What are the major side effects and risks of Depo‑Provera (medroxyprogesterone acetate)?

Major Side Effects and Risks of Depo-Provera

The most significant risks of Depo-Provera include bone mineral density loss (particularly with use beyond 2 years), menstrual irregularities affecting nearly all users initially, weight gain, and delayed return to fertility lasting 9-18 months after discontinuation. 1

Bone Health Concerns (Most Serious Long-Term Risk)

• Depo-Provera causes reductions in bone mineral density (BMD), which prompted the FDA to issue a black box warning in 2004. 1
• Despite this warning, the American College of Obstetricians and Gynecologists does not recommend limiting use to 2 years, as the benefits of preventing unwanted pregnancy generally outweigh the risks of bone density loss. 1
• Substantial recovery of BMD occurs after discontinuation of Depo-Provera. 1
• Rare cases of osteoporosis including osteoporotic fractures have been reported postmarketing. 2

All patients using DMPA beyond 2 years must be counseled about skeletal health measures: 1

• Daily intake of 1300 mg calcium and 600 IU vitamin D 1, 3
• Regular weight-bearing exercise 1, 3
• Smoking cessation 1, 3

For patients with existing risk factors for osteoporosis, alternatives to DMPA should be considered for long-term contraception. 1

Menstrual Irregularities (Most Common Side Effect)

• Nearly all patients experience menstrual irregularities initially, with irregular bleeding, spotting, and amenorrhea being the predominant patterns. 4
• These changes typically improve over time, with a high percentage of users becoming amenorrheic with prolonged use. 5
• Pre-injection counseling about expected menstrual changes significantly reduces discontinuation rates and improves patient satisfaction. 3, 4

Management approach: 6, 4

• Provide reassurance that menstrual changes are expected and generally not harmful 4
• For persistent irregular bleeding, offer NSAIDs for 5-7 days 6, 4
• If bleeding remains unacceptable despite treatment, offer counseling on alternative contraceptive methods 6, 4

Weight Gain

• Weight gain is a common side effect with long-term use. 1, 3
• Weight gain status at 6 months is a strong predictor of future excessive weight gain with ongoing DMPA use. 1, 3
• Adolescents and adults who gain more than 5% of body weight at 6 months are at higher risk for continued significant weight gain. 1, 3
• Not all patients experience weight gain, but early weight gain is a critical predictor. 1

Delayed Return to Fertility

• Long-term DMPA use is associated with a delayed return to fertility, typically 9 to 18 months after discontinuation. 1
• This delay occurs while the endometrial lining returns to its pre-DMPA state and ovulatory function returns. 1
• Both subcutaneous and intramuscular DMPA formulations show similar delays to fertility. 1
• Women considering the method should be fully aware of this delayed return of fertility. 7

Additional Side Effects from FDA Label

The FDA-approved label lists the following adverse reactions that may or may not be related to Depo-Provera use: 2

Common effects:

• Weakness or fatigue 2
• Changes in appetite 2
• Headache 1
• Breast pain (mastalgia) 1
• Hair loss 1
• Changes in libido 1, 2

Less common but serious:

• Convulsions 2
• Pulmonary embolus 2
• Thrombophlebitis and deep vein thrombosis 2
• Anaphylaxis and anaphylactoid reaction (rare postmarketing reports) 2
• Allergic reactions 2

Other reported effects:

• Melasma or chloasma 2
• Gastrointestinal disturbances 2
• Genitourinary infections 2
• Pain at injection site 2
• Breast lumps or changes in breast size 2

Critical Counseling Points Before Initiation

Patients must understand: 7

• Inability to withdraw the drug promptly in the event of a serious reaction 7
• Expected disruption of menstrual patterns 7
• Delayed return of fertility after discontinuing therapy 7
• Required return visits every 12-13 weeks for reinjection 3

STI Protection Requirement

• Patients must be counseled to use condoms at all times for STI protection, as DMPA provides no protection against sexually transmitted infections. 3
• Unscheduled vaginal bleeding in adolescents using DMPA may indicate a sexually transmitted infection and warrants appropriate STI testing. 1

Common Pitfall to Avoid

Do not fail to counsel about menstrual irregularities before the first injection—this significantly reduces discontinuation rates and improves patient satisfaction. 3, 4