A Glimpse Into The World Of Hormones
I have a question for you.
What makes a chick so different from a rooster? Sure, they look very different, but why do they behave so differently?
Characteristically, roosters tend to be more dominant creatures. They make their presence known, whether that be through strutting around and displaying their feathers, their loud and aggressive behavior, and the most notable of all, their crowing during sunrise.
In order to become a rooster, a chick undergoes a plethora of physical and behavioral changes. Physically, the chick becomes larger, more colorful, and more decorated. But behaviorally, the chick begins to exhibit more mature behaviors — strutting and crowing, trying to mate with hens, and other aggressive behaviors.
In the mid 19th century, there was a German scientist named Arnold Berthold. Back then, people didn’t really know about hormones.
Berthold took a prepubescent male chick and castrated it, removing its testes, which were the chick’s source of testosterone. This chick became a capon, an undeveloped male who showed no typical behaviors of a rooster. It had a small comb and wattles, no interest in mating, and showed no aggression towards other males.
The capon showed that the testes clearly had a role in the pubertal development of the male chick. However, Berthold did not know how much of a role they played.
Berthold took two more prepubescent male chicks. In one, he castrated and reimplanted the testes. When this chick matured, it underwent normal male development.
In the other prepubescent male chick, Berthold castrated and reimplanted the testes of another prepubescent male chick, to see if their function was specific to each individual chick. This chick also underwent normal male development, becoming a typical male rooster.
In essence, Berthold’s experiment was testing if whatever was coming from the male testes had a hard path for signaling.
In order to understand this, we have to look at our central nervous system.
All of the nerves in our CNS communicate through smaller paths, called cellular axons, which are part of neurons themselves. However, when the cellular axons between neurons are severed, they are very hard to reattach. Most of the time, it induces permanent damage.
Berthold’s study showed that even when these connections were severed, development proceeded normally, as shown in the second and third chick he castrated.
Berthold realized that whatever was being released from the testes had to be a soluble factor, instead of being reliant on a physical path. Moreover, the third castrated chick also proved that whatever was being released from the testes was not specific to the individual chick.
And that begs the question — what is a hormone?
In its simplest form, a hormone is nothing but a chemical messenger. Hormones are produced and released by endocrine glands in the body. Any organ that makes and releases hormones is an endocrine gland.
Upon being released, these chemical messengers travel through the bloodstream and interact with cells in target tissues through receptors. It is also important to note the significance of hormonal receptors.
A hormone is unable to act unless it can bind with a receptor. The location of the receptor signals to the hormone that it is within a target tissue. Once the hormone is bound to a receptor, it can exert some biological response.
Endocrine cells are only capable of making hormones. When hormones need to be released from the cells, the vesicle fuses with the plasma membrane, spilling the hormones from inside the cell into the extracellular space.
In order for the hormones to be utilized, they have to enter the blood vessels. Once entering the blood vessels, the hormones can travel a variable distance; anywhere from 1 millimeter to 2 meters.
Let’s take testosterone as an example. When testosterone is released from the testes and needs to act on the brain, it leaves the bloodstream and binds directly with androgen receptors in the brain.
A System Run Entirely On Hormones
The endocrine system is a ductless system. Hence its name, the endocrine system circulates hormones through the bloodstream inside the body. On the other hand, ductal systems allow for the collection of fluids to be excreted outside of the body — usually sweat, saliva, tears, or milk.
The endocrine system is also well vascularized. Blood vessels play a crucial role within the endocrine system. Once the hormones are released into the bloodstream, the blood vessels distribute the hormones to their respective receptors placed within target tissues. Therefore, the target cells need to be close to the blood supply.
Endocrine glands are the same in both sexes. In the brain, these include the hypothalamus and the pineal gland, the pituitary gland just outside the brain, the thyroid gland, the adrenal gland.
However, hormones are also produced by the pancreas, the gut, the gonads (testes in males and ovaries in females), fat and fat cells, and the placenta, which acts as a temporary endocrine gland.
The pineal gland is a small structure located within the brain. In the midsaggital view of the brain, the pineal gland is represented as a tiny red dot; you can see that it is only about the size of a pea.
When you cut through the pineal gland, you can see the pinealocytes within it; the cells responsible for the production of melatonin.
Melatonin, a hormone that regulates our circadian rhythm, is the only hormone produced by the pineal gland.
As shown in the image, the hypothalamus consists of several spherical shapes (cellular clusters) shown, which resemble marbles. Although the hypothalamus looks quite large, it is a very tiny structure within the brain and is also only about the size of a pea. Despite its size, the hypothalamus is the body’s master endocrine gland.
Many of the hormones we make in other organs are directed by the hippocampus. In the image shown, each of the “marbles,” or clusters of cells, makes or directs the production of different types of hormones in the body.
Many of the hypothalamic hormones are releasing hormones, meaning that they initiate a cascade by signaling other endocrine glands to produce more hormones. In the hypothalamus, these include TRH (thyrotropin-releasing hormone), GHRH (growth hormone-releasing hormone), GnRH (gonadotropin-releasing hormone), MRH (melanotropin-releasing hormones), CRH (corticotropin-releasing hormone), and PRH (prolactin-releasing hormone).
On the other hand, inhibiting hormones inhibit other endocrine glands from secreting the hormones at all, negatively regulating the production of hormones. Within the hypothalamus, these are somatostatin (growth hormone-inhibiting hormone) and prolactin inhibitory factors.
However, to understand the significance of these hormones produced in the hypothalamus, we have to look at the pituitary gland.
The pituitary gland is also called the hypophysis, as it is located on the underside of the brain, and communicates directly with the hypothalamus.
The hypothalamus communicates differently with the anterior and posterior pituitary glands, both of which make up the entirity of the pituitary gland. Hormones travel from the hypothalamus, through the infundibulum, and to the anterior and posterior pituitary glands.
In the anterior pituitary, the purple neurons are hypothalamic neurons. They send their long, cellular projections (axonal projections) down into the anterior pituitary gland. The axonal projections terminate right at the median eminence, or the stalk of the pituitary.
Those axon terminals release neurohormones, shown by the red dots. The anterior pituitary has a very rich blood supply. In the anterior pituitary, the blood flows from the top to the bottom. Therefore, as soon as the hormones are released, they are absorbed by the blood. The hormones released are transported from the median eminence down into the anterior pituitary, which is rich in cells and hormonal receptors.
The hypothalamic hormones bind to their receptors on the pituitary cells, which respond by secreting their own pituitary hormones into the blood supply.
Therefore, anterior pituitary has two different types of cells producing hormones; the hormones produced by the hypothalamic neurons, but also those produced by the anterior pituitary cells.
The anterior pituitary itself produces 7 key hormones, all of which are stimulated by the releasing hormones produced by the hypothalamus.
Luteinizing Hormone (LH): a gonadotropin crucial in sexual development and function. In women, regulates the menstrual cycle and triggers ovulation.
Follicle Stimulating Hormone (FSH): a gonadotropin that regulates menstrual cycle in women. Stimulates egg growth in the ovaries in the Follicular Phase of the menstrual cycle.
Adrenocorticoropic Hormone (ACTH): stimulates the production of cortisol from the adrenal gland, which regulates blood sugar, blood pressure, and memory formulation.
Melanocyte Stimulating Hormone (MSH): protext the skin from UV rays, regulate development of pigmentation, as well as appetite.
Thyroid Stimulating Hormone (TSH): a thyrotropin that regulates the production of hormones by the thyroid gland, which regulates energy, weight, body temperature, muscel strength, and mood.
Growth Hormone (GH): stimulates the production of insulin-like growth factor in the liver, and acts on tissues to control metabolism and growth. Also affects sleep, food intake, memory, and helps to maintain, build, and repair tissue in the brain and other organs.
Prolactin (PRL): critical for milk production
The anterior pituitary gland produces a lot of “tropic” hormones, meaning that they nourish, stimulate, or support something. Many of these “tropic” hormones are made to nourish another endocrine organ.
For example, FSH and LH, which are gonadotropins, stimulate the gonads (testes in males, ovaries in women). TSH, a thyrotropin, stimulates the thyroid gland to secrete thyroid hormones.
This relationship between the hypothalamus and anterior pituitary is also referred to as the hypophyseal portal system, a system of blood vessels in microcirculation at the base of the brain, which transports and exchanges hormones between the arcuate nucleus in the hypothalamus and the anterior pituitary gland.
The purple and beige cells are hypothalamic neurons. The axonal projections of these neurons do not terminate at the median eminence, and instead, travel through the infundibulum. Their terminals are located inside the posterior pituitary.
They produce vasopressin, a hormone that regulates blood pressure, sodium, and kidney function, as well as oxytocin, which controls key aspects of the reproductive system and aspects of human behavior. Together, both oxytocin and vasopressin affect social processes in mammals.
As soon as these hormones are released, they end up in the general circulation of the blood.
In the posterior pituitary, no pituitary cells are producing hormones. All of the hormones released by the posterior pituitary into general circulation are produced by the hypothalamic cells themselves.
The thyroid gland wraps around the esophagus. When looking at a cross-section of the thyroid gland, a very interesting cellular architecture can be observed. The dark purple dots are epithelial cells, which form a ring-like structrue around larger follicles.
The thyroid hormones are produced by these epithelial cells and are stored within the larger follicles. They are then released periodically to the rest of the body, as necessary.
These hormones include thyroxine and triiodothyronine, which are important in metabolism, energy regulation, development, and mental health:
Thyroxine (T4): a relatively inactive prohormone, which means that it has to be converted into an active form before being utilized by the body. It is converted into T3 when it is in an active form.
Triiodothyronine (T3): T3 plays a vital role in digestion, heart and muscle function, brain development, and bone density. It is an active form of thyroxine. Approximately 20% of T3 is secreted into the bloodstream directly by the thyroid gland, while the other 80% is produced by the conversion of thyroxine by organs such as the liver and the kidneys.
The adrenal glands are two endocrine glands, shown as the yellow structure surrounding the top of the kidney.
If you slice through the adrenal glands, you notice two distinct sections; the adrenal medulla (middle section) and the adrenal cortex (outer shell). Both sections contain different types of cells, each of which specializes in the production of a different steroid hormone.
Steroid hormones are hormones secreted by any three of the “steroid glands,” the adrenal cortex, the testes, and the ovaries (and the placenta during pregnancy). All steroid hormones are derived from cholesterol.
The adrenal cortex produces glucocorticoid hormones which regulate blood sugar, mineralocorticoid hormones which regulate stress response, and weak androgens, other androgens not including testosterone.
The adrenal medulla produces epinephrine and norepinephrine which are crucial in our “fight-or-flight” stress response. Within the body, they act as both neurotransmitters and hormones. Their release into the bloodstream initiates increased blood pressure, heart rate, and blood sugar levels.
The pancreas is both an exocrine and endocrine organ. As an endocrine organ, the pancreas secretes critical hormones that are important for the regulation of blood glucose levels.
However, the pancreas is a ductal system. The ducts extending off of the pancreas feed directly into the intestines and the stomach, secreting chemicals that help our body digest food. Therefore, the pancreas plays a large role in appetite regulation.
When we look at a cross-section of the pancreas, we see a very complex circle with a heterogeneous population of cells in the center. This is an islet of Langerhans, groups of pancreatic cells that secrete several different hormones:
alpha cells: secrete glucagon, which promotes the breadown of glycogen, the storage form of carbohydrates in mammals, into glucose, within the liver.
beta cells: secrete insulin, which control the body’s blood sugar and regulate metabolism.
PP cells: secrete pancreatic polypeptide, which control the release of other substances made by the pancreas. It inhibits pancreatic secretion and acid secretion, and increases with age.
delta cells: secrete somatostatin, a neurotransmitter and hormone, which prevents the production of other hormones and stops the unnatural rapid reproduction of cells, such as those that occur in tumors.
epsilon cells: secrete ghrelin, which stimulate appetite, increase food intake, and promote fat storage.
Specifically, alpha and beta cells are critical endocrine cells.
The glucagon produced by the alpha cells is secreted by the pancreas when an individual is not hungry. When there is a limited quantity of food to digest in the small intestine, an individual’s blood sugar drops, increasing the production of glucagon.
Glucagon is responsible for secreting an increase of blood sugar within the body between meals since we eat episodically. The excess energy, or calories, within the foods we consume is stored as glycogen. When our blood sugar drops between meals, we need some source of sugar as energy as we aren’t constantly consuming foods.
On the other hand, the beta cells work in opposition to alpha cells by secreting insulin. The beta cells increase insulin when blood sugar levels are high, right as food is being consumed and digested. As nutrients are digested and move through the small intestine, they are transferred to the blood supply, substantially increasing an individual’s blood sugar.
Initially, this is beneficial because it energizes all parts of the body through the bloodstream. However, this isn’t useful for your cells who want glucose inside them.
Insulin plays a key role in allowing glucose to move into the cells from the bloodstream, as it allows the transfer of sugar from the blood to the cells.
Stomach and GI Tract
The hormones within the stomach and GI tract consist of those that regulate satiety and others that are released when the stomach is empty, and are responsible for stimulating hunger cues to the brain.
Ghrelin, which is also secreted by the pancreas, is the main hormone secreted by the stomach. Its main function is in appetite regulation, as the stomach is stimulated to secrete ghrelin when it is physically empty.
If an individual is not eating when hungry, the body is stimulated to break down other sugars and starches; any other short-term storage of energy, which lasts about 8 to 12 hours.
After short-term energy storages are depleted, the body begins to break down fat stores, a long-term energy source. It will also begin to break down muscles for as long as possible.
While in theory, one can survive for a while without eating between short-term sugar storage, fat storage, and muscle storage, a plethora of hormonal changes sends panic signals to your brain that you are starving and about to die.
Our adipocytes cells (fat cells) and enterocytes (cells in our intestinal lining) produce a key hormone, leptin, which regulates our energy balance by inhibiting hunger. In turn, this diminishes fat storage within adipocytes.
Leptin is a satiety signal that communicates to the brain that you are full and satisfied, and therefore, should stop consuming food.
On the left, we see a mouse that has leptin, but the mouse on the right is leptin-deficient.
Most standard animals, despite constant access to food, can more or less regulate their eating. However, the leptin-deficient mouse consumes a surplus of food, and most often, becomes obese, as it doesn’t receive satiety cues.
Since being identified in the mid-1990s, we have discovered that leptin does a lot more than appetite regulation and satiety.
Let’s say you run an experiment where you measure the food consumed by a standard lab animal, and it consumes 5 grams of some food. Therefore, you set up the experiment where you restrict to a mouse so it only has 5 grams of food every day.
If you run this experiment with a mouse with leptin and a leptin-deficient mouse, you will see that in a 24 hour period, both mice will consume the entirity of the food. They cannot overeat as they are consuming the same amount of food.
In this case, you would expect both animals to be the same size. However, the leptin-deficient mouse is still larger than the one that is producing leptin, although it might not quite be overweight.
This shows us that leptin is not just a satiety signal, but helps to regulate metabolism. In essence, leptin increases the rate at which calories are burned.
The testes are a crucial, yet complicated aspect of the male endocrine system. Within the testes, we see many different subfeatures, including various different cells in varying stages of development.
In a cross-section of the testes in the image on the right, we can see long strands representing the seminiferous tubules. The middle of the seminiferous tubules contains a very particular architecture. The lumen space is filled with liquid and longer strands, which are the tails of mature sperm.
The heads of the mature sperm are the dark purple circles at the edge of the lumen space. The dark purple heads of the mature sperm increase in size, becoming larger and rounder, when moving towards the outer edge of the tubule.
The larger round purple cells are the nuclei of immature sperm cells. As they mature, they move from the outer edge to the middle of the seminiferous tubule, where the mature sperm are. As the sperm cells mature, the nucleus and cytoplasm become much smaller and more compact.
The seminiferous tubules also include very large cellular masses, represented by the pink space in the image. These are called the Sertoli cells. The maturing sperm cells are embedded within the Sertoli cells.
When considering spermatogenesis, the development of the sperm, they need to be packed in the tightest form possible, with a conical nucleus, making the sperm more aerodynamic. The immature sperm has a lot of cytoplasm, shown by the blue space surrounding the nucleus. However, the fully mature sperm has nearly no cytoplasm and has developed tails allowing the sperm to swim.
The Sertoli cells provide a lot of nutrients that are necessary for the development and maturing of the sperm cells. The Sertoli cell can generate a lot of amino acids and energy to provide to the maturing sperm cells, and also serve as a garbage reservoir for the sperm who shed their cytoplasm and nucleoplasm.
Although it can take several weeks for an immature spermatogonium to become a mature sperm cell, the process happens continuously, meaning that the seminiferous tubules are very long.
In the space between seminiferous tubules are Leydig cells, which are responsible for the production of androgen hormones, which are steroid hormones. In males, this is the major source of testosterone, the most common androgen that males produce at very high levels.
The ovaries play a crucial role in reproduction and in the female endocrine system, due to the amount of reproductive hormones they secrete, and their role in menstruation.
If we draw a horizontal line across the middle of the ovary, we will find that the structures at the top and the bottom of the ovary are completely different. The maturing follicles, which house the eggs are located at the top of the ovary, and the corpus lutea, the follicles that have ruptured following ovulation, are located at the bottom of the ovary. In between, is the stroma, or the liquid space.
Not only do ovaries have a structural function, but they also have a cyclical pattern as to how they function over time.
Once males go through puberty, the processes involved in spermatogenesis and the production of testosterone stay constant. The production of sperm and androgens stay relatively the same over their lifetime.
However, ovaries function cyclically. In primates, one full cycle of ovarian function takes place in about one month. Therefore, we call it the menstrual cycle.
In other female animals, the length can vary. Therefore, we call it the estra cycle, as estrogens are one of the main hormones being secreted by the ovaries.
If we follow one cycle through the female ovary, we see a large range of hormonal and structural changes that take place.
If we start on the upper left of the ovary, we see the primary follicle. In the center of the follicle, we see a small blue dot, which is the egg. The egg contains the genetic content from the mother, which is to be passed onto the offspring. On the outside of the egg are the follicular cells, which line and protect the egg inside as it develops.
As a female begins her menstrual cycle, a subset of these primary follicles begin to mature and increase in size. Although the egg does not increase much in size, the follicle, consisting of the follicular cells lining the egg, thickens and increases in size. Towards the end of the follicular phase, nearing ovulation, the antrum, or the liquid space between the follicle increases as well.
The follicles get much larger until they become extremely mature. Follicular development occurs for about 2 weeks until one of the follicles physically ruptures, releasing an egg into the fallopian tube. The follicular cells and antrum evolve into the corpus luteum, at the bottom of the ovary, which secretes hormones for approximately 2 weeks until it degenerates.
These follicles are responsible for the production of estrogens, which trigger ovulation in the middle of the menstrual cycle, after about 2 weeks of follicular development.
At the start of the menstrual cycle, estrogen levels are very low. As the follicles get bigger, estrogen levels increase, as the follicles themselves are responsible for the production of estrogen. Ovulation occurs when estrogen levels peak, rupturing the extremely mature follicle and releasing the egg inside.
Right before the follicle ruptures, it briefly secretes progestins. As “pro” means to support and “gestins,” stands for gestation, progestin hormones, especially progesterone, are important during the gestation period — the period when the fetus is carried in the womb.
Once the follicle has ruptured and released an egg, it secretes very high levels of progestins. Once the egg has not signaled to the corpus luteum that it has been fertilized between a period of about two weeks, menstruation occurs.
One of the key roles of progestin hormones is also to stop follicular development. Progestins only start to be secreted when the extremely mature follicle is about to rupture and continue to be secreted for approximately two weeks thereafter.
In a high progestin state, follicle maturation is halted. This allows for the menstrual cycle to be completed, without the development of another follicle before the degeneration of the corpus luteum. The only times that a woman will be in a high progestin state are in the last two weeks of her menstrual cycle and during pregnancy.
If the egg is fertilized, the progestins need to remain high for the majority of the 40 weeks an individual is carrying a baby. The progestins cause increased fluid and vascular retention within the uterine lining, as the developing embryo needs a lot of blood flow and support.
If a woman is pregnant, the blastocyst, a mass of cells that develops soon after fertilization, embeds itself into the uterine wall and the placenta is built as an intermediate organ between the mother and the baby. The placenta is a temporary endocrine organ in the uterus that provides nutrients to the growing baby and removes waste, while also secreting many hormones.
The placenta is a very rich endocrine organ due to the number of different hormones it produces. It makes estrogens and progestins to support the ovaries, as well as placental lactogen, a hormone that prepares the breasts for milk production.
Some of the most important hormones produced by the placenta are the chorionic gonadotropins (hCG), which are produced by the chorionic cells in the placenta. The role of hCG is to stimulate the corpus luteum to continue the secretion of progestins. It is one of the earliest hormones released from the placenta and signals back to the mother’s ovaries to keep the corpus luteum alive and function in order to maintain high progestin levels throughout the duration of the pregnancy. This not only keeps the uterine lining thick during the duration of the pregnancy but is responsible for halting follicular development.
So there you have it; the quickest glimpse I can give you into our biochemistry. Albeit complicated, hormones dictate our lives. From our energy regulation to our stress response, our hormones regulate our most basic functions while also navigating our body through the complex world of modern society which places huge demands on our bodies that evolution has not prepared us to face.
Our biochemistry is a dictator of how our bodies interact and function in a world where convenience comes before cost. In a world of endocrine-disrupting compounds, instant access to food, and a toxic hustle culture.
By paying more attention to our epigenetic makeup — how our environment and our conscious decisions influence our biochemistry — we can begin to understand how to decisively change the outcome of our lives.
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