Cushing syndrome and the HPA axis
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- Cushing syndrome and the HPA axis
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Cushing syndrome and the HPA axis
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[post_date] => 2024-12-23 18:17:54
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[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Cushing syndrome, or hypercortisolism, results from abnormally high levels of the glucocorticoid hormone cortisol circulating in the body. The symptoms of Cushing syndrome can vary between individuals, but the classic signs in humans include rounded face, upper body obesity, fat deposits in the neck, and thin arms and legs.
The causes of Cushing syndrome can be exogenous - for instance, due to people taking cortisol-like medications such as prednisone - or endogenous, having an internal cause or origin. Endogenous Cushing syndrome is less common and is most often caused by hormone-secreting tumors of the adrenal or the pituitary glands. Cushing disease, for instance, is a form of Cushing syndrome in which hypercortisolism results from the overproduction of adrenocorticotropic hormone (ACTH) caused by either a pituitary adenoma or a non-pituitary tumor.
Under normal conditions, cortisol regulates the production of corticotropin releasing hormone (CRH) from the hypothalamus and ACTH from the anterior pituitary, via negative feedback inhibition. In individuals with Cushing syndrome, levels of hormones involved in the hypothalamic-pituitary-adrenal (HPA) axis can be measured in the blood, and the results of these measurements can help determine the underlying etiology of Cushing syndrome.
Table 1 shows data from a study investigating abnormalities in the HPA axis. In this study, CRH, ACTH, and cortisol levels were measured in rats injected with saline, cortisol, hormone X, or drug Y.
Table 1 Levels of hormones found in blood for three different treatments
Data adapted from: Cushing's Disease. UCLA Pituitary Tumor Program, Pituitary Tumor Surgery
[post_title] => Cushing syndrome and the HPA axis
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[quiz_unique_key] => 602779517
[question] => What is the function of the rats injected with saline?
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[answer] => 3
[description] => Reason for Correct Answer:
The purpose of a negative control group is to provide a baseline condition, helping isolate the effect of the one variable that differs between the control and experimental group. On the other hand, a positive control group, which is less commonly used, is not exposed to the experimental treatment but is exposed to some other treatment that is known to produce the expected effect.
In this case, the rats injected with saline serve as a negative control group, with the purpose of the saline injection being to standardize conditions between the control and experimental groups (e.g. to standardize the potential dilution of blood levels cause by the injection).
The control group is rats merely treated with saline, with nothing else unusual about the rats, so they cannot be an animal model of Cushing syndrome, as in D. Instead, the rats serve as a negative control showing baseline physiologic hormone levels in rats, as in C, allowing the experimenters to determine whether injection with cortisol, hormone X, and drug Y result in increases or decreases in these baseline hormones
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[answers] => Array
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[each_answer] => A. A positive control showing typical hormone levels in Cushing syndrome
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[1] => Array
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[each_answer] => B. A positive control showing the effects of serum dilution on hormone levels
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[each_answer] => C. A negative control showing baseline physiological hormone levels in rats
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[each_answer] => D. A negative control showing hormone levels in Cushing syndrome absent hormone or drug treatment
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => Rats injected with hormone X would serve as the best animal model for which of the following?
[value] => Array
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[answer] => 1
[description] => Reason for Correct Answer:
The third row of Table 1 shows the effects of hormone X on the HPA hormones.
The saline group (row 1) is the control group, so you can determine the effect of hormone X by comparing hormone levels in row 3 to those in row 1.
Compared to the control (saline) group, treatment hormone X resulted in reduced CRH levels but increased ACTH and cortisol levels.
This increase in ACTH (and therefore cortisol) and decrease in CRH mimics the affects of a pituitary adenoma. Pituitary adenomas produce high levels of ACTH without need for stimulation by CRH (and the high levels of ACTH then inhibit CRH release from the hypothalamus but stimulate cortisol release from the adrenal glands).
A pituitary ademona is by nature an “endogenous” or internal form of Cushing syndrome; therefore, hormone X mimics endogenous Cushing syndrome caused by a pituitary adenoma. Although hormone X is given exogenously, it is mimicking the effects of an endogenous disorder.
Reason for Incorrect Answer:
B. An adrenal tumor would result in high levels of cortisol but lower levels of ACTH in the blood.
C. A tumor is by definition an endogenous cause of Cushing syndrome. And, a non-pituitary tumor producing cortisol would result in a lower level of ACTH in the blood.
D. Cushing syndrome from administration of a drug would not result in the elevated levels of ACTH as seen with hormone X.
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[each_answer] => A. Endogenous Cushing syndrome caused by a pituitary adenoma
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[each_answer] => B. Endogenous Cushing syndrome caused by an adrenal tumor
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[each_answer] => C. Exogenous Cushing syndrome caused by a non-pituitary tumor
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[each_answer] => D. Exogenous Cushing syndrome caused by a cortisol-like drug
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[quiz_unique_key] => 1403770772
[question] => Which of the following can result in a chronic increase in a patient’s ACTH and CRH levels?
[value] => Array
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[answer] => 3
[description] => Reason for Correct Answer:
Remember that in the HPA, the hypothalamus produces CRH, which stimulates ACTH release from the pituitary, which then stimulates cortisol release from the adrenal glands.
Under normal conditions, cortisol provides negative feedback to the hypothalamus and anterior pituitary, decreasing the concentrations of CRH and ACTH respectively.
In the case of destruction of the adrenal glands, the body would not produce cortisol, and CRH and ACTH would be produced from the hypothalamus and pituitary at high levels, with no feedback mechanism.
Reason for Incorrect Answer:
A. Medicinal glucocorticoids would transiently increase a patient’s ACTH and CRH levels but would not explain a chronic increase.
B. A pituitary tumor causes high ACTH levels despite resulting in high cortisol levels in the blood; however, cortisol still exerts negative feedback on the hypothalamus, resulting in low (not high) CRH levels.
D. ACTH and CRH are hormones upstream of cortisol, and excess cortisol would normally decrease ACTH and CRH through a negative feedback mechanism.
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[each_answer] => A. Taking medicinal glucocorticoids, such as prednisone
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[each_answer] => B. Pituitary tumor
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[each_answer] => C. Destruction of the adrenal glands
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[each_answer] => D. Hypersecretion of cortisol from the hypothalamus
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[quiz_unique_key] => 1403770772
[question] => Which of the following would exacerbate the symptoms of Cushing disease?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
The passage states that Cushing disease is a form of Cushing syndrome that results from high levels of ACTH. High levels of ACTH lead to high levels of cortisol, the cause of the symptoms observed in Cushing disease (and other forms of Cushing syndrome as well).
Something that exacerbates the symptoms of Cushing disease would either (a) increase the secretion of cortisol or (b) promote its function and effects.
Taking exogenous medicinal glucocorticoids is itself something that can cause Cushing syndrome and associated symptoms. Taking more medicinal glucocorticoids ON TOP of already having Cushing disease could definitely worsen the effects of the disease, as the exogenous glucocorticoids would act on the same receptors as cortisol and worsen its effects.
Reason for Incorrect Answer:
A. Enhanced negative feedback by cortisol would help decrease ACTH levels, helping to control the overproduction of ACTH (and therefore cortisol) in Cushing disease.
C. If a pituitary adenoma was the cause of Cushing disease, then treating it should help improve symptoms.
D. A glucocorticoid receptor antagonist would help to block the effects of cortisol and alleviate symptoms of Cushing disease.
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[each_answer] => A. Enhanced negative feedback by cortisol
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[1] => Array
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[each_answer] => B. Taking glucocorticoids to treat asthma
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[each_answer] => C. Radiation therapy to treat a pituitary adenoma
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[each_answer] => D. Taking a glucocorticoid receptor antagonist
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[quiz_unique_key] => 1403770772
[question] => What is the most likely identity of Drug Y?
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[answer] => 1
[description] => Reason for Correct Answer:
The table shows a decrease of all hormones in rats given Drug Y.
As the passage states, prednisone is a cortisol-like compound, which could also have negative feedback on the hypothalamus and pituitary hormones (CRH and ACTH).
A drug that inhibits the hypothalamus and pituitary gland would result in a decrease in CRH and ACTH and a resulting decrease in cortisol levels, as is consistent with the data shown for drug Y..
Reason for Incorrect Answer:
B. Inhibition of hormone production in the pituitary and adrenal glands would cause a decrease in ACTH and cortisol, but it would not cause a decrease in CRH, as is also shown with drug Y.
C. Stimulating hormone secretion in the pituitary and adrenal glands would result in an increase in ACTH and cortisol production, not a decrease as is shown with drug Y.
D. Inhibiting hormone production in the adrenal glands would cause a decrease in cortisol. This would cause ACTH and CRH levels to rise due to loss of feedback inhibition; however, drug Y results in a decrease in ACTH and CRH according to the table.
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[each_answer] => A. A prednisone analog that inhibits hormone production in the hypothalamus and pituitary
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[each_answer] => B. A CRH antagonist that inhibits hormone production in the pituitary and adrenal glands
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[each_answer] => C. A CRH agonist that stimulates hormone secretion in the pituitary and adrenal glands
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[each_answer] => D. An ACTH antagonist that inhibits hormone production in the adrenal glands
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[quiz_unique_key] => 1325138223
[question] => After cortisol binds with its receptor, the hormone-receptor complex exerts its effects by which of the following mechanisms?
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[answer] => 4
[description] => Reason for Correct Answer:
Since hormones’ mechanisms of action depend on their category (defined in terms of molecular structure), the first step is to recognize that the passage describes cortisol as a glucocorticoid. Glucocorticoids belong to the more general category of steroid hormones, which exert their effects through mechanisms distinct from those of peptide hormones.
Steroid hormones are nonpolar and pass through the cell membrane to interact with intracellular receptors.
Once steroid hormones bind with their receptors, the receptor-hormone complex interacts with DNA in the nucleus to alter gene regulation. The correct answer should capture both the intracellular location of cortisol receptors and the gene regulation-based mechanism of its effects.
Reason for Incorrect Answer:
A. Occupying enzymes’ active sites would be associated with competitive inhibition; this mechanism is not characteristic of steroid hormones, to which cortisol belongs.
B. Cortisol, a glucocorticoid, belongs to the more general category of steroids, which predominantly exert their effects by binding to intracellular receptors to alter gene expression.
C. Protein hormones bind to receptors in the cell membrane and generate secondary messengers like Ca2+, IP3, and cAMP, which brings about biochemical and physiological changes in the cell. However, steroid hormones like cortisol diffuse into the cells and bind to intracellular receptors.
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[each_answer] => A. Occupying the active sites of enzymes involved in metabolic pathways
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[each_answer] => B. Causing voltage-gated sodium channels to open in the cell membrane
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[each_answer] => C. Binding cell membrane receptors to generate second messengers like IP3 and cAMP
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[each_answer] => D. Altering the transcription levels of genes involved in metabolism and the immune response
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