ENDOCRINE SYSTEM OVERVIEW

Hormones are one area of health that are commonly referred to, yet not commonly understood.

More often than not, hormones have become an excuse for causing inexplicable mood swings, excessive cravings for unhealthy food and other impulsive behaviors that we supposedly have little control over. This has also caused hormones to gain a bad reputation, being perceived as the villains behind several health conditions and states of being. Unfortunately, hormones can’t really be blamed for any of our actions as they are merely innocent chemical messengers!

Through developing a deeper understanding of the endocrine system, it becomes clear that we are not at the mercy of our hormones and that they are in fact conducive to living a happy, healthy life. The following overview briefly details the endocrine system and how its many faucets come together to ensure that the body functions at its optimum.

Brief Look at the Functioning of the Endocrine System

The endocrine system refers to all aspects of the entire body that use hormones to produce effects[1]. It governs many finer points of both our lived experience and our health, through its control over vital bodily functions. Some of these functions include growth and development, the balance of electrolytes and other minerals in the body, our metabolism and appetite, our state of alertness and many facets of reproduction.

Hormones as Basic Chemical Messengers

No state of health can be achieved without a fantastic sense of biological communication. This is where our hormones come into play, serving to communicate relevant information between different systems of the body that allows it to function in harmony. Without hormones, the body would not be able to coordinate responses and create a sense of order from the millions of chemical reactions occurring in each of our cells on a daily basis.

Hormones are able to communicate on a chemical level in a variety of different ways. Endocrine organs tend to respond to specific stimuli, such as temperature or mineral balance in the body. They then release hormones in response to these stimuli in an attempt to maintain perfect homeostasis or balance. The hormones instruct receptive cells and organs to produce certain chemical compounds or act in specific ways that ensure this balance is achieved. When a hormone has sufficiently served its purpose, the net effects of its actions tend to inform the endocrine organs responsible (either directly or indirectly via the brain). The production of the specific hormone then becomes inhibited, often by the release of an inhibiting or counter-active hormone. In this way, hormones regulate many aspects of our physiology.

In terms of the nervous system, hormones play a special role as chemical translators. Neuro-endocrine cells form part of every organ in the body and act as go-betweens for neurons and all other cell types. The neuro-endocrine cell is capable of translating electrical impulses from nearby neurons into hormones that then signal to the other cell types what to do. In this way, the endocrine system feeds into the nervous system and helps the brain maintain control over all bodily functions.

Hypothalamus-Pituitary Coordination

Little are aware that the brain is in charge of all endocrine actions in the body and thus can be viewed as the actual culprit behind most hormonal perturbations. The hypothalamus and pituitary are two parts of the brain that regulate the entire endocrine system and form a central hub for all hormonal activity in the body. The hypothalamus is a part of the brain while the pituitary is an endocrine gland in its own right that resides next door to the hypothalamus.

Both the bloodstream and the nervous system run through the hypothalamus, allowing it to monitor all hormonal activity in the body at any given time. Temperature, osmotic pressure, hormones, nerve impulses and other chemical signals alert the hypothalamus as to what is required for balance. Once informed of something irregular, the hypothalamus releases stimulating or inhibiting hormones that are picked up by the pituitary gland. In response, the pituitary then sends out the actual hormones to act upon specific endocrine organs in the body. This has special relevance for the adrenal glands, the reproductive organs and the thyroid.

The hypothalamus can also send out nerve signals to other endocrine organs, having actions independent of the pituitary in order to effect hormonal instructions to distant body tissues.

3 Most Important Neuro-Endocrine Circuits

As mentioned, the hormonal communication between the hypothalamus and pituitary are especially relevant for the adrenal glands, gonads and thyroid. These interactions have been classified into the following three very important axis’s in the body:

1. HPA or Hypothalamic-Pituitary-Adrenal Axis, which governs our state of arousal, our response to stress or relaxation, fluid retention, mineral electrolyte balance and osmotic pressure throughout the body.

2. HPG or Hypothalamic-Pituitary-Gonadal Axis, which is responsible for controlling reproduction, sexual arousal and other related functions, such as menstruation, pregnancy, and sex differences in pubertal development.

3. HPT or Hypothalamic-Pituitary-Thyroidal Axis,  which controls for certain aspects of cellular metabolism as well as calcium homeostasis in the body.

All other organs in the body respond to hormonal signals too however, with the pancreas being another vital endocrine organ that deserves further discussion.

Types of Hormones

There are several different types of hormones that exert unique effects throughout the body. Each hormone type has a different molecular structure and size, which allows for them to interact with specific sites at the cellular level and thus exert their different effects[2]. These include:

• Steroids. Steroids include the sex hormones such as testosterone, estrogen, progesterone, prolactin and more. They are produced by the reproductive organs and the adrenal glands through stimulation via the brain. Steroids have a similar structure to that of cholesterol and tend to enter cells in a similar way, through “cholesterol rafts” that pass through cell membranes. Once inside their target cell, they either bind to molecules in the cytoplasm (cell fluid) or attach directly to receptors on cellular genes, found in the mitochondria or nucleus of the cell. When they bind, they instruct the cell to carry out instructions at the genetic level and tend to have far-reaching effects on growth, metabolism, reproduction and many other vital bodily functions.
• Amino Acid Derivatives. The thyroid and adrenal glands produce amino acid derivative hormones, which can be viewed as building blocks to fully-fledge proteins. This type of hormone passes through cell walls as well, like steroids, and tends to bind at specific receptors in genetic material. These hormones typically affect cellular metabolism.
• Proteins and Polypeptides. Proteins and complex molecules made of multiple peptides (protein building blocks) also have hormonal actions throughout the body. These types are commonly found in the hypothalamus, pituitary and pancreas. These hormones are largely unable to cross over inside cells and are active on the cell membrane. The membrane of the cell is littered with hundreds of cell receptors that take substances in and exude substances out. Proteins and polypeptides dock in at relevant cell wall receptors to exert their effects. Once cell wall receptors are activated in this way, it often initiates a chemical cascade that eventually translates into modulating cellular activity and function. Proteins and polypeptides can also serve to block the action of cell membrane receptors, inducing effects specific to the cell membrane and not the cell’s interior.

In this way, the definition of a hormone is far larger than what people realize. Many components of the food we eat, for instance, serve to interact with our biology in ways similar to hormones.

Hormonal Transport

As mentioned, hormones travel through the bloodstream to reach their target sites or are stimulated in target sites by nerves. In the case of the bloodstream, steroidal hormones are found bound to the proteins albumin[3] and sex hormone-binding globulin (SHBG)[4]. This helps them to reach their desired destinations and to be excreted if they are not required. Adrenal hormones, growth hormone and growth factors have unique binding globulins or proteins that facilitate their transport around the body.[5]

Free-floating hormones tend to be troublesome as they are known to activate target sites in an uncontrolled fashion. Serum albumin is generally needed to pick up the slack where other binding proteins fall short, helping to mop up these “free-floaters.”

Endocrine Organs and Their Hormones

The most important hormone-producing organs in the body are the thyroid, parathyroid, pancreas, adrenal glands and the reproductive organs in both men and women, as discussed below. All of these organs are stimulated in various degrees by the hypothalamus and pituitary in the brain, which serve as the primary centers for endocrine control in the body.

 In spite of these being the most important endocrine organs, every cell is hormonally active and responsive, meaning that the endocrine system can be extended to all areas of the body. The skin, pineal gland, liver and several other body sites promote the conversion of hormones into more potent forms that are essential for our functioning as well.

Hypothalamus

As explained above, the hypothalamus is constantly surveying signals from both the internal and external environments via the nervous system and bloodstream in order to ascertain what hormonal signals ought to be produced at any given time to achieve homeostasis. For the most part, all hypothalamus releases instruct the pituitary gland, which instructs the remainder of the endocrine system from there on out.

The main hormones the hypothalamus releases are as follows[6]:

• Thyrotropin-Releasing Hormone (TRH). TRH is responsible for stimulating the pituitary to release hormones that stimulate the thyroid gland, which governs all processes of cellular metabolism. This hormone is also responsible for aspects of lactation in breast-feeding mothers.
• Gonadotropin-Releasing Hormone (GnRH). GnRH can also be referred to as Luteinizing Hormone-Releasing Hormone due to the action it has of stimulating the release of Luteinizing Hormone (LH) from the pituitary. It also stimulates the pituitary’s secretion of Follicle Stimulating Hormone (FSH). Together, LH and FSH go on to reach the reproductive tract in both males and females, promoting the production and release of sex steroids such as testosterone and estrogen.
• Corticotropin-Releasing Hormone (CRH). CRH stimulates corticotropin from the pituitary, which in turn gets the adrenal glands to produce the main adrenal hormones: glucocorticoids and mineralocorticoids. Glucocorticoids are involved in the stress response and our state of arousal while mineralocorticoids are responsible for controlling fluid balance in the body, largely involved in regulating kidney function.
• Growth Hormone-Releasing Hormone (GHRH). GHRH causes the pituitary to release growth hormone, which is as straight forward as the name suggests, being involved in the overall growth of any organism.
• Somatostatin. Somatostatin is released when there is enough GHRH, having an inhibitory effect on it and suppressing bodily growth.
• Dopamine. Dopamine is a neurotransmitter with a small subset of endocrine actions, such as inhibiting lactation during pregnancy (until after the child is born).

Pituitary Gland

When looking at its role in the endocrine system, the pituitary takes the endocrine signals from the hypothalamus and translates them into hormonal signals that other systems of the body understand and can act upon.

At the same time as producing hormones that affect the rest of the body, the pituitary’s hormones tend to act as inhibitors on hypothalamic hormone release. This ensures that the hypothalamus does not keep endlessly promoting hormone secretion and helps to regulate the endocrine system as whole.

The pituitary is divided into two parts: the anterior pituitary and posterior pituitary.

Anterior Pituitary

The anterior pituitary plays a bigger role in hormonal regulation than the posterior portion of the gland. The hormones the pituitary releases either get target organs to produce their own hormones or has a direct interaction on the organs at the cellular level. These hormones include:

• Growth Hormone (GH). Growth hormone directly affects the majority of tissues in the body and as the name implies, it is involved in stimulating the growth of all of them. Other than promoting growth, GH also plays a role in controlling cellular energy metabolism by preventing muscles and fat from absorbing glucose, while simultaneously promoting glucose production in the liver. These actions are the opposite actions to that of insulin. GH is inhibited by somatostatin, a hypothalamic hormone.
• Luteinizing Hormone (LH). LH is released by the pituitary in response to hypothalamic gonadotropin-releasing hormone and promotes the reproductive organs in both sexes to produce testosterone and estrogen.
• Follicle Stimulating Hormone (FSH). FSH is released at the same time as LH and stimulates the reproductive organs to grow, as well as to produce germ cells (sperm and ova). Both LH and FSH are vital to reproductive function.
• Thyroid-Stimulating Hormone (TSH). TSH gets the thyroid to produce thyroid hormones, thyroxine (T4) and triiodothyronine (T3). These are involved in cellular metabolism throughout the entire body. T4 and T3 also inhibit TSH release, helping to control the feedback from the pituitary.[7]
• Adrenocorticotropic Hormone (ACTH). ACTH stimulates the adrenal glands to produce glucocorticoids, such as cortisol, as well as a small amount of steroidal hormones like DHEA ( a form of adrenal testosterone).
• Prolactin. Prolactin is mainly involved in breast development and breast-milk production. It may play other roles as it is present in both genders and appears to modulate other areas of the body in ways that are not yet entirely understood.

Posterior Pituitary

The posterior pituitary doesn’t release any hormones but serves as a storage site for vasopressin and oxytocin. Both of these hormones are generated by the hypothalamic neurons that extend into the back end of the pituitary, where they are stored. Their functions are as follows:

• Vasopressin. Vasopressin is involved in managing fluid balance in the body and promotes re-absorption of water from urine in the kidneys, thus helping to conserve bodily water. This hormone also regulates sodium in the bloodstream as well as blood pressure. When blood pressure or sodium increases, vasopressin decreases in an attempt to lower bodily water as well as blood pressure. When blood pressure is low, vasopressin is increased in order to conserve water and maintain osmotic pressure in the bloodstream. Adrenal mineralocorticoids also play a role in regulating fluids and blood pressure in the body together with vasopressin.
• Oxytocin. Oxytocin is the “trust hormone,” released when we feel relaxed, safe and trusting of others. In females, it also stimulates breast-feeding and contractions during child birth. New research is revealing that oxytocin is involved in a large variety of neurological processes; however its involvement remains to be fully explained.[8]

Thyroid and Parathyroid Glands

The thyroid gland and four parathyroid glands are endocrine organs that are responsible for governing many aspects of metabolism at the cellular level, influencing each and every tissue in the body.

Without the hormones that the thyroid produces, the body would be incapable of sustaining energy production, growth would be inhibited to a large degree and many protective mechanisms of cells would cease to function optimally. The parathyroid plays a smaller, yet also essential role in regulating energy production through ensuring all tissues receive an adequate supply of the right form of calcium.

The hormones produced by the thyroid and parathyroid glands are as follows:

• Thyroxine (T4). Up to 90% of thyroid hormones are stored in this form, which is an amino acid derivative hormone that arises from the chemical transformation of tyrosine. While T4 exerts some functions in the body, the majority of it is transformed into T3 by the liver and kidneys. They have similar effects, yet T3 is a more potent form and is required more by the cells of the body. If conversion of T4 is hampered, one may experience fatigue and symptoms associated with hypothyroidism.
• Triiodothyronine (T3). T3 is required by all cells in order to ramp up cellular energy production for specific functions such as growth, heat generation, metabolism, nutrient absorption, nerve transmission, heart function and digestion.
• Calcitonin. The thyroid also produces calcitonin, which lowers blood calcium levels by inhibiting its excretion from bone tissues and reabsorption in the kidneys from the urine. Calcitonin regulates the pro-calcium activities of parathyroid hormone and keeps calcium levels balanced throughout the body. Calcium is a vital component for energy production at the cellular level and this balancing action of the thyroid and parathyroid is yet another way energy metabolism is supported by these glands. Calcitonin is a form of Vitamin D that is converted from dietary D2 into vitamin D3 after its precursors have been exposed to sunlight. The precursors of calcitonin are chemically transformed in this way in the skin.
• Parathyroid Hormone (PTH). PTH is produced by the four pea-sized parathyroid glands, which rest behind the thyroid gland. This hormone does the opposite to calcitonin, promoting higher blood calcium levels, ejection of calcium from the bones, reabsorption of bone calcium as well as reabsorption of calcium from urine in the kidneys. Furthermore, PTH is required for absorbing calcium from food in the digestive tract during digestion. PTH operates independently of the pituitary and is stimulated when calcium levels are too low, or inhibited when they are too high. Vitamin D3 (a form of calcitonin) is required to promote and regulate the actions of PTH. Estrogen, glucocorticoids and growth hormone can also impact PTH’s functions by promoting heightened blood calcium levels.

Pancreas and other Digestive Organs

The pancreas is the most hormonally active of all the digestive organs alongside the liver, which is involved less in hormonal production and more in the metabolism of nearly all bodily hormones. The pancreas is responsible for producing digestive enzymes and the main hormones responsible for regulating glucose metabolism in the body: insulin and glucagon.

• Insulin. Insulin is the only hormone in the entire body that lowers blood sugar levels. It does this by ensuring that glucose is stored in forms that can be later utilized for energy production, however while present, insulin also prevents these stored forms of glucose from being broken down. Insulin also promotes muscle building by facilitating the transport of proteins into muscle tissue, as well as stimulating the release of insulin-like growth factors, which promote growth and regeneration all-round. Glucagon inhibits the activity of insulin, as does cortisol, thyroid hormones and growth hormone (in spite of the fact that many of these hormones have similar stimulatory effects on growth and energy production).
• Glucagon. Glucagon has the opposite action to insulin in that it increases blood sugar levels, as well as the functional breakdown of stored nutrients in order to promote energy production. Insulin inhibits the action of glucagon in the same way that glucagon inhibits the actions of insulin, with each hormone regulating one another for optimal digestion, blood sugar levels and energy metabolism.

The stomach, liver, and gallbladder are also stimulated via the vagus nerve through neurological stimulation from the hypothalamus. Neuro-endocrine cells in these organs take signals from the vagus nerve and translate them into hormonal instructions that help the release of digestive enzymes, such as stomach acids, bile acids and many liver by-products.

Adrenal Glands

The adrenal glands are endocrine organs situated on top of the kidneys. The outer layer, known as the adrenal cortex, is responsible for producing most adrenal hormones. These are steroidal by type and consist of:

• Glucocorticoids. Cortisol is the most famous of the glucocorticoids with many other varieties being derivatives of it. Corticoids regulate various processes in the body pertaining to the immune system, trauma, cognition, wakefulness and metabolism. A small amount of them keep us awake and alert throughout the day, with levels peaking first thing in the morning to wake us up from sleep. This little amount is also important for cognitive function, focus, memory and learning. In higher amounts, it detracts from these functions and in lower amounts it causes one to feel too drowsy to focus.

Whenever the body experiences high levels of inflammation, such as during traumatic injury, allergy or states of disease, glucocorticoids are released to suppress inflammation. Too many glucocorticoids over a prolonged period of time however have been seen to cause tissue damage as they also suppress the body’s ability to regenerate[9]. The activity of corticoids are opposing to that of insulin, preventing muscles and fat from taking up glucose as well as promoting resources in these tissues to be broken down and used to produce energy.

• Mineralocorticoids. These are a different set of hormones that regulate mineral and fluid balance in the body, having a primary action in the kidneys. Mineralocorticoids, like aldosterone, are not governed by the hypothalamus and pituitary. Instead they are regulated internally by the adrenal glands themselves through the release of various hormones such as renin and angiotensin.
• Sex steroid hormones. The adrenal glands produce a fraction of steroidal hormones in the body of both men and women, namely DHEA, a specific form of testosterone. DHEA is released every time cortisol is released to help mitigate any negative effects it may produce. The adrenals also produce a small fraction of estrogen in both genders.

The inner layer of the adrenal glands, known as the adrenal medulla, produces epinephrine and norepinephrine. The former is released alongside cortisol and other glucocorticoids during the stress response, while the latter is released to inhibit the former when one is relaxed. Epinephrine and norepinephrine also play vital roles in regulating muscle contraction and nerve transmission.

Reproductive Organs

The main hormones active in the reproductive hormones are the sex steroids, androgen and estrogen. There are many different forms of these hormones and they have a wide set of actions in tissues all throughout the body. Between estrogen and androgen, growth and development is kept in balance, with sex-specific differences being evident in the physical characteristics of man and woman respectively. Both of these main sex hormones are produced in the reproductive tract when stimulated by LH and FSH release from the pituitary.

• Estrogens. Estrogens are produced in the adrenal glands of both genders, as well as from the conversion of testosterone in various organs, such as skin and the reproductive tract. In females, most estrogen is produced in the ovaries and regulates the growth and function of the reproductive organs and breasts. They also promote female libido, lactation, the female phenotype and feminine growth spurts during puberty. Estrogens are also produced in the placenta and the corpus luteum (a cellular structure produced during ovulation). In males, estrogens are produced in much smaller amounts and aid the development of a specific portion of the reproductive tract known as the epididymis (a tube connecting the testis to the vas deferens). Estrogen is produced by fat cells (adipocytes) and having high estrogen levels tends to result in weight gain. In other tissues, estrogen is associated with promoting growth inhibition, such as in muscle, with testosterone counteracting its actions.
• Androgens. Testosterone is also produced in the adrenal glands of both men and women, as well as in skin and the reproductive tract. In men, androgens play a leading role in the development of physical masculine characteristics, with the majority of them being produced in the testes. Just like estrogens in females, androgens in males are required to keep the growth and development of the reproductive tract intact, as well as regulating libido and sperm production. Androgens tend to promote the growth of bone and muscle, which is why men tend to be taller than women on average with an increased capacity for physical activity.
• Progesterone. Progesterone has multiple functions in the body and is primarily a hormone that can be converted into either testosterone or estrogen, as required. In females, progesterone, as is, stimulates breast development and lactation together with estrogen. Furthermore it plays a role during menstruation and gestation by preparing the lining of the uterus.

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Sources:

• [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761896/
• [2] https://www.ncbi.nlm.nih.gov/books/NBK541112/
• [3] https://www.ncbi.nlm.nih.gov/books/NBK459198/
• [4] https://www.ncbi.nlm.nih.gov/books/NBK20/
• [5] https://www.metabolismjournal.com/article/0026-0495(72)90048-0/fulltext
• [6] https://www.ncbi.nlm.nih.gov/books/NBK538498/
• [7] https://academic.oup.com/endo/article/150/3/1091/2455538
• [8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689929/
• [9] https://link.springer.com/article/10.1007/s42000-018-0023-7

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