BHRT and Inflammation

Overview

• The presentation explores the anti-inflammatory effects of Bioidentical Hormone Replacement Therapy (BHRT), focusing on estrogen, progesterone, testosterone, DHEA, cortisol, and low-dose naltrexone.

Inflammation

• Inflammation serves as an immune response aimed at eliminating damaged tissue and foreign substances.
• Acute inflammation occurs due to injuries/infections like splinters, cuts, and sprains.
• Chronic inflammation occurs due to sustained aggravation from diet, autoimmune disorders, and general stress.
• Acute inflammation starts after a specific injury, it causes soluble mediators like cytokines, acute phase proteins, and chemokines to promote neutrophils and macrophages migration to the inflammation area.
• Failure to resolve acute inflammation after six weeks leads to its development into subacute and then chronic inflammation. The migration of T lymphocytes and plasma cells then occur. The tissue damage and fibrosis will ensue.
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Inflammatory Conditions

• Inflammatory conditions includes diseases like cancer, diabetes, cardiovascular issues, neurological disorders, Alzheimer's, autoimmune diseases, arthritis, and pulmonary diseases.
• Bio-identical hormones and low-dose naltrexone (LDN) have changed medicine in the last 45 years.
• Every disease process after age 45 has inflammatory nature.
• The best anti-aging therapy involves decreasing inflammation.

Steroid Hormones

• Steroid hormones are recognized as endogenous regulators of inflammation and cytokine production.

BHRT: Anti-Inflammatory Effects

• BHRT with compounded bioidentical hormones relieves menopausal symptoms in peri/postmenopausal women due to regulated dose.
• BHRT has been shown to favorably impact cardiovascular biomarkers, inflammatory factors, immune signaling factors, and overall health

Estrogen

• Estradiol and progesterone exhibit immuno-modulatory and anti-inflammatory actions through estrogen and progesterone receptors.
• Estrogen and progesterone receptors are expressed in all immune and epithelial cells, macrophages, dendritic cells, CD4+, CD8+ lymphocytes, and B cells.
• Estrogen decreases inflammation via:
  • Modulating inflammatory proteins produced by the liver
  • Direct vascular effects
  • Indirectly stimulating the hypothalamic-pituitary-adrenal axis.
  • Transdermal E2 decreases IL-6, TNF-alpha, and IL-1.
• Transdermal estrogen application has anti-inflammatory effects. The analysis of electronic health records of over 68,000 COVID-19 patients revealed that estrogen therapy is associated with more than 50% reduction in mortality
• Acute loss of estrogens increases ROS levels and activates nuclear factor-kB , leading to cytokine production.
• Pro-inflammatory cytokine expression can be attenuated by estrogen replacement.
• Estrogen receptor activation shortens the LPS-induced pro-inflammatory phase. E2 accelerates the resolution of inflammation in macrophagic cells.
• E2 and progesterone decrease innate immune cell inflammation, enhances T cell functions, promotes tolerance, and increases antibody production.

Progesterone

• Modulates the immune system through nuclear and membrane receptors.
• Progesterone exerts anti-inflammatory effects by acting nonspecifically, and specifically.
  • Non-specifically by inhibiting NF-kB and COX
  • Specifically, it regulates T-cell activation and production of anti-inflammatory cytokines.
• Has three proposed mechanisms of progesterone's immunomodulatory effects
  • Progesterone induces progesterone-induced blocking factor (PIBF) and leukemia inhibitory factor (LIF) production. Both then inhibits the Th1 pathway and reduce the production of proinflammatory cytokines.
  • Progesterone upregulates Th2 differentiation and anti-inflammatory cytokine synthesis, downregulating Th1 differentiation.

Progesterone Inhibits NF-kB Activation

• Progesterone inhibits the NF-kB pathway through:
  • Direct RelA(p65) subunit binding
  • Indirectly activating signal proteins TGFβ and immunophilins FKBP51/52.
• It attenuates LPS-stimulated TNF-a, iNOS, and COX-2, decreasing phosphorylation, and inhibiting p65 translocation. Decreases the LPS-mediated phosphorylation of p38, c-Jun N-terminal kinase, and extracellular regulated kinase

Progesterone Regulates Inflammation & Regulates T-Cell Activation

• The action of progesterone is realized through nuclear, mitochondrial, membrane
• The active progesterone receptor complex works in dynamic interactions with chaperones and immunophilins.
• Progesterone inhibits action of HP90 which allows the inhibtion of the NLRP3 inflammasome release
• The controlled destruction of NLRP3 is a potential route to regulate chronic inflammation.
• It has potential against COVID-19 because of recent findings
• Further studies are needed to test effects against inflammatory and immunity.

Progesterone Influences Chemokine Production

• Progesterone suppresses chemokine production, changing receptor profiles, causing 50-70% inhibition of RANTES, MIP1a, and MIP1ẞ in CD8+ cells.

Progesterone: Anti-Inflammatory Effect and COVID-19

• Progesterone displays anti-inflammatory effects with its role in COVID-19 therapy.
• Sex steroid hormones, especially progesterone and estrogen, assist in preventing/managing severe COVID-19.
• The neuroprotective role against necrotic damage has been confirmed against behavioral abnormalities caused by injury

Testosterone

• Essential for vaginal tissue structure, modulates nociception/inflammation, and mucin secretion.
• Low testosterone levels are associated with increased metabolic risk and systemic inflammation.
• Serum testosterone shares an inverse relationship with inflammatory markers in men
• Testosterone influences the inflammation status of patient.
• Test supplementation is speculated to modulate the inflammation and improve conditions.
• Adipose tissue converts testosterone to estradiol, reducing testosterone levels. Adipose has also been linked to an increase in fat mass.

The role of male Progesterone

• In men, progesterone supports spermatogenesis, testosterone production, and neuroprotection.
• A 2021 study of 42 men with severe COVID-19 found that the patients were improved as a result of standard care with progesterone.

DHEA

• Lower DHEA levels have been seen in people with inflammatory disease
• Is a cytokine inhibitor
• Potent inhibitor of IL-6
• Regulates certain responses to inflammation

Cortisol

• affects nearly every organ system: (i.e., nervous, immune, cardiovascular, reproductive, etc…)
• Mediates stress response and regulates immune function

LDN - Low Dose Naltrexone

• Enhance Immune function and down regulates TH-17
• Potential short-term side effects:
  • Insomnia
  • Vivid dreams
  • Fatigue
• Contraindications include:
  • Acute hepatitis
  • Liver failure
  • Recent opioid/alcohol use
• Usual Dosing:
• One 1.5 mg capsule qhs x 7 days
• Titrate up 1 capsule per week
• Target dose is 4.5 mg as a single capsule qhs