How Hormones Work — Letters Only the Addressee Reads, Replies That Say Stop

When You Jump in Surprise and When You Grow Over a Year

If something suddenly pops out in a dark alley, your body flinches without time to think. It takes only the blink of an eye for the signal entering your eyes to travel along nerves to your muscles. Nerves act like electrical wires, quickly delivering messages to a fixed destination.

A child growing taller is different. Over months and years, bones, muscles, and organs grow a little bit larger together. This is a job of telling the same message across the whole body for a long time. Growth hormone, which comes from a gland beneath the brain and travels through the blood, plays a major part in making a child grow (PMID 20020365).

There are two such pathways for the body to send messages to distant places. One is nerves, and the other is blood. Many things in the body—such as growing and developing, using and storing energy, the balance of water and salt inside the body, and having children—are directed by substances carried in the blood (PMID 15706790). Values that must be kept constant, such as body temperature, the amount of water in the body, and blood pressure, are maintained through the interlocking action of nerves and these substances (PMID 26140719).

A hormone is a substance made in one part of the body that travels through the blood to a distant place and changes what the cells there do. Comparing a hormone to a letter, the blood is the postal route the letter travels on. The letter arrives later than a nerve signal, but once mailed, it goes anywhere the postal route reaches.

Hormones are letters loaded into the blood going to the whole body, and instead of being slower than nerves, they deliver messages to the entire body all at once. This article follows who sends those letters, why they do not overflow, who reads them, and why they come out at the appointed time.

Glands That Send Letters

Saliva comes out inside the mouth, and sweat comes out onto the surface of the skin. Salivary glands and sweat glands flow what they make along narrow tubes to designated places. Glands that make hormones do not use such tubes. An endocrine gland is a gland that sends the hormones it makes directly into the blood without going through a tube.

One organ can use both paths. The pancreas is an organ placed horizontally behind the stomach, doing the work of making digestive juices and sending them to the intestine, and the work of sending hormones that handle blood sugar into the blood together. Digestive juices go to the intestine along tubes, and hormones go to the blood. Blood sugar is the amount of sugar dissolved in the blood. The hormones that the pancreas sends into the blood are insulin and glucagon (PMID 15706790).

Insulin is a hormone that comes out of the pancreas when blood sugar rises, and tells the liver, muscles, and fat to "gather glucose from the blood and store it." Glucagon is a hormone that comes out of the pancreas and tells the liver to "take out stored glucose and send it to the blood." How the two letters hold blood sugar in place during the day was followed in the article that covers How Blood Sugar Stays Steady — A Letter to Store, a Letter to Release.

The glands that send letters are scattered throughout the body. There are endocrine glands in the front of the neck, above both kidneys, and below the brain, and the ovaries and testes also send sex hormones into the blood (PMID 15706790). Places that were not called glands also send letters. Fatty tissue is an actively working endocrine organ that sends various substances that signal other organs into the blood (PMID 15181022).

Glands all over the body float their own different letters onto the same postal road.

Letters Sent Layer by Layer, and a Reply That Says "Stop Sending Now"

There is a gland just beneath the skin at the front of the neck. The thyroid is a gland at the front of the neck that makes thyroid hormone and releases it into the blood. Thyroid hormone is essential for brain and nerve growth, for growing taller, and for using energy and producing heat (PMID 27347897). The thyroid does not decide all by itself how much of this hormone to make. A letter comes down from above.

The floor above is at the base of the brain. The hypothalamus is a small area deep in the lower part of the brain that receives nerve signals and releases hormones. The pituitary gland is a gland hanging by a thin stalk right below the hypothalamus, releasing hormones into the blood that tell other glands what to do. The two are tucked tightly against the base of the brain, and hormones that spur or suppress work travel through the stalk connecting them (PMID 33549603). The hormone from the hypothalamus tells the pituitary what to do, and among the hormones from the pituitary, some act on other glands while others act directly on target organs. Many hormones sit within a tiered chain running from the hypothalamus through the pituitary to the glands at the end (PMID 15706790).

The chain for the thyroid looks like this. Thyroid-stimulating hormone is a letter the pituitary sends to the thyroid telling it to "make and release hormone." A letter from the hypothalamus draws out this letter from the pituitary, and this letter boosts every step by which the thyroid makes and releases hormone (PMID 27347897).

If letters only ever cascaded down like this, thyroid hormone would multiply endlessly. A reply is what stops that end point. Feedback is a method where, once the results of a letter accumulate, those results reach the sender of the letter to notify it to "stop sending now." Because the result works to reduce the cause, it is also called negative feedback. Thyroid hormone in the blood reaches back to the hypothalamus and pituitary to reduce the letters from the two layers above, and thus the hormones in this chain stay at their proper levels (PMID 27347897). Thanks to this chain, thyroid hormone in the blood is kept at a nearly constant level (PMID 28174093).

Because the reply exists, the values of the upper and lower layers in the thyroid chain can move in opposite directions. If work in the thyroid itself drops and thyroid hormone in the blood falls, the letters from the hypothalamus and pituitary increase, and if thyroid hormone overflows, they decrease in turn (PMID 27347897). In the thyroid chain, the values of the upper and lower layers move in a locked gear, so the meaning of one layer's value is revealed when placed alongside the value of the other layer. However, when there is trouble in the upper layer itself, reading this pairing is much trickier, and the ways multiple chains entangle with one another are not yet fully uncovered (PMID 33549603). How to read this pairing on a test sheet will be taken up by a following article on the thyroid.

The same tiered structure repeats above the kidneys. The adrenal glands are small glands perched one on top of each kidney, and the hormone they mostly release is cortisol (PMID 15706790). Cortisol is a hormone that comes out of the adrenal glands, its amounts rising and falling according to the time of day and the burdens the body bears. The amount of cortisol changes predictably depending on the time of day, increases when external environments or mental burdens arise, and nearly every cell and organ in the body reads this letter (PMID 27871862).

Cortisol is commonly called the "stress hormone." Cortisol is a hormone essential for sustaining life (PMID 26611548), and whether it is too little or too much, it causes illness (PMID 28068807). Making the body reroute and use energy to match demands it has encountered or expects to encounter is the major job cortisol does. Whether the same response is beneficial or harmful depends on the situation in which that burden occurs (PMID 27065163).

Cortisol also connects with the letters of blood sugar. One review covering situations where the body undergoes heavy burdens noted that cortisol helps increase the enzymes the liver uses to build new glucose, boosts glucagon secretion, and suppresses insulin secretion (PMID 12386486). This is a job that assists the side of the letter to "pull it out and use it" seen in the article on blood sugar. How often this happens under everyday conditions is not covered by this review.

This chain also has a reply attached to it. When a burden arises, a letter from the hypothalamus draws out a letter from the pituitary, and finally the adrenal glands release cortisol (PMID 17290797). Cortisol reaches back to the pituitary and hypothalamus to reduce the letters from the two layers above, and this feedback jointly regulates ordinary secretion and secretion when a burden arises (PMID 26140713). Yet the reply does not always win. Some of the burdens the body receives can bypass or override this feedback (PMID 26140713).

Hormones do not overflow because the results of the letter send a reply back to the sender telling it to "stop sending now."

A Letter Read Only by the Recipient

The letter that the pituitary gland sends to the adrenal gland telling it to "release cortisol" is called the adrenocorticotropic hormone (PMID 26140713). The receptor that receives this letter is extremely picky. The only known messenger in the body that activates this receptor is the adrenocorticotropic hormone itself, and it requires a small helper protein attached nearby to settle on the cell surface and do its job (PMID 27547198).

A receptor is a protein located on a cell that recognizes and grabs only a specific hormone. Compared to mail, the receptor is the recipient. A target cell is a cell that has the receptor for a certain hormone, so it reads that letter and changes what it does. Even when the same letter travels throughout the entire body, only the target cells that have the receptor for that letter read the contents.

The name of a letter does not even tell you everything that letter does. Prolactin, which was named for its role in producing milk, is produced not only by the pituitary gland but also by the brain, the immune system, the uterus, and the mammary glands themselves, and its jobs go far beyond reproduction (PMID 11015620).

The actions that the recipient takes after reading the letter are also not limited to just one. Muscle and fat tissue that read the letter of insulin move glucose channels that they had kept inside the cell to the cell surface, and bring glucose from the blood through those channels (PMID 21401839). Growth hormone sometimes attaches to its own receptor to work directly, and sometimes makes other substances so that it works through those substances (PMID 20020365). Growth hormone is well known as the letter that makes children and adolescents grow taller, but it also plays various roles in metabolism in the adult body (PMID 20020365). The same letter commands different tasks depending on who reads it and when.

The letter goes out to the entire body, but only cells with the receptor read it.

Letters That Dissolve in Oil

When blood is drawn and cortisol is measured, most of that value is cortisol in a state that cells cannot read right away. Steroid hormones are a family of hormones that share the same backbone structure, like cortisol and sex hormones, and are made by the adrenal glands, ovaries, and testes (PMID 26140719). Because blood is mostly water, cortisol—which dissolves well in oil—rides along carried by other proteins (PMID 28068807). Transport proteins are proteins that catch and haul hormones through the blood.

Cortisol mostly travels attached to transport proteins in the blood, and only about 10% that is unattached and free acts in the body (PMID 28068807). Because blood cortisol tests measure the attached and free parts combined, the results can be misread in a person whose blood protein levels have changed (PMID 28068807).

Where the recipient stands also differs from letter to letter. That picky receptor from the previous section was on the cell surface (PMID 27547198). Unlike that, the receptors for steroid hormones and thyroid hormones belong together to a family of receptors that work inside the cell nucleus (PMID 24679540). Cortisol does most of its work by attaching to receptors inside the cell, and that bundle moves into the cell nucleus, which contains genetic information, to change how much genes are used (PMID 29685454). Thyroid hormones also mainly change how much genes are used by way of receptors inside the cell nucleus. However, the amount of thyroid hormone that can work inside the cell is determined by transport channels in the cell membrane and enzymes that change the hormone into its working form (PMID 27347897).

The situation on the receiving end also varies. Cortisol receptors are all over the body, but the degree to which different tissues respond to the exact same cortisol varies quite a bit (PMID 26611548). Because thyroid hormone has each tissue regulate the amount it receives through these channels and enzymes, the concentration in the blood does not fully show the amount each cell actually receives (PMID 28174093).

The amount of hormone floating in the blood and the amount cells actually read are not the same.

Letters Sent in Batches at Set Times

Growth hormone comes out in short bursts, bunched together, and quickly vanishes from the blood. As a result, its concentration in the blood fluctuates wildly, and a single measured concentration cannot even distinguish whether growth hormone was administered from the outside, which is why doping tests use a different method (PMID 20020365). Pulsatile secretion is a method where a hormone is not sent out evenly, but rather sent in bursts at short intervals. Most pituitary hormones come out this way (PMID 30075152).

The interval between deliveries itself makes sense. Hormones are released in pulses spaced about an hour apart, and these pulses are used like a code of time. In many cases where the body's hormonal state changes, what changes is the frequency of the pulses (PMID 1891479). Just like the content of a letter, the interval at which it is sent speaks to the receiving side.

Overlaid on top of the pulses is a daily rhythm. Circadian rhythm is a roughly day-long cycle created by the body's internal clock, and various bodily functions, including sleepiness and wakefulness, rise and fall along this cycle. The order in which hormones are released on a daily cycle is matched to the cycle of light and dark, and the most important among the internal clocks that create that rhythm is the central clock in the brain (PMID 1891479).

Melatonin is a hormone released in large amounts at night from a small gland deep in the brain to signal to the body that night has arrived. Melatonin comes out in small amounts during the day and large amounts at night (PMID 2932708). Signaling the daily cycle of light and dark to the body is melatonin's main job (PMID 25908646).

Cortisol also comes out in pulses, and its daily rhythm is created as the size of those pulses changes throughout the day (PMID 12386486, PMID 32060528). In humans, cortisol is high during the active daytime hours (PMID 24944037). The value of the same hormone in the same person differs depending on when it was measured. In studies measuring cortisol right after waking, whether saliva is collected at precise times starting the moment of waking determines whether the measurement is reliable (PMID 26563991).

The pattern of sending letters also changes across a lifetime. As people age, the release pattern of hormones in the chain leading to the hypothalamus and pituitary gland changes, and the degree to which the upper levels respond to the reply sent by the peripheral hormones also changes. However, changes due to aging are difficult to untangle from the influence of other factors common in older adults, such as chronic illness, inflammation, and poor nutrition (PMID 30017799). The decline in hormone action with age has traditionally been considered a harmful thing. The authors of a review wrote that some of those changes are clearly beneficial adaptations tailored to age, and interventions to restore hormones that declined with age often produce significant side effects (PMID 30017799).

A single hormone value is a single snapshot taken on top of pulses, a daily rhythm, and age.

The Body Waking in the Morning — The Night's Letter and the Morning Letter

You fall asleep at eleven o'clock at night. While you sleep, a large amount of melatonin is released to signal that night has arrived in the body. The rhythm of this secretion is created by the central clock in the brain and adjusted to the cycle of light and darkness, and the timing of melatonin release is tuned to the length of the night (PMID 25908646).

At six-thirty in the morning, the alarm rings and you pull back the curtains. Light acts to suppress melatonin production or adjust its timing according to the timetable by which it is received (PMID 25908646). Around the same time, letters from the adrenal glands pour out. In healthy individuals, the majority of daily cortisol secretion occurs during the few hours around the time of waking up, and cortisol rises rapidly during the 30 to 45 minutes after waking (PMID 39177247).

Regarding what this morning surge does, one explanation has been proposed. One review proposes an integrative model in which this surge helps mobilize the body's resources in preparation for the day's tasks, and the body's internal clock, the surrounding environment, and the brain's judgment together gauge the amount of cortisol needed for that day in advance (PMID 39177247). This explanation is still at the stage of a model proposed by the authors.

When cortisol rises, a reply is sent back as well. Cortisol reaches the pituitary gland and hypothalamus to reduce the letters from the upper floors (PMID 26140713). If you draw blood from the same person again in the afternoon, cortisol shows a different value than in the morning. This is because the amount of cortisol varies predictably depending on the time of day (PMID 27871862).

Within a single morning scene, a gland sends a letter, the result sends a reply, and that process runs on a set schedule.

Where to Look Further

Questions remain unsolved as well. Most pituitary hormones are released in pulses, and the true advantage of releasing them in pulses remains a core open question (PMID 30075152).

You can follow how insulin and glucagon hold blood sugar in place throughout the day in "How Blood Sugar Stays Steady — A Letter to Store, a Letter to Release". How melatonin and circadian rhythm handle sleep is covered by "Sleep Pressure and the Body Clock — One Hourglass, One Wall Clock". The postal routes themselves that the letters travel are in "How the Heart Moves Blood — Four Chambers, Four Doors, Two Loops".

This series continues with a piece on diabetes, a piece on blood sugar test numbers, a piece on obesity and GLP-1, and a piece on the thyroid reading its up-and-down pair on a test paper. These pieces are not out yet.

Source Papers

• "Growth hormone." (2010) — PMID 20020365 — Growth hormone is a protein hormone secreted by the pituitary gland, acting directly through receptor binding or inducing IGF-I production, promoting growth in children and adolescents and metabolic function in adults, with pulsatile secretion and a short half-life creating large blood concentration fluctuations that make external administration impossible to prove from concentration alone.
• "The endocrine system: an overview." (1998) — PMID 15706790 — Hormones regulate growth, development, metabolism, electrolytes, and reproduction, via a hypothalamus→pituitary→target gland cascade, with the adrenal glands=cortisol, gonads=sex hormones, thyroid, parathyroid, and pancreas=insulin and glucagon.
• "Endocrine-Autonomic Linkages." (2015) — PMID 26140719 — Interactions between the autonomic nervous system and the neuroendocrine system are central to maintaining homeostasis such as body temperature, body fluids, and blood pressure, influenced by adrenal and gonadal steroids.
• "Adipose tissue as an endocrine organ." (2004) — PMID 15181022 — Adipose tissue is an active metabolic and endocrine organ secreting endocrine functional factors such as leptin and adiponectin.
• "Mapping insulin/GLUT4 circuitry." (2011) — PMID 21401839 — One of the core metabolic actions of insulin is promoting glucose uptake in skeletal muscle and adipose tissue.
• "Hypothalamus-Pituitary-Thyroid Axis." (2016) — PMID 27347897 — TRH→TSH→thyroid hormones, with negative feedback of T4 and T3 regulating TRH and TSH secretion, increasing TRH and TSH upon thyroid hypofunction or the reverse upon excess, essential for neurodevelopment, growth, energy metabolism, and thermogenesis, regulating gene expression mainly through nuclear receptors.
• "The hypothalamus-pituitary-thyroid (HPT)-axis and its role in physiology and pathophysiology of other hypothalamus-pituitary functions." (2021) — PMID 33549603 — The hypothalamus and pituitary gland are located close to the base of the brain, with stimulating and inhibiting hormones passing through the pituitary stalk, while the interaction mechanisms of multiple axes are still unclear, and diagnosing central hypothyroidism is complex in itself and becomes harder when other axis abnormalities overlap.
• "New insights into thyroid hormone action." (2017) — PMID 28174093 — The axis keeps blood thyroid hormone levels nearly constant, but tissues regulate intracellular availability via transporters and deiodinases, so blood concentrations do not fully represent the amount seen by each cell.
• "A users guide to HPA axis research." (2017) — PMID 27871862 — Cortisol levels change predictably according to the time of day and increase in response to stressors, utilized by almost all cells and physiological systems, representing a system easily reduced to a single measurement.
• "Corticosteroids: Mechanisms of Action in Health and Disease." (2016) — PMID 26611548 — Glucocorticoids are essential for life, and GR is expressed systemically while sensitivity and responses differ across tissues.
• "Measuring cortisol in serum, urine and saliva - are our assays good enough?" (2017) — PMID 28068807 — Cortisol is essential for maintaining health and both deficiency and excess cause disease, transported fat-solubly bound to CBG and albumin, with only about 10% free and active, and serum assays measure total amount which can be misleading when protein concentrations change.
• "Regulation of the Hypothalamic-Pituitary-Adrenocortical Stress Response." (2016) — PMID 27065163 — The HPA axis is necessary for stress adaptation, with glucocorticoids reallocating energy resources to match actual and anticipated demands, negative feedback, and context determining whether outcomes are adaptive or maladaptive.
• "The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress." (2006) — PMID 17290797 — During stress, CRF initiates the cascade leading to adrenal cortical glucocorticoid secretion, and glucocorticoid feedback inhibition regulates the magnitude and duration of secretion.
• "Hypothalamic-Pituitary--Adrenal Axis-Feedback Control." (2015) — PMID 26140713 — Corticosteroid negative feedback limits pituitary ACTH and hypothalamic CRH and AVP secretion to regulate basal and stress secretion, with some stressors overriding or bypassing feedback.
• "Prolactin: structure, function, and regulation of secretion." (2000) — PMID 11015620 — Prolactin is an anterior pituitary protein hormone named for promoting lactation, but it is also synthesized in the central nervous system, immune system, uterus, and mammary glands, and its actions are not limited to reproduction.
• "The physiology of endocrine systems with ageing." (2018) — PMID 30017799 — Aging alters the secretory patterns of hypothalamic-pituitary axis hormones and target hormone negative feedback sensitivity, aging effects are hard to isolate from other factors like chronic disease, inflammation, and nutrition, and regarding the concept of hormone replacement to reverse declines, some changes are beneficial adaptations and hormone interventions often carry significant side effects.
• "ACTH Antagonists." (2016) — PMID 27547198 — ACTH acts via a highly selective receptor of the melanocortin receptor family (MC2R), which requires the accessory protein MRAP to express and function on the cell surface, with ACTH being the only known natural agonist.
• "Nuclear Receptors, RXR, and the Big Bang." (2014) — PMID 24679540 — Steroid, retinoid, vitamin D, and thyroid hormone receptors share an evolutionarily conserved nuclear hormone receptor framework.
• "Pathophysiology of Glucocorticoid Signaling." (2018) — PMID 29685454 — Glucocorticoids bind to GR and then translocation to the nucleus occurs to bind DNA, activating target gene transcription.
• "The Cortisol Awakening Response: Regulation and Functional Significance." (2025) — PMID 39177247 — In healthy individuals, the majority of cortisol secretion occurs in the hours around morning awakening, surging 30 to 45 minutes after waking (CAR), with the authors proposing a dual-regulation integration model of circadian, environmental, and neurocognitive processes alongside a resource mobilization function.
• "Models in neuroendocrinology." (2018) — PMID 30075152 — Most pituitary hormones exhibit pulsatile secretion (with vasopressin as an exception), and what the true advantage of pulsatility is remains a core unresolved question.
• "Neuroendocrine rhythms." (1991) — PMID 1891479 — Hormones are secreted in hourly, circadian, and seasonal rhythms, with hourly pulses acting as a temporal code where much of the change in neuroendocrine state is mediated by changes in pulse frequency, and circadian secretion is synchronized to light-dark cycles with the suprachiasmatic nucleus as the most important pacemaker.
• "[Melatonin]." (1985) — PMID 2932708 — Melatonin is synthesized in the pineal gland, showing low daytime and high nighttime circadian secretion.
• "Melatonin: Physiological effects in humans." (2015) — PMID 25908646 — Melatonin is secreted by the pineal gland at night under normal light-dark conditions, with light inhibiting or entraining production, secretion matching night length, and its primary function being the transmission of light-dark cycle information while also participating in circadian tissues such as immunity, hemostasis, and blood sugar regulation.
• "Steroids." (2002) — PMID 12386486 — Corticosteroids are secreted according to CRH pulsatile secretion, and changes in pulse amplitude create the circadian rhythms of ACTH and cortisol, with cortisol helping lipolysis, inducing gluconeogenic enzymes, enhancing glucagon secretion, and suppressing insulin secretion (a review in the context of injury, fever, and severe stress).
• "Dynamics of ACTH and Cortisol Secretion and Implications for Disease." (2020) — PMID 32060528 — The circadian rhythm of cortisol consists of pulses varying in amplitude, with oscillating signals decoded at the cellular level.
• "HPA axis-rhythms." (2014) — PMID 24944037 — In the basal state, glucocorticoids exhibit a circadian rhythm peaking in the active phase (daytime in humans), with rapid ultradian oscillations driven by adrenal pulsatile secretion.
• "Assessment of the cortisol awakening response: Expert consensus guidelines." (2016) — PMID 26563991 — The validity of CAR measurement depends crucially on adherence to collecting saliva at scheduled times from the exact moment of awakening, according to an expert consensus statement by the International Society of Psychoneuroendocrinology.