FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, December 12, 2025

The ICV Axis: A Practical, Clinically Actionable Breakthrough for BHRT and Metabolic Medicine

Richard Z. Cheng, M.D., Ph.D., with Thomas E. Levy, M.D., J.D., and Ron Hunninghake, M.D.

(Based on the full academic review now online at: Cheng R., Levy T., Hunninghake R. The Insulin-Cortisol-Vitamin C Axis: A Missing Regulatory Framework in Metabolic and Hormonal Homeostasis. Preprints 2025 [1]).

🌟 Clinical Highlights

BHRT is now one of the most widely used interventions in functional and anti-aging medicine, yet a large proportion of patients experience persistent symptoms despite "perfect" hormone labs.

• Metabolic Syndrome and metabolic dysfunction (obesity, diabetes, hypertension, ASCVD, autoimmunity, and even cancer) dominate today's patient population - profoundly impairing hormonal signaling.
• BHRT cannot work reliably when insulin is high, cortisol is dysregulated, and vitamin C is depleted.
• The Insulin-Cortisol-Vitamin C (ICV) Axis provides the missing regulatory framework that determines whether hormone therapy succeeds or fails.
• Integrating the ICV Axis into BHRT is a breakthrough for Orthomolecular Medicine, demonstrating how micronutrients, metabolism, and redox biology regulate hormonal homeostasis.
• For clinicians: stabilizing insulin, cortisol, and vitamin C often fixes BHRT non-responders without increasing hormone doses.

Introduction: BHRT Is Booming-But Treatment Failures Are Everywhere

Bioidentical hormone replacement therapy (BHRT) has become a cornerstone of functional, integrative, and anti-aging medicine. Clinics worldwide now rely on BHRT to support:

• perimenopause and menopause
• andropause
• thyroid disorders
• mood instability
• sleep disorders
• cognitive decline
• metabolic dysfunction
• low libido and sexual health
• longevity optimization

Yet despite its popularity and biochemical logic, clinicians repeatedly encounter frustrating scenarios:

• "My estrogen/progesterone/testosterone labs look perfect, but I still feel awful."
• "My weight won't budge."
• "My hot flashes came back."
• "I still can't sleep."
• "My stress feels uncontrollable."

These are not "hormone problems."
They are metabolic-endocrine-redox problems.

Last year, Dr. Thomas Levy introduced the first description of the Insulin-Cortisol-Vitamin C triad [2]. Building on that insight, we have now published the complete mechanistic framework on Preprints.org - a synthesis of endocrinology, metabolic medicine, redox biology, and orthomolecular science.

This OMNS editorial is the practical, clinician-focused version - the "what to do in the clinic on Monday morning."

Why BHRT Often Fails: The Missing Axis

Traditional BHRT is built around a familiar triad:

1. Sex hormones (E2, P4, T)
2. Thyroid hormones
3. Adrenal hormones (cortisol/DHEA)

But this triad neglects the deeper regulatory system that determines whether hormones can actually work:

The Insulin-Cortisol-Vitamin C (ICV) Axis

This axis governs:

• metabolic flexibility
• inflammatory tone
• oxidative stress balance
• mitochondrial energy output
• SHBG regulation
• receptor sensitivity
• thyroid conversion
• adrenal resilience
• menopausal symptom variability
• weight regulation
• GLP-1 response

If the ICV axis is unstable, BHRT will be unstable. Always.

This explains why:

• Two patients with identical hormone labs respond very differently
• A "perfect" BHRT protocol produces inconsistent outcomes
• Chronic stress destroys BHRT progress
• Vitamin C deficiency worsens hot flashes, insomnia, and mood swings
• Some patients are "low-carb non-responders"
• GLP-1 agonists work brilliantly in some, not in others

Metabolic Dysfunction Dominates Modern Health - and BHRT Outcomes

The overwhelming majority of BHRT patients are not metabolically healthy.

They have:

• insulin resistance
• visceral obesity
• fatty liver
• hypertension
• cardiometabolic disease
• autoimmune conditions
• chronic inflammation
• mitochondrial exhaustion
• high cortisol
• vitamin C depletion

This is not a side issue - this is the clinical landscape of the 21st century.

BHRT cannot overcome metabolic dysfunction by adjusting hormone doses.

Hormones cannot act effectively when receptors are inflamed, oxidized, or insulin-resistant.

Why Tom Levy's Work Matters: The ICV Axis as the Root Problem

Dr. Levy's OMNS paper identified the core loop:

• Oxidative stress → insulin resistance
• Insulin resistance → cortisol dysregulation
• Cortisol dysregulation → vitamin C depletion
• Vitamin C depletion → more oxidative stress

A self-reinforcing metabolic-endocrine spiral.

Our full academic review expands this into a unifying systems-biology model linking:

• endocrinology
• mitochondrial biology
• stress physiology
• micronutrient science
• BHRT clinical patterns
• GLP-1 mechanisms
• metabolic resilience

This OMNS piece turns the model into a clinical protocol.

THE CLINICAL MESSAGE (The One Sentence Clinicians Must Remember)

**You cannot fix hormones unless you fix insulin, cortisol, and vitamin C.

And you cannot fix insulin and cortisol unless you replenish vitamin C.**

This is the missing key to modern BHRT.

How to Apply the ICV Axis in Your Clinic

Step 1 - Add Insulin Assessment to Every BHRT Visit

Check:

• fasting insulin
• post-prandial insulin
• HOMA-IR
• optional CGM variability

Insulin > 6 fasting
or > 30 post-prandial
= BHRT instability.

Step 2 - Treat Cortisol as a Metabolic Hormone

Evaluate:

• diurnal pattern
• sleep
• stress load
• nighttime cortisol
• circadian rhythm

Insulin follows cortisol.
Cortisol depends on vitamin C.

Step 3 - Restore Vitamin C as a Foundational Hormone-Modulating Molecule

Vitamin C is required for:

• cortisol synthesis AND shutdown
• catecholamine balance
• mitochondrial ATP generation
• nitric oxide regulation
• glutathione regeneration
• insulin signaling
• ovarian/testicular redox function

Low vitamin C clinically presents as:

• hot flashes
• insomnia
• emotional volatility
• insulin resistance
• estrogen/progesterone instability
• low testosterone response
• adrenal fatigue

Vitamin C is the most overlooked hormonal stabilizer in integrative medicine.

Step 4 - Fix the ICV Axis BEFORE escalating BHRT doses

Do not raise estrogen, progesterone, or testosterone when symptoms persist.

First correct:

• insulin
• cortisol
• vitamin C
• redox balance
• sleep
• inflammation
• mitochondrial function

After ICV correction, BHRT becomes predictable.

Step 5 - Reassess Hormones Only After ICV Stability

Once insulin and cortisol normalize:

• SHBG stabilizes
• thyroid conversion improves
• estrogen response smooths out
• progesterone sensitivity rises
• testosterone response becomes predictable
• weight loss accelerates
• vasomotor symptoms diminish

This is the physiology BHRT expects.

Why This Matters: A New Standard of Care for Functional & Orthomolecular Medicine

The ICV Axis explains:

• BHRT failures
• weight-loss resistance
• GLP-1 nonresponders
• menopausal symptom variability
• adrenal exhaustion
• lab/symptom mismatch
• metabolic crashes under stress

This framework elevates BHRT from trial-and-error hormone dosing to predictable, physiology-based treatment.

It also reinforces a central truth of Orthomolecular Medicine:

Micronutrient biology and redox balance are foundational determinants of hormone action.

Vitamin C - the signature orthomolecular molecule - is not only an antioxidant but a master regulator of endocrine and metabolic homeostasis.

The ICV Axis therefore represents one of the most significant conceptual advancements in Orthomolecular Medicine in the last decade.

ICV-Axis Clinical Checklist (For Every BHRT Patient)

• ☐ Fasting insulin < 6
• ☐ Post-prandial insulin < 30
• ☐ HOMA-IR < 1.2
• ☐ Stable cortisol curve
• ☐ Adequate vitamin C intake (oral or IV)
• ☐ Good sleep/circadian rhythm
• ☐ Low oxidative stress (hsCRP, GGT)
• ☐ Healthy mitochondrial status
• ☐ Adequate nitric oxide/endothelial function

If any box is unchecked →
Fix the ICV axis before increasing hormone doses.

Most "BHRT failures" resolve here.

Conclusion: A Transformative Update to BHRT and Metabolic Care

The ICV Axis is the missing regulatory framework for 21st-century hormone therapy.

By restoring insulin sensitivity, cortisol physiology, vitamin C sufficiency, redox health, and mitochondrial resilience, clinicians finally achieve:

• consistent BHRT outcomes
• metabolic stability
• hormonal sensitivity
• stress resilience
• weight regulation
• improved GLP-1 response
• predictable symptom control

This is the future of integrative endocrinology and Orthomolecular Medicine.

About the Author

Richard Z. Cheng, M.D., Ph.D. is Editor-in-Chief of the Orthomolecular Medicine News Service. He is a U.S.-based, NIH-trained, board-certified physician specializing in integrative oncology, orthomolecular medicine, and metabolic/functional medicine, with clinical practices in both the United States and China.

Dr. Cheng is a Hall of Fame inductee of the International Society for Orthomolecular Medicine and a Fellow of the American Academy of Anti-Aging and Regenerative Medicine (A4M). He has been active in advancing nutrition-based, root-cause approaches to chronic disease, co-founding the China Low Carb Medicine Alliance and serving as an expert reviewer for the South Carolina Board of Medical Examiners.

He is the author of the forthcoming book 21st Century Medicine: Integrative Orthomolecular Medicine for Chronic Disease Reversal and Longevity, which summarizes insights from five decades of clinical practice and research.

More of Dr. Cheng's writings are available at: https://substack.com/@rzchengmd

References

1. Cheng, R.Z.; Levy, T.E.; Hunninghake, R. The Insulin-Cortisol-Vitamin C Axis: A Missing Regulatory Framework in Metabolic and Hormonal Homeostasis A Narrative Review. 2025. DOI: 10.20944/preprints202512.0217.v1; Available online: https://www.preprints.org/manuscript/202512.0217.

2. Levy, T.E. GLP-1 Receptor Agonists and Vitamin C: A Powerful Anti-Aging Combination. Orthomolecular Medicine News Service 2025, 21, (66).; Available online: https://orthomolecular.org/resources/omns/v21n66.shtml.

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