17-alpha-Estradiol vs Thyroid (Levothyroxine / Liothyronine T3/T4)

Mechanism

Non-feminizing estrogen that extends lifespan in male mice via metabolic improvements. Reduces hepatic mTOR signaling, improves glucose homeostasis, and reduces inflammation without estrogenic effects on reproductive tissues.

Contraindications

• Not FDA-approved for human use
• Theoretical hormone-sensitive cancer risk

Mechanism

Levothyroxine (T4) is a prohormone converted to the active triiodothyronine (T3) by type 1 and type 2 deiodinase enzymes (DIO1/DIO2) in peripheral tissues. T3 binds nuclear thyroid hormone receptors (TRa and TRb), forming heterodimers with retinoid X receptors (RXR) that bind thyroid response elements (TREs) in DNA, directly modulating transcription of genes controlling basal metabolic rate, thermogenesis, mitochondrial biogenesis (via PGC-1a), cardiac output, and neuronal development. T3 also exerts rapid non-genomic effects on mitochondrial respiration, ion channels, and cell membrane transport.

Standard Dosing

Research indicates Levothyroxine (T4): 25-200 mcg daily based on TSH and free T4 levels. Liothyronine (T3): 5-25 mcg daily, often split into 2-3 doses. Combination T4/T3 ratio typically 4:1 to 3:1 when using both.

Timing

Levothyroxine: Take on empty stomach, 30-60 minutes before breakfast or at bedtime (3+ hours after last meal). Separate from calcium, iron, and antacids by 4 hours. Liothyronine: Split into 2-3 daily doses due to short half-life (2.5 hours for T3 vs. 6-7 days for T4).

Cycle Duration

Ongoing for diagnosed hypothyroidism. Optimization protocols may be shorter-term (3-6 months) with reassessment.

Side Effects

• Tachycardia and palpitations (overdose or too-rapid titration)
• Anxiety and insomnia (particularly with T3)
• Tremor
• Weight loss (excessive dosing)
• Hair loss (temporary during initiation or dose changes)
• Heat intolerance and sweating
• Bone density loss at suppressive doses (TSH <0.1)

Contraindications

• Untreated adrenal insufficiency (correct cortisol before thyroid replacement)
• Acute myocardial infarction
• Thyrotoxicosis
• Known hypersensitivity to levothyroxine or liothyronine

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