Dr. Mike Ren also contributed to this post.
At first, the endocrine system might seem like an elusive topic—no singular organ to visualize or dissect. Without a big sexy organ (like a heart, brain, or lungs) to rally behind, it is everywhere and nowhere at the same time. However, inside your body, hormones keep the train moving. The health of your patients depends on such an exquisite balance of hormones that are easy to take for granted. That is, until they get out of balance, and we suffer the effects.
The endocrine system is the body’s internal communication network, regulating everything from metabolism and blood pressure to mood and growth. It’s subtle but mighty, and mastering its feedback loops and hormone pathways is key to acing the USMLE Step 1.
Let’s break down the most high-yield concepts in endocrine physiology and pathology, with explanations, examples, and study tips to keep this vital system from slipping through the cracks.
Don’t Let Endocrine Leave You Endo-Cryin’: A High-Yield Endocrinology Guide for Step 1
Feedback Inhibition: The Endocrine Core Principle
At the heart of the endocrine system lies feedback inhibition, and if you understand this, you’ve got a foot in the door. Nearly every hormone is regulated by a loop that ensures homeostasis. Think of it like a thermostat: when the temperature (hormone level) gets too high, the system turns off the heat.
A classic example is the hypothalamic-pituitary-thyroid (HPT) axis: the hypothalamus releases thyrotropin-releasing hormone (TRH), which signals the pituitary to secrete thyroid-stimulating hormone (TSH), prompting the thyroid to produce T3 and T4. When T3/T4 levels are high enough, they signal back to the hypothalamus and pituitary to reduce TRH and TSH production. This negative feedback loop keeps things in check.
Understanding these relationships allows you to understand why lab values can be the way they are. In primary endocrine failure (e.g., hypothyroidism due to thyroid damage), target hormone levels drop while stimulating hormones rise. In secondary or tertiary failures (pituitary or hypothalamic), both hormone levels drop. Get comfortable thinking in this layered fashion—it’s a foundation for interpreting almost every hormone disorder.
Primary hypothyroidism (e.g., Hashimoto’s) results in low T3/T4 and elevated TSH (the pituitary tries to compensate).
Secondary hypothyroidism (pituitary failure) leads to low TSH and low T3/T4 (lack of signal from the pituitary).
The Adrenal Gland: Layers, Hormones, and Insufficiency
The adrenal cortex is a tri-layered factory of critical hormones, and a great way to remember them is by thinking GFR—just like the kidney beneath it. The zona glomerulosa produces aldosterone, the zona fasciculata makes cortisol, and the zona reticularis synthesizes androgens (DHEA). The adrenal medulla, deeper still, produces catecholamines like epinephrine and norepinephrine.
Next, write ACAC alongside GFR. On the left are your layers, and on the right are the products of them:
Glomerulosa | Aldosterone
Fasiculata | Cortisol
Reticularis | Androgens (DHEA)
(Medulla) | Catecholamines
If you want me to spell it out for you:
Zona Glomerulosa produces aldosterone, which increases blood pressure via sodium retention and potassium excretion (regulated by the renin-angiotensin-aldosterone system, RAAS).
Zona Fasciculata secretes cortisol, a stress hormone that raises blood glucose and suppresses inflammation.
Zona Reticularis releases weak androgens like DHEA, contributing to sex hormone production.
The medulla produces epinephrine and norepinephrine, driving the fight-or-flight response.
When the adrenals stop working, you can lose the function of all of these crucial hormone classes. Without aldosterone, your blood pressure will suffer, Na goes down, K goes up. Without cortisol, blood pressure will suffer, and hypoglycemia will ensue. The lack of catecholamines can also lead to low blood pressure, and missing any and all of the above will lead to a deep sense of fatigue. If you suspect adrenal insufficiency based on H&P and lab values, definitely consider autoimmune disease and tuberculosis at the top of your list.
A factoid worth mentioning: lack of cortisol leads to an increase of the hormone POMC (pro-opiomelanocortin). This protein is cleaved to form endogenous OPIOids, MELANin, and CORTIcotropin, or ACTH (which stimulates cortisol production). The melanin leads to skin darkening, and that’s why adrenal insufficiency can cause hyperpigmentation! How cool is that?
The HP-X Axis: Command Central
Every major endocrine pathway flows from the hypothalamus to the pituitary and then down to a target organ—this is the hypothalamic-pituitary (HP) axis.
Hypothalamus secretes a releasing hormone (e.g., TRH, CRH, GnRH).
Pituitary secretes a tropic hormone (e.g., TSH, ACTH, FSH/LH).
Then the target organ produces the final hormone (e.g., T3/T4, cortisol, estrogen/testosterone).
Key Pathologies:
Sheehan’s syndrome (postpartum pituitary necrosis) → panhypopituitarism (deficiency of all pituitary hormones).
Prolactinoma (most common pituitary tumor) → hyperprolactinemia, causing galactorrhea and amenorrhea.
For Step 1, don’t just memorize the hormones—understand how dysfunction at each level (hypothalamus, pituitary, or end organ) affects hormone levels up and down the chain. When something goes wrong, these patterns determine the diagnosis.
Congenital Adrenal Hyperplasia: Think Enzyme Block, Hormone Shift
CAH is a group of autosomal recessive disorders caused by enzymatic defects in cortisol synthesis. The most common is 21-hydroxylase deficiency, which leads to reduced cortisol and aldosterone and increased androgens. This explains the classic presentation of hypotension, hyponatremia, and virilization of female infants.
Some tips:
Cortisol and aldosterone production drops → adrenal crisis (salt-wasting, hypotension).
Androgen precursors accumulate → virilization (female infants may present with ambiguous genitalia).
Here’s the golden rule: if one pathway is blocked, hormone production is shunted to the others. So if you can’t make mineralocorticoids or glucocorticoids, you’ll overproduce androgens. If instead 11β-hydroxylase is deficient, you’ll have excess deoxycorticosterone, which has mineralocorticoid activity and leads to hypertension.
A chart to guide you:
|
Enzyme Deficiency |
Cortisol |
Aldosterone |
Androgen |
BP |
K+ |
|
21-hydroxylase |
↓ |
↓ |
↑ |
↓ |
↑ |
|
11β-hydroxylase |
↓ |
↓ |
↑ |
↑ |
↓ |
|
17α-hydroxylase |
↓ |
↑ |
↓ |
↑ | ↓ |
Cortisol and Cushing’s Syndrome: Stress Gone Wild
Cortisol, released from the zona fasciculata of the adrenal cortex, is the body’s main stress hormone. It boosts blood glucose through gluconeogenesis, increases blood pressure via α1 receptor upregulation, and suppresses both the immune system and inflammation.
Cushing’s syndrome refers to the clinical signs and symptoms of chronic cortisol excess: moon facies, buffalo hump, abdominal striae, glucose intolerance, easy bruising, and osteoporosis. The most common cause is iatrogenic—long-term use of corticosteroids. Cushing’s disease, however, is specifically due to a pituitary ACTH-secreting adenoma.
To diagnose, use the low-dose dexamethasone suppression test. If cortisol isn’t suppressed, measure ACTH. High ACTH suggests a pituitary tumor or ectopic ACTH production (like small cell lung cancer); low ACTH suggests an adrenal tumor.
Cortisol has widespread effects:
- ↑Blood glucose (via gluconeogenesis and insulin resistance).
- Immunosuppression (explaining why steroids treat autoimmune diseases).
- Catabolic state → muscle wasting, thin skin, purple striae.
Cushing’s Syndrome vs. Cushing’s Disease
- Syndrome = any cause of excess cortisol (e.g., exogenous steroids, adrenal tumor, ectopic ACTH from lung cancer).
- Disease = pituitary ACTH-secreting adenoma (most common endogenous cause).
Parathyroid Hormone: Calcium’s Puppet Master
PTH increases serum calcium through three mechanisms: stimulating bone resorption, increasing renal reabsorption of calcium (while decreasing phosphate), and activating vitamin D, which enhances GI calcium absorption. This makes PTH the prime mover in calcium balance.
In primary hyperparathyroidism (often due to parathyroid adenoma), you’ll see hypercalcemia, hypophosphatemia, and symptoms like kidney stones, bone pain, abdominal discomfort, and depression—the classic “stones, bones, groans, and psychiatric overtones.” In secondary hyperparathyroidism, such as in chronic kidney disease, the parathyroids are overactive due to hypocalcemia, but serum calcium levels are often low or normal.
PTH increases serum calcium by:
- Stimulating bone resorption (releasing Ca²⁺).
- Enhancing renal Ca²⁺ reabsorption while excreting phosphate.
- Activating vitamin D, increasing gut Ca²⁺ absorption.
Hyperparathyroidism
- Primary (↑PTH, ↑Ca²⁺) – Usually due to a parathyroid adenoma; causes osteoporosis, kidney stones, and hypercalcemia symptoms (fatigue, polyuria, abdominal pain).
- Secondary (↑PTH, ↓Ca²⁺) – Seen in chronic kidney disease (impaired vitamin D activation → chronic hypocalcemia → PTH overproduction).
The Thyroid: Metabolism’s Master Switch
The thyroid produces T3 and T4 in response to TSH stimulation. These hormones increase basal metabolic rate and oxygen consumption. Hyperthyroidism results in anxiety, weight loss, heat intolerance, and tachycardia, while hypothyroidism causes fatigue, weight gain, cold intolerance, and constipation.
For Step 1, know the autoimmune diseases: Graves’ disease is caused by TSH receptor-stimulating antibodies and presents with exophthalmos and diffuse goiter. Hashimoto’s thyroiditis, the most common cause of hypothyroidism in developed countries, is linked to anti-TPO antibodies and carries an increased risk of lymphoma.
Papillary thyroid cancer is the most common thyroid malignancy, often showing Orphan Annie eye nuclei, psammoma bodies, and good prognosis.
Pheochromocytoma: A Dangerous Surge
Though rare, pheochromocytomas offer excellent learning. These catecholamine-secreting tumors arise from adrenal medullary chromaffin cells. Their hallmark is episodic hypertension, along with headaches, palpitations, sweating, and anxiety.
Diagnosis starts with plasma metanephrines or 24-hour urinary catecholamines. Pre-surgical management requires alpha-blockade (phenoxybenzamine) before starting beta-blockers, to avoid unopposed α-stimulation and hypertensive crisis.
Remember the Rule of 10s:
10% are bilateral, malignant, extra-adrenal, or familial (though newer genetic studies suggest higher familial percentages).
Diabetes Mellitus, DKA, and HHS: The Crown Jewel
You’ll almost certainly get tested on diabetes, so understand it well. Type 1 DM is autoimmune, destroying pancreatic β-cells and leading to insulin deficiency. It typically presents in youth and carries a risk of diabetic ketoacidosis (DKA). Type 2 DM, by contrast, is insulin resistance progressing to β-cell burnout and is closely tied to obesity and metabolic syndrome.
Complications of both types include microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (CAD, stroke, PAD) damage. Chronic hyperglycemia damages the vasculature, nerves, and kidneys.
DKA occurs mostly in Type 1 and involves ketone production due to unopposed glucagon and stress hormones. Symptoms include nausea, Kussmaul respirations, fruity breath, and altered mental status. Labs show high anion gap metabolic acidosis, hyperkalemia (despite total body potassium depletion), and positive ketones.
HHS (hyperosmolar hyperglycemic state) is seen in Type 2 and is marked by extreme hyperglycemia without ketones, due to partial insulin activity.
Treatment tip: Start with IV fluids, correct electrolytes (especially K⁺), then start IV insulin. Don’t forget that rapid shifts can cause cerebral edema, especially in children.
Final Takeaways
Endocrinology is logic-driven and highly testable. Learn it through patterns and physiology, not just memorization. If you’re pressed for time, prioritize feedback inhibition, adrenal and thyroid pathologies, and diabetes management. Sketch hormone pathways, quiz yourself on hormone levels in disease states, and get fluent in recognizing classic clinical presentations.
Don’t let endocrine leave you endo-cryin’. Master the high-yield, reinforce with practice, and you’ll be ready to crush this section on exam day!
Looking for more high-yield tips? Check out these other posts from the “Now That’s What I Call High-Yield” series:
