Adrenal hormone synthesis inhibitors

Definitions & Key takeaways

Adrenal hormone synthesis inhibitors are medicinal drugs that act to suppress the production of adrenal hormones. These drugs can be used to manage conditions where excess adrenal hormone production leads to symptoms such as Cushing's syndrome or Conn's syndrome. There are a variety of adrenal hormone synthesis inhibitors available, with different mechanisms of action and potencies. Some common examples include ketoconazole, metyrapone, and etomidate. Selection of the most appropriate drug depends on the individual patient's condition and other factors such as other medications being taken.

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Introduction0:00–0:18

Adrenal hormones synthesis inhibitors or AHSIs are a group of medications which basically inhibit the synthesis of adrenocortical hormones, more specifically cortisol, which is a glucocorticoid hormone produced by the adrenal cortex.

Physiology0:18–2:40

Normally, the hypothalamus, which is located at the base of the brain, secretes corticotropin-releasing hormone, known as CRH, which stimulates the pituitary gland to secrete adrenocorticotropic hormone, known as ACTH.
ACTH, then, travels to the pair of adrenal glands, on top of each kidney, where it specifically targets cells in the adrenal cortex.
This causes the adrenocortical cells to take up cholesterol from the blood, and it also stimulates an enzyme called cholesterol desmolase inside these cells, which converts cholesterol to pregnenolone.
Then, another enzyme called 3 beta- hydroxysteroid dehydrogenase, (or 3 beta- HSD) turns some of this pregnenolone into progesterone.
Now, the synthesis of cortisol starts when pregnenolone and progesterone move into the zona fasciculata. The enzyme 17 alpha-hydroxylase turns pregnenolone into 17 alpha- hydroxypregnenolone and turns progesterone into 17 alpha hydroxyprogesterone.
17 alpha hydroxypregnenolone is then turned into 17 alpha hydroxyprogesterone by the enzyme 3 beta- hydroxysteroid dehydrogenase.
Then, all of the 17 alpha hydroxyprogesterone is turned into 11 deoxycortisol by the enzyme 21 hydroxylase. 11 deoxycortisol is finally turned into cortisol by the enzyme 11 beta-hydroxylase.
Cortisol is also known as the stress hormone. In times of stress, the body needs to have plenty of energy substrates around, so cortisol increases gluconeogenesis, which is the synthesis of new glucose molecules, proteolysis, which is the breakdown of protein and lipolysis, which is the breakdown of fat.
Cortisol also helps to maintain the blood pressure by increasing the sensitivity of peripheral blood vessels to catecholamines- epinephrine and norepinephrine, and this narrows the blood vessel lumen.
Cortisol helps to dampen the inflammatory and immune response by reducing the production and release of inflammatory mediators, like prostaglandins and interleukins, as well as inhibiting the proliferation of T-lymphocytes.
Finally, cortisol receptors are present in the brain, where their full effect is still actually unclear but might influence things like mood and memory.

Pathology2:40–4:21

Now, in Cushing syndrome, there’s increased cortisol levels over a long period of time. This could be due to Cushing disease, which is caused by a benign pituitary adenoma that secretes too much ACTH.
Another cause is adrenocortical carcinomas, which overproduce cortisol. Excess cortisol leads to severe muscle and skin breakdown which are the major protein stores in the body.
Bones are also broken down which could lead to osteoporosis. It also elevates blood glucose levels, and that leads to high insulin levels.
Insulin, among its many actions, preferentially targets adipocytes or fat cells in the center of the body - around the waist and buttocks.
In those cells, the insulin activates lipoprotein lipase, which is an enzyme that helps those adipocytes accumulate more fat molecules.
The result is central obesity, which is fat build up in the abdomen, buffalo hump, which is fat build up between the shoulders, and moon facies which is fat build up in the face.
Excess cortisol also dampens the inflammatory and immune response, making individuals more susceptible to infections. Alright, so, whatever the cause, the problem is high cortisol level.
So, to solve all these problems, we have to decrease the level of cortisol in the body. We can do this by inhibiting the synthesis of cortisol with the help of adrenal hormone synthesis inhibitors, or AHSIs, like metyrapone and aminoglutethimide.
Ketoconazole is an antifungal medication that also has similar effects. If these medications fail, we can also destroy the adrenocortical cells with mitotane.

Ketoconazole4:21–6:10

Let’s begin with Ketoconazole, which is the first line medication for cushing syndrome. This medication is an antifungal, but it also inhibits 17, 20-lyase in the adrenal cortex, which prevents the synthesis of androgens, and 17 alpha-hydroxylase, which prevents the synthesis of cortisol.
The antiandrogenic effect is particularly useful for pituitary adenomas producing too much ACTH. ACTH leads to increased production of all adrenocortical hormones like cortisol and androgens.
Excess androgen causes symptoms like hirsutism, or excessive facial hair growth, and acne. The main side effects of ketoconazole include nausea, vomiting, hepatotoxicity, decreased libido, and sedation.
It’s also teratogenic so it should not be given during pregnancy. If ketoconazole is ineffective, we can use aminoglutethimide which is peroral.
This medications goes to the adrenal cortex and inhibits multiple enzymes. Most importantly, they inhibit the conversion of cholesterol to pregnenolone, leading to the inhibition of the subsequent steps of cortisol synthesis and androgen production.
Side effects of aminoglutethimide include skin rash and neurological symptoms like blurred vision and sedation. Next, is metyrapone which is given perorally.
It enters the adrenal gland and inhibits the enzyme 11 beta-hydroxylase. This leads to inhibition of the final step of cortisol biosynthesis, which is the conversion of 11 deoxycortisol to cortisol.
Since it doesn’t block the synthesis of androgens, symptoms like hirsutism could actually worsen, so this medication is commonly used in combination with ketoconazole or aminoglutethimide.

Aminoglutethimide6:10–6:46

It’s other side effects include nausea, vomiting and edema. Lastly, is mitotane which is also taken peroral.
Once it goes to the adrenal cortex, it selectively destroys all the adrenocortical cells by inhibiting their mitochondria.
Due to its destructive nature, it’s often only given to people suffering from adrenocortical carcinoma. Once adrenal cortical cells are destroyed, synthetic corticosteroids replacement therapy with prednisone or dexamethasone should be started.

Metyrapone6:46–9:46

Side effects of mitotane include hypercholesterolemia, rash, low white blood cell count, vomiting and diarrhea. All right, as a quick recap… Adrenal hormone synthesis inhibitors are a group of medications that inhibit the synthesis of adrenocortical hormones, more specifically cortisol, and sometimes androgen.
Medications like metyrapone, aminoglutethimide, and ketoconazole block key enzymes in steroid hormone synthesis while mitotane destroys adrenocortical cells.

Mitotane9:46–10:43

Etomidate10:43–11:07

Review11:07–7:19