What are the long-term health risks of using Depo-Provera (medroxyprogesterone acetate)?

Long-Term Risks of Depo-Provera (DMPA)

Long-term use of Depo-Provera beyond 2 years carries significant bone density loss that is substantially reversible after discontinuation, along with predictable menstrual changes, weight gain, and delayed return to fertility, but ACOG does not recommend limiting use to 2 years when other contraceptive options are inadequate. 1

Bone Mineral Density Loss

The most significant long-term risk is bone mineral density (BMD) loss, which increases with duration of use but is largely reversible after discontinuation. 1, 2

• The FDA issued a black box warning in 2004 specifically addressing BMD loss with DMPA use 1, 2
• Women using DMPA experience approximately 5% bone density deficit at the lumbar spine and hip, particularly when started before age 20 years 3
• Bone loss is greater with increasing duration of use and may not be completely reversible 2
• However, systematic reviews demonstrate that BMD consistently returns toward or to baseline values following DMPA discontinuation, with recovery seen as early as 24 weeks after stopping therapy 4
• Fracture risk increases with longer DMPA exposure, particularly in women under 30 years with ≥10 prescriptions (OR 3.04) and in women in late reproductive years with past use (OR 1.72) 5

Bone Health Management

All patients using DMPA beyond 2 years must receive counseling about skeletal health promotion: 1

• Daily intake of 1300 mg calcium 1
• 600 IU vitamin D daily 1
• Regular weight-bearing exercise 1
• Smoking cessation 1
• Evaluation for other osteoporosis risk factors before initiating long-term use 1

For patients with pre-existing osteoporosis risk factors, alternative contraceptive methods are preferable for long-term use. 1

Menstrual Irregularities

Nearly all patients (57%) experience menstrual irregularities initially, which typically improve over time, with 55% achieving amenorrhea by 12 months and 68% by 24 months. 1, 2

• Initial bleeding patterns include irregular or unpredictable bleeding, spotting, prolonged bleeding, and heavy bleeding 2
• These changes are generally not harmful but affect patient satisfaction and continuation rates 1
• Rule out organic pathology if abnormal bleeding persists or is severe 2

Weight Gain

Weight gain is a common and significant side effect, with women gaining an average of 5.4 lb at 1 year, 8.1 lb at 2 years, 13.8 lb at 4 years, and 16.5 lb at 6 years. 1, 2

• Weight gain status at 6 months strongly predicts future excessive weight gain with ongoing DMPA use 1
• Patients showing early weight gain (>5% at 6 months) may experience significant BMI increases with continued use 1
• Two percent of women in clinical trials withdrew due to excessive weight gain 2

Return to Fertility

DMPA causes a delayed return to fertility of 9 to 18 months after discontinuation, regardless of duration of use. 1

• This delay occurs while the endometrial lining returns to its pre-DMPA state and ovulatory function returns 1
• Both subcutaneous and intramuscular formulations show similar delays 1

Cardiovascular and Thromboembolic Risks

While serious thrombotic events have been reported, DMPA has not been causally associated with inducing thrombotic or thromboembolic disorders. 2

• Active thrombophlebitis, current or past history of thromboembolic disorders, or cerebrovascular disease are absolute contraindications 2
• Discontinue DMPA if thrombosis develops during therapy 2
• Long-term surveillance has not shown increased risk of cardiovascular events 6

Cancer Risks

Breast Cancer

Women with current or past breast cancer should not use DMPA; those with strong family history require careful monitoring. 2

• Recent users (within past 5 years) who used DMPA for ≥12 months show statistically significant increased breast cancer risk 2
• Three of five large case-control studies suggest slightly increased risk in overall users 2
• Based on SEER data, a doubling of risk would increase breast cancer incidence from 72 to 144 cases per 100,000 women ages 20-49 years 2

Cervical Cancer

A statistically nonsignificant increase in invasive squamous-cell cervical cancer risk (RR 1.22-1.28) has been associated with DMPA use in women first exposed before age 35. 2

Other Cancers

Long-term surveillance found no overall increased risk of ovarian or liver cancer. 2

Other Long-Term Effects

• Headache, mastalgia, hair loss, and changes in libido may occur with continued use 1
• Decreased glucose tolerance can occur; diabetic patients require careful monitoring 2
• Fluid retention may affect patients with epilepsy, migraine, asthma, or cardiac/renal dysfunction 2
• Rare cases of convulsions have been reported, though causation is unclear 2

Clinical Approach to Duration of Use

Despite the FDA black box warning, ACOG does not recommend limiting DMPA use to 2 years when other contraceptive options are inadequate, as the benefits of preventing unwanted pregnancy generally outweigh the risks of bone density loss. 1

• The recommendation states DMPA "is not recommended as a long-term (i.e., longer than 2 years) birth control method unless other options are considered inadequate" 2
• This reflects a balance between bone health concerns and the critical importance of effective contraception 1
• Counseling about potential side effects before initiation improves continuation rates 1