What are the side effects of systemic progesterone (progestin) therapy for treating irregular uterine bleeding?

Side Effects of Systemic Progesterone for Irregular Uterine Bleeding

The most common side effects of systemic progesterone therapy for irregular uterine bleeding include breakthrough bleeding, spotting, amenorrhea, breast tenderness, weight changes, mood disturbances, and injection site reactions (for parenteral formulations). 1, 2

Common Side Effects

Bleeding Pattern Changes

• Breakthrough bleeding and spotting are the most frequently reported side effects, particularly during the first 3 months of treatment 2, 3
• Amenorrhea occurs in approximately 22% of women using progestin-only contraceptives and does not require medical treatment—reassurance is sufficient 4
• Changes in menstrual flow patterns (increased or decreased) are common and generally not harmful 1, 2

Physical Side Effects

• Fluid retention and edema may occur because progestational drugs can cause some degree of fluid retention, requiring careful observation in women with epilepsy, migraine, asthma, cardiac or renal dysfunction 1
• Weight changes (both increases and decreases) are commonly reported 1, 2
• Breast tenderness and galactorrhea occur frequently 2
• Injection site reactions including pain, irritation, and redness are specific to intramuscular formulations 2

Dermatologic Effects

• Skin sensitivity reactions including urticaria, pruritus, edema, and generalized rash 2
• Acne, alopecia (hair loss), and hirsutism (excessive hair growth) 2
• Changes in cervical erosion and cervical secretions 2

Serious but Less Common Side Effects

Neuropsychiatric Effects

• Mental depression is significant enough that patients with a history of psychic depression should be carefully observed and the drug discontinued if depression recurs to a serious degree 1
• Headache, nervousness, insomnia, and somnolence 1, 2
• Fatigue and dizziness 2

Thromboembolic Events

• A statistically significant association exists between estrogen-progestin combination drugs and pulmonary embolism, cerebral thrombosis and embolism, requiring careful patient observation 2
• Evidence suggests association with neuro-ocular lesions including retinal thrombosis and optic neuritis 2

Hepatic Effects

• Cholestatic jaundice can occur 2
• Increased sulfobromophthalein retention and alterations in other hepatic function tests 2

Metabolic Effects

• Decreased glucose tolerance has been observed in a small percentage of patients, making careful observation of diabetic patients essential 1
• Inconsistent effects on lipid metabolism with both increases and decreases in total cholesterol, triglycerides, LDL and HDL cholesterol 1

Cardiovascular Considerations

• Rise in blood pressure may occur in susceptible individuals 2
• Increased coagulation factors (prothrombin Factor II, and Factors VII, VIII, IX, and X) 1, 2

Management of Side Effects

For Persistent Bleeding

• If irregular bleeding persists beyond 3 months, treatment options include NSAIDs for 5-7 days or low-dose combined oral contraceptives for 10-20 days (if medically eligible) 4, 5
• Enhanced counseling about expected bleeding patterns and reassurance that irregularities are generally not harmful reduces discontinuation rates 4

When to Discontinue

• If side effects are unacceptable despite counseling and management attempts, alternative contraceptive methods should be offered 4, 5
• Depression recurring to a serious degree warrants discontinuation 1

Important Caveats

Before attributing symptoms to progesterone therapy, rule out underlying gynecological problems including medication interactions, sexually transmitted diseases, pregnancy, or pathologic uterine conditions such as polyps or fibroids 4, 5. In cases of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures must be conducted to rule out malignancy 1.