What Do the Adrenal Glands and Cortisol Do? — The Letter That Sets the Day, the Gland That Rests When a Drug Writes in Its Place

"They say cortisol goes up when you're stressed"

You've probably heard it said that when you're stressed, cortisol goes up and you gain weight. You might also have heard the term "adrenal fatigue," suggesting that long-piled-up stress has worn out the adrenal glands.

There are people who use inhalers for asthma, people who apply steroid ointment to their skin, and people who take steroid pills for months to treat inflammation in their joints or lungs. When prescribed these drugs, they sometimes hear that they "must not stop taking them suddenly." Others are told during a health checkup or other scan of the abdomen that "a small lump is visible on the adrenal gland."

This article follows in order: what the small glands above the kidneys secrete, what cortisol actually does, what happens when it is in excess or deficient, the relationship between steroid medication and these glands, and "adrenal fatigue" alongside accidentally discovered lumps.

This is a follow-up piece added after the six-part series "Hormones and Blood Sugar — Letters Carried in the Blood". The first piece, which dealt with the letters the body carries in the blood, stopped at noting that cortisol is commonly called the "stress hormone," and that both a shortage and an excess cause disease. This article picks up from there.

The Glands Above the Kidneys, in Two Layers

A hormone is a substance made in one part of the body that travels through the blood to a distant site, changing what the cells there do. If you compare a hormone to a letter, the blood is the postal route the letters travel on. The adrenal glands are small glands sitting one on top of each kidney. The adrenal glands play a key role in managing blood pressure, metabolism, the body's salt balance, and the body's response to stress (PMID 40250885).

The adrenal gland has two layers, and the letters sent out by each layer are different. The adrenal cortex is the outer layer of the adrenal gland, where steroid hormones are made and released into the blood. Steroid hormones are a group of hormones with the same backbone structure, like cortisol and sex hormones. The adrenal cortex is further divided into three zones, with each zone making different hormones (PMID 40250885).

One of these is cortisol. Cortisol is a hormone that comes from the adrenal glands and rises and falls in amount depending on the time of day and the stress the body is under.

Aldosterone comes from a different zone. Aldosterone is a hormone released from the adrenal cortex that tells the kidneys, "Keep salt and water in the body". Aldosterone causes the kidneys to retain salt and water in the body and excrete potassium, and the amount released is determined by changes in the amount and pressure of water in the body and the concentration of salt and potassium in the blood (PMID 9076902).

The adrenal medulla is the inner layer of the adrenal gland, where adrenaline is released into the blood under the direction of nerves. The adrenal medulla belongs to a branch of the body's nervous system and releases adrenaline when a stressful stimulus strikes (PMID 9076902). Adrenaline is a hormone released into the blood by the adrenal medulla that urges the body to face or flee a sudden threat, and is also called epinephrine.

If the adrenaline delivered directly by the nerves is an urgent dispatch, cortisol is a letter that reorganizes the body's entire daily schedule.

The inner layer of the adrenal gland releases adrenaline, an urgent dispatch sent by nerves, while the outer layer releases letters called cortisol and aldosterone.

The Chain Where Upstairs Sends and Cortisol Replies

The amount of cortisol that comes out is not decided by the adrenal gland alone. It is decided by a letter coming down from the pituitary gland (PMID 9076902).

The hypothalamus is a small region deep beneath the brain that releases hormones upon receiving nerve signals. The pituitary gland is a gland dangling by a thin stalk right beneath the hypothalamus, releasing hormones into the blood that tell other glands what to do. Adrenocorticotropic hormone is the letter the pituitary gland sends to the adrenal gland telling it to "release cortisol." When a burden arises, the letter from the hypothalamus draws this letter out from the pituitary gland, and the adrenal gland releases cortisol (PMID 26140713).

A reply is attached to this chain. Feedback is a mechanism where, as the results of a letter accumulate, those results reach the side that sent the letter to notify it to "stop sending now." Cortisol reaches the pituitary gland and hypothalamus to reduce the upstairs letters, and this feedback regulates both ordinary secretion and secretion when a burden arises. However, certain physical burdens can bypass this feedback, and certain mental burdens can amplify the response to the next burden (PMID 26140713).

Cortisol comes out upon receiving the upstairs letter, and the released cortisol in turn sends a reply back upstairs saying "stop sending now."

What Cortisol Does — The Other Half of the 「Stress Hormone」

In healthy people, the majority of daily cortisol secretion occurs during the few hours around the time of waking up in the morning, and cortisol rises rapidly during the 30 to 45 minutes after waking up (PMID 39177247). The amount of cortisol varies predictably depending on the time of day, increases when there is an external environment or mental burden, and almost every cell and organ in the body writes this letter (PMID 27871862).

That it increases under stress is true, which is why cortisol is called the 「stress hormone」. Glucocorticoids is a name that collectively refers to the group of hormones that come from the adrenal cortex like cortisol, and drugs made to mimic their actions. One review calls glucocorticoids the premier stress hormone, noting in the same sentence that they govern multiple physiological processes and are essential for life (PMID 26611548). The name 「stress hormone」 does not belong solely to cortisol either. Another review calls adrenaline the archetype of a stress hormone (PMID 22124970).

A major job of cortisol is to redirect energy use. It makes various organs redistribute and use energy in response to demands the body has encountered or expects to encounter (PMID 27065163). Glucocorticoids in the body are essential for metabolism, development, and inflammation (PMID 28192415). Human-made glucocorticoids, commonly called steroid drugs, have been used since 1948 to treat various diseases involving immunity (PMID 28192415).

When it comes to blood sugar, cortisol also takes a side. Blood sugar is the amount of sugar dissolved in the blood. Insulin is a hormone that comes out of the pancreas when blood sugar rises and tells the liver, muscles, and fat to 「gather up and store the glucose in the blood」. Cortisol is a hormone that strongly opposes the work of insulin (PMID 33995272). It is a letter that stands on the opposite side of the 「gather up」 letter, on the side of 「take it out and use it」. When the body faces a major burden from an acute or severe illness like a myocardial infarction, stroke, or severe infection and blood sugar rises, hormones like adrenaline, cortisol, and inflammatory substances intertwine to make the liver release more glucose and make insulin less effective. A mild or moderate rise in blood sugar may be a protective response to withstand stress, but if it lasts long or is excessive, it contributes to worse outcomes in such diseases, according to the summary of one systematic review (PMID 40317019).

What cortisol does when stress strikes has long been a subject of debate. According to one review, this hormone lays the groundwork for the response to stress to occur properly, amplifies the response, suppresses the response from running away excessively, and prepares for the next stress. Which way it works differs markedly depending on what you look at, such as the heart and blood vessels, water in the body, immunity and inflammation, and metabolism (PMID 10696570).

Cortisol is a hormone that increases under stress, and along with that, it is a letter essential to life that regulates the body's energy, blood sugar, and inflammation according to the time of day.

When Letters Overflow — Cushing's Syndrome

When the body receives more glucocorticoids than it naturally makes for a long time, a specific set of features appears. The extent varies depending on the amount received, the duration, and the individual (PMID 36963757). Cushing's syndrome is a collection of symptoms and signs that appear when the body is exposed to excessive glucocorticoids for a long time.

Depending on where the overflowing letters came from, there are two paths. There are cases that enter as medication, and cases where the body itself makes too much cortisol (PMID 36036941). Cushing's syndrome that arises spontaneously inside the body is a rare but harmful disease, so finding and treating it early is important (PMID 35979805).

The most common cause of Cushing's syndrome is glucocorticoids used for treatment (PMID 42236015, PMID 17344139). The very first thing done when screening for Cushing's syndrome is also to check whether steroid medications being taken orally or applied are being used (PMID 36036941, PMID 18334580).

It also happens with topical drugs. Ointments applied for skin inflammation such as psoriasis deliver amounts actually entering the body that depend greatly on the user, so Cushing's syndrome not anticipated by the prescribing doctor sometimes occurs (PMID 36963757).

In Cushing's syndrome caused by medication, notable features include weight gain concentrated around the waist, rising blood pressure, a state where the body does not respond to insulin as before along with type 2 diabetes, and osteoporosis where bones become weak (PMID 37253115). Whether caused by medication or inside the body, when glucocorticoids overflow for a long time, the disruption of blood sugar management is a common complication, and this frequently leads to diabetes. When both are present, blood sugar treatment and treatment to correct the overflowing glucocorticoids are performed together (PMID 28368467). Among cases arising inside the body, the most common is when a pituitary tumor secretes too much adrenocorticotropic hormone. There are also cases where a tumor in the adrenal gland itself directly secretes too much cortisol (PMID 19945026).

Because these features resemble other common conditions, recognizing Cushing's syndrome early is difficult (PMID 36036941), and confirmation is done through tests. The 2008 Endocrine Society guidelines recommend performing one high-accuracy test initially, and if the result is abnormal, seeing an endocrinologist for a second test. If both tests are normal, no further investigation is needed, but if the two results conflict, if periodic overflows of cortisol are suspected, or if features accumulate over time even though the initial test was normal, further testing is recommended (PMID 18334580). All tests used have pitfalls, so the results must be read carefully (PMID 35979805). Untreated Cushing's syndrome leaves behind a risk of serious illness and death (PMID 16698415).

Cushing's syndrome is the appearance left behind by long-term overflowing glucocorticoids, spontaneous cases arising inside the body are rare, and confirmation is done through tests that do not end with just one.

When Letters Fall Short — Adrenal Insufficiency

The disease in which the adrenal glands fail to produce their hormones was first recorded by Thomas Addison in 1855, and in his era, most patients lost their lives within a few years of diagnosis. The availability of adrenocortical hormones as medications in the 1940s greatly improved patients' life expectancy and quality of life (PMID 35534201).

Adrenal insufficiency is a state where cortisol is in short supply. It can happen when the adrenal glands themselves break down, when the letter from the layer above is cut off, or because of glucocorticoid medications. Cases caused by a breakdown in the adrenals themselves or the layer above are rare, at fewer than 279 per 1 million people, but cases caused by medication are common (PMID 40522647).

Addison's disease is a condition where the adrenal cortex itself collapses, leaving both cortisol and aldosterone in short supply. Addison's disease is the most common cause of insufficiency due to a breakdown in the adrenal glands themselves in adults (PMID 41587556). Autoimmunity is when the immunity that protects the body mistakenly recognizes its own body cells as enemies and attacks them. In developed countries, autoimmunity is the most common cause of Addison's disease (PMID 31321757).

When cortisol is lacking, it is common to feel easily exhausted, nauseated or vomit, lose appetite, and lose weight (PMID 40522647). Blood pressure may drop when standing up, muscles and the abdomen may hurt, and when the adrenal glands themselves are damaged, the skin may darken and salty foods may be craved (PMID 33484633). Because the initial signs are often not distinct, diagnosis is frequently delayed (PMID 33484633). Confirmation is made through blood tests measuring values such as cortisol and adrenocorticotropic hormone in the early morning (PMID 40522647).

Treatment involves replacing the missing hormones with medications, and in cases where the adrenal glands themselves are damaged, aldosterone-side hormones are also replaced together (PMID 40522647). Even with medication replacement, people with Addison's disease have a high risk of death and a lower quality of life. The reasons cited for this include the inability to properly handle adrenal crises and the failure of current medications to closely mimic cortisol's daily rhythm and short pulses (PMID 41587556). Another review notes that as replacement therapy has improved, patients have become able to live ordinary lives, and concludes that ongoing education for patients and medical staff on the ever-present risk of adrenal crisis is essential to protecting lives (PMID 31321757).

The most dangerous thing is an adrenal crisis. An adrenal crisis is a life-threatening emergency where cortisol suddenly drops sharply, causing blood pressure to fall and potentially leading to shock. If untreated, salt levels in the blood drop, consciousness clouds, and life can be lost (PMID 40522647). An adrenal crisis can come as the first sign of insufficiency or happen to someone already taking medication (PMID 31223468).

The biggest trigger is infection, but physical stress such as surgery or trauma, forgetting or stopping medication, heavy physical activity, and psychological stress also serve as triggers (PMID 31223468). Because the presentation of an adrenal crisis is not unique to it, misdiagnosis as another illness and delayed treatment are common (PMID 31223468). One review notes that an adrenal crisis should be suspected if a person diagnosed with insufficiency shows a general worsening of their physical condition, symptoms like vomiting and diarrhea resembling enteritis, signs of bodily fluid loss, or widespread infection throughout the body (PMID 40690931).

Emergency treatment consists of promptly administering glucocorticoids via injection and replenishing water and salt with intravenous fluids (PMID 31223468). Another review addressing adrenal crisis notes that timely injections can completely prevent loss of life from an adrenal crisis (PMID 40690931). Even so, adrenal crises still occur and remain a major cause of disease, death, and suffering for patients. Patient and medical staff education, along with helping patients self-inject when a crisis strikes, form the core of management (PMID 31223468). A 2016 endocrine society guideline on primary adrenal insufficiency recommends learning in advance how to increase medication doses when sick, and equipping oneself with a steroid card and emergency injectable medication (PMID 26760044).

An adrenal crisis is a life-threatening emergency, its presentation resembles common illnesses making it easy to miss, and the core of preventing it is education for times of illness.

A Letter Written by a Drug in Our Place — Steroid Drugs and the Axis

Glucocorticoid drugs ease symptoms that leave people debilitated or threaten life in various diseases where inflammation and immunity are intertwined (PMID 39371659). One review notes that there is no doubt the strong power of these drugs to suppress inflammation provides a therapeutic benefit (PMID 37253115). At least 1% of the population uses these drugs long-term (PMID 38714321).

A glucocorticoid entering as a drug is like having letters that the adrenal glands should send written from the outside instead, and this comes with a price. Glucocorticoid-induced adrenal insufficiency is a state where a glucocorticoid entering as a drug presses down on the axis, making the body unable to produce enough cortisol on its own. It is the most common form of adrenal insufficiency (PMID 35302603).

The reason lies in the reply we saw earlier. Hormones like cortisol reach the upper floor and trigger a feedback loop that reduces adrenocorticotropic hormone (PMID 26140713). Glucocorticoids entering from the outside also press down on this axis (PMID 35302603), and when the axis is pressed down, the adrenal glands' production of cortisol is also suppressed (PMID 38561211).

The risk depends on the dose of the drug, the duration of use, the potency of the drug, the route of administration, and individual differences in sensitivity (PMID 38714321). Not only oral medications but also inhaled drugs, topical creams, nasal sprays, and joint injections can suppress the axis (PMID 33923971). There are reports of it occurring even after small amounts, short durations, or gradual tapering and discontinuation (PMID 27105755), and the exact line below which it does not occur cannot be drawn precisely with current data (PMID 23806261).

One review notes that adrenal insufficiency is identified in about half of people currently using or just finishing oral medications (PMID 35302603). In a systematic review combining 73 studies, this proportion varied widely across studies (PMID 27105755). The previous review notes that what mild or moderate impairment after stopping the drug actually means, and therefore whether treatment is needed, has not yet been established. This impairment is frequently missed, with over 70% of cases identified only upon emergency admission, and it remains easy to miss even at that point (PMID 35302603).

If you stop the drug suddenly, the suppressed axis cannot recover in time, easily plunging you into a state where cortisol is lacking (PMID 39371659). This state can lead to a life-threatening adrenal crisis (PMID 35302603). Tapering the drug gradually is a way to buy time for the axis to recover while also reducing the risk of a flare-up of the original disease (PMID 39371659). However, there are cases where the adrenal glands remain suppressed even after gradual tapering following recommended methods (PMID 33923971, PMID 27105755), and in some people, the suppression lasts from months to years after stopping the drug (PMID 23806261). Therefore, one review notes that reducing and stopping the drug is done step-by-step while monitoring the recovery of the axis through clinical examination and blood tests (PMID 17344139), and another review notes that the drug is not stopped completely until recovery of adrenal function is confirmed (PMID 34253540).

Guidelines published jointly for the first time by the European Society of Endocrinology and the Endocrine Society in 2024 note that how long the axis remains suppressed after stopping the drug depends on the cumulative dose of the drug received, and the speed of adrenal recovery varies greatly among individuals (PMID 38714321). There are no randomized trials yet comparing which tapering method is best and safest. However, new data on tapering long-term drugs are emerging, and one trial in asthma patients proposed a method of tapering tailored to each individual while sequentially checking adrenal function (PMID 36876715).

Withdrawal symptoms may also occur during the tapering process. They arise because the body has grown accustomed to high levels of glucocorticoids, and this is a state that resembles adrenal insufficiency but must be viewed separately (PMID 36876715). Loss of appetite, nausea, fatigue, aching muscles and joints, and headaches are what it looks like (PMID 18209866). One review notes that the foundation of management is to inform people in advance and reassure them that these symptoms are expected and usually transient. These symptoms are often missed and can significantly reduce quality of life (PMID 36876715). These symptoms overlap with both a flare-up of the original disease and adrenal insufficiency, making them difficult to distinguish, and another review notes the need for careful tapering and thorough consultation with medical staff (PMID 34253540).

Regarding increasing the dose when ill, one review notes that anyone taking steroid medications should receive guidance on appropriately increasing the dose during acute illness or surgery and should carry a steroid card (PMID 39371659). Another review notes that it is not yet clear in which cases it is necessary to supplement medication when falling ill while on drugs. The same review concludes that among people in whom this impairment is identified, many lack the confidence to manage it themselves, and delays in taking medication when a crisis strikes are frequent, pointing to the need for more education for both medical staff and patients (PMID 35302603).

Steroid drugs are medications that provide great benefits in many diseases, and when used long-term, they reduce letters from the upper floor and suppress the work of the adrenal glands, so stopping them suddenly can plunge you into a state lacking cortisol, and in some people, suppression remains even after a gradual taper.

"Adrenal Fatigue" and Measuring Stress

Those who talk about "adrenal fatigue" claim that countless people suffer from vague symptoms such as fatigue, insomnia, joint pain, and weight gain because the adrenal glands run down from repeated stress (PMID 30182895). In 2016, a research team gathered and examined 58 studies that met their criteria using a set method. The results of the studies were almost uniformly contradictory, and the researchers concluded that there is no evidence "adrenal fatigue" is a real medical condition and that it remains an unproven myth (PMID 27557747).

The methods used to gauge "adrenal fatigue" produced mixed results, and studies actually examining the cortisol chain were few. Pointing this out, the authors of a commentary concluded that current evidence does not support the existence of "adrenal fatigue" or the usefulness of supplements claimed to support the adrenals (PMID 30182895).

The verdict that there is no evidence is directed at the diagnosis name "adrenal fatigue." Fatigue itself is a real symptom, and in adrenal insufficiency, where cortisol is genuinely lacking, fatigue is a symptom that appears in anywhere from half to most patients. However, this fatigue is a vague symptom seen in various conditions, and insufficiency caused by trouble in the adrenals themselves or the upper tiers is rare (PMID 40522647). Endocrine society guidelines recommend screening everyone with symptoms or signs pointing to primary adrenal insufficiency through testing (PMID 26760044).

Then, can long-accumulated stress be measured with cortisol? Hair cortisol is a relatively newer method intended to measure cortisol accumulated over a long period and is increasingly used in research. In an analysis pooling data from 10,000 people across 66 studies, the group experiencing stress had on average 22% higher hair cortisol, which was pronounced when stress was ongoing and absent in past stress. Conversely, it was rather lower in anxiety disorders such as post-traumatic stress disorder, and showed no consistent link with self-perceived stress or mood disorders. Age, sex, hair-washing frequency, hair treatments, and oral contraceptives also moved the values. Meanwhile, higher hair cortisol was linked to higher body mass index, waist-to-hip ratio, and systolic blood pressure. Because this is an association, this analysis does not tell which side is the cause (PMID 28135674).

There is also an analysis that looked at the slope of how cortisol drops from morning to evening over the course of a day. In an analysis gathering 80 studies, a flatter slope was linked to poorer physical and mental health, and the authors discuss that a flat slope could be a marker of disease or part of the mechanism that creates disease (PMID 28578301).

The response of the cortisol chain to chronic stress is not in a single direction. Sometimes baseline secretion simply increases, sometimes it reacts more sensitively to a load, and sometimes it rather decreases. Which shape it takes depends on how long, how intensely, and how frequently the burden comes, and varies by person depending on genetics, childhood experiences, sex, and age. The same review writes that the context in which the burden strikes determines whether this response is an adaptation by which the body adjusts or a path toward disease (PMID 27065163). When examining Cushing's syndrome, hair cortisol also has uses in helping gauge long-term exposure (PMID 36036941).

While an association between long-accumulated stress and cortisol is seen in research, its shape branches into various directions depending on the person and situation, and methods to measure it remain tools still used in research.

An Incidental Adrenal Lump, and Aldosterone

About 4% of people who undergo abdominal imaging tests have an adrenal lump incidentally seen (PMID 26038204). An adrenal incidentaloma is an adrenal lump unexpectedly discovered on imaging performed for other reasons without suspicion of adrenal disease.

Most are asymptomatic and benign, but a significant minority secrete hormones excessively or are malignant (PMID 40304946). The most common type is a non-secreting benign lump of the adrenal cortex (PMID 37318239). The 2023 guideline of the European Society of Endocrinology recommends that all patients with incidentalomas undergo evaluation and testing to determine whether hormone hypersecretion is present, and that all lumps undergo separate adrenal imaging tests to gauge the likelihood of malignancy. Even without overt features of Cushing's syndrome, some lumps autonomously secrete cortisol in slight excess, prompting the guideline to advise checking whether such individuals have high blood pressure and type 2 diabetes. It notes that a unilateral lump that is asymptomatic, non-secreting, and clearly benign on imaging is generally not a candidate for surgery (PMID 37318239). Lumps that secrete hormones or are suspected of malignancy are recommended for surgery, while small, non-secreting lumps are sometimes monitored with imaging (PMID 40304946).

Primary aldosteronism is a disease in which the adrenal glands produce aldosterone in excess, regardless of the body's needs. High blood pressure is a state in which elevated blood pressure persists, and guidelines draw the line at which value is considered high. Primary aldosteronism is a common cause of high blood pressure and carries a higher risk of heart and blood vessel complications than high blood pressure with no distinct underlying cause. Despite the existence of effective methods for diagnosis and treatment, it remains vastly underdiagnosed and undertreated. The 2025 Endocrine Society guideline suggests screening for this disease with a blood test measuring aldosterone and related substances in everyone with high blood pressure (PMID 40658480).

There is also a rare lump on the adrenal medulla side. A pheochromocytoma is a rare lump arising from the adrenal medulla and other sites that excessively secretes hormones like adrenaline. It is usually benign. Blood pressure rises, and severe headaches, palpitations, and sweating may appear, but its presentation is highly variable and resembles many other diseases. If unrecognized or untreated, it can be life-threatening, and it is usually cured with surgery (PMID 17082709).

An incidentally found lump in the adrenal gland is common and mostly benign, but guidelines recommend using tests and imaging to evaluate whether the lump secretes hormones in excess and whether there is a possibility of malignancy.

The Morning of Someone Taking Steroid Medication

Let us picture someone who has been taking glucocorticoid pills for months because of inflammation in their joints or lungs. This medicine is easing the inflammatory symptoms that were distressing that person (PMID 39371659).

Before taking the medication, this person's adrenal glands poured out most of their daily cortisol around the time of waking up in the morning (PMID 39177247). That cortisol reached the upper floor and sent a reply saying, "Stop sending them now" (PMID 26140713).

While taking the medicine, glucocorticoid entering from the outside presses down on this chain (PMID 35302603). The letters from the upper floor decrease, and the adrenal glands' job of producing cortisol is also suppressed (PMID 38561211). Just how much it is suppressed depends on the dose and duration of the medication, the route of administration, and the individual (PMID 38714321).

If this person suddenly stops the medication one day, the suppressed chain cannot bounce back in time, easily plunging them into a state where cortisol is lacking (PMID 39371659). If a major burden such as an infection strikes in that state, it can trigger an adrenal crisis (PMID 31223468).

Tapering the medication gradually can buy time for the chain to return (PMID 39371659). However, even with a gradual taper, suppression remains for some people (PMID 33923971), the recovery speed varies greatly from person to person (PMID 38714321), and the best tapering method has not yet been compared through trials (PMID 36876715). During the taper, fatigue and aching withdrawal symptoms can occur, and these symptoms overlap in appearance with a flare-up of the original disease or adrenal insufficiency (PMID 34253540). This functional decline is often confirmed only when someone is urgently hospitalized (PMID 35302603).

The medication does the job of suppressing inflammation, and the chain that was suppressed during that time takes varying amounts of time for different people to recover, sometimes lasting from months to years (PMID 23806261).

Where to Look Further

There are still questions that have not been solved. In the treatment of Addison's disease, drugs that more closely mimic the daily rhythm of cortisol and methods to make the adrenal glands produce hormones again on their own are being researched (PMID 41587556).

The chain descending from the hypothalamus through the pituitary gland to the adrenal glands and the morning surge of cortisol were first traced in "How Hormones Work — Letters Only the Addressee Reads, Replies That Say Stop". The article that looked at the same "when it is short and when it is excessive" in the gland in front of the neck is "What Does the Thyroid Do? — The Letter That Sets the Body's Pace, the Reminder That Grows When It Runs Short". Cortisol's side of "take it out and use it" and insulin's letter to "store it" continue in "How Blood Sugar Stays Steady — A Letter to Store, a Letter to Release", and the diabetes that can be called upon when glucocorticoids are excessive is connected in "What Is Diabetes? — The Letter That Never Comes, the Letter That Isn't Read". High blood pressure, in which primary aldosteronism may be hidden, can be seen in "What Blood Pressure Measures — Two Numbers, and an Answer That Changes With Where You Measure".

Source Papers

• "Adrenal Anatomy and Physiology." (2025) — PMID 40250885 — The adrenal glands are central to regulating blood pressure, metabolism, electrolytes, and the stress response, consisting of the cortex (steroid hormones, three layers) and the medulla (adrenaline and noradrenaline under sympathetic nerve control).
• "Adrenal physiology." (1997) — PMID 9076902 — The medulla acts as part of the sympathetic nervous system and secretes epinephrine in response to stress stimuli, aldosterone is regulated by extracellular fluid volume, pressure, Na, and K and acts in the kidneys to retain Na and water while excreting K, glucocorticoids are regulated by ACTH, and cortisol exerts diverse actions on almost all tissues along with negative feedback on ACTH.
• "Epinephrine and the metabolic syndrome." (2012) — PMID 22124970 — Epinephrine is the archetype of a stress hormone (a review including numerous animal studies).
• "The Cortisol Awakening Response: Regulation and Functional Significance." (2025) — PMID 39177247 — Most cortisol secretion in healthy individuals occurs in the hours around waking, surging rapidly 30 to 45 minutes after waking and acting via rapid non-genomic and slow genomic pathways (a model proposed by the authors).
• "Hypothalamic-Pituitary--Adrenal Axis-Feedback Control." (2015) — PMID 26140713 — The HPA axis triggers adrenal corticosteroid secretion in response to stress, and negative feedback by corticosteroids limits ACTH and CRH to regulate basal and stress-induced secretion (via GR and MR).
• "A users guide to HPA axis research." (2017) — PMID 27871862 — Cortisol changes predictably according to the time of day and increases in response to stress, being utilized by almost all cells.
• "Corticosteroids: Mechanisms of Action in Health and Disease." (2016) — PMID 26611548 — Glucocorticoids are the premier stress hormones, regulating diverse physiological processes and essential for life.
• "Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response." (2016) — PMID 27065163 — Glucocorticoids rearrange energy to match actual and anticipated demands, and the HPA response to chronic stress takes various forms such as basal hypersecretion, sensitization, and adrenal exhaustion depending on the persistence, intensity, and frequency of stress, with individual differences driven by genetics, early experience, sex, and age.
• "Immune regulation by glucocorticoids." (2017) — PMID 28192415 — Endogenous glucocorticoids are central to metabolism, development, and inflammation, synthetic glucocorticoids have been used to treat immune disorders since 1948, and the mechanistic picture remains unclear.
• "How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions." (2000) — PMID 10696570 — The actions of glucocorticoids during stress are divided into permissive, stimulatory, suppressive, and preparative, and which one occurs differs markedly depending on physiological indicators (the purpose of which is debated).
• "Factitious, or iatrogenic but unexpected Cushing's syndrome." (2023) — PMID 36963757 — Long-term exposure to exogenous glucocorticoids beyond physiological amounts causes iatrogenic Cushing's, with severity depending on dosage, duration, and individual susceptibility, and topical steroids for conditions like psoriasis can lead to Cushing's unanticipated by the prescriber depending on patient exposure.
• "Approach to the Patient: Diagnosis of Cushing Syndrome." (2022) — PMID 36036941 — Cushing's syndrome is exogenous (corticosteroid administration) or endogenous, and early diagnosis is difficult because it mimics other common conditions; diagnosis starts by excluding local and systemic corticosteroid use, and scalp hair cortisol helps evaluate long-term exposure.
• "Diagnostic workup of Cushing's syndrome." (2022) — PMID 35979805 — Cushing's syndrome is a rare but harmful condition, and confirmatory tests all have pitfalls requiring careful interpretation.
• "The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline." (2008) — PMID 18334580 — Start with a single highly accurate test after excluding exogenous use, proceed to a second test with an endocrinologist if abnormal, and no further evaluation is needed if both tests are normal.
• "Biochemical diagnosis of hypercortisolism: When and how?" (2026) — PMID 42236015 — Iatrogenic corticosteroid administration is the most common cause of Cushing's syndrome, and the most common cause of endogenous cases is a pituitary adenoma.
• "[Treatment of iatrogenic Cushing syndrome: questions of glucocorticoid withdrawal]." (2007) — PMID 17344139 — Iatrogenic Cushing's syndrome is the most common form of hypercortisolism, characterized by individual differences in axis suppression and recovery, and three complications of discontinuation (relapse of the underlying disease, secondary adrenal insufficiency, and withdrawal syndrome).
• "Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management." (2017) — PMID 28368467 — A common complication of endogenous and exogenous glucocorticoid excess is glucose metabolism abnormalities, frequently leading to diabetes and contributing to morbidity and mortality.
• "The Interaction of Insulin and Pituitary Hormone Syndromes." (2021) — PMID 33995272 — Cortisol and growth hormone are strong insulin-antagonistic hormones, and impaired glucose tolerance, elevated fasting blood sugar, and diabetes are common in Cushing's disease and acromegaly.
• "Relationship between stress hyperglycaemic ratio (SHR) and critical illness: a systematic review." (2025) — PMID 40317019 — Stress hyperglycemia involves intertwined catecholamines, cortisol, and inflammatory mediators that lead to increased hepatic glucose production and insulin resistance; mild to moderate levels may be a protective mechanism, but persistence and excess contribute to poor outcomes.
• "Treating the Side Effects of Exogenous Glucocorticoids; Can We Separate the Good From the Bad?" (2023) — PMID 37253115 — Anti-inflammatory benefits are unquestionable, while side effects such as central weight gain, hypertension, insulin resistance, type 2 diabetes, and osteoporosis are commonly referred to as iatrogenic Cushing's.
• "Cushing's disease." (2009) — PMID 19945026 — The most common cause of endogenous Cushing's is a pituitary ACTH adenoma (Cushing's disease), with ectopic ACTH and direct hypersecretion by adrenal tumors being rare causes.
• "Cushing's syndrome." (2006) — PMID 16698415 — Untreated Cushing's syndrome entails substantial morbidity and mortality.
• "Adrenal insufficiency." (2022) — PMID 35534201 — First described by Addison in 1855, when most patients died within years; the discovery of cortisone in the 1940s improved life expectancy and quality of life, diagnosis is often delayed by months, and sudden long-term glucocorticoid cessation is the most common cause.
• "Adrenal Insufficiency in Adults: A Review." (2025) — PMID 40522647 — Adrenal insufficiency is a cortisol deficiency syndrome (primary, secondary, or glucocorticoid-induced); primary and secondary are rare at under 279 cases per 1 million people, whereas glucocorticoid-induced is common; features include fatigue in 50 to 95%, nausea/vomiting, and anorexia/weight loss; diagnosis utilizes early morning cortisol and ACTH, treatment involves glucocorticoids (with mineralocorticoids added for primary), and adrenal crisis involves hypotension, shock, hyponatremia, altered consciousness, and death.
• "Clinical features, investigation, and management of Addison's disease." (2026) — PMID 41587556 — Addison's disease is T-cell mediated destruction of the adrenal cortex leading to glucocorticoid and mineralocorticoid deficiency, representing the most common cause of primary adrenal insufficiency in adults; despite replacement therapy, mortality is increased and quality of life is reduced because existing treatments fail to mimic circadian and ultradian rhythms, prompting research into rhythm-mimicking treatments and adrenal regeneration.
• "Epidemiology, pathogenesis, and diagnosis of Addison's disease in adults." (2019) — PMID 31321757 — In developed countries, the most common cause of adult Addison's disease is autoimmunity, and adrenal crisis education is essential to saving lives.
• "Adrenal insufficiency." (2021) — PMID 33484633 — Features include unintended weight loss, anorexia, orthostatic hypotension, severe fatigue, muscle/abdominal pain, and hyponatremia, with primary cases also showing skin hyperpigmentation and salt cravings, leading to diagnostic delays due to their non-specific nature.
• "Adrenal crisis: prevention and management in adult patients." (2019) — PMID 31223468 — Adrenal crisis is an acute, life-threatening emergency that can be the initial presentation or occur during replacement therapy, with infection being the primary trigger alongside surgery, trauma, medication cessation, intense activity, and psychological stress; non-specific features lead to misdiagnosis and delay, emergency treatment consists of parenteral hydrocortisone and fluids, and education is the cornerstone of prevention.
• "[Adrenal Crisis]." (2025) — PMID 40690931 — Adrenal crisis carries a particularly high risk of death, timely intravenous or subcutaneous glucocorticoids can completely avert this fatal crisis, and adrenal crisis should be suspected if diagnosed patients exhibit deteriorating general status, gastroenteritis symptoms, dehydration, or sepsis-like presentations.
• "Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline." (2016) — PMID 26760044 — Screening tests to rule out primary adrenal insufficiency are recommended for all patients with suggestive symptoms and signs, alongside stress-dose education, steroid cards, and the provision of parenteral emergency medication.
• "The Glucocorticoid Taper: A Primer for the Clinicians." (2024) — PMID 39371659 — Glucocorticoids ameliorate debilitating or life-threatening inflammatory and immune symptoms, sudden cessation causes adrenal insufficiency due to HPA axis suppression, tapering minimizes axis recovery time and disease relapse risk, and all users should receive instructions on dose escalation during acute illness and carry a steroid card.
• "European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency." (2024) — PMID 38714321 — At least 1% of the population uses them long-term, risks depend on dose, duration, potency, route, and individual susceptibility, withdrawal symptoms overlap with insufficiency and complicate tapering, tapering should be fast in the supra-physiological range and slow in the physiological range, and the degree and duration of suppression depend on total exposure while recovery shows wide individual variation.
• "Approach to the Patient With Glucocorticoid-induced Adrenal Insufficiency." (2022) — PMID 35302603 — This is the most common adrenal insufficiency caused by HPA axis suppression from exogenous glucocorticoids, carrying a risk of life-threatening adrenal crisis, with insufficiency occurring in about 50% of patients during oral treatment or immediately after cessation; the clinical significance and treatment indications for mild to moderate deficiency remain undetermined, as do indications for adding stress doses during treatment.
• "Glucocorticoid-induced adrenal insufficiency and glucocorticoid withdrawal syndrome: Two sides of the same coin." (2024) — PMID 38561211 — HPA axis suppression leads to secondary adrenal insufficiency (adrenal suppression), with exogenous steroids being the most common cause.
• "Glucocorticoid Withdrawal-An Overview on When and How to Diagnose Adrenal Insufficiency in Clinical Practice." (2021) — PMID 33923971 — Not only oral administration but also inhaled, topical, nasal, intra-articular, and intravenous administration can cause adrenal suppression, and long-term glucocorticoids are the most common cause of adrenal insufficiency.
• "Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review." (2016) — PMID 27105755 — Across 73 studies, the proportion of insufficiency was heterogeneous, ranging from 0% to 100% (median 37.4%), with insufficiency confirmed even after low-dose, short-term, or tapered cessation, necessitating vigilance at all exposure levels.
• "Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself." (2013) — PMID 23806261 — The lower limit of dose and duration that avoids insufficiency cannot be accurately estimated, and individual differences prevent prediction based on dose and duration alone.
• "Glucocorticoid withdrawal syndrome: what to expect and how to manage." (2023) — PMID 36876715 — Withdrawal syndrome arises from physical dependence on supra-physiological exposure and resembles insufficiency while being distinct; education and reassurance that symptoms are expected and usually temporary form the basis of management, and no randomized studies compare tapering methods.
• "[Exogenous Cushing's syndrome and glucocorticoid withdrawal]." (2007) — PMID 18209866 — Symptoms of withdrawal syndrome include anorexia, nausea, vomiting, weight loss, fatigue, myalgia, arthralgia, and headaches.
• "Glucocorticoid induced adrenal insufficiency." (2021) — PMID 34253540 — Withdrawal symptoms can overlap with the underlying disease and insufficiency, requiring careful tapering and counseling.
• "We are tired of 'adrenal fatigue'." (2018) — PMID 30182895 — Proponents of adrenal fatigue make claims based on assessment methods with mixed results and inadequate methodology, few studies have actually examined the HPA axis, and current evidence does not support the existence of adrenal fatigue or the usefulness of supplements.
• "Adrenal fatigue does not exist: a systematic review." (2016) — PMID 27557747 — Across 58 studies, results are nearly systematically conflicting, and there is no evidence that adrenal fatigue is a real medical condition—it remains a myth.
• "Stress-related and basic determinants of hair cortisol in humans: A meta-analysis." (2017) — PMID 28135674 — In 66 studies involving 10,289 individuals, hair cortisol was 22% higher in stress-exposed groups (+43% for ongoing stress, with no difference for past stress), 17% lower in anxiety disorders, and showed no consistent association with mood disorders or self-reported stress, with age, sex, hair washing, hair treatments, and oral contraceptives acting as covariates.
• "Diurnal cortisol slopes and mental and physical health outcomes: A systematic review and meta-analysis." (2017) — PMID 28578301 — Across 80 studies, a flattened diurnal cortisol slope was associated with poor health, sparking debate over whether it serves as a marker or a mechanism.
• "Adrenal incidentalomas: a disease of modern technology offering opportunities for improved patient care." (2015) — PMID 26038204 — Adrenal incidentalomas are found in about 4% of patients undergoing abdominal imaging.
• "The Landmark Series: Evaluation and Management of Adrenal Incidentalomas." (2025) — PMID 40304946 — Driven by the proliferation of cross-sectional imaging, these are increasing particularly in the elderly; most are benign and asymptomatic, but a significant minority are hormonally active or malignant.
• "European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors." (2023) — PMID 37318239 — Most are non-functioning adrenocortical adenomas, evaluation to rule out hormone excess is recommended for all patients, patients with mild autonomous cortisol secretion should be screened for hypertension and type 2 diabetes, and unilateral masses with asymptomatic, non-functioning, and benign features generally do not require surgery.
• "Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline." (2025) — PMID 40658480 — Primary aldosteronism is a common cause of hypertension carrying a higher risk of cardiovascular complications than essential hypertension, while remaining vastly underdiagnosed and undertreated; screening with aldosterone and renin is suggested for anyone with hypertension.
• "Pheochromocytoma: presentation, diagnosis and treatment." (2006) — PMID 17082709 — A rare and mostly benign catecholamine-secreting tumor of the adrenal medulla and other sites, presenting with hypertension, headache, palpitations, and sweating, which is life-threatening if unrecognized or untreated.