Does progesterone (a hormone) cause weight gain?

Does Progesterone Cause Weight Gain?

Yes, progestins (synthetic progesterone compounds like megestrol acetate and medroxyprogesterone acetate) do cause weight gain, but this weight gain is primarily fat mass rather than muscle, and the effect varies significantly by formulation, dose, and patient population. 1

Weight Gain Mechanism and Characteristics

Progestins increase appetite and body weight through appetite stimulation, but critically, the weight gained is predominantly adipose tissue rather than lean body mass or muscle. 1 This distinction is clinically important because fat gain without muscle preservation does not improve functional capacity or strength. 1

Specific Progestin Effects:

• Megestrol acetate (a high-dose progestin used in cancer cachexia) demonstrates robust evidence for weight gain, with patients 1.55 times more likely to gain weight compared to placebo. 2 However, this represents stabilization or improvement in body fat mass with no impact on fat-free or muscle mass. 1

• Depot medroxyprogesterone acetate (DMPA) as contraception shows variable weight effects. Mean weight gain at 6-12 months is typically less than 2 kg (4.4 lb) for most users. 3 However, specific subgroups show greater gains: adolescent DMPA users who are overweight or obese may gain more weight than normal-weight users. 4

• Natural progesterone (as in progesterone capsules for hormone therapy) lists weight changes in both directions (weight increased and weight decreased) as postmarketing adverse reactions, but controlled trials show no consistent pattern of significant weight gain. 5

Clinical Context: When Weight Gain Occurs

Cancer Cachexia Setting:

Progestins are intentionally used to promote weight gain in cancer patients with anorexia-cachexia syndrome. 1 In this context:

• Megestrol acetate at 480-800 mg daily increases appetite and body weight. 2
• Weight gain of 2.5 kg treatment-placebo difference has been documented at 8 weeks. 1
• Two systematic reviews confirm significant benefit on appetite, weight gain, and quality of life. 1

Contraceptive Use:

• About one-fourth of DMPA users experience early weight gain (>5% baseline weight within 6 months). 6
• Early weight gainers continue on a steeper trajectory: mean gains of 8.04 kg at 12 months, 10.86 kg at 24 months, and 11.08 kg at 36 months, compared to 0.63 kg, 1.48 kg, and 2.49 kg in non-early gainers. 6
• Risk factors for early weight gain include BMI <30, higher parity, and self-reported increased appetite. 6

Comparative Data:

• Retrospective studies show DMPA users gain more weight than copper IUC users: 2.28 kg vs baseline at year 1,2.71 kg at year 2, and 3.17 kg at year 3. 3
• DMPA adolescents showed an 11% greater increase in body fat and 4% greater decrease in lean body mass compared to non-hormonal method users. 3

Important Caveats and Safety Concerns

The weight gain from progestins comes with serious risks that must be weighed against any potential benefit:

• Thromboembolic events occur with a relative risk of 1.84 (95% CI 1.07-3.18) for megestrol acetate. 7, 2 This means approximately 1 in 6 patients will develop thromboembolism. 2

• Increased mortality risk with megestrol acetate shows a relative risk of 1.42 (95% CI 1.04-1.94) compared to placebo. 7, 2 This translates to 1 in 23 patients dying from treatment-related complications. 2

• Other adverse effects include edema (RR 1.36), impotence, vaginal spotting, and adrenal suppression requiring monitoring in long-term users. 1, 7, 2

Practical Clinical Approach

For Contraception:

• Counsel patients that most DMPA users gain less than 2 kg in the first year. 3
• Monitor weight at 6 months; early weight gain (>5% baseline) predicts continued excessive gain. 6
• Consider alternative contraceptive methods for patients who gain >5% weight in first 6 months, particularly adolescents who are already overweight or obese. 6, 4

For Therapeutic Use (Cancer Cachexia):

• Reserve megestrol acetate for patients where appetite stimulation is an important quality-of-life goal and life expectancy is limited. 2
• Use liquid formulation (more bioavailable and less expensive than tablets) at 480-800 mg daily. 2
• Assess for thromboembolic phenomena regularly given the 1.84-fold increased risk. 7, 2
• Consider corticosteroids as an alternative with similar appetite effects but different toxicity profile and lower cost. 2
• Limit duration of therapy rather than indefinite use due to cumulative risks. 2

For Hormone Replacement:

• Progesterone capsules (200-400 mg daily) used with estrogen in postmenopausal women show minimal consistent weight changes in controlled trials. 5
• Abdominal bloating (12% vs 5% placebo) and swelling of hands/feet (6% vs 9% placebo) are reported but not consistent weight gain. 5

Bottom Line

Progestins cause weight gain primarily through appetite stimulation leading to increased fat mass, not muscle. The magnitude varies by formulation (high-dose therapeutic progestins > contraceptive doses), patient population (adolescents and those with early weight gain > adults), and individual factors. For contraceptive use, appropriate counseling about typical modest weight gain may reduce discontinuation. 3 For therapeutic use in cancer cachexia, the benefits must be carefully weighed against serious risks including thromboembolism and increased mortality. 7, 2