TSH: Thyroid Stimulating Hormone (TSH) is also called thyrotropin. The pituitary releases this hormone after the hypothalamus releases TRH (thyrotropin-releasing-hormone). This is the most common marker used to assess thyroid function and it is also the most sensitive. The TSH levels increase when the T4 levels drop, and the TSH falls when T4 levels increase. This is the only test performed in the traditional health care model as a means to screen the patient for thyroid disorders; this is because they are only concerned for screening the thyroid for hormone replacement and not optimal physiological function. A TSH test alone does not consider thyroid-pituitary feedback loops, peripheral thyroid metabolism, or potential or active risk factors as identified by antibody testing. A high TSH with or without changes in T4 or T3 is diagnostic to determine hypothyroidism. If the thyroid is not making enough T4 the pituitary will pump out TSH to stimulate its production. A low TSH is used to determine hyperthyroid activity. If the thyroid is overactive, such as in Grave’s disease, the antibodies bind to active thyrotropin (TSH) receptors on the thyroid cells and stimulate T4 production without the influence of TSH. Please note that some antibodies may inhibit thyroid function by inactivating instead of stimulating thyrotropin receptors. This is called an autoimmune hypothyroid. These patterns will demonstrate a hypothyroid pattern (elevated TSH) with elevated thyroid antibodies.
Laboratory Reference Range: 0.5 – 5.5 (varies from one lab to another)
Functional or Optimal Reference Range: 1.5 – 3.5
Total Thyroxine (TT4): The TT4 test measures both bound and unbound thyroxine levels. Therefore, it does not give the activity of T4 when measured alone. This test is best completed with a T3 uptake. The free thyroxine index (FT4) can be calculated by using the T3 uptake and demonstrate a level of T4 activity. Total T4 levels can be altered by many drugs (see Category of drugs that interfere with thyroid activity).
Free Thyroxine Index: As stated earlier, the total thyroxine and the T3 uptake must be used together to calculate the FT4. The index is measured by multiplying the TT4 levels by the T3 uptake levels. The result is the FT4 and it determines the amount of active T4 available. The impact of drugs, as will be discussed, will always impact T4 and resin T3 uptake levels in opposite directions due to their impact on binding sites. If the TT4 level is depressed, then the T3 uptake is high; if the TT4 is elevated, the resin uptake is low. Please note that even if you are taking drugs that may impact thyroid binding, the free thyroxine index should be within the normal range if your thyroid is functioning normally.
Free Thyroxine (FT4): The free thyroxine test is used to measure the amount of free or active T4 in the blood. All the factors such as drugs and physical conditions that may impact the TT4 do not impact the FT4. The level of T4 in the blood is high with hyperthyroidism or low with hypothyroidism. Please note that even a TSH with normal T4 is enough to diagnose hypothyroidism. A rare pattern is and elevated T4 without hyperthyroidism which may be related to a hereditary condition of thyroid resistance. Elevated free T4 may also be caused by patients taking heparin or by and acute illness the may briefly cause the binding protein levels to suddenly fall. If an illness becomes severe and chronic it may decrease the FT4 levels but it is not a thyroid disease.
Resin T3 Uptake: The resin T3 uptake measures the amount of sites for active (unbound) T3 to bind with thyroxine binding proteins. This test is performed by mixing the blood with radioactive thyroid hormones. These radioactive hormones then combine with binding sites on thyroxine-binding proteins. The blood is then exposed to a substance called a resin which will bind the unbound thyroid hormones and measure for radioactivity. The result can be expressed as the percent of radioactivity found on the resin, compared to the original radioactivity that was added. The more binding sites that are open on the proteins, the lower the resin uptake result will be, and vice versa. For example, anything that reduces the binding sites, such as elevated testosterone or testosterone replacement therapy, can cause a low T4 measurement because it leaves very few binding sites for any thyroid hormone to bind to. If T3 is added to the sample of the blood, little T3 will be bound. This pattern would have low TT4 levels and high resin T3 uptake levels. On the other hand, anything that raises the binding sites such as estrogen or birth control pills would cause a pattern of high TT4 and low T3 uptake.
Free Triiodothyroxine (FT3): This test measures the free T3 hormone levels. This test is rarely completed in traditional endocrinology. It is typically only used in a situation when a patient has hyperthyroid, yet the FT4 levels are normal. However, the FT3 test is the best marker for measuring the amount of active thyroid hormones available for the thyroid receptor sites.
Reverse T3 (rT3): This test measures the amount of reverse T3 that is produced. The production of rT3 typically takes place in cases of extreme stress, such as major trauma, surgery or severs chronic stress. It appears that the increased production of reverse T3 is due to an inability to clear rT3m as well as from elevated cortisol.
Thyroid Antibodies: Thyroid auto-antibodies indicate that the body’s immune system is attacking itself. Production of thyroid auto-antibodies may create a hypothyroid or a hyperthyroid state. Some antibodies attach to the TSH receptors but do not cause a response; therefore, the patient will complain of low thyroid symptoms. However, the serum TSH may not be altered. It is just not able to cause a cellular change. On the other hand, some antibodies will bind t the receptor sites and cause over activation of the thyroid. This will present as elevated T4 levels, a low TSH, and elevated thyroid antibodies.
The Influence of Thyroid Hormones on Physiological and
Metabolic Function
Thyroid Hormones and Bone Metabolism
Deficiency of thyroid hormones in early life leads to both a delay in the development of, and an abnormal, stippled appearance of epiphyseal centers of ossification. The serum calcium is within the normal reference range, but is usually below the functional range in hypothyroidism.
Hypercalcemia (too much calcium) can occur in patients with thyroid hyper function and is generally associated with increased excretion of calcium and phosphorus in the urine and stool with the demineralization of bone. In thyroid hyper function, decreased densitometry changes are noted, and increased risk for pathological fractures, especially in the elderly, are common. There is increased turnover of collagen and therefore the urinary collagen breakdown markers (DPD) are elevated.
The Influence of Thyroid Hormones on Gastrointestinal Function
The gastrointestinal transit time is often reduced in low thyroid states. In addition, intestinal absorption rates are altered. The rates of absorption fir substances are decreased, but may be increased due to decreased bowel motility. Malabsorption (inability to absorb nutrients) potential may exist in a state of low thyroid function.
The Influence of Thyroid Hormones on Male Steroids
Hypothyroidism in men has been shown to cause diminished libido, impotence, and oligospermia (low sperm count in men). It appears that hypothyroidism alters the metabolism of both androgens and estrogens. Although hypothyroidism is rare in males, it must be ruled out with altered states of male hormone steroidogenesis.
The Influence of Thyroid Hormones on the Gallbladder and Liver
In hypothyroidism, the liver enzymes are generally normal, but reduced hepatic clearance has been observed with elevations in the aminotransaminases (SGOT, SGPT). Gallbladder function has also shown to be impaired in hypothyroidism; cholecystography (testing of the bile ducts) often reveals a distended gallbladder that contracts sluggishly.
The Influence of Thyroid Hormones on Growth Hormone and IGF-1
Growth hormone (GH) is released by the anterior pituitary to promote anabolic expressions of metabolism. GH then stimulates the production of insulin-like growth hormone (IGF-1), also known as somatomedian, in the liver. It is IGF-1 that is responsible for the many physiological impacts of GH on tissues. Although the human growth gene does not contain a thyroid hormone response, the thyroid does have influences on the synthesis of IGF-1 in the liver. Adequate amounts of thyroid hormones are required for the healthy production of IGF-1. Anytime reduced IGF-1 markers are demonstrated, thyroid dysfunction must be ruled out. The reduced potential to synthesize IGF-1 may be partly due to the loss of anabolism in hypothyroidism.
The Influence of Thyroid Hormones on Body Compensation
A common symptom of low thyroid status is an inability to lose weight. This is due to several factors. First, since thyroid hormones are responsible for reducing metabolic activity, the loss of metabolic activity potential directly leads to inability to lose weight and even to gain weight. Low thyroid status also decreases the mobilizations of free fatty acids, thereby hindering the response of catecholamines to lipolysis. Both of the above metabolic shifts also contribute to fatigue. A third pattern impacts body compensation related to growth hormone. In states of low thyroid status, if growth hormone response is hindered, there is greater potential to become catabolic and therefore loose muscle mass or lose the ability to gain muscle mass.
The Influence of Thyroid Hormones on Insulin and Glucose Metabolism
In states of low thyroid status the response of insulin to glucose is delayed. With oral glucose tolerance testing, there is a characteristic flat curve response to glucose stimulation in hypothyroidism because there is a slow rate of glucose uptake by tissues and decreased rate of glucose absorption by the gut. In addition, in states of hypothyroidism there is slower degradation of insulin, and therefore, there is increased sensitivity to exogenous insulin. This response accounts for decreased exogenous insulin requirements where there is a presentation of co-existing hypothyroidism and insulin dependent diabetes mellitus.
The hindered response to glucose, the slow rate of glucose uptake, the decreased rate of glucose absorption, and the slower rate of glucose clearance present clinically as hypoglycemia. In hypothyroidism, despite glucose consumption, the ability for glucose to get into the cells is hindered, and therefore, although the patient presents with symptoms of hypoglycemia, the glucose levels are normal on the serum due to decreased uptake of cells. When a fasting glucose is conducted, they will not present as a hypoglycemic. This pattern leads to increased stress on the hypothalamus-pituitary-adrenal (HPA) axis because the adrenals will make attempts to release cortisol to increase the glucose load for the cells that require it, but are unable to utilize glucose efficiently. The end result of hypothyroidism on glucose metabolism is deceased cell exposure with symptoms of hypoglycemia and up-regulation of the HPA axis. In addition, in states of low thyroid hormones, it has been found that the response of plasma cortisol to insulin-induced hypoglycemia may be impaired.
Thyroid Hormones, Lipid Metabolism, and Cholesterol
In hypothyroidism, both the synthesis and degradation of lipids are depressed, but the degradation of lipids is far slower than the synthesis, so the net result is elevated total serum cholesterol, triglycerides and LDL. The decrease in the lipid degradation rate may reflect the decrease in postheparin lipolytic activity, as well as reduced LDL receptors. In states of hypothyroidism, plasma free fatty acid levels are decreased. The mobilization of free fatty acids in response to fasting, as well as catecholamines and growth hormone expressions, are impaired.
Anytime a lipid profile presents with hypercholesterolemia, the thyroid must be ruled out since it may be the culprit for the abnormal thyroid level. If an accompanying hypothyroid is present with and abnormal lipid panel, management of the profile should be directly focused on the thyroid imbalance. Correction of the thyroid disorder will usually correct the abnormal lipid presentation.
The Influence of Thyroid Hormones on Neurotransmitter Expression
The responsiveness of the cAMP pathway response to epinephrine appears to be hindered with low thyroid hormone states, and therefore, decreased adrenergic activity may be present. The underlying mechanism of the adrenergic response is uncertain. A loss of adrenergic response may be the primary mechanism in depression, weight gain, mood disorders, and reduced initiative.
The Influence of Thyroid Hormones on Cortisol Metabolism
As estrogens are metabolized in the phase I reactions into secondary metabolites, thyroid hormones may influence the activity of cytochrome P450 1A1 and 1A2. As estrogens are hydroxylated in phase I, they may have a hydroxyl group attached to the 2-cardon, the 4-cardon or the 16-alpha-carbon. The 4 and 16-alpha-carbons produce 4 or 16-alpha hydroxyestrone or ostradiol. The 2-hydroxy metabolites are considered protective for estrogen proliferation disorders, especially breast cancer. The 4 and 16-carbon metabolites are considered proliferative and have been shown to increase the risk of breast cancer. In states of hypothyroidism, the metabolism of estrigens is shifted in such a way to favor the 16-alpha-hydroxylation over the 2-hydroxylation. THerefor, hypothyroidism decreases the 2:16 estrogen metabolite ratio in such a way to increase the risk for estrogen-related proliferation.
The Influence of the Thyroid Hormones on Cortisol Metabolism
In states of hypothyroidism, the urinary excretion of cortisol, 17-hydroxycorticosteroids and aldosterone is decreased. There have been no changes observed in the serum with these changes in hypothyroidism, so it appears to be a matter of clearance, not synthesis. The use of urinary hormone tests for cortisol, 17-hyroxycorticosteroids, and aldosterone may not reflect levels found in the serum due to the influence of thyroid hormones on urinary excretion.
The Impact of Thyroid Hormones on Phase II Detoxification
Thyroid hormones have some degree of influence on all cells of the body, especially with hepatic cells responsible for enhancing the integrity of phase II detoxification. The liver is responsible for converting responsible for fat-soluble substances into water-soluble substances via phase I oxidation/reduction reactions and phase II conjugation reactions. Once compounds go through both phases, the compounds may be eliminated via the feces, sweat, or urine. Thyroid hormones are important in phase II metabolism, because the maturation of phase II conjugating enzymes is influenced by thyroid hormones. In states of low thyroid hormone status, the maturation of phase II conjugating enzyme pathways may be hindered, and therefore, detoxitication may be hindered. Clinically it is not uncommon to see patients that present with chronic throid disorders and have presentations of altered hepatic clearance potentials. When these chronic thyroid disorders and have presentations of altered hepatic clearance potentials. When these patterns exist, nutritional support to improve hepatic clearance usually presents with poor clinical outcomes until the thyroid function is restored or replacement therapy is initiated.
The Influence of Thyroid Hormones on Hypochlorhydria (Acid Reflex)
Gastrin is important for proper gastric function and the production of hydrochloric acid (HCL). In states of hypothyroidism, gastrin levels are usually reduces, and therefore, concomitant hypochlorhydria is present. HCL is important for acidifying the bolus, which is nessary to stimulate the enteric reflexes involved with both pancreatic and bile output. Compromised thyroid function may have adverse reactions on healthy digestion. Any time a pattern of hypachlorhydria is observed, thyroid dysfunchion must be considered.
Always, use HCL support with these patterns until the thyroid pattern is resolved.
The Influence of Thyroid Hormones on Protein Metabolism
In states of low thyroid function, the permeability to proteins is increased, and therefore, an increase in the total concentrations of serum proteins may be increased. In addition, the albumin pools are increased due to decreased albumin degradation as a consequence of thyroid hormones. The above influences of low thyroid status may creatr a false presentation of hypochlorhydria. In hypochlorhydria, functionally elevated albumin and total protein levels may be present. The clinician must evaluate the patient’s subjective indicators of hypochlorhydria to distinguish between a true HCL need and secondary shifts due to a thyroid imbalance.
*Note that in most cases, the patient does not have a true hypochlorhydria pattern that is positively supported with HCL supplementation.
Thermoregulation, Hot Flashes, and Thyroid Hormones
Since the thyroid modulates basal metabolic activity in patterns of thyroid insufficiency, patters may exhibit symptoms of hot flashes, night sweats, and abnormal thermoregulation. This becomes especially complex in women that have perimenopause in adjunct with a thyroid disorder. Many times clinicians are assuming their symptoms are due to a loss of optimal estradiol output that accompanies menopause; however, the symptoms may in fact be due to an underlying thyroid disorder, or both. Hormone profiles are especially important in these cases. Remember, three main glands have an influence on thermorgulation: thyroid, ovarian, and adrenal. The symptoms of altered thermoregulation from ovarian influence versus thyroid influence may be hard to discern in perimenopause; however, the clinician would expect to see other expressions of thyroid symptoms if the thyroid was involved. With adrenal influences of hot flush presentations, the patient usually does not notice major changes in temperature fluctuations, but rather is just experiencing sweating attacks confused as hot flushes. This is caused by mineralcorticoid shiftd that take place with adrenal dysregulation.
The Progesterone- Thyroid Connection
There are interactive influence of progesterone on thyroid metabolism and there are interactive influences of thyroid hormones on progesterone receptor site expression. Progesterone has the potential to influence the metabolic expreeion of thyroid peroxidase (TPO) activity, which is the rate-limiting enzyme in the thyroid for thyroxine synthesis. It is this influence that is partially responsible for the increased body temperature woman may express during ovulation. Ovulation takes place from a LH surge, and therefore, an immediate surge of progesterone up-regulates the avtivity of TPO and causes an increased fluctuation of thyroid hormanes. It is these fluctuations of thyroid hormones that increase metabolic activity, and therefore, body temperature. Clinically, one observes patients that suffer from subclinical thyroid insufficiency symptoms and concomitant symptoms of progesterone insufficiency. These patients do not typically have abnormal thyroid profile but the T4 levels are on the lower end of the normal range with a normal TSH. Their progesterone insufficiency symptoms include heavy menstrual cycles, inability to lose weight, mid-cycle/luteal phase depression, headaches, ect. The management of their progesterone imbalance generally resolves their symptoms of thyroid insufficiency. With menstruating women that have patterns of progesterone insufficiency the use of exogenous progesterone is not recommended. When menstruating women have symptoms of progesterone insufficiency, it is rarely because their bodies have lost the ability to produce progesterone, but rather a disorganized ovarian-pituitary feedback loop. This usually occurs when the LH surge is compromised, due to chronic adrenal axis over-activity, pituitary suppression from post-contraceptive use, or pituitary suppression from post pregnancy. It is important to remember that in both menstruating women and menopausal women, the adrenal glands contribute to a significant portion of the total progesterone pools of the body, and therefore, the impact of adrenal function on progesterone status should always be investigated.
In adult women, severe hypothyroidism has been shown to cause elevations of prolactin and loss of ovulation; therefore, insufficient progesterone may provoke endometrial proliferation, resulting in excessive and irregular breakthrough bleeding. The changes in progesterone receptor site resistance in the early stages and the loss of ovulation in severe hypothyroidism may reduce fertility and increase the risk of spontaneous abortion.
Not only does progesterone influence thyroid metabolism but thyroid hormones have an impact on progesterone receptor site expression. Thyroid hormones like thyroxine (T4) and triiodothyronine (T3) influence the sensitivity of progesterone receptor sites.
When progesterone receptor sites are not exposed to an adequate amount of thyroid hormones, the progesterone receptor sites lose their sensitivity to progesterone exposure. Clinically, patients may present may present with abnormal fluctuations and surges of progesterone on an expanded female hormone profile when they have patterns of hypothyroidism. It is always important to rule out thyroid dysfunction with abnormal patterns of progesterone.
The Influence of Thyroid Hormones on the Hematopoietic System and Anemia
The hematopoietic system has the potential to become compromised in different ways with states of low thyroid activity. Red blood cell mass becomes decreased in response to decreased production of erythropoietin and may present a pattern of normocytic normochromic anemia.
Other times a macrocytic anemia may present itself as a consequence of low thyroid activity. The macrocytic anemia may be related to decreased absorption of vitamin B-12 and folic acid from the concomitant shifts of hypochlorhydria induced by hypothyroidism. Research has shown that achlorhydria after maximal histamine stimulation may be present in patients with primary hypothyroidism. A macrocytic anemia may also be present in association with pernicious anemia. Over pernicious anemia is present and reported in about 12% of patients with hypothyroidism, and 9% of patients with hyperthyroidism. The coexistence of pernicious anemia, which is an autoimmune response against intrinsic factor, and the presence of thyroid disorders with positive thyroid antibodies, supports the view that the pathogenesis of the pattern is an overzealous immune disorder. To distinguish a B-12 macrocytic anemia due to malabsorption or inadequate diet from as autoimmune pernicious anemia, the clinician must request an Intrinsic Factor Autoantibody test (IF Ab). If the IF Ab is positive, the diagnosis of pernicious anemia may be made. In pernicious anemia, since intrinsic factor is compromised, these patients respond better to sublingual vitamin B-12 or injections. Oral B-12 may be used, but high doses are required to improve the pattern.
Since hypothyroidism is associated with altered iron absorption secondary to hypochlorhydria and menorrhagia from progesterone receptor site resistance, the possibility of a microcytic hypochromic anemia is also present.
The astute clinician should always screen for thyroid disorders with abnormal CBC patterns, and always screen for hematopoietic shifts with thyroid disorders. If the patient presents with patters of normocytic normochromic anemia, treatment should be focused on the thyroid. If the patient presents with macrocytic anemia, it is important to rule out diagnosis of pernicious anemia by requesting an IF Ab test. With a non-pernicious anemia, vitamin B-12 and folate supplementation, in conjunction with hydrochloric acid support, should be considered. With pernicious anemia, the patient should be supported with sublingual vitamin B-12 and clinical management related to autoimmune disorders. If the patient presents with microcytic anemia, iron supplementation in conjunction with hydrochloric acid should be considered until the thyroid is restored.
The Influence of Thyroid Hormones and Sex-Hormone-Binding-Globulin
Research has shown that sex-hormone binding globulin (SHBG) levels may be reduced in states of thyroid deficiency. SHBG levels have an influence on the free-fraction states of steroid hormones such as estradiol. Remember, hormones bind to SHGB and travel around in the tissue while in an inactive state. When a hormone binds to its receptor site, it must lose its binding protein; therefore, we can see in this study that thyroid hormones can influence the amount of protein binding, and therefore, influence the amount of free-fraction hormones available. These shifts may influence the test results of hormones strongly associated with SHBG, such as estradiol when compared in a free-fraction state, saliva, or a protein-bound state such as serum estradiol.
The Influence of Thyroid Hormones on Homocysteine and methylation
When there is low thyroid hormone tissue exposure, it appears that there are altered methylation reactions as evidenced by an increase in serum homocysteine levels. Homocysteine elevations have been shown to be an associated risk factor for cardiovascular disease, dementia, neurodegenerative diseases, cervical dysplasia, etc.
