Is the evidence strong to suggest that medroxyprogesterone acetate (MPA) can cause hyperglycemia?

Can Medroxyprogesterone Acetate (MPA) Cause Hyperglycemia?

Yes, there is moderate-to-strong evidence that medroxyprogesterone acetate can cause hyperglycemia and impair glucose metabolism, particularly in high-risk populations and with prolonged use.

Evidence from FDA Drug Labeling

The FDA label for medroxyprogesterone acetate explicitly warns that "a decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment" and specifically states that "diabetic patients should be carefully observed while receiving such therapy" 1. This represents the highest level of regulatory guidance available.

Effects on Glucose Metabolism

General Population Effects

• MPA has documented adverse effects on carbohydrate metabolism that can manifest as decreased glucose tolerance 2
• The CDC acknowledges that "hormonal contraceptives can have some adverse effects on glucose metabolism in healthy and diabetic women, although the overall clinical effect is minimal" in most cases 2
• Long-term users (≥5 years) show significantly higher plasma insulin levels compared to non-users, suggesting compensatory hyperinsulinemia in response to insulin resistance 3

High-Risk Populations Show Pronounced Effects

The evidence becomes substantially stronger in vulnerable populations:

• In Navajo women (a high-risk population for diabetes), DMPA users were 3.8 times more likely to develop diabetes compared to combination oral contraceptive users (OR 3.8; 95% CI 1.8-7.9), and this risk persisted after adjusting for BMI 4
• Risk increased with duration of use, with longer exposure associated with greater diabetes risk 4
• In Latino breastfeeding women, injectable DMPA was associated with a two- to threefold increase in diabetes risk 2

Severe Cases in Insulin-Resistant Patients

• In a patient with generalized lipodystrophy (severe insulin resistance), a single DMPA injection caused profound hyperglycemia requiring up to 1,700 units of insulin daily for control 5
• This case demonstrates that MPA can dramatically worsen glucose metabolism in patients with pre-existing insulin resistance or diabetes 5

Dose-Dependent Effects

• High-dose MPA therapy (used in men for sex-offending behavior) caused statistically insignificant increases in insulin response in all patients, with one patient developing overt diabetes mellitus 6
• Patients on high-dose MPA should be carefully monitored for diabetes mellitus development 6

Comparative Effects Among Contraceptive Methods

• Both combined oral contraceptives and progestogen-only pills impair glucose tolerance as early as 1 month of use, with significantly elevated mean areas under glucose curves 7
• One study found that MPA did not impair oral glucose tolerance for the first 6 months of use in healthy women, showing lower fasting glucose initially 7, though this conflicts with other evidence showing longer-term effects

Clinical Implications and Monitoring

Who Is at Highest Risk?

1. Women with pre-existing diabetes or insulin resistance (including lipodystrophy, metabolic syndrome)
2. Populations at high baseline risk for diabetes (e.g., Native American, Latino populations)
3. Long-term users (risk increases with duration)
4. Patients on high-dose MPA therapy

Practical Monitoring Approach

• Screen for diabetes risk factors before initiating DMPA, though routine glucose testing is not required in healthy women 2
• In diabetic patients, close monitoring of glucose tolerance is essential when using progestin-only contraceptives 5
• Consider alternative contraceptive methods in women at high risk for diabetes, as progestin-only agents should be used with caution 2
• For patients requiring MPA with diabetes risk, monitor blood pressure, glucose tolerance, and weight regularly 6

Important Caveats

• The overall clinical effect on glucose metabolism is minimal in healthy women without risk factors 2
• The evidence shows inconsistent effects on lipid and carbohydrate metabolism, with both increases and decreases reported 1
• Natural micronized progesterone has a more favorable metabolic profile than synthetic progestogens like MPA, though it has not been extensively studied in all populations 2, 8

Bottom line: While MPA can cause hyperglycemia, the risk is substantially elevated in women with pre-existing insulin resistance, diabetes, or high baseline diabetes risk. In healthy women, the effect is generally minimal but monitoring remains prudent with long-term use.