Are Hormones Inflammatory or Anti-Inflammatory?

By Wayne Persky

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When treating MC, sometimes the smallest details can foil an otherwise valid treatment program. For those of us using hormone replacement therapy (HRT), or even something as simple as thyroid hormones, for example, hormones may have different effects at different times, depending on the situation. Some hormones (such as estrogen and thyroid hormones) can be pro- or anti-inflammatory depending on their levels and the surrounding environment. Balance is critical. The body carefully balances these hormones, and too little or too much of almost any hormone can tip the scale toward unwanted inflammation.

Pro-inflammatory hormones include:

• Estrogen (at high levels or depending on balance) stimulates immune responses and can increase the risk of autoimmune diseases (but low levels may be protective).
• Insulin (at high levels, for example, in insulin resistance) drives systemic inflammation and promotes pro-inflammatory cytokines.
• Leptin (from fat tissue) is pro-inflammatory, and enhances T-cell activation and cytokine production when it's elevated in obesity.
• Catecholamines (Epinephrine, and Norepinephrine) can be both pro- and anti-inflammatory depending on the situation — acute stress (high norepinephrine) often promotes inflammation.
• Thyroid hormones (such as excessive T3/T4) at high thyroid levels (hyperthyroidism) can increase oxidative stress and inflammation.
• Parathyroid hormone (PTH) at high levels (seen in calcium imbalance) promotes systemic inflammation and vascular damage.

Anti-inflammatory hormones include:

• Cortisol (Glucocorticoids) is a major anti-inflammatory hormone that suppresses immune responses and cytokine production (which is the basis of steroid therapies).
• Melatonin reduces oxidative stress, inhibits pro-inflammatory cytokines, and regulates immune balance (especially at night).
• Progesterone suppresses inflammatory pathways and helps to maintain pregnancy by calming the maternal immune system.
• Testosterone is moderately anti-inflammatory, and reduces some pro-inflammatory cytokine production (men tend to have fewer autoimmune issues partly due to this).
• Adiponectin (from fat tissue) reduces systemic inflammation and insulin resistance, and is protective for vascular and gut health.​
• Growth hormone (GH) promotes tissue repair and may have local anti-inflammatory effects, although it can also stimulate immune cells depending on the situation.

Summarizing:

Cortisol, melatonin, progesterone, testosterone, and adiponectin are mainly anti-inflammatory. And high estrogen, high insulin high leptin, high catecholamines, and high thyroid hormones are inflammatory.  

Women have to deal with complex hormonal issues associated with:

• The menstrual cycle
• Pregnancy
• Menopause

During the menstrual cycle:

• Estrogen rises during the first half (follicular phase", peaks at ovulation, then drops slightly.
• Progesterone rises during the second half (luteal phase).
• Both plunge before menstruation.

This typically results in mild anti-inflammatory effects during the follicular stage, increased inflammation during ovulation, and anti-inflammatory effects during the luteal stage. During the premenstrual stage, progesterone and estrogen levels crash, resulting in a pro-inflammatory spike, with an increase in cytokines, that can lead to an MC flare as a result of increased gut hypersensitivity.

During pregnancy:

• Progesterone skyrockets and stay high.
• Estrogen rises steadily, but is balanced by progesterone.
• Cortisol levels also gradually increase.

The result of rising progesterone is anti-inflammatory as many immune responses are suppressed in order to protect the fetus. The effects of rising estrogen are inflammatory, but these effects are buffered by progesterone. And high cortisol levels further dampen inflammation. Consequently, many inflammatory diseases (including MC), often improve during pregnancy due to:

• Mast cell stabilization
• Reduced gut inflammation
• Lower intestinal mucosal immune hyperactivity

Note, however, that infections and stress can still trigger inflammatory issues.

During menopause:

• Estrogen and progesterone sharply fall, and stay low.
• Cortisol baseline level may be slightly higher with aging.
• Leptin and insulin resistance often increase after menopause​

Low estrogen and progesterone levels result in a mild pro-inflammatory state, accompanied by more mast cell activation, and less gut barrier protection. Associated metabolic changes can cause increased systemic inflammation due to higher TNF-α and IL-6.

This can lead to increased MC activity in existing cases, and new diagnoses of MC, where MC didn't exist previously, because of:

• Increased gut permeability
• Loss of hormonal protection (that allows increased baseline gut inflammation)
• Increased mast cell activity
• An aging immune system (inflammaging) that can fuel subtle chronic inflammation

The take away message for female MC patients suggests that:

• MC symptoms can fluctuate as cyclical hormonal shifts occur.
• Pregnancy usually improves MC, but the hormone crash during the postpartum period may trigger a relapse.
• Postmenopausal women may need anti-inflammatory strategies in order to preserve gut health.
• HRT using bioidentical progesterone may be helpful for some postmenopausal women, but must be approached with caution under medical supervision.