Thyroid System Control Theory

Many different hormones work together to control the body's energy production. They are usually referred to by their initials: TRH, TSH, T4, T3, and rT3:

TRH (Thyroid Releasing Hormone)

The hypothalamus in the brain produces TRH, which signals the pituitary gland to release TSH.

TSH (Thyroid Stimulating Hormone or Thyrotropin)

The pituitary gland in the brain produces TSH, which signals the thyroid gland to release thyroxine (T4).

T4 (Thyroxine)

Thyroxine is called T4 because it has 4 iodines. It is produced by the thyroid gland in response to the TSH released by the pituitary gland. The fancy chemical name is 3,5,3',5'-tetraiodothyronine, which indicates that the 4 iodine atoms are placed in the four locations called 3, 5, 3', 5'. T4 is also the synthetic drug called Synthroid.

T3 (liothyronine)

Liothyronine is called T3 because it has 3 iodines. It is Produced in the body by removing one iodine atom from T4 in various tissues throughout the body. Stimulates mitochondria to make energy. The fancy chemical name is 3,5,3'-triiodothyronine, which reveals the important fact that each molecule has only three iodines - the iodine atom at position 5' was removed (yellow circle in the diagram below). T3 is also a synthetic drug called Cytomel.

rT3 (reverse T3)

rT3 is called reverse T3 because it also has 3 iodines, but it has the opposite effect from T3 by acting as a brake to reduce mitochondrial energy production. It is produced in the body by removing a different iodine atom from T4. The fancy chemical name is 3, 5, 5'-triiodothyronine, which indicates that the iodine atom at position 3' was removed (yellow circle in the diagram below).

Note that T3 and rT3 have the same chemical formula except for the exact position where the iodine atoms (magenta in the above diagrams) are placed on the thyronine molecule. This slight difference completely changes their effects on the body:

• T3 acts like the gas pedal of a car,
• rT3 acts like the brake pedal.

The bottom line is that T3 is the hormone that mainly promotes energy production in the body, and TSH is the hormone that primarily controls the production of T3. The other hormones are part of a complex regulatory system that will be discussed next.

Thyroid function can be understood like the children's story of Goldilocks and the three bears:

• TOO HOT: If the body produces too much T3, then symptoms of hyperthyroidism (fever, high blood pressure, nervousness, weight loss, etc.) will occur.
• TOO COLD: IIf not enough T3 is produced, the opposite symptoms are produced (low body temperature, high cholesterol, depression, weight gain, etc.).
• JUST RIGHT: The optimal balance between too much and too little. Easy to say, but not so easy to achieve.

In order to keep the body's energy production in the "Goldilocks zone" of "just right," the body uses a complex regulatory mechanism called a "negative feedback loop," which is also well known to engineers.

It is easiest to understand the concept of a negative feedback loop by considering the engineering implementation of a simple household heating and cooling system. The system's job is to maintain the temperature inside at a constant temperature called the set point. For a house, a set point of about 73°F is typically chosen. The homeowner chooses the set point and enters into a device on the wall called a thermostat.

In its simplest form, a negative feedback controller loop consists of three components:

Sensor

The sensor measures the current value of the controlled parameter (in this example, the temperacts ature).

Controller

Establishes the set point of the parameter being controlled (in this example, the knob or lever on the wall unit sets the temperature you want), compares the current environmental value (room temperature) to the set point (thermostat setting), and sends a control signal to the actuator (in this example, turns the heat pump on or off).

Actuator (also called the Effector)

The actuator changes the environmental value (room temperature) to be closer to the set point (thermostat setting) by pumping heat out of the room (cool) or pumping heat into the room (warm).

A more sophisticated system might also sense the time of day, and the controller would consider variable electricity costs depending on that time.

A still more sophisticated system might also sense the outdoor temperature. The controller would consider the temperature difference between outside and inside and signal the actuator to work at maximal energy consumption for extreme differences or more efficiently at lower energy consumption for smaller differences.

The most sophisticated system would also be sensitive to the homeowner's presence or absence (and the homeowner's schedule) and less aggressive (more energy efficient) when the homeowner is absent (or expected to be absent).

By analogy, a simplified view of the thyroid system works the same way but with greater complexity in the details. Many sensors in the brain measure the body's energy reserves, needs, and T3 levels. The hypothalamus and pituitary glands act as both the sensor and controller, which calculates an appropriate set point for energy expenditure, compares that to the current status measured by the sensors, and sends a control signal to the actuator. The control signal is the hormone TSH, and the actuator is the thyroid gland, which produces T4, which is converted into T3 by various tissues throughout the body, and which tells the mitochondria in all cells of the body how much energy to make. Not only does T3 stimulate mitochondria, but it also "feeds back" to sensors in the hypothalamus and pituitary gland to help control how much TSH is released.

Many different sensors are involved in the thyroid control system, and the controller logic is complex. A complete discussion of all the parameters that are sensed and integrated by the controller is beyond the scope of this discussion.

These concepts are enough to make your head swim. But don't feel bad. The idea is both simple in overview AND complex in detail. As Karl Johan Åström and Richard M. Murray pointed out in their book Feedback Systems: An Introduction for Scientists and Engineers:

Simple causal reasoning about a feedback system is difficult because the first system [sensor] influences the second [actuator], and the second system influences the first, leading to a [circular] argument. This cycle makes reasoning based upon cause and effect tricky, and it is necessary to analyze the system as a whole.

In the simplified thyroid system model described above, the two hormones TSH and T3 are crucial in troubleshooting the system (diagnosing what is wrong when a patient presents with symptoms of either hyperthyroidism or hypothyroidism). TSH represents the control signal derived by the hypothalamus and pituitary from all the sensor data, and T3 represents the actuator response produced by the thyroid gland.

In our simplified view, the following diagnostic reasoning can be applied:

Case	TSH	T3	Medical Decision
1	low	low	Hypothalamus or pituitary failure
2	low	normal	Uncertain diagnosis (T3 suggests the patient is fine, but TSH is out of range)
3	low	high	Thyroid medication overdose, thyroid tumor, or autoimmune disease (Hashimoto's or Graves')
4	normal	low	Thyroid failure, malnutrition or autoimmune disease (Hashimoto's)
5	normal	normal	The patient is fine
6	normal	high	Thyroid medication overdose, thyroid tumor, or autoimmune disease (Hashimoto's or Graves')
7	high	low	Thyroid failure, malnutrition or autoimmune disease (Hashimoto's)
8	high	normal	Uncertain diagnosis (T3 suggests the patient is fine, but TSH is out of range)
9	high	high	Hypothalamus or pituitary tumor

However, if only TSH is ordered, then the above decision table reduces to the following:

Case	TSH	Medical Decision
1, 2, 3	low	Thyroid medication overdose if the patient is being prescribed thyroid or autoimmune disease otherwise (generally ignoring possible hypothalamus failure or pituitary failure)
4, 5, 6	normal	The patient is fine (generally ignoring possible thyroid failure, malnutrition, thyroid medication overdose, or autoimmune disease)
7, 8, 9	high	Thyroid failure - prescribe (more) T4 (generally ignoring possible malnutrition, hypothalamus tumor, pituitary tumor, or autoimmune disease)

If only TSH is measured, some patients in cases 4 and 6 may be misdiagnosed as being fine when they are actually hyperthyroid or hypothyroid. Furthermore, patients in cases 2 and 3 who are being prescribed thyroid medication may have their dose inappropriately reduced, and patients in cases 8 and 9 who are being prescribed thyroid medication may have their dose inappropriately increased.

From the above, it can be seen that both TSH and T3 need to be measured to properly diagnose and treat autoimmune disease and that, in some cases, additional tests for thyroid, hypothalamus, or pituitary failure/tumors are also necessary.

If the above is not enough to overload your brain, another feature of the thyroid system can be important in some cases.

In our simple model, we considered the hypothalamus and pituitary as a single entity that served both as sensor and controller, and so could not distinguish between problems arising from the hypothalamus (called tertiary thyroid problems) and problems arising from the pituitary (called secondary thyroid problems). In our intermediate view of the thyroid system, we note that the hypothalamus acts as the first sensor and controller, producing the hormone TRH that travels to the pituitary gland. The pituitary gland then acts as an actuator for the hypothalamus but also acts as a sensor and controller in producing TSH to stimulate the thyroid gland.

The TRH stimulation test can evaluate the pituitary gland's ability to respond to TRH produced by the hypothalamus.

Just when you think you understand how the thyroid system works, there is another wrinkle. The T3 hormone is carried by the blood to all cells in the body. The thyroid hormones T4 and T3 are not soluble in water, so they must be carried attached to proteins in the blood called albumin and thyroid binding globulin (TBG). When T3 and T4 are tightly bound to these carrier proteins, they are not "free" to do their job.

When more T3 (and T4) than normal are bound to carrier proteins, the effective available amounts of T3 (and T4) in the blood are reduced, and symptoms of hypothyroidism can be experienced even though "normal" amounts of T3 (and T4) are found.

Similarly, when less T3 (and T4) than normal are bound to carrier proteins, the effective available amounts of T3 (and T4) in the blood are increased, and symptoms of hyperthyroidism can be experienced even though "normal" amounts of T3 (and T4) are found.

These factors can be evaluated indirectly by comparing measurements of both the total T3 (T3) and free T3 (fT3) (and the corresponding total and free T4).

In addition, the albumin and thyroid binding globulin levels can be measured directly with the CMP (comprehensive metabolic panel) and TBG tests. Liver disease or malnutrition can reduce the amount of available albumin and TBG (thereby increasing fT3 and fT4 and promoting hyperthyroid symptoms), as can certain drug interactions. Certain hormone interactions (e.g., estrogen) can have the opposite effect of enhancing the amount of available albumin and TBG (thereby decreasing fT3 and fT4 and promoting hypothyroid symptoms).

There is one additional major consideration. The discussion above focused focused on the role of T3 in stimulating mitochondrial activity and mentioned only in passing that the thyroid gland produces (mainly) T4, which is converted to T3 in various tissues throughout the body. It is not that simple. The conversion from T4 to T3 is also a part of the feedback control of the thyroid system. The tissues that convert T4 to T3 form yet another sensor/controller component and, based on various environmental conditions in the body, may produce some mixture of T3 and reverse T3 (rT3). The possibilities include:

• Normal conversion of T4 to T3 (if tT4 and fT4 are normal then then so should be tT3, fT3), and rT3;
• Reduced conversion of T4 to both T3 and rT3;
• Conversion of T4 mostly to rT3.

Recall that rT3 acts as a brake and reduces mitochondrial energy production. In contrast, regular T3 acts as a gas pedal, increasing mitochondrial energy production.

Another new piece of information is that BOTH regular and reverse T3 exert a negative feedback effect on the hypothalamus or pituitary sensors/controllers, so high levels of either fT3 or rT3 reduce TSH production. This point leads to the observation that low TSH combined with low T3 may be due to excessive production of reverse T3. Reverse T3 (rT3) may also exert a negative feedback effect on the conversion of T4 to T3.

Deiodinase enzymes remove iodine atoms from the various thyroid hormones (T4, T3, rT3, etc.). Three different deiodinase enzyme types (D1, D2, and D3) are found in the pituitary and peripheral tissues. D1 and D2 convert T4 to T3, D3 converts T4 to rT3, D2 converts rT3 to T2, and D3 converts T3 to T2 [Bianco2006]. The role of T2 is unclear, but it has been proposed that T2 may have a role in treating edema and moderating the effects of T3.

The adrenal cortex produces many steroid hormones, including cortisol, which has been dubbed the "stress hormone." The thyroid control system senses cortisol and stress levels and adjusts TSH production and T4 conversion to T3/rT3 accordingly. Dr. Weyrich uses the analogy of an automobile to explain this concept:

Imagine your car has four bald tires that could "blow out" at any moment. How would driving such a car affect your driving? Most people would agree that they would use the gas pedal lightly so as to not go too fast because the tires cannot handle too much speed. The same happens in your body. If your adrenal gland is fatigued, then it cannot produce enough cortisol to handle stress. The thyroid control system responds by cutting back on the "gas pedal" and not allowing too much T3 to be made because your body cannot handle too much energy.

The adrenal medulla produces neurostimulating hormones called catecholamines, which include epinephrine (adrenaline) and norepinephrine. These hormones promote a "fight or flight" reaction that can resemble hyperthyroidism.

Nutritional deficiencies (iodine, protein, vitamins, and minerals) can also interfere with the thyroid system's proper functioning, usually causing hypothyroidism symptoms.

The Spinal Connection

Environmental Toxins

Medications

Other Causes