When is progesterone intake harmful?

When Progesterone Intake is Harmful

Progesterone intake is harmful in postmenopausal women taking combined estrogen-progestin therapy, particularly those over 65 years of age, due to significantly increased risks of stroke, venous thromboembolism, breast cancer, dementia, and gallbladder disease. 1

Absolute Contraindications

Progesterone should never be used in the following situations:

• Known or suspected pregnancy with progesterone capsules - Cases of cleft palate, cleft lip, hypospadias, ventricular septal defect, patent ductus arteriosus, and other congenital heart defects have been reported 2
• Active or history of arterial thromboembolic disease (stroke, myocardial infarction) 2
• Active venous thromboembolism (deep vein thrombosis, pulmonary embolism) 2
• Known or suspected breast cancer or other hormone-sensitive malignancies 2
• Peanut allergy - Oral progesterone capsules contain peanut oil 2
• Undiagnosed abnormal vaginal bleeding 2
• Acute liver disease or hepatic dysfunction 2

High-Risk Populations Where Harm Exceeds Benefit

Postmenopausal Women on Combined Hormone Therapy

The cardiovascular and cancer risks are particularly elevated in specific subgroups:

• Women >65 years: 9 additional strokes per 10,000 woman-years, 12 additional DVTs per 10,000 woman-years, 9 additional pulmonary emboli per 10,000 woman-years, and 22 additional cases of probable dementia per 10,000 woman-years 1
• Women with obesity or factor V Leiden: Elevated thrombotic risk with estrogen-progestin combinations 1
• After 11 years of follow-up: 8 additional invasive breast cancers per 10,000 woman-years, with risk increasing with longer duration of therapy 1
• Additional risks: 20 additional cases of gallbladder disease per 10,000 woman-years and 872 additional cases of urinary incontinence per 10,000 woman-years 1

Cardiovascular Disease Risk Factors

Progesterone-containing contraceptives carry specific cardiovascular warnings:

• Multiple arterial cardiovascular risk factors (older age, smoking, diabetes, hypertension): Category 2-3 risk depending on formulation 3
• Severe hypertension (systolic ≥160 mm Hg or diastolic ≥100 mm Hg): Category 2-3 risk, with DMPA carrying higher risk (Category 3) than other progestin-only methods 3
• Vascular disease: Category 2-3 risk across progestin formulations 3
• Limited evidence suggests women with hypertension using progestin-only pills or injectables had small increased risk for cardiovascular events 3

Conditions Where Progesterone is Ineffective and Should Not Be Used

Using progesterone in these scenarios exposes patients to risks without benefit:

• Multiple gestations (twins, triplets): Multiple RCTs totaling over 1,000 women showed no effect on preterm birth rates or perinatal morbidity/mortality with either 17P or vaginal progesterone 3, 4
• Active preterm labor as primary tocolysis: Insufficient evidence to recommend 3, 4
• Preterm premature rupture of membranes (PPROM): No effect on delivery interval, gestational age at delivery, or neonatal outcomes 3, 4

Serious Adverse Effects Requiring Immediate Discontinuation

Stop progesterone immediately and seek emergency care if these occur:

• Acute neurological symptoms: Sudden severe headache, changes in vision or speech, dizziness with loss of consciousness, convulsions, transient ischemic attack 2
• Thromboembolic events: Severe chest pain, leg pain with swelling, shortness of breath, visual loss or blindness 2
• Cardiovascular collapse: Severe weakness, fatigue, hypotension, circulatory collapse 2
• Acute hepatic dysfunction: Jaundice, cholestatic hepatitis, hepatic failure, acute pancreatitis 2
• Severe CNS depression constellation: Extreme dizziness/drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, feeling drunk - reported during initial therapy in some women 2

Conditions Requiring Extreme Caution

Progesterone may cause harm in these situations and requires careful risk-benefit assessment:

• Cardiac or renal dysfunction: Progesterone causes fluid retention 2
• Depression or mood disorders: Depression reported in 19% of users versus 12% with placebo 2
• Driving or operating machinery: Transient dizziness and drowsiness are common; 24% experienced dizziness versus 4% with placebo 2
• Breastfeeding <1 month postpartum: Category 2 risk due to theoretical concerns about progestin exposure effects on the developing neonatal brain, though direct evidence shows no significant negative effects 3

Common Pitfalls to Avoid

Do not confuse different progesterone formulations - Injectable 17-alpha-hydroxyprogesterone caproate (17P) has different dosing, indications, and safety profiles than oral micronized progesterone 5. Using the wrong formulation or dose can lead to ineffective treatment or increased adverse effects.

Do not use excessive doses - In twin gestations, 17P 250 mg IM weekly showed no benefit for preterm birth prevention, demonstrating that higher doses do not improve outcomes and only increase exposure to potential harms 3, 1

Recognize that synthetic progestins carry different risks than natural progesterone - Medroxyprogesterone acetate and 19-nortestosterone derivatives have non-progesterone-like effects that potentiate estrogen's proliferative actions, increasing breast cancer risk more than natural progesterone 6, 7