Adrenal Fatigue / HPA Axis Dysfunction Protocol

Beyond “Adrenal Fatigue”

The term “adrenal fatigue” has been dismissed by conventional endocrinology — and they’re half right. The adrenal glands themselves rarely “fatigue” in the way a muscle fatigues. They don’t run out of cortisol-producing capacity in most cases (Addison’s disease — true adrenal insufficiency — is a separate, rare condition). What actually happens is far more nuanced and clinically important: the hypothalamic-pituitary-adrenal (HPA) axis becomes dysregulated.

The HPA axis is a three-tier communication system. The hypothalamus senses stress (physical, emotional, inflammatory, infectious, toxic) and releases CRH (corticotropin-releasing hormone). CRH signals the anterior pituitary to release ACTH (adrenocorticotropic hormone). ACTH signals the adrenal cortex to produce cortisol, DHEA, aldosterone, and other adrenal hormones. Cortisol then feeds back to the hypothalamus and pituitary, suppressing further CRH and ACTH release. It is a thermostat — elegant when working, devastating when broken.

Chronic stress — whether from overwork, sleep deprivation, emotional trauma, chronic infection, mold exposure, gut inflammation, blood sugar dysregulation, or toxic burden — keeps this axis firing. Initially it compensates. Eventually it maladapts. The signaling becomes aberrant: the rhythm flattens, the feedback loops distort, and the patient enters a state where their stress response is simultaneously overactive and underperforming. The term “HPA axis dysregulation” is more accurate than “adrenal fatigue,” and it is increasingly recognized even in conventional literature.

Stages of HPA Axis Dysfunction

Stage 1: Alarm (High Cortisol, High DHEA)

The body is mounting a full stress response. Cortisol is elevated — especially in the morning and often remaining elevated throughout the day instead of following its normal diurnal decline. DHEA (the counter-regulatory “anabolic” adrenal hormone) is also elevated, matching the cortisol output.

Symptoms: “Wired but tired.” Anxiety, especially morning anxiety. Racing thoughts at bedtime. Insomnia — difficulty falling asleep because cortisol isn’t dropping at night, or 2-4 AM waking from cortisol surges. Weight gain concentrated in the midsection (cortisol drives visceral fat deposition through increased insulin resistance and lipogenesis via 11-beta-HSD1 in abdominal adipocytes). Elevated blood sugar. High blood pressure. Increased appetite, especially for sugar and carbohydrates. Reduced immunity — frequent colds that linger. Impaired digestion (cortisol suppresses digestive enzyme secretion and diverts blood away from the gut). Irritability, short fuse, emotional reactivity.

This stage can persist for months to years. The person functions — sometimes at a high level — but they’re burning through reserves. It’s running an engine at redline continuously. The machine keeps going, but the oil is burning, the seals are wearing, and eventually something gives.

Stage 2: Resistance (Cortisol Dysregulated, DHEA Declining)

The axis begins losing coherence. Morning cortisol may still be adequate (or even high), but the curve is wrong — instead of the normal peak-and-decline pattern, cortisol might be low in the morning, rise inappropriately in the afternoon, or crash mid-afternoon and then spike at night. DHEA production is declining as the adrenals preferentially shunt pregnenolone toward cortisol production (the “pregnenolone steal” — whether this operates at the substrate level or the hypothalamic-pituitary signaling level is debated, but the clinical pattern is real).

Symptoms: Fatigue that is worse in the morning and mid-afternoon, with a paradoxical “second wind” at night (10 PM to midnight — finally feeling alert when they should be sleeping). Energy is a rollercoaster throughout the day. Brain fog increasing. Blood sugar instability — getting “hangry,” shaky, or lightheaded between meals as cortisol fails to maintain gluconeogenesis. Increased reliance on caffeine (borrowing from tomorrow’s reserves). Libido declining. PMS worsening (progesterone falling as pregnenolone diverts). Thyroid function declining (cortisol dysregulation impairs T4 to T3 conversion and increases Reverse T3). Exercise recovery is prolonged — workouts that used to energize now exhaust for 1-2 days afterward.

Stage 3: Exhaustion (Low Cortisol, Low DHEA)

The HPA axis has downregulated. Cortisol output is low across the entire day — the morning cortisol awakening response (CAR) is blunted or absent. DHEA is depleted. Pregnenolone is depleted. The entire adrenal hormone cascade is suppressed. The hypothalamus and pituitary have turned the volume down — not because the adrenal glands are incapable, but because the signaling axis has maladapted to chronic demand.

Symptoms: Severe, unrelenting fatigue. Cannot wake up in the morning regardless of sleep duration — hitting the snooze button repeatedly, feeling like gravity has doubled. Need 10-12 hours of sleep and still feel unrefreshed. Orthostatic hypotension (dizziness upon standing — aldosterone, co-produced in the adrenal cortex, is also low, causing sodium wasting and blood pressure drops). Salt cravings (the body craving sodium to compensate for aldosterone deficiency). Cannot handle stress — minor events (traffic, a rude email, a child crying) trigger a disproportionate physiological and emotional response. Hypoglycemia between meals (cortisol normally maintains blood sugar through gluconeogenesis — without it, blood sugar crashes 2-3 hours after eating). Depression, apathy, flat affect. Muscle weakness. Low body temperature (consistently below 98.0F). Chronic infections that won’t resolve (cortisol modulates immune function — without it, the immune response is both overactive and ineffective). Fibromyalgia-like pain (cortisol is the body’s primary anti-inflammatory hormone).

Testing

The DUTCH Complete (Gold Standard)

The DUTCH (Dried Urine Test for Comprehensive Hormones) test by Precision Analytical is the most informative single test for HPA axis assessment. The patient collects 4-5 dried urine samples over a 24-hour period (upon waking, 2 hours after waking, afternoon, evening, bedtime).

The DUTCH measures:

• Free cortisol at each time point (reveals the diurnal rhythm — the PATTERN matters more than any single value)
• Free cortisone at each time point (cortisone is the inactive form; the cortisol:cortisone ratio reveals 11-beta-HSD enzyme activity — whether cortisol is being inactivated too quickly or not quickly enough)
• Cortisol metabolites (tetrahydrocortisol, allo-tetrahydrocortisol, tetrahydrocortisone): These reveal TOTAL cortisol production, which can differ dramatically from free cortisol. A patient can have low free cortisol but HIGH metabolized cortisol — meaning production is adequate but clearance is excessive (common in hypothyroidism and liver dysfunction). Or high free cortisol with low metabolites — meaning production is normal but clearance is impaired. This distinction changes treatment entirely.
• Cortisol Awakening Response (CAR): The surge of cortisol in the first 30-45 minutes after waking. A healthy CAR shows a 50-75% rise above the waking baseline. A blunted CAR (less than 30% rise or no rise) is one of the most sensitive early markers of HPA axis dysfunction, often appearing before total cortisol levels themselves drop to “abnormal.”
• DHEA-S and DHEA metabolites: Reveals adrenal androgen production capacity
• Sex hormones and metabolites: Estrogens, progesterone, androgens — the full hormonal picture contextualized with adrenal status
• Melatonin metabolite (6-hydroxymelatonin sulfate): Confirms circadian rhythm status

Cost: approximately $300-400. Replaces multiple inferior tests and provides actionable precision.

Salivary Cortisol x4

The traditional functional medicine adrenal test: four saliva samples collected at waking (within 30 minutes), noon, late afternoon (4-5 PM), and bedtime (10-11 PM). Maps the diurnal cortisol curve. Less comprehensive than DUTCH (no metabolites, no cortisone ratio, no CAR), but more accessible and less expensive ($100-200). Labs: ZRT Laboratory, DiagnosTechs, Genova Diagnostics.

Interpreting the curve: Normal is high morning (10-20 nM), declining through the day, lowest at bedtime (<2 nM). Stage 1 shows elevated across all four points. Stage 2 shows an abnormal pattern (low AM / high PM, or adequate AM with crash at noon). Stage 3 shows low across all four points with no meaningful variation.

Blood Tests (Supporting Data)

• AM cortisol (drawn at 8 AM, fasting): Reference range 6-23 mcg/dL. Below 10 is suspicious for significant HPA dysfunction. Below 3 warrants an ACTH stimulation test to rule out Addison’s disease. Above 20 at 8 AM is reassuring for adrenal production capacity. Limitation: a single blood draw captures ONE moment — cortisol fluctuates with meals, stress, sleep, and circadian rhythm.
• ACTH: Differentiates primary adrenal failure (ACTH high, cortisol low — Addison’s disease, where the adrenal glands themselves are damaged) from secondary/central failure (ACTH low or inappropriately normal, cortisol low — pituitary or hypothalamic origin, which is what most HPA dysfunction actually is).
• DHEA-S serum: The most stable adrenal androgen marker (long half-life, minimal diurnal variation). Optimal range varies by age: roughly 200-350 mcg/dL for adult women, 300-500 mcg/dL for adult men. Low DHEA-S with high cortisol indicates pregnenolone steal. Low DHEA-S with low cortisol confirms Stage 3 exhaustion.
• Pregnenolone serum: The “mother hormone” — precursor to all adrenal and sex hormones. Low pregnenolone (below 30 ng/dL) indicates upstream depletion. Optimal: 50-100 ng/dL.
• Fasting glucose and insulin: Cortisol dysregulation drives blood sugar instability. Calculate HOMA-IR (fasting insulin x fasting glucose / 405). Above 2.0 indicates insulin resistance.
• Comprehensive metabolic panel: Sodium may be low in aldosterone deficiency, potassium may be elevated, CO2 (bicarbonate) often low reflecting metabolic acidosis.

Stage 1 Protocol (High Cortisol)

The goal is to calm the overactive HPA axis, lower cortisol, protect tissues from cortisol excess, and restore the normal diurnal decline.

Supplements

Phosphatidylserine: 400-800mg at night (some protocols split 200mg with dinner, 400-600mg at bedtime). Phosphatidylserine directly blunts the cortisol response to stress by attenuating ACTH release from the pituitary. Research by Monteleone et al. (1992) demonstrated that 800mg reduced cortisol and ACTH responses to exercise stress by 20-30%. This is the most directly cortisol-lowering supplement available without a prescription.

Ashwagandha KSM-66: 600mg daily (300mg twice daily or 600mg at night). The most studied adaptogen for cortisol reduction. A double-blind RCT (Chandrasekhar et al., 2012, Indian Journal of Psychological Medicine) showed KSM-66 reduced serum cortisol by 27.9% versus placebo over 60 days. Ashwagandha modulates the HPA axis at the hypothalamic level, reducing CRH output. Also improves sleep quality (significant improvement in sleep onset latency and quality), reduces anxiety via GABAergic activity, and supports thyroid function (shown to raise T4 in subclinical hypothyroid patients).

Holy basil (Tulsi): 500mg twice daily (standardized extract). Adaptogen that reduces cortisol, lowers blood sugar, reduces anxiety without sedation. In Ayurveda, Tulsi is considered “the incomparable one” — a sattvic herb that calms the mind while clarifying it. Modern research confirms HPA-axis modulation, antioxidant effects, COX-2 inhibition, and anti-inflammatory activity.

L-theanine: 200mg twice daily (or 200mg as needed for acute stress/anxiety). An amino acid from Camellia sinensis (green tea) that increases alpha brain wave activity (the calm-alert state), boosts GABA, serotonin, and dopamine, and blunts the cortisol response to acute stress. Crosses the blood-brain barrier within 30-40 minutes of ingestion. No sedation, no dependency, no tolerance development. Suntheanine is the most studied form.

Magnesium glycinate: 400-600mg at bedtime. Magnesium is the “relaxation mineral” — cofactor for over 300 enzymatic reactions, calms the nervous system via NMDA receptor modulation, supports GABA-A receptor binding, and is actively depleted by cortisol (cortisol promotes renal magnesium excretion, creating a vicious cycle: stress depletes magnesium, low magnesium increases stress reactivity). The glycinate form provides both superior absorption and the calming benefit of glycine as an inhibitory neurotransmitter.

Magnolia bark (Honokiol) + Phellodendron (Relora): 250mg 2-3 times daily. Honokiol modulates GABA-A receptors (similar anxiolytic mechanism to benzodiazepines but without dependency or tolerance). Combined as the patented formula Relora, this has been studied for cortisol reduction, stress-related eating, and anxiety.

Lifestyle (Non-Negotiable)

• No caffeine after noon. Caffeine has a half-life of 5-6 hours (longer in CYP1A2 slow metabolizers — test with DUTCH or genetic panel). A 2 PM coffee still has 50% of its caffeine circulating at 7-8 PM, stimulating cortisol when it should be declining toward its nighttime nadir.
• Blue light blocking after sunset. Blue light (460-480nm wavelength) suppresses melatonin secretion via melanopsin receptors in retinal ganglion cells and signals daytime wakefulness to the suprachiasmatic nucleus. Wear amber/orange-tinted glasses (blue-blocking) after 8 PM or use f.lux/Night Shift on all devices.
• Meditation: 10-20 minutes daily. Mindfulness-Based Stress Reduction (MBSR, Jon Kabat-Zinn’s protocol) documented to reduce cortisol 25-30% in multiple meta-analyses. Transcendental Meditation, Vipassana, or simple breath awareness — consistency matters more than tradition.
• Yin yoga or restorative yoga: Slow, supported postures held 3-5 minutes each, activating the parasympathetic nervous system through sustained stretch and stillness. Evening practice. Avoid vigorous vinyasa, hot yoga, or power yoga in Stage 1 — these generate cortisol.
• Sleep by 10 PM: The cortisol nadir occurs around midnight. Growth hormone pulses in the first 90 minutes of deep sleep (NREM Stage 3-4), typically between 10 PM and midnight when circadian timing is honored. Missing this window impairs tissue repair and HPA recovery.
• Nature exposure: 20+ minutes in green space daily. Japanese “shinrin-yoku” (forest bathing) documented to lower salivary cortisol, blood pressure, and sympathetic nervous system activity.

Stage 3 Protocol (Low Cortisol)

The goal is to support adrenal output, provide raw materials for hormone synthesis, restore the cortisol awakening response, prevent further depletion, and create the conditions for HPA axis recovery.

Supplements

Adrenal glandulars: 250-500mg upon waking and at noon (never after 2 PM — can disrupt sleep). Whole adrenal cortex extract from bovine or porcine sources provides bioidentical cortisol precursors, peptides, and cofactors that directly support adrenal recovery. Brands: Thorne Adrenal Cortex, Standard Process Drenamin, Nutri-Meds Adrenal Cortex. Start with one capsule in the morning, add noon dose after 1-2 weeks if tolerated. Some patients with very low cortisol need these just to get through the day while other interventions take effect.

Licorice root (Glycyrrhiza glabra): 200-400mg of whole root extract in the MORNING ONLY (with breakfast). Glycyrrhizin, the active compound, inhibits 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2) — the enzyme that converts active cortisol into inactive cortisone in target tissues. By blocking this conversion, licorice effectively EXTENDS the half-life of whatever cortisol the body is producing, making each molecule work longer. This is not producing more cortisol — it is conserving what exists.

CRITICAL WARNING: Licorice is CONTRAINDICATED in hypertension. By preserving cortisol (which has mineralocorticoid activity through aldosterone receptor cross-reactivity), licorice raises blood pressure and promotes potassium loss. Monitor blood pressure weekly. Do NOT take in the afternoon or evening. Do NOT exceed 400mg daily of whole root. Do NOT combine with aldosterone-sparing diuretics or potassium-wasting medications. Deglycyrrhizinated licorice (DGL) does NOT have this effect — the glycyrrhizin has been removed. DGL is for gut healing, not adrenal support.

Pantothenic acid (Vitamin B5): 500mg twice daily. The adrenal glands contain the highest concentration of pantothenic acid of any organ. B5 is converted to coenzyme A (CoA), which is required for every step of steroid hormone synthesis from cholesterol to cortisol, DHEA, aldosterone, and all downstream hormones. Depletion of B5 directly impairs adrenal hormone output. This is the single most adrenal-specific B vitamin.

Vitamin C: 1-3g daily in divided doses. The adrenal glands contain the highest concentration of vitamin C of any tissue in the body — approximately 100 times the blood concentration. Vitamin C is consumed as a cofactor during the hydroxylation steps of cortisol synthesis (specifically at CYP11B1 and CYP21A2). Under stress, adrenal vitamin C stores are rapidly depleted. A study in Psychopharmacology (2001) found that 3000mg daily attenuated both cortisol and subjective stress responses.

DHEA: 5-25mg in the morning only. Women start at 5mg (DHEA converts to androgens via peripheral aromatase and 17-beta-HSD — excessive dosing causes acne, hirsutism, irritability). Men can start at 25mg. MUST test DHEA-S before supplementing and recheck at 6-8 weeks. Target: age-appropriate optimal range (roughly 200-350 mcg/dL). DHEA opposes many of cortisol’s catabolic effects: it supports immune function, bone density, mood, cognitive function, and libido.

Pregnenolone: 10-30mg in the morning. The “mother hormone” — cholesterol is converted to pregnenolone via the StAR protein and CYP11A1 enzyme in mitochondria, and from there pregnenolone branches into cortisol, DHEA, progesterone, testosterone, and estrogen pathways. Low pregnenolone means the entire cascade is substrate-limited. Supplementing upstream provides the body raw material to allocate according to its own priorities. Test serum pregnenolone before and after starting.

Rhodiola rosea: 200-400mg in the morning (standardized to 3% rosavins, 1% salidroside). A true bidirectional adaptogen — normalizes cortisol regardless of direction (raises low, lowers high). Studies demonstrate improved fatigue, cognitive function, mental performance under stress, and exercise recovery. Acts at the hypothalamic level and also enhances mitochondrial ATP production via AMPK activation. Take in the morning only — mildly energizing, can interfere with sleep if taken late.

Salt loading: 1/4 teaspoon unrefined sea salt (Celtic grey salt, Himalayan pink salt) in morning water. Stage 3 often involves low aldosterone (co-regulated with cortisol in the zona glomerulosa), causing sodium wasting, low blood volume, and orthostatic hypotension. The salt cravings that Stage 3 patients experience are the body’s signal. Celtic sea salt provides sodium plus 82 trace minerals.

Lifestyle (Critical — These Are Interventions, Not Suggestions)

• No fasting. Intermittent fasting is popular but CONTRAINDICATED in Stage 3. Cortisol is required for gluconeogenesis — maintaining blood sugar between meals by converting protein and glycerol to glucose. When cortisol is low, the body cannot maintain blood sugar during even short fasts. Hypoglycemia triggers emergency adrenaline (epinephrine) release — the shaking, anxiety, lightheadedness, and irritability that Stage 3 patients experience between meals. Eat regularly, every 3-4 hours.
• Eat within 1 hour of waking. Include protein (20-30g), healthy fat, and complex carbohydrates. Do NOT start the day with coffee alone — this stimulates cortisol demand without providing substrate for the adrenals to work with.
• No intense exercise. Counterintuitive but biochemically essential. Intense exercise (HIIT, CrossFit, long-distance running, heavy resistance training) is a physiological stressor that demands cortisol. Stage 3 patients don’t have the cortisol to support recovery — they crash for 1-3 days after intense workouts, feeling worse than before. Post-exertional malaise is a hallmark. Appropriate exercise during recovery: walking 20-30 minutes, gentle yoga, tai chi, swimming, light resistance training. The test: if you need a nap after a workout or feel worse the next day, you have exceeded your current capacity. As adrenal function recovers (tracked by DUTCH or salivary cortisol), gradually and carefully reintroduce intensity.
• Sleep by 10 PM. The regenerative growth hormone pulse occurs in the first 90 minutes of deep NREM sleep, typically between 10 PM and midnight when circadian timing is honored. Cortisol nadir is around midnight. Every hour of sleep before midnight is worth more than sleep after.
• Reduce stressors mercilessly. This is the hardest prescription and the most important. Say no to commitments. Delegate. Drop obligations that are not essential. Reduce screen time. Limit news and social media. Create boundaries with energy-draining relationships. The HPA axis cannot recover if the incoming stress load exceeds the repair capacity. This is not weakness — it is biology.

The Adrenal-Thyroid Connection

The adrenals and thyroid are so deeply intertwined that treating one while ignoring the other is a clinical mistake that explains many treatment failures. Cortisol affects thyroid function at every level of the axis:

• High cortisol suppresses TSH secretion from the pituitary (masking hypothyroidism on lab work)
• High cortisol inhibits D1 and D2 deiodinase enzymes that convert T4 to active T3
• High cortisol increases D3 deiodinase, shunting T4 toward inactive Reverse T3
• High cortisol decreases thyroid hormone receptor sensitivity at the cellular level
• Low cortisol means thyroid hormones cannot be utilized at the cellular level — cells need cortisol to respond to T3. Starting thyroid medication in a patient with Stage 3 HPA dysfunction can precipitate an adrenal crisis: increased metabolic rate without the cortisol to support it causes anxiety, palpitations, tremor, and worsening fatigue

Clinical rule: Always test both axes simultaneously (DUTCH or salivary cortisol + complete thyroid panel including Free T3, Reverse T3, and antibodies). If both are dysfunctional, address the adrenals FIRST or simultaneously with thyroid support. Starting thyroid medication alone in a cortisol-depleted patient often makes them feel dramatically worse — and the practitioner mistakenly concludes “their thyroid is fine” or “they don’t tolerate thyroid medication.”

Recovery Timeline

HPA axis recovery is not linear. Expect good days, bad days, and setbacks with any new stressor. The trajectory matters more than any single day.

• Stage 1 to normal: 3-6 months with appropriate cortisol-lowering protocol plus lifestyle modification. The most responsive stage — removing the stressor and calming the axis often produces rapid improvement.
• Stage 2 recovery: 6-12 months. The transitional stage is the messiest — symptoms fluctuate as the axis attempts to recalibrate its rhythm. Testing every 3-4 months guides supplement adjustments.
• Stage 3 recovery: 6-24 months. The deeper and longer the depletion, the longer the recovery. Patients who have been in Stage 3 for years may require 18-24 months. Adrenal glandulars, DHEA, and pregnenolone serve as bridges while the axis rebuilds. Severe cases (chronic fatigue syndrome, long-term burnout, PTSD) may require physiologic-dose hydrocortisone (Jefferies protocol: 15-20mg daily in divided doses, physician-supervised) as temporary support.

The adrenals are resilient organs. They want to recover. Given the conditions — reduced stress load, adequate sleep, nutrient repletion, and time — they rebuild. The supplements are scaffolding. The lifestyle changes are the foundation. And the hardest truth is this: the body heals at the speed of biology, not the speed of ambition.

In the yogic tradition, there is a concept called “tapas” — the heat of disciplined practice. But tapas without “ahimsa” (non-harming) becomes self-destruction. The Stage 3 patient has practiced tapas to the point of burning out the fire. Recovery requires ahimsa — toward the body, toward the nervous system, toward the self that has been running on empty for too long. Rest is not laziness. Rest is medicine. The HPA axis recovers not through force, but through the radical act of allowing the body to be still.