 women 2

• Low-dose norethindrone (500 mcg) combined with ethinyl estradiol actually increased HDL cholesterol by 10% and was associated with one of the most favorable metabolic profiles among combined oral contraceptives 3

• In women with a past history of elevated blood pressure, a low-dose formulation (0.4 mg norethindrone + 35 mcg ethinyl estradiol) did not cause mean blood pressure increases over 3-24 months, though 8.2% discontinued due to redevelopment of hypertension 4

Mechanism and Context

Why Progestins May Affect Blood Pressure

• Progesterone promotes leptin-mediated endothelial dysfunction in obese premenopausal women through aldosterone and endothelial mineralocorticoid receptors, which may enhance sodium sensitivity 1, 5, 6

• The progestogenic component of oral contraceptives may contribute to increased stroke and ischemic heart disease risk, likely mediated at least in part through blood pressure elevations 7

• First-generation progestins like norethindrone have potent off-target effects on androgen and glucocorticoid receptors, though these effects are dose-dependent 1

Comparative Risk Profile

• Combined oral contraceptives containing levonorgestrel showed significantly higher blood pressure increases (+4.3 mmHg systolic, +2.6 mmHg diastolic) compared to norethindrone formulations 2

• Norethindrone and desogestrel combinations demonstrated the most favorable profiles with little impact on blood pressure 2

Clinical Recommendations for Women with Hypertension

Risk Stratification

• Women over 35 years of age who smoke face the highest cardiovascular risk with any hormonal contraception 1

• Women with multiple major cardiovascular risk factors may reach unacceptable risk levels even with small blood pressure increases from oral contraceptives 1

• History of oral contraceptive-induced hypertension, preeclampsia, or essential hypertension increases risk of blood pressure elevation with reintroduction 4

Monitoring Protocol

• Women with past history of elevated blood pressure using norethindrone-containing contraceptives require close blood pressure monitoring, as approximately 8% may redevelop hypertension 4

• Blood pressure should be checked before initiation and monitored regularly during use, particularly in the first 3-6 months 1, 4

Treatment Considerations

• ACE inhibitors and angiotensin receptor antagonists should be avoided in women of childbearing age using any contraception due to teratogenic effects 1

• For hypertensive women requiring contraception, progestin-only norethindrone pills represent a reasonable option with appropriate monitoring 1

Important Caveats

• The 2023 Hypertension guidelines note that cardiovascular risk begins at approximately 10 mmHg lower blood pressure levels in women compared to men, making even small elevations potentially significant 1

• Insufficient large-scale outcome data exist specifically for progestin-only norethindrone regarding cardiovascular events, stroke, and mortality 1

• Women with uterine fibroids, polycystic ovary syndrome, or history of adverse pregnancy outcomes have independent cardiovascular risk that may be compounded by any hormonal contraception 1, 5