A Physiology-First Approach to Hormone Replacement
By Chris Duffin
Most TRT protocols are still built around pharmacokinetics. Half-life charts. Ester duration. Serum stability. What they are not built around is human biology. Testosterone is not meant to be continuously elevated. It is meant to follow a daily rhythm. When delivery ignores that rhythm, downstream systems compensate. Many of the common “side effects” of TRT are not dose problems. They are timing problems.
Testosterone Is a Circadian Signal
In healthy men, endogenous testosterone follows a diurnal pattern:
- Highest concentrations occur in the early morning
- Levels decline progressively throughout the day
- Nighttime concentrations are lower
- Sleep quality strongly influences next-morning levels
This pattern has been repeatedly demonstrated in human studies. Testosterone secretion is sleep-dependent, particularly tied to REM cycles. Sleep restriction reduces both total and free testosterone.
This matters because hormone systems are designed around timing separation. Morning biology is different from nighttime biology.
Morning physiology favors:
- Cortisol rise
- Dopaminergic tone
- Sympathetic activation
- Androgen signaling
Night physiology favors:
- Parasympathetic dominance
- Growth hormone pulses
- Tissue repair
- Memory consolidation
When TRT creates large peaks that extend into the evening, that separation blurs.
The Problem With Large, Infrequent Dosing
Traditional weekly or biweekly injections generate:
- Supraphysiologic peaks shortly after injection
- Prolonged decay curves
- No true on and off signal
Pharmacologically, levels remain present. Biologically, the signal shape changes.
Large peaks increase substrate availability for downstream pathways. That includes erythropoiesis and aromatization.
Hematocrit
Testosterone stimulates erythropoiesis through multiple mechanisms:
- Suppression of hepcidin
- Increased erythropoietin signaling
- Direct marrow stimulation
Hematocrit elevation is one of the most documented adverse effects of TRT in clinical trials. The magnitude of hematocrit rise correlates more strongly with peak concentrations than with steady physiologic exposure.
Large infrequent spikes produce stronger erythropoietic signaling than smaller repeated exposures.
Estrogen
Aromatase converts testosterone to estradiol based on substrate availability. Large testosterone peaks increase aromatization potential. This is why estradiol elevation is often seen after bolus injections.
When peak amplitude is reduced, conversion tends to become proportional rather than reactive.
This is not about suppressing estrogen. Estradiol is necessary for vascular, bone, and neurologic health. It is about avoiding exaggerated peaks that force corrective medication.
Why Daily Microdosing Changes the Signal
Daily microdosing is not about flattening levels. It is about restoring pulse characteristics.
When testosterone is administered in small, morning-aligned doses:
- Peak amplitude is reduced
- Clearance occurs later in the day
- Nighttime hormonal separation is preserved
- Downstream overreactions are reduced
From a receptor biology perspective, pulsatile exposure preserves sensitivity. Continuous ligand exposure can reduce receptor responsiveness over time.
In practice, men often report:
- Improved sleep depth
- More stable mood
- Reduced “wired but tired” sensation
- Improved training recovery
These are consistent with better alignment between androgen signaling and autonomic balance.
IM Versus Subcutaneous With Daily Dosing
Delivery method matters once frequency increases.
Subcutaneous administration:
- Slower absorption
- Flatter pharmacokinetic curve
- Lower peak amplitude
Intramuscular microdosing:
- Faster absorption
- Higher but brief peak
- Faster clearance
Testosterone clearance is not inherently negative. Physiologic systems expect fluctuation. Persistent low-grade elevation may blunt responsiveness over time.
The choice between IM and subcutaneous should be individualized based on response, hematocrit trends, estradiol behavior, and symptom resolution.
Cortisol, Sleep, and Long-Term Metabolic Health
Testosterone and cortisol interact temporally.
Cortisol rises early in the morning and declines throughout the day. Nighttime cortisol should be low. When androgen signaling remains elevated late into the evening, sympathetic tone may remain higher than ideal.
Chronic sympathetic dominance is associated with:
- Impaired sleep quality
- Reduced parasympathetic recovery
- Worsened insulin sensitivity
- Increased glucose variability
Long-term metabolic deterioration does not typically appear in the first months of TRT. It is a concern over years and decades, especially when therapy begins early in life.
Circadian-aligned testosterone administration reduces overlap between daytime drive and nighttime repair.
Best Ways to Support Circadian-Aligned TRT
Microdosing alone is not enough. Timing must be reinforced system-wide.
1. Morning Light Exposure
Within 30 minutes of waking:
- Direct outdoor light if possible
- At least 5 to 10 minutes
- No sunglasses
This anchors the suprachiasmatic nucleus and reinforces hormonal timing.
2. Consistent Sleep Timing
- Fixed wake time
- Dark sleeping environment
- No late blue light exposure
Sleep duration below 6 hours has been shown to reduce testosterone levels.
3. Nutrient Sufficiency
Ensure adequacy of:
- Zinc
- Magnesium
- Vitamin D
- Iron status within normal range
Micronutrient insufficiency impairs endocrine responsiveness.
4. Training Timing
Intense training earlier in the day supports androgen alignment. Late high-intensity sessions can delay parasympathetic shift.
Stacking Red Light and Near Infrared in the Evening
Red and near-infrared light do not replace circadian discipline. They can support it.
Appropriately dosed evening red or near-infrared exposure:
- Supports mitochondrial cytochrome c oxidase activity
- Enhances cellular respiration
- Improves local blood flow
- Promotes parasympathetic tone
Unlike bright blue-spectrum light, red wavelengths do not strongly suppress melatonin. Used 60 to 90 minutes before bed, red light can support sleep onset and reinforce the separation between daytime androgen drive and nighttime recovery.
This helps preserve:
- Growth hormone pulses
- Sleep architecture
- Next-morning testosterone signaling
The key is dosing and timing. It is a support tool, not a substitute for morning light and proper hormone timing.
Compliance Comes First
Optimization only matters after adherence is solved.
If daily injections increase stress or reduce compliance, they are not appropriate. Weekly administration may be preferable if consistency improves.
This is not ideology. It is physiology applied practically.
TRT Is Not the Default
Many cases of low testosterone are secondary suppression driven by:
- Sleep deprivation
- Chronic stress
- Caloric restriction
- Obesity and insulin resistance
In these cases, restoring circadian rhythm and metabolic health may significantly improve testosterone without replacement.
TRT is a tool. It is not the starting point for everyone.
The Takeaway
Hormones operate on timing, not just dosage.
When TRT respects circadian biology:
- Fewer side effects emerge
- Fewer ancillary medications are required
- Long-term sustainability improves
Microdosing TRT is not about more control.
It is about removing interference and allowing physiology to work as designed.
If you want to join live discussion on this topic and other real world protocols head over to my Skool Community
