Metin Ozata, MD
Professor of Endocrinology and Medicine
There is no organ or tissue that thyroid hormones do not affect in the body. Therefore, the thyroid is at the center of all events. A) THYROID-SKIN AXIS
Thyroid hormone plays a role in the elasticity of the skin by affecting the synthesis of hyaluronic acid and collagen in the skin. If thyroid hormone is low, collagen and hyaluronic acid are reduced, and wrinkles, dryness, coarseness, coldness, and edema occur. Therefore, itching and flushing of the skin develops. Pigmentation, ie, color change develops. This is why it is understandable. Face shape changes. Edema around the eyes. Shedding occurs in eyebrows and hair loss. Thyroid hormone is more than the skin thinning, oil makes. There is an increase in allergic events called urticaria. Thyroid hormone excess increases the breakdown of collagen. Externally excreted thyroid hormone increases the thickening of the skin. Eczema, psoriasis, allergic skin diseases and xantelasma are common in thyroid patients. Optimal thyroid treatment may improve most of the skin lesions. Those with dry skin should also drink at least 2.5 liters of water per day. Moisturizing cream is useful. In addition, excessive soap should be given up. Studies have shown that the hormones of the hypothalamus-pituitary-thyroid axis, namely TRH, TSH, T3 and T2 , are effective in the hair follicle and affect the hair follicle mitochondrium
B) THYROID- CONNECTİVE TISSUE AXIS AND ROMATOLOGIC DISEASESThyroid hormones increase the production of collagen 1, biglycan and cartilage oligomeric matrix protein (COMP) especially in the connective tissue called the extracellular matrix. Connective tissue disease is common in autoimmune thyroid diseases. Rheumatoid arthritis, rheumatic diseases such as lupus, ankylosing spondylitis, spine diseases, spinal hernia, meniscus, joint and knee diseases, hernias are common in thyroid patients. The underlying factor is the deterioration of the connective tissue matrix. Degenerative joint diseases were found in 45% of patients with autoimmune thyroid disease. There was a relationship between hand and spine diseases and autoimmune thyroid disease. Fibromyalgia was found in 62% of the patients. Seronegative joint diseases are also common in autoimmune thyroid diseases. Degradation of intestinal microbiota plays an important role in the development of these diseases. Disruption of hyaluronic acid and collagen synthesis as a result of disruption of bile flow, absorption of fat digestion and absorption of vitamins A, D, E and K in fat, plays an important role in the development of these diseases, as well as poor nutrition and toxic effects disrupt intestinal microbiota. Like ghrelin secreted from the gut, imbalance in hormones also plays a role in this phenomenon. Vitamin D deficiency and vitamin K deficiency also trigger the development of connective tissue disease. This supports the presence of an axis such as thyroid-liver-bile-intestinal-connective tissue. Dr. Henry R. Harroweer's theory of the pluriglandular hormone supports this. Sound changes also occur due to collagen and hyalanuric acid reduction.
C) THYROID-INTESTINAL AXISIntestinal diseases are common in thyroid diseases. Autoimmune thyroid diseases (Hashimoto and Graves) are common in ulcerative colitis, Crohn's disease and Celiac disease.
If there is hypothyroidism , the upper part of the small intestine, the duodenum and jejunum, which normally should not be in excessive bacterial growth begins. This is called SIBO (small intestinal bacterial overgrowth). The cause of excessive bacterial growth in the small intestine is due to the decrease in gastric acid release in hypothyroidism. As stomach acid is low, foods are not fully digested and bacteria begin to grow in the duodenum and jejunum. In addition, the movement of the stomach and intestines slows down in hypothyroidism and makes it suitable for bacterial growth. On the other hand, in intestinal flora disorders (dysbiosis), the conversion from hormone T4 to T3 decreases. In case of increased permeability in the intestine (leaky gut), toxic substances can trigger the autoimmune disease of the intestinal epithelium and cause thyroid diseases.
D) THYROID-LIVER-GALLBLADDER AXISFatty liver is common in thyroid patients. This condition is more common especially in hypothyroidism. Hypothyroidism is also associated with decreased bile flow, slowing of gallbladder contraction and gallstones and sludge. For this reason, thyroid hormone analogue or mimetic drug studies are made. Most of the hormone T4 is converted to T3 in the liver. If there is fatty liver or disease, the conversion from T4 to T3 decreases and hypothyroidism develops in the tissues. For a healthy thyroid function, the liver must be intact.
There is an axis between the thyroid and the liver. Thyroid dysfunction changes the bile acid composition or profile in the blood. Deoxycholic acid / cholic acid ratio is parallel to thyroid functions. This is because thyroid hormones affect the hydroxylase enzymes that cause bile acid to form cholesterol. In short, thyroid hormones alter bile acid metabolism. Bile acids are also effective in metabolism and thyroid hormone secretion. Bile acids play an important role in the absorption of fat-soluble vitamins. If bile acids cannot go to the intestine enough, vitamins such as vitamin A and D have an indirect effect on thyroid hormone metabolism. Autoimmune thyroid disease is common in vitamin D deficiency. Vitamin A is very important for intestinal health. In vitamin A deficiency, permeable bowel disease and microbiota degradation occurs in the intestine.
In animal studies, it has been shown that thyroid dysfunction causes gallstone formation. In the case of hypothyroidism, it was found that Trbeta was increased and lithium Rxr was decreased. In the case of hyperthyroidism, Lxralfa, Rxr and Cyp / alpha1 genes were activated and Fxr gene activity was decreased. In both hypothyroidism and hyperthyroidism, there is an increase in cholesterol gallstones. In the case of hypothyroidism, cholesterol biosynthesis is associated with increased production, whereas in hyperthyroidism gallstones develop due to the nucleus receptor genes Lxralfa and Rxr genes in the liver cells. A Danish screening study also found that autoimmune thyroid disease and other autoimmune diseases were more common in patients with gallstones. It is possible that a change in the intestinal microbiota due to disruption of bile acid flow may trigger these diseases.Serum levels of fibroblast growth factor 21, fetuin-A, fetuin-B, retinol-binding protein and selenoprotein P, which are secreted from the liver and called hepatokin, vary in thyroid diseases.
E) Thyroid-Testis-Prostate AxisIt has been demonstrated in animal studies that TRH is secreted from the prostate and stimulates the thyroid gland. Some clinical studies have found thyroid hormone changes in patients with prostate cancer or prostate enlargement. Erectile dysfunction and testosterone deficiency may be seen in thyroid failure. Thyroid hormones play a role in the development of testicles. In patients with prostate cancer, TSH levels increase in peripheral tissues without hypothyroidism after the treatment to decrease testosterone levels. This is thought to be due to the high leptin hormone secreted from increased adipose tissue.
On the other hand, a low level of testosterone reduces the conversion of T4 to T3 by decreasing the type 1 deiodinase activity in tissues without altering Type 2 deiodinase activity in the pituitary. Therefore, TSH level does not change. Pesticides, plastics and other toxic substances reduce the average testosterone level in men. In these tissue thyroid hormone is low. The same situation occurs in men with insulin resistance and diabetes. Free testosterone is low in these individuals and intracellular active T3 hormone is decreased. Therefore, weight gain as well as difficulty in giving weight may occur, and this situation further progresses.
F) THYROID-OVER AXIS
Normal regular menstruation is important in terms of entering puberty. In case of thyroid failure, menstrual deterioration occurs. In girls with hypothyroidism, that is, thyroid insufficiency, delayed entry into puberty occurs. Polycystic ovarian disease is common in thyroid failure. Thyroid hormone has a role in the onset or formation of polycystic ovary. 11-36% of polycystic ovary patients have subclinical hypothyroidism. In patients with hypothyroidism, there is a syndrome like polycystic ovary .
G) THYROID-BRAIN AND CRANIAL NERVE AXIS AND SLEEP
Thyroid hormones play an important role in brain and nerve tissue development and physiology. Movement, differentiation, myelinization and synapses of nerve cells (neurons) depend on thyroid hormones. Reduction in thyroid hormones can impair brain development and cause irreversible neurological damage. GABAergic neurons and glutaminergic neurons are affected by thyroid hormones. It is also thought that thyroid hormones affect the stimulatory and inhibitory neurons and affect contraction or epilepsy. Treatment-resistant epilepsy and partial epilepsy are seen in patients with thyroid autoantibodies. Hashimoto's encephalopathy may also develop epilepsy and antithyroid antibodies are high.
In the case of hypothyroidism, changes occur in the peripheral and central nervous system. Brain stem hearing potentials (BAEP), visual stimulation potentials (VEP) and electrophysiological studies were performed for this purpose. Peripheral neuropathy can occur at an early stage. Cranial nerve involvement is common as sensory neural hearing loss and ophthalmopathy. 37% of hypothyroid patients have decreased hearing.
In patients with hypothyroidism, there are also changes in taste and smell, indicating cranial nerve involvement. Disorder in the olfactory system that provides olfactory triggers autoimmune disease. Those with hypothyroidism have odor and taste disturbance. It cures with treatment.
Thyroid hormones are also effective on sleep. Insomnia is common in patients with hyperthyroidism or hypothyroidism. Intravenous TRH hormone changes sleep parameters.
Thyroid hormones affect the cholinergic system and strengthen memory and learning.H) THYROID-INTESTINAL-EYE AXIS
Strabismus and ophthalmopathy may occur in autoimmune thyroid diseases. Hashimoto's disease, especially Graves' disease, also results in eye growth, swelling of the eye muscles, edema, increased fat, and inflammation called ophthalmopathy. The role of the intestines (increase in inflammation Th17 cells, decrease in regulatory T cells) can be mentioned in the presence of thyroid-intestine-eye axis in immune system disruption and the emergence of autoimmune disease
I) THYROID-BREAST AXIS
The breast and thyroid gland are tissues that hold iodine and show some similarities. During breastfeeding and in breast cancer patients, iodine channels called sodium-iodine simporters (NIS) that increase iodine uptake increases in the breast epithelial tissue . Breast epithelial cells also have TSH-receptors.
Breast cancer and fibrocystic breast disease are common in thyroid patients. The frequency of breast cancer is higher in patients with thyroid cancer.In addition, breast milk from the mother with thyroid hormone deficiency are decreased. . For a healthy breastfeeding, the mother's thyroid hormones should be normal. Thyroid disease should be investigated in mothers whose milk is low or which is discontinued quickly.
Breast cancer is common in patients with Hashimoto and Graves' disease. On the other hand, anti-TPO elevation is common in patients with breast cancer. It has also been found that the presence of high anti-TPO in women with breast cancer is a challenge. It has been suggested that anti-TPO and anti-thyroglobulin antibodies in the blood are protective against breast cancer in hypothyroid patients. On the other hand, high levels of TSH receptor antibodies have been suggested to pose a risk for breast cancer.
The integrin αvβ3 receptor, which is found in the membrane (membrane) in breast cancer cells, is a receptor to which thyroid hormones bind and the cancer increases the spread of the cell by forming new vessels. T4 hormone binds to these receptors more. Therefore, it is recommended that these patients be given T3 instead of T4.
J) THYROID-PROLACTIN AXIS
In the case of hypothyroidism, as the TSH hormone increases, the level of blood prolactin increases. This is because the hormone TRH increases prolactin secretion. The decrease in breast milk in mothers with thyroid diseasea indicates that prolactin hormone cannot function adequately in these mothers. On the other hand, anti-TPO antibodies and IL-4 are high in patients with very high prolactin levels. Prolactin elevation triggers autoimmune thyroid disease. These observations reveal the thyroid-prolactin axis.
Prolactin is not only secreted by the pituitary, but also by ovaries, prostate, breast, adipose tissue, brain and immune system cells. However, the molecular structure and activity of the prolactin secreted therein are different. During lactation prolactin secretion increases. In addition, prolactin levels increase in pituitary tumors, when thyroid gland is under-worked and in adrenal gland failure. Cytokines such as IL-1, IL-2 and IL-6 increase prolactin secretion. Interferon gamma reduces. The cells of the immune system to which prolactin binds are monocyte, lymphocyte, macrophage, natural killer cells, granulocyte and thymus epithelial cells. Therefore, prolactin may cause autoimmune disease.
K) THYROID-HEART AXIS
It is known that the risk of heart disease is increased in thyroid diseases. Thyroid hormones regulate potassium channels in the heart. KCNE2 and KCNQ1 potassium channels are found in both thyroid gland and heart. Most patients with heart rhythm disorder, called atrial fibrillation, have a rapid thyroid function (hyperthyroidism). Myxoma in the heart called tumors are more common in thyroid patients.
L) VITAMIN D- THYROID-PARATHYROID--BONE AXIS
Few studies have shown that TSH elevation causes parathormone elevation. Although the cause of this has not been fully clarified, it has been suggested that the hormone TRH may have increased Parathormone secretion or that hypothyroidism may prolong the parathormone half-life. No pituitary hormone that controls the parathyroid gland has ever been found. The anatomical placement of the parathyroid glands behind the thyroid gland also suggests a relationship between them. Parathyroid adenoma in Graves' disease has been reported in case reports. 60% of patients with primary hyperparathyroidism have thyroid disease or thyroid nodule. . In pseudohypoparathyroid disease, there is resistance to parathormone and TSH hormone in the tissue.Some studies have suggested that the relationship between thyroid and parathyroid may be through vitamin D. Active vitamin D (1,25 dihydroxy D3) has been shown to secrete TSH hormone from the pituitary. Parathormon secretion decreases when vitamin D increases.
In patients with hypothyroidism, vitamin D is low in the blood, and in patients with autoimmune thyroid who receive vitamin D, TPO antibodies are reduced and TSH is slightly improved.
Another interesting finding is the decrease in parathyroid hormone levels in Graves' patients who underwent total thyroidectomy even without parathyroid lesions.
The TSH hormone not only secretes thyroid hormone from the thyroid gland but also increases bone formation by acting directly on the bones. As TSH increases, bone structure strengthens. As TSH decreases, bone destruction increases. Osteoporosis is seen in mice where TSH cannot bind to bone. In other words, bone resorption seen in overworked thyroid gland is not only due to excess thyroid hormone but also partly due to decrease in TSH hormone.It should also be noted here; The hormones secreted from the pituitary gland do not secrete hormones from the hormone secreting glands. They also have direct effects on tissues such as bone and adipose tissue. In other words, there are pituitary-tissue axes as well as thyroid tissue axes. In particular, the pituitary-bone axis and the pituitary-adipose tissue axis have been demonstrated.
M) THYROID-THYMUS-LYMPH SYSTEM, IMMUNE SYSTEM AND MAST CELL AXIS
The thymus gland is a lymph organ, a soft, pink-gray gland located in the area called mediastinum, located between the two lungs, behind the sternum bone called the faith board, under the neck at the top of the chest. The function of the thymus began to be understood after the 1970s. The thymus is an important organ of the immune system and the T cells of the immune system grow, develop, acquire characteristics, and when matured, are given to the lymph nodes to fight infection and foreign matter. Thymus, which is 25 grams in infancy, grows up to 35 grams in 12-19 years. Between the ages of 20-60, it gets smaller. In most cases, it shrinks after puberty and is replaced by adipose tissue. The stem cells, the main cells that make up the T cells (lymphocytes) in the bone marrow, come into the thymus and are called thiomocytes. Thymopoietin and thymosin hormones secreted from thymus enable these cells to become T cells. These hormones secreted by the thymus are formed in the presence of zinc. Growth occurs as a reaction to certain conditions in the thymus gland. Growth occurs during stress, chemotherapy, cortisone treatment. Thymus grows in the form of growth in the lymph glands. Myasthenia gravis, Graves' disease, Addison's disease, lupus, rheumatoid arthritis, scleroderma diseases such as the thymus gland grows. In these diseases, lymph nodes also grow. Relationship between thymus lymphatic system and endocrine system In addition to the thymus, tonsils also develop T cells. Therefore, the immune system is not strong and susceptibility to infections and autoimmune diseases occur in those who undergo tonsillectomy. There are also those with appendicitis surgery in the same condition.
The thymus and thyroid gland develop embryologically from the common site. Thymus gland growth occurs in Graves' patients and this was first demonstrated in 1912. It is not clear whether Graves 'disease enlarges the thymus gland or if thymus growth causes Graves' disease. Thyroid hormones cause to grow epithelial cells in thymus gland and cortical lymph nodes of thymus gland. On the other hand, there are TSH receptors in the thymus gland. In Graves' disease, increased TSH receptor antibodies in blood can bind to these receptors and enlarge the thymus gland. As the thymus shrinks, TSH receptor antibodies also decrease. That is, there is a correlation between the severity of Graves' disease and TSH-receptor antibody levels and thymus gland volume. When antibodies decrease, thymus shrinks. Thymus growth was reported in 38% of Graves' patients. Screenings in patients with thyroid cancer sometimes show involvement of the thymus gland. This is because the thymus gland contains NIS (sodium-iodine transporters) that hold iodine. Circulating thymic factor, Timulin (Zinc-FTS) is high in hyperthyroid patients and low in hypothyroid patients. In a study published in the Journal of Allergy and Clinical Immunology in 2018, it was found that autoimmune thyroid disease was more common in 5600 people who had undergone surgery before congenital heart disease for 5 years before the age of 5 years. Infection, cancer and autoimmune thyroid diseases and allergic events were more common in these people due to insufficient T cells.
Thyroid hormones are effective in the cells of the immune system such as monocytes, macrophages, lymphocytes outside the thymus. Therefore, it plays a role in inflammation, autoimmunity and excretion of pathogens.The axis between the thyroid gland and mast cells is interesting. Mast cells secrete histamine in allergic events. With TSH effect, T3 synthesis occurs in mast cells. In the inflammation of the thyroid gland (thyroiditis) mast cells secrete histamine and T3. The number of mast cells in the thyroid gland increases before the formation of thyroid cancer.
N) THYROID-ADRENAL-PANCREAS AXISThyroid hormones affect the pancreas gland and insulin secretion. The function of the pancreas is impaired in autoimmune thyroid diseases. As a result, metabolism is impaired. Thyroid hormones reduce oxidative stress in the pancreas, and endoplasmic reticulum stress and regulate insulin secretion. Blood sugar levels in mice whose pancreas is removed are improved when thyroid hormone is given. There are thyroid hormone receptors that function in the pancreas. Autoimmune thyroid disease is common in patients with type 1 diabetes. In other words, autoimmune thyroid disease is associated with autoimmune pancreatic disease. Thyroiditis has also been claimed to be a risk for pancreatic cancer. The baby must have enough thyroid hormones for the development of the pancreas. Recent studies have also shown that insulin and T3 hormone interact in skeletal muscles, lungs and liver. Insulin increases the conversion of T4 to T3 by increasing D2 activity. When T3 increases, it decreases insulin signaling in the tissue. In children with high insulin resistance, the formation of nodules in the thyroid gland increases. Thyroid hormone resistance develops in patients with diabetes and metabolic syndrome to provide homeostasis. On the other hand, hypoglycemia is seen in patients with thyroid insufficiency (hypothyroidism). Metformin, which is used in the treatment of diabetic patients, also reduces TSH secretion.
Without thyroid hormones, epinephrine and norepinephrine cannot act on the tissue. Therefore, there is an axis between the thyroid and the adrenal medulla. When the hypothalamus-pituitary-adrenal axis is disrupted due to chronic stress, the hypothalamus-pituitary-thyroid axis is also disrupted. In the early stages of stress-induced hypothalamic-pituitary-adrenal axis disorder, increased cortisol in the blood prevents the formation of T3 from the hormone T4 ’. In depression and sleep disorders, these two axes fail together. On the other hand, in adrenal gland failure (Addison's disease), subclinical insufficiency may develop. This only improves with cortisone treatment. In the case of hypothyroidism, cortisol rises in the blood. The thyroid hormones increase the receptors of the epinephrine hormone and increase its effect. Without thyroid hormone, epinephrine cannot show its full effect. Control of blood pressure in the body is partially controlled by epinephrine and norepinephrine secreted from the adrenal gland medulla. Development of hypotension disrupts the nutrition of body tissues and prepares the ground for connective tissue diseases. Norepinephrine increases thyroglobulin synthesis. Recent studies have shown that the thyroid hormone β1 receptor is in the adrenal gland. Thyroid hormones are responsible for the development of the adrenal gland. In the case of hyperthyroidism, catecholamine release from the adrenal gland is greatly increased. Hypothyroidism also decreases. On the other hand, in Cushing's disease with cortisol over-release or during treatment with cortisone, the serum TSH level is reduced, ie suppressed. In this case, excessive release of TSH hormone at night is disrupted. In this suppression, cortisol decreases TRH secretion as well as increased conversion of T4 to T3 due to increased type 2 deiodinase activity in the pituitary and another decrease in TSH secretion. Central hypothyroidism occurs in 16% of Cushing's patients. inappropriateTSH oscillations occur in patients undergoing surgery for Cushing.
Glucocorticoids, namely cortisone drug, inhibit T4 coversion to T3 by inhibiting type 1 deiodinase in tissues. So T3 in the blood decreases.DHEA levels decrease in autoimmune thyroid patients whose hypothalamus-pituitary-adrenal axis is impaired in response to chronic stress. When cortisol and ACTH increase in response to chronic stress, the conversion from T4 to T3 decreases.
The interaction between these three organs explains why diabetes and thyroid disease are together.
O) THYROID-EAR AXIS:Anti-TPO antibody elevation was found in 17-38% in patients with Meniere disease. Meniere's disease improves after treatment of hypothyroidism in Meniere's patients with hypothyroidism. Autoimmune thyroid disease is also common in patients with benign positional vertigo and anti-TPO antibodies are high in their blood. Hashimoto has been shown to have hearing difficulties in half of the patients. Hearing loss may occur in 30-50% of patients with congenital hypothyroidism. Thyroid hormones provide myelinization of cochlea and vestibulococlear nerves in the ear. In a study conducted in patients with hypothyroidism in adults in Turkey it was determined to hearing decline. In case of hypothyroidism, vertigo may occur.
P) THYROID-KIDNEY AXIS
Thyroid hormones regulate kidney development, dynamics, glomerular filtration rate, sodium and water balance. In the case of hypothyroidism and hyperthyroidism, renal function is affected. In case of hypothyroidism, serum creatinine level increases and glomerular filtration rate decreases. In the case of hyperthyroidism, the opposite occurs. These changes improve with treatment. Renal diseases also impair thyroid function. Mild thyroid failure and low T3 are common in patients with chronic kidney disease. Thyroid hormones affect the renin-angiotensin-aldosterone system by increasing beta-adrenergic receptors in the kidney, making them susceptible to catecholamines. Hashimoto patients have increased protein excretion in the urine. Since patients with nephrotic syndrome have protein loss in the urine, total T4 and total T3 fall, while free T4 and T3 remain normal. It is interesting to note that in traditional Chinese medicine, hypothyroidism is attributed to renal and spleen dysfunction and is considered a part of Kidney-Yang deficiency syndrome.