How does progestin (a synthetic form of progesterone) increase the risk of breast cancer?

Why Progestin Increases Breast Cancer Risk

Progestin increases breast cancer risk primarily through direct mitogenic (cell proliferation) effects on breast tissue and by reactivating dormant cancer stem cells in occult pre-existing breast cancers, with the Women's Health Initiative demonstrating a 26% increased relative risk (HR 1.24) when combined with estrogen compared to placebo. 1, 2

The Paradox: Estrogen Alone vs. Estrogen Plus Progestin

The most striking finding from major trials is that estrogen alone does not increase breast cancer risk and may even reduce it (HR 0.80), while adding progestin to estrogen creates the increased risk. 1, 3 This paradox reveals that progestin—not estrogen—is the primary driver of increased breast cancer risk in hormone replacement therapy. 1

Mechanisms of Progestin-Induced Breast Cancer Risk

Direct Proliferative Effects on Breast Tissue

Progestins directly stimulate proliferation of breast epithelial cells in the terminal duct lobular units, with studies demonstrating higher cell proliferation during the luteal phase (high progesterone) than the follicular phase of the menstrual cycle. 4 Long-term exposure to estrogen plus progestin results in marked enhancement of proliferation and increased breast density compared to estrogen alone. 4

Laboratory studies confirm that progestins stimulate breast cancer cell growth for multiple, potentially unlimited cell cycles while preventing cell death. 5 This occurs through:

• Upregulation of the anti-apoptotic protein Bcl-xL, which prevents programmed cell death 5
• Sustained mitogenic signaling that drives continuous cell division 5
• Enhanced breast tissue density, making mammographic detection more difficult 1

Reactivation of Cancer Stem Cells

A critical mechanism is that progestins reactivate dormant estrogen receptor-negative (ER-), progesterone receptor-negative (PR-) cancer stem cells within occult, pre-existing breast cancers. 6 This hypothesis explains why breast cancer risk increases rapidly in the first year of combined therapy—the progestin awakens dormant malignancies rather than initiating new ones. 6

The sequence occurs as follows:

1. Women harbor undiagnosed nascent breast cancers containing rare ER(-), PR(-) cancer stem cells 6
2. Progestin reactivates these receptor-negative stem cells in a non-proliferative step 6
3. Reactivated cells reacquire hormone receptors 6
4. Estrogen then drives proliferation of these now receptor-positive cells 6

Metabolic and Systemic Effects

Synthetic progestins (particularly medroxyprogesterone acetate and 19-nortestosterone derivatives) exert non-progesterone-like metabolic effects that potentiate estrogen's proliferative actions. 7 These include:

• Decreased insulin sensitivity 7
• Increased levels and activity of insulin-like growth factor-I (IGF-I), a potent mitogen 7
• Decreased sex hormone-binding globulin (SHBG), increasing free estrogen levels 7

These metabolic changes contrast with the opposite (protective) effects induced by oral estrogen alone. 7

Clinical Evidence from Major Trials

Women's Health Initiative Findings

The WHI trial using conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg demonstrated:

• Relative risk of invasive breast cancer: 1.24 (95% CI, 1.01-1.54) 1, 2
• Absolute risk: 41 vs. 33 cases per 10,000 women-years 2
• Among prior hormone therapy users: RR 1.86 (46 vs. 25 cases per 10,000 women-years) 2
• Cancers were larger, more likely node-positive, and diagnosed at more advanced stages in the progestin group 1, 2

Duration and Regimen Effects

Risk increases logarithmically with duration of use, becoming particularly significant beyond 5 years. 8, 4 Both continuous-combined and sequential progestin regimens appear to have comparable impact on breast cancer risk. 8

Continuous-combined regimens may be particularly problematic because they inhibit the sloughing of mammary epithelium that occurs after progesterone withdrawal in cyclic regimens. 7 This prevents the natural clearance of proliferating cells. 7

Type of Progestin Matters

The majority of data demonstrating increased breast cancer risk comes from regimens using medroxyprogesterone acetate (MPA). 4 Recent evidence suggests that natural micronized progesterone in cyclic regimens may not increase breast cancer risk to the same degree as synthetic progestins. 7

The differential effects may be due to:

• Synthetic progestins having androgenic or glucocorticoid properties that natural progesterone lacks 7
• Different metabolic pathways: synthetic progestins may be metabolized into stimulatory 5-alpha-reduced pregnanes rather than inhibitory pregnenes 4
• Continuous vs. cyclic administration patterns 7

Critical Clinical Implications

The burden of proof has shifted—one must now prove that an estrogen/progestin combination is safe with respect to breast cancer rather than having to prove it harmful. 4 The attributable risk during use for 5 years or less is small but increases substantially during long-term use. 4

Common Pitfalls to Avoid

• Do not assume all progestins carry equal breast cancer risk—synthetic progestins (especially MPA) have the strongest evidence for harm 7, 4
• Do not continue HRT beyond symptom management needs—breast cancer risk increases with duration 1
• Do not overlook that estrogen alone in women with hysterectomy does not increase breast cancer risk and may be protective 1, 3
• Recognize that increased breast density from progestins interferes with mammographic detection, potentially delaying diagnosis 1