B/B 10 · Endocrine axes and feedback
Four Patients and the Thyroid Axis
Use hormone levels and a TRH test to locate a fault along the hypothalamus–pituitary–thyroid axis.
Passage
Many hormones are controlled by feedback loops that link the hypothalamus, the anterior pituitary and a target gland. The thyroid axis follows this pattern. The hypothalamus releases thyrotropin-releasing hormone (TRH), which stimulates the pituitary to release thyroid-stimulating hormone (TSH). TSH stimulates the thyroid gland to make and release thyroxine (T4) and, to a lesser extent, triiodothyronine (T3). T4 and T3 raise the metabolic rate in many tissues, and they inhibit the release of TRH and TSH by negative feedback. The thyroid needs iodine to make its hormones, and high TSH levels cause the thyroid gland to grow.
The levels of T4 in the blood are measured as free T4, the small fraction that is not bound to carrier proteins and is available to tissues. Because the pituitary reacts to small changes in the free hormone, TSH is a sensitive indicator of how the thyroid is doing: a small fall in T4 causes a large rise in TSH, and the reverse. A doctor therefore reads TSH and free T4 together, and the direction in which the two numbers differ from normal gives the first clue about where the problem lies.
The TRH stimulation test checks whether the pituitary can respond when it is given the signal it normally receives. The test is useful when a low TSH has two possible explanations: the pituitary may be unable to make TSH, or it may be healthy but not receiving enough TRH, or it may be suppressed by an excess of thyroid hormone. The result is read together with the baseline values, and a normal response means that the pituitary cells that make TSH are present and are able to respond.
In a clinic, four patients are evaluated because of symptoms that suggest a problem with the thyroid axis. Table 1 shows the results of blood tests and an examination of the neck. The normal range for TSH is 0.5 to 4 mU/L, and the normal range for free T4 is 0.8 to 1.8 ng/dL.
Table 1. Blood tests and neck examination.
| Patient | TSH (mU/L) | Free T4 (ng/dL) | Thyroid size on examination |
|---|---|---|---|
| A | 15 | 0.3 | Enlarged |
| B | <0.01 | 3.5 | Enlarged |
| C | 0.2 | 0.3 | Small |
| D | 0.2 | 0.3 | Small |
The doctors then perform a TRH stimulation test. TRH is injected intravenously, and the TSH level is measured before the injection and 30 minutes afterward. A normal pituitary responds with a clear rise in TSH. Table 2 shows the results.
Table 2. Response of TSH to a TRH injection.
| Patient | TSH before (mU/L) | TSH 30 minutes after TRH (mU/L) |
|---|---|---|
| A | 15 | 60 |
| B | <0.01 | <0.01 |
| C | 0.2 | 0.2 |
| D | 0.2 | 5 |
Patient A lives in a region where the diet contains very little iodine. The other three patients have no known problem with their diet. The four patients have four different problems, and the doctors use the pattern of results to find where in the axis each problem lies. In general, a problem in the target gland is called primary, a problem in the pituitary is called secondary, and a problem in the hypothalamus is called tertiary.
Questions
Question 1 of 6
Patient A has a high TSH and a low T4. Which location of the problem is most likely?
TSH is high in patient A, so the pituitary is making plenty of it.
A lack of TRH would lead to a low TSH, not a high one.
A conversion problem would not by itself give a low T4 and a high TSH.
Why the answer is what it is
A low T4 with a high TSH means that the pituitary is responding appropriately to the lack of thyroid hormone. The failure is in the gland itself, which is the pattern of primary hypothyroidism.
Review: Endocrine Axes & Feedback · Endocrinology · Growth & Metabolic Hormones
Question 2 of 6
Why is Patient A’s thyroid enlarged?
TSH is high in Patient A, and TSH promotes growth of the gland.
Patient A’s T4 is low, not high.
T4 is low in Patient A, which is not what a hormone-secreting tumor would produce.
Why the answer is what it is
Without iodine, the thyroid cannot make enough T4. The loss of negative feedback causes TSH to rise, and sustained TSH stimulation makes the gland enlarge, which produces a goiter.
Review: Endocrine Axes & Feedback · Endocrinology · Growth & Metabolic Hormones
Question 3 of 6
Patient B has a very high T4 and a TSH that cannot be detected. Which explanation fits best?
TSH is not detectable in Patient B, so the pituitary is not the source of the stimulation.
Excess TRH would raise TSH. In Patient B the TSH is suppressed.
The thyroid is overactive. The low TSH results from feedback by high T4, not from failure of the thyroid.
Why the answer is what it is
Something other than TSH, such as an antibody that mimics TSH at its receptor, is driving the thyroid, so it makes large amounts of T4 whatever the TSH level. The high T4 shuts off TSH release by the pituitary through negative feedback, so TSH is undetectable, and no rise is seen after TRH (Table 2).
Review: Endocrine Axes & Feedback · Endocrinology · Growth & Metabolic Hormones
Question 4 of 6
Patients C and D have the same hormone levels in Table 1. What does the TRH test show about the location of each problem?
With a defect in the thyroid, TSH would be high, as in Patient A.
This swaps the two patients. The pituitary of Patient C does not respond to TRH, while that of Patient D does.
The test gives a different result in the two patients (0.2 and 5 mU/L).
Why the answer is what it is
The injected TRH replaces the missing hypothalamic signal. In Patient D, the pituitary responds (TSH rises to 5), so the lack of TRH explains the low TSH. In Patient C, the pituitary does not respond, so the damage is in the pituitary itself.
Review: Endocrine Axes & Feedback · Endocrinology · Growth & Metabolic Hormones
Question 5 of 6
In Patient B, why does the TSH level not rise after TRH is injected?
The same injection raises TSH in Patients A and D, so the TRH reaches the pituitary.
Patient C has the pituitary tumor. Patient B’s low TSH has an explanation through feedback.
T4 does not turn into TRH. It acts on the pituitary and the hypothalamus through feedback.
Why the answer is what it is
Negative feedback from the very high T4 acts at the pituitary and reduces its response to TRH. This is why TSH remains undetectable.
Review: Endocrine Axes & Feedback · Endocrinology · Growth & Metabolic Hormones
Question 6 of 6
Which feature of the thyroid axis explains why a patient with primary hypothyroidism has a high TSH?
TSH travels through the blood to act on the thyroid gland, so it is an endocrine signal.
The pituitary makes TSH, not T4. The relationship is a negative feedback loop.
This is not a description of how TSH is regulated.
Why the answer is what it is
In negative feedback, a hormone suppresses its own releasing signals. When T4 and T3 are low, the suppression is reduced and TRH and TSH levels rise.
Review: Endocrine Axes & Feedback · Endocrinology · Growth & Metabolic Hormones
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