Pituitary - Endocrine Axis Pathology

New lecture, new organ! This time we're focusing on the thyroid, which I mentioned briefly a couple of posts ago.

Recognise the components of the Hypothalamic-Pituitary-Thyroid and -Adrenal Axes

I feel like I've already written about these before, but oh well.

Hypothalamic-Pituitary-Thyroid Axis: The hypothalamus releases TRH (thyrotropin-releasing hormone), which stimulates the pituitary to release TSH (thyroid-stimulating hormone), which stimulates the thyroid gland to release T3 and T4.

Hypothalamic-Pituitary Adrenal Axis: The hypothalamus releases CRH (corticotropin-releasing hormone), which stimulates the pituitary to release ACTH (adrenocorticotropic hormone), which stimulates the adrenal cortex to release cortisol.

Know the clinical signs/symptoms of thyroid and adrenal diseases
Incorporate understanding of endocrine feedback control in differentiating between primary and secondary disease

Hypothyroidism

Hypothyroidism, or a deficiency of thyroid hormone, is relatively common, affecting around 5% of adults. It can be primary (originating from the thyroid gland) or secondary (originating elsewhere) and can be treated by simply replacing the missing hormones with Synthroid.

Some of the main causes of hypothyroidism include autoimmune destruction of the thyroid, as happens in Hashimoto's disease. Thyroiditis (inflammation of the thyroid) initially causes hyperthyroidism, but can lead to hypothyroidism later on. Some hypothyroidism is congenital (i.e. the thyroid gland doesn't develop). Other exogenous factors, such as iodine deficiency or aggressive treatments (surgery and radiation) for other thyroid diseases, may also cause hypothyroidism to develop.

Now for a little bit more on congenital hypothyroidism! One of the main causes of this is an iodine deficiency, so it is more prevalent in iodine-deficient areas. If congenital hypothyroidism is not treated by giving extra thyroxine (T4) and/or iodine, cretinism, a condition characterised by mental retardation and growth restriction, may also develop. This is a bit of a double-whammy, since many iodine-deficient areas are poorer countries that are probably also unable to give these children the support they need. Nowadays neonatal screening, testing for TSH and T4, can help to detect hypothyroidism. (I've mentioned how primary and secondary hypo- and hyperthyroidism can be differentiated by these tests in an earlier post.)

A reduction in thyroid hormones results in reduced metabolism. This results in symptoms such as cold intolerance, slow heart rate, lethargy, decreased appetite and weight gain. Primary hypothyroidism can also result in goitre (enlarged thyroid), which sounds counter-intuitive until you consider negative feedback: a reduction in thyroid hormones means a reduction in negative feedback on TSH, which continues to stimulate the thyroid. TSH is also responsible for growth of the thyroid, so goitre develops.

Hyperthyroidism

Hyperthyroidism is an excess of thyroid hormones. It can be caused by Graves disease, thyroid nodules (adenomas that produce thyroid hormone), through overmedicating hypothyroidism or, more rarely, through adenomas that secrete TSH. Graves Disease is an autoimmune disease that is kind of unique because it stimulates the thyroid rather than destroys it. In Graves Disease, there are antibodies called LATS (long-acting thyroid stimulators) that can stimulate TSH receptors on the thyroid gland, leading to excess secretion of thyroid hormone and goitre.

The symptoms of hyperthyroidism are basically the opposite of those of hypothyroidism, with the exception of goitre (both primary hypothyroidism AND both kinds of hyperthyroidism have goitre). Another common sign is exophthalmos, which is basically a fancy way of saying "bulging eyes." Other symptoms are related to increased metabolism: increased weight loss without loss of appetite, fatigue, muscle weakness, tachycardia, nervousness or irritability, heat intolerance and a higher risk of osteoporosis.

Hyperthyroidism can be helped with some medications. β-blockers can help with some of the symptoms. Anti-thyroid medications can also help by interfering with thyroperoxidase (TPO), which essentially catalyses the formation of thyroid hormone from iodine and tyrosine (I think that's how it works, anyway). If that fails, getting rid of the gland might be required. Radioactive iodine targets the thyroid gland. This usually produces hypothyroidism, but that can be treated with exogenous thyroxine (T4). Surgery can be used too, but it's a last resort, saved more for cases where there's cancer or really bad goitre.

Cushing's Syndrome

Now we're moving onto issues with the adrenal glands! Cushing's syndrome, as mentioned in my post for PHYL2001, is caused by excess glucocorticoids. This might be due to an ACTH-secreting tumour from the pituitary or otherwise (yep, sometimes there might be new growths that can secrete ACTH), glucocorticoid-secreting adrenal tumours, or glucocorticoid therapy. Symptoms of Cushing's Syndrome include central/truncal obesity (basically obesity around the stomach etc.), a "moon face," stria (stretch marks), increased hair growth, osteoporosis, insulin resistance (cortisol is gluconeogenic like glucagon, so it makes too much glucose for the body's insulin stores to handle) and delayed healing and increased infection (due to the immune suppression caused by glucocorticoids). The stress response may also be decreased due to desensitisation to glucocorticoids.

Adrenal Insufficiency

Primary adrenal insufficiency (Addison's Disease) is basically a problem with the adrenal gland, resulting in decreased production of all adrenocortical hormones (i.e. glucocorticoids, mineralocorticoids and androgens). This might be caused by autoimmune disease, tumours or infection. Symptoms include weight loss, loss of appetite, weakness, fatigue, hypotension (due to salt loss caused by excess aldosterone), body hair loss and hypoglycaemia.

Secondary adrenal insufficiency, in contrast, is a deficiency in ACTH secretion. This could be caused by a problem in the pituitary or in the hypothalamus or by suddenly stopping glucocorticoid therapy (you need to taper off to give the pituitary gland more time to restore its supply of ACTH). Since secondary adrenal insufficiency is only a deficiency in ACTH, secretion of aldosterone and androgens are normal.

How can these conditions be definitively diagnosed via labwork? Remember our negative feedback loops and the logic there: low cortisol but high ACTH suggests a primary condition, whereas low cortisol and low ACTH suggest a secondary condition. Interestingly enough though, in the ACTH stimulation test, where the patient is given an injection of ACTH, all patients with adrenal insufficiency do not have an increase in cortisol, regardless of whether their condition is primary or secondary. This is because, in secondary adrenal insufficiency, ACTH has been suppressed for so long that a single injection doesn't really do a lot.

To really differentiate the two, you need to perform the CRH stimulation test, which stimulates release of ACTH. If ACTH increases straight away, then you have primary adrenal insufficiency/Addison's. (Remember, in Addison's, the adrenals are the problem, not anything else.) If there is no change at all, then there is secondary adrenal insufficiency caused by a defect in the pituitary gland. Finally, if there is a change, but it is delayed, then there is secondary adrenal insufficiency caused by a defect in the hypothalamus: the pituitary is perfectly capable of producing ACTH, but it just hasn't received the stimulation to do so in a long time.