Corey Schuler, PhD, FNP, CNS
A Case Study
It is not always obvious which endocrine axis is the prime mover and which is compensating. Thyroid labs may draw the eye, glucose patterns may shift, and symptoms may blur across systems. The following case illustrates a scenario in which hypothalamic-pituitary-adrenal (HPA) axis failure masquerades as evolving hypothalamic-pituitary-thyroid (HPT) axis dysfunction, and where treating the wrong axis first could destabilize the entire hormonal architecture.
Patient Presentation
A 36-year-old woman with a 12-year history of type 1 diabetes presents to clinic feeling “unwell.” Over the past few months, she has lost 15-16 pounds (7 kg) unintentionally. She reports several recent hypoglycemic episodes despite no intentional change in her insulin regimen. On examination, she appears pale and mildly dehydrated. Her blood pressure is 104/70 mmHg.
Laboratory results show:
- HbA1c 7% (High)
- Sodium 131 mmol/L (Low)
- Potassium 6.2 mmol/L (High)
- TSH 7 mU/L (High)
- Free T4 0.7 ng/dL (Low)
At first glance, one might fixate on the thyroid labs. An elevated TSH and low-normal free T4 suggest that Hypothyroidism seems to be emerging. But this is not a thyroid case. This is an HPA axis case, specifically one focused on the adrenals.
The Electrolytes Are Telling a Story
Hyponatremia. Hyperkalemia. Relative hypotension. This constellation should immediately shift your attention toward primary adrenal insufficiency. Loss of aldosterone leads to renal sodium wasting and potassium retention. Volume depletion follows. Blood pressure drops. Sodium falls. Potassium rises. [1][2] And then loss of cortisol adds additional layers: fatigue, weight loss, and, critically in this case, enhanced insulin sensitivity. [3]
So, what role does cortisol play in all of this? Cortisol is a counter-regulatory hormone. It supports gluconeogenesis and tempers insulin’s effects. When cortisol falls, insulin becomes more potent, and a patient previously stable on basal-bolus insulin may suddenly experience unexplained hypoglycemia despite no change in dosing. [3] This is why long-standing type 1 diabetes that suddenly becomes “easier” to manage, may suggest that something else is failing. Improved glycemic control is not always a victory. Sometimes it’s a warning.
The Autoimmune Context Matters
This patient already has type 1 diabetes. This alone places her at increased risk for other autoimmune endocrinopathies. [4] So, now we see:
- Type 1 diabetes
- Biochemical evidence of evolving primary hypothyroidism
- Electrolyte abnormalities consistent with adrenal insufficiency
This triad strongly suggests Autoimmune Polyglandular Syndrome Type 2 (APS-2). APS-2 classically includes:
- Primary adrenal insufficiency
- Autoimmune thyroid disease
- Type 1 diabetes [1][2]
And these disorders do not occur in isolation. Once the immune system has targeted one endocrine gland, others often follow, and endocrine autoimmunity clusters. This is not dysregulation, but it is a structural failure of hormone-producing tissue.
The Most Important Next Step
The priority now becomes confirming adrenal function. A morning serum cortisol with ACTH measurement is appropriate, followed by a short ACTH (cosyntropin) stimulation test if needed. In primary adrenal insufficiency, we expect:
- Low cortisol
- Elevated ACTH
- Impaired cortisol response to stimulation [5][6]
Identifying adrenal failure is not just diagnostically satisfying, but it is clinically urgent. Because here lies the trap. For now, the thyroid is a red herring. The labs suggest primary hypothyroidism, and this of course deserves attention, but in this case, it does not deserve attention first. That is because initiating thyroid hormone replacement in a patient with unrecognized adrenal insufficiency can precipitate adrenal crisis. [6] Why? Because thyroid hormone increases metabolic demand and enhances cortisol clearance. In a patient who is already cortisol-deficient, this can destabilize blood pressure and metabolic homeostasis rapidly. [6]
This clearly shows that the therapeutic sequence matters. Stabilize adrenal function must come first, then the thyroid can be addressed.
Medical Treatment Focus
Once the diagnosis is suspected or confirmed, the focus shifts from recognition to stabilization. Management must follow physiology, and the order of intervention matters.
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Stabilize Adrenal Function: The immediate therapeutic focus in confirmed primary adrenal insufficiency is physiologic adrenal hormone replacement and stabilization of volume and electrolytes. [5][6]
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Reassess Glucose Dynamics: In patients with type 1 diabetes, anticipate that insulin requirements may shift as adrenal function is corrected. Glucose management must be reassessed dynamically. This is not about adding another medication. It is about restoring hormonal architecture. [3][5][6]
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Address the Thyroid: Only after adrenal function is secured should thyroid replacement be considered after reassessment of labs and patient symptoms. [6]
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Confirm Etiology and Screen Longitudinally: In suspected autoimmune adrenal insufficiency, testing for 21-hydroxylase antibodies helps confirm autoimmune etiology. In patients with established autoimmune endocrinopathies, periodic screening for additional gland involvement is prudent. Thyroid peroxidase antibodies, celiac serologies, B12 status, and other autoimmune markers may also be relevant depending on the clinical picture. [3][7] Autoimmune surveillance is not over-testing. It is pattern recognition applied longitudinally.
So, What If the Numbers Were Borderline?
Let’s soften the picture and take some of the medical urgency out of the discussion. What if the sodium and potassium were technically within range but drifting? Sodium at 135. Potassium at 5.0. Still “normal.” Still defensible. But directionally similar. In that setting, we are no longer diagnosing adrenal failure. We are asking about resilience.
Borderline hyponatremia and upper-range potassium, especially alongside fatigue, weight change, and increased hypoglycemia may reflect evolving HPA axis strain, altered aldosterone signaling, or early-stage endocrine autoimmunity. The physiology may be compensating, but less efficiently.
And what if we see this type of presentation, but there is no autoimmune history? Now our lens widens. We consider medication effects, hydration status, overtraining, chronic stress load, caloric deficit, low carbohydrate intake, sleep disruption, or relative energy deficiency. We might assess renin-aldosterone dynamics, diurnal cortisol rhythm, micronutrient sufficiency, and total metabolic demand.
In this terrain, we are not treating collapse. We are supporting capacity. Endocrine patterns often whisper before they shout. Sometimes there is a fine line between functional patterns and medical urgency and it’s good to be prepared for both.
Final Thoughts
This case reinforces several high-yield clinical principles worth memorizing:
- Hyponatremia plus hyperkalemia equals adrenal until proven otherwise.
- Recurrent hypoglycemia in a patient with type 1 diabetes warrants evaluation beyond insulin dosing errors.
- Autoimmune diseases cluster. Always screen the axes.
- Hold on treatment of hypothyroidism using exogenous thyroid hormones before ruling out adrenal insufficiency in an unwell patient.
We often speak about “axis dysregulation” in functional and integrative frameworks, but this is different. This is axis collapse. The HPA axis here is not overstimulated or under-recovered. The adrenal cortex itself is failing. The signaling may be intact, but the effector organ is not, and that distinction matters.
And for practitioners who think in terms of HPA, HPT, and metabolic integration, this case is a vivid reminder that these axes do not operate in isolation. Cortisol deficiency alters glucose regulation. Volume depletion alters renal electrolyte handling. And thyroid replacement alters cortisol demand.
The endocrine system behaves less like a set of independent pathways and more like an orchestra. When you remove one instrument, the entire sound changes. Sometimes dramatically.
This is why pattern recognition matters. When a chronic condition suddenly improves or destabilizes, pause. The body rarely changes course without reason. If a patient with longstanding type 1 diabetes starts having unexplained hypoglycemia, losing weight, and developing subtle hypotension, do not congratulate the pancreas. Look at the HPA axis as well as the HPT axis. Endocrinology rewards those who listen to patterns. And in this initial presenting case, the pattern is loud.
Disclaimer:
The information provided is for educational purposes only. Consult your physician or healthcare practitioner if you have specific questions before instituting any changes in your daily lifestyle including changes in diet, exercise, and supplement use.
Corey Schuler, PhD, FNP, CNS has dedicated his career to advancing the science and clinical art of integrative medicine and serves as director of medical affairs for Allergy Research Group. He is a family nurse practitioner and practices holistic primary care at Synergy Family Physicians in White Bear Lake, Minnesota.