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Physiological Basis for the Etiology, Diagnosis, and Treatment of Adrenal Disorders: Cushing's Syndrome, Adrenal Insufficiency, and Congenital Adrenal Hyperplasia

Hershel Raff, Susmeeta T. Sharma, Lynnette K. Nieman

10.1002/cphy.c130035

Source: Volume 4, Issue 2, April 2014

Published online: March 2014

Full Article on Wiley Online Library



Abstract

The hypothalamic‐pituitary‐adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing's syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing's syndrome). Endogenous Cushing's syndrome can be subdivided into ACTH‐dependent and ACTH‐independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing's syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long‐term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary‐adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control. © 2014 American Physiological Society. Compr Physiol 4:739‐769, 2014.

Keywords: Cortisol adrenocorticotropic hormone (ACTH); proopiomelanocortin (POMC); steroidogenesis aldosterone

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Figure 1. Figure 1. The hypothalamic‐pituitary‐adrenal axis. Inputs from the hypothalamic circadian rhythm generator in the suprachiasmatic nucleus (SCN) and neural stress pathways in the central nervous system (CNS) control the activity of the corticotrophin‐releasing hormone (CRH) neuronal cell bodies in the paraventricular nucleus. These neurons are also capable of synthesizing arginine vasopressin (AVP), which can augment the pituitary response to CRH. CRH (and AVP) are released into the portal circulation in capillaries in the median eminence and drain onto the anterior pituitary where they stimulate the pituitary corticotrophs to release adrenocorticotropic hormone (ACTH). ACTH stimulates the zona fasciculata (ZF) and zona reticularis (ZR) via the MC2R (melanocortin 2 receptor, also known as the ACTH receptor). This G‐protein coupled receptor increases intracellular cAMP release, which activates StAR‐mediated cholesterol transport into the mitochondria (the rate‐limiting step of steroidogenesis). Once cholesterol reaches the inner mitochondrial (Mito) membrane, it is acted on by the first steroidogenic enzyme, and then by subsequent sequential enzymes in the smooth endoplasmic reticulum (SER) and Mito with cortisol as an end product (see Fig. 12). Cortisol is released into the plasma compartment where it binds reversibly to corticosteroid‐binding globulin (CBG; also known as cortisol‐binding globulin). As CBG‐bound plasma cortisol enters the capillaries in target tissue, it dissociates from CBG and diffuses into the target cell. In the pituitary and hypothalamus, negative feedback inhibition is exerted with the binding of cortisol to glucocorticoid (GR) and mineralocorticoid (MR) receptors.
Figure 2. Figure 2. The mechanisms of glucocorticoid (GC)‐induced decreases in growth in children and suppression of growth hormone (GH) in adults. GHRH is growth‐hormone release hormone, IGF1 is insulin‐like growth factor 1; GnRH is gonadotropin‐releasing hormone, LH is luteinizing hormone, and FSH is follicle‐stimulating hormone. Adapted from (7) with kind permission from WB Saunders through the Copyright Clearance Center.
Figure 3. Figure 3. The use of late‐night salivary cortisol (LNSC) for screening patients with suspected Cushing's syndrome. Note that because Cushing's syndrome is relatively rare and its phenotype very common, most patients screened will have normal LNSCs and Cushing's syndrome will be ruled out. Conversely, most patients with true Cushing's syndrome will have consistently increased LNSCs. Even so, the diagnosis is usually confirmed with urine free cortisol (UFC) measurements and/or the overnight low‐dose dexamethasone suppression test (oDST). Occasionally, the LNSCs are discordant as shown or the samples are suspicious for contamination with over‐the‐counter hydrocortisone creams. In that case, measurement of cortisol and cortisone by liquid chromatography/tandem mass spectrometry (LC‐MS/MS) will resolve the problem. Adapted from (211) with kind permission from Springer.
Figure 4. Figure 4. The physiological basis for the approach to the differential diagnosis of Cushing's syndrome. CT is computed tomography radiography and MRI is magnetic resonance imaging. Once the diagnosis is established (see Fig. 3), measurement of a suppressed plasma level of adrenocorticotropic hormone (ACTH) identifies ACTH‐independent (adrenal) Cushing's syndrome. *Adrenal computed tomography (CT) is then performed, and a more detailed analysis is needed to differentiate among the subtypes of adrenal Cushing's syndrome. The most challenging problem is the differential diagnosis of ACTH‐dependent Cushing's syndrome. The high‐dose dexamethasone suppression test is no longer recommended. If the results of magnetic resonance imaging (MRI) of the pituitary show a mass > 6 mm, referral to a neurosurgeon is appropriate. If not, bilateral inferior petrosal sinus sampling with administration of corticotropin‐releasing hormone (CRH) is performed. This method reliably distinguishes pituitary Cushing's disease from occult ectopic ACTH syndrome. For a more thorough discussion, see text. From (214) with kind permission of the Annals of Internal Medicine/American College of Physicians.
Figure 5. Figure 5. Plasma ACTH concentrations in patients with established ACTH‐dependent Cushing's syndrome (Cushing's disease [pituitary corticotroph adenomas] and ectopic ACTH) and ACTH‐independent Cushing's syndrome (Adrenal tumor). Note that plasma ACTH is often within the reference range (blue shading) in Cushing's disease and that, on average, patients with ectopic ACTH have very high plasma ACTH. To convert to pmol/L, multiply pg/mL by 0.2202.
Figure 6. Figure 6. Summary of inferior petrosal sinus (IPS) sampling in the differential diagnosis of ACTH‐dependent Cushing's syndrome. IPS:P is the ratio of plasma ACTH concentration between an inferior petrosal sinus sample and a sample from a peripheral vein (usually the inferior vena cava) drawn simultaneously. Adapted from (77) with permission from John Wiley and Sons.
Figure 7. Figure 7. Adrenal insufficiency. In primary adrenal insufficiency, the adrenal cortex is typically destroyed (indicated by an X). This relieves the hypothalamus of cortisol negative feedback such that, presumably, corticotrophin‐release hormone (CRH) is increased, although sampling portal vein blood is not possible in humans. The loss of negative feedback at the pituitary leads to a large increase in plasma ACTH. In secondary adrenal insufficiency, adequate ACTH secretion is lost (indicated by an X) resulting in suboptimal plasma ACTH and adrenal atrophy.
Figure 8. Figure 8. Typical plasma glucose, ACTH, and cortisol response to insulin‐induced hypoglycemia in a healthy subject and a patient with secondary adrenal insufficiency (hypopituitarism). Notice there is a small increase in ACTH and cortisol in this patient with secondary adrenal insufficiency indicating there are still a few remaining functioning pituitary corticotrophs. To convert glucose to mmol/L, multiply mg/100 ml by 0.056; to convert ACTH to pmol/L, multiply pg/mL by 0.2202. To convert cortisol to nmol/L, multiply μg/dL by 27.59.
Figure 9. Figure 9. Plasma ACTH in patients with untreated primary and secondary adrenal insufficiency, and in patients on chronic pharmacological glucocorticoid therapy. Notice that plasma ACTH is often within the reference range (blue shading) in patients with secondary adrenal insufficiency. To convert to pmol/L, multiply pg/mL by 0.2202.
Figure 10. Figure 10. The large protein proopiomelanocortin (POMC) is produced by transcription and translation of the POMC gene. Adrenocorticotropic hormone is then produced by posttranslational processing. Note that other products of POMC can be produced (for example, beta and gamma‐lipotropic hormone [LPH], N‐terminal POMC fragment [N‐POC], and melanocyte‐stimulating hormone [M]). Also notice that ACTH contains the sequence of MSH within it. Ectopic ACTH‐secreting tumors can perform the same processing but often produce large amounts of precursors (particularly pro‐ACTH). From (214) with kind permission of the Annals of Internal Medicine/American College of Physicians.
Figure 11. Figure 11. Pattern of the recovery of ACTH from the pituitary and cortisol from the adrenal after discontinuation of chronic pharmacological glucocorticoid therapy. From (71) with kind permission of McGraw Hill.
Figure 12. Figure 12. The normal human steroidogenic pathway. Under normal conditions, the human adrenal cortex produces only small amounts of estrone, estradiol, testosterone, and adrenostenediol. The main adrenal secretory products are aldosterone (produced in the zona glomerulosa), and cortisol, dehydroepiandrosterone (DHEA), and androstenedione (produced in the zonae fasciculata and reticularis). StAR, steroidogenic acute regulatory protein; P450scc, side‐chain cleavage, HSD, hydroxysteroid dehydrogenase; P450c17, 17‐hydroxylase; POR, P450 oxoreductase; P450c21, 21‐hydroxylase; P450c11, 11‐hydroxylase; P450aro, aromatase; 5α‐red, 5‐alpha‐reductase; DHT, dihydrotestosterone. Reproduced from (118) with kind permission from Elsevier.
Figure 13. Figure 13. Mechanism of virilization in female fetuses with congenital adrenal hyperplasia. An enzyme defect (usually partial; in this case to P450c21) in the steroidogenic pathway leads to decreased production of cortisol and a shift of precursors into the adrenal androgen pathway. Because cortisol negative feedback is decreased, ACTH release from the fetal pituitary gland increases. Although cortisol can eventually be normalized, it is at the expense of ACTH‐stimulated adrenal hypertrophy and excess fetal adrenal androgen production. Adapted from (276) with kind permission from McGraw‐Hill.


Figure 1. The hypothalamic‐pituitary‐adrenal axis. Inputs from the hypothalamic circadian rhythm generator in the suprachiasmatic nucleus (SCN) and neural stress pathways in the central nervous system (CNS) control the activity of the corticotrophin‐releasing hormone (CRH) neuronal cell bodies in the paraventricular nucleus. These neurons are also capable of synthesizing arginine vasopressin (AVP), which can augment the pituitary response to CRH. CRH (and AVP) are released into the portal circulation in capillaries in the median eminence and drain onto the anterior pituitary where they stimulate the pituitary corticotrophs to release adrenocorticotropic hormone (ACTH). ACTH stimulates the zona fasciculata (ZF) and zona reticularis (ZR) via the MC2R (melanocortin 2 receptor, also known as the ACTH receptor). This G‐protein coupled receptor increases intracellular cAMP release, which activates StAR‐mediated cholesterol transport into the mitochondria (the rate‐limiting step of steroidogenesis). Once cholesterol reaches the inner mitochondrial (Mito) membrane, it is acted on by the first steroidogenic enzyme, and then by subsequent sequential enzymes in the smooth endoplasmic reticulum (SER) and Mito with cortisol as an end product (see Fig. 12). Cortisol is released into the plasma compartment where it binds reversibly to corticosteroid‐binding globulin (CBG; also known as cortisol‐binding globulin). As CBG‐bound plasma cortisol enters the capillaries in target tissue, it dissociates from CBG and diffuses into the target cell. In the pituitary and hypothalamus, negative feedback inhibition is exerted with the binding of cortisol to glucocorticoid (GR) and mineralocorticoid (MR) receptors.


Figure 2. The mechanisms of glucocorticoid (GC)‐induced decreases in growth in children and suppression of growth hormone (GH) in adults. GHRH is growth‐hormone release hormone, IGF1 is insulin‐like growth factor 1; GnRH is gonadotropin‐releasing hormone, LH is luteinizing hormone, and FSH is follicle‐stimulating hormone. Adapted from (7) with kind permission from WB Saunders through the Copyright Clearance Center.


Figure 3. The use of late‐night salivary cortisol (LNSC) for screening patients with suspected Cushing's syndrome. Note that because Cushing's syndrome is relatively rare and its phenotype very common, most patients screened will have normal LNSCs and Cushing's syndrome will be ruled out. Conversely, most patients with true Cushing's syndrome will have consistently increased LNSCs. Even so, the diagnosis is usually confirmed with urine free cortisol (UFC) measurements and/or the overnight low‐dose dexamethasone suppression test (oDST). Occasionally, the LNSCs are discordant as shown or the samples are suspicious for contamination with over‐the‐counter hydrocortisone creams. In that case, measurement of cortisol and cortisone by liquid chromatography/tandem mass spectrometry (LC‐MS/MS) will resolve the problem. Adapted from (211) with kind permission from Springer.


Figure 4. The physiological basis for the approach to the differential diagnosis of Cushing's syndrome. CT is computed tomography radiography and MRI is magnetic resonance imaging. Once the diagnosis is established (see Fig. 3), measurement of a suppressed plasma level of adrenocorticotropic hormone (ACTH) identifies ACTH‐independent (adrenal) Cushing's syndrome. *Adrenal computed tomography (CT) is then performed, and a more detailed analysis is needed to differentiate among the subtypes of adrenal Cushing's syndrome. The most challenging problem is the differential diagnosis of ACTH‐dependent Cushing's syndrome. The high‐dose dexamethasone suppression test is no longer recommended. If the results of magnetic resonance imaging (MRI) of the pituitary show a mass > 6 mm, referral to a neurosurgeon is appropriate. If not, bilateral inferior petrosal sinus sampling with administration of corticotropin‐releasing hormone (CRH) is performed. This method reliably distinguishes pituitary Cushing's disease from occult ectopic ACTH syndrome. For a more thorough discussion, see text. From (214) with kind permission of the Annals of Internal Medicine/American College of Physicians.


Figure 5. Plasma ACTH concentrations in patients with established ACTH‐dependent Cushing's syndrome (Cushing's disease [pituitary corticotroph adenomas] and ectopic ACTH) and ACTH‐independent Cushing's syndrome (Adrenal tumor). Note that plasma ACTH is often within the reference range (blue shading) in Cushing's disease and that, on average, patients with ectopic ACTH have very high plasma ACTH. To convert to pmol/L, multiply pg/mL by 0.2202.


Figure 6. Summary of inferior petrosal sinus (IPS) sampling in the differential diagnosis of ACTH‐dependent Cushing's syndrome. IPS:P is the ratio of plasma ACTH concentration between an inferior petrosal sinus sample and a sample from a peripheral vein (usually the inferior vena cava) drawn simultaneously. Adapted from (77) with permission from John Wiley and Sons.


Figure 7. Adrenal insufficiency. In primary adrenal insufficiency, the adrenal cortex is typically destroyed (indicated by an X). This relieves the hypothalamus of cortisol negative feedback such that, presumably, corticotrophin‐release hormone (CRH) is increased, although sampling portal vein blood is not possible in humans. The loss of negative feedback at the pituitary leads to a large increase in plasma ACTH. In secondary adrenal insufficiency, adequate ACTH secretion is lost (indicated by an X) resulting in suboptimal plasma ACTH and adrenal atrophy.


Figure 8. Typical plasma glucose, ACTH, and cortisol response to insulin‐induced hypoglycemia in a healthy subject and a patient with secondary adrenal insufficiency (hypopituitarism). Notice there is a small increase in ACTH and cortisol in this patient with secondary adrenal insufficiency indicating there are still a few remaining functioning pituitary corticotrophs. To convert glucose to mmol/L, multiply mg/100 ml by 0.056; to convert ACTH to pmol/L, multiply pg/mL by 0.2202. To convert cortisol to nmol/L, multiply μg/dL by 27.59.


Figure 9. Plasma ACTH in patients with untreated primary and secondary adrenal insufficiency, and in patients on chronic pharmacological glucocorticoid therapy. Notice that plasma ACTH is often within the reference range (blue shading) in patients with secondary adrenal insufficiency. To convert to pmol/L, multiply pg/mL by 0.2202.


Figure 10. The large protein proopiomelanocortin (POMC) is produced by transcription and translation of the POMC gene. Adrenocorticotropic hormone is then produced by posttranslational processing. Note that other products of POMC can be produced (for example, beta and gamma‐lipotropic hormone [LPH], N‐terminal POMC fragment [N‐POC], and melanocyte‐stimulating hormone [M]). Also notice that ACTH contains the sequence of MSH within it. Ectopic ACTH‐secreting tumors can perform the same processing but often produce large amounts of precursors (particularly pro‐ACTH). From (214) with kind permission of the Annals of Internal Medicine/American College of Physicians.


Figure 11. Pattern of the recovery of ACTH from the pituitary and cortisol from the adrenal after discontinuation of chronic pharmacological glucocorticoid therapy. From (71) with kind permission of McGraw Hill.


Figure 12. The normal human steroidogenic pathway. Under normal conditions, the human adrenal cortex produces only small amounts of estrone, estradiol, testosterone, and adrenostenediol. The main adrenal secretory products are aldosterone (produced in the zona glomerulosa), and cortisol, dehydroepiandrosterone (DHEA), and androstenedione (produced in the zonae fasciculata and reticularis). StAR, steroidogenic acute regulatory protein; P450scc, side‐chain cleavage, HSD, hydroxysteroid dehydrogenase; P450c17, 17‐hydroxylase; POR, P450 oxoreductase; P450c21, 21‐hydroxylase; P450c11, 11‐hydroxylase; P450aro, aromatase; 5α‐red, 5‐alpha‐reductase; DHT, dihydrotestosterone. Reproduced from (118) with kind permission from Elsevier.


Figure 13. Mechanism of virilization in female fetuses with congenital adrenal hyperplasia. An enzyme defect (usually partial; in this case to P450c21) in the steroidogenic pathway leads to decreased production of cortisol and a shift of precursors into the adrenal androgen pathway. Because cortisol negative feedback is decreased, ACTH release from the fetal pituitary gland increases. Although cortisol can eventually be normalized, it is at the expense of ACTH‐stimulated adrenal hypertrophy and excess fetal adrenal androgen production. Adapted from (276) with kind permission from McGraw‐Hill.
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Teaching Material

 

Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr Physiol 4:739-768, 2014

 

Didactic Synopsis

 

Major Teaching Points:

 

1. Understanding the HPA axis is necessary to master the diagnosis of pituitary-adrenal diseases.

 

2. Diagnosis of excess cortisol secretion (spontaneous Cushing’s syndrome):

a. Late-night salivary cortisol interrogates the lack of a normal nadir in cortisol.

b. The low-dose dexamethasone assesses a decrease in the sensitivity to glucocorticoid negative feedback.

c. Urine-free cortisol assesses increased renal filtered load of cortisol.

 

3. Adrenal insufficiency (AI) - the lack of normal cortisol secretion – is due to adrenal destruction (primary AI; Addison’s disease) or hypopituitarism (secondary AI).

a. ACTH is increased in AI due to the loss of cortisol negative feedback.

b. ACTH is not increased in secondary AI because of pituitary dysfunction.

 

4. Congenital adrenal insufficiency is due to a mutation in one of the steroidogenic enzymes. If adrenal androgen production is increased in utero, masculinization of a female fetus can occur.

 

 

Didactic Legends

 

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

 

Figure 1. Teaching Points: Understanding the control of the HPA axis allows the clinical correlation of the diagnosis and treatment of Cushing’s syndrome and adrenal insufficiency. The physiological control system is described in the formal figure legend. ACTH-secreting pituitary tumors usually have decreased sensitivity to cortisol-negative feedback allowing testing with dexamethasone (a glucocorticoid agonist). Cortisol-producing adrenal adenomas suppress plasma ACTH via negative feedback allowing its differential diagnosis. Finally, loss of adrenal function can be due to direct destruction of the adrenal gland (primary adrenal insufficiency) or loss of pituitary function (secondary adrenal insufficiency).

 

Figure 2. Teaching Points: Growth suppression in children with Cushing’s syndrome is devastating. It is caused by the direct effect of increased cortisol (or exogenous glucocorticoids) on bone, on the liver to decrease IGF-1 production, on the pituitary to suppress GH secretion, and on the hypothalamus to decrease GHRH and increase somatostatin secretion.

 

Figure 3. Teaching Points: Understanding the physiology of the HPA axis circadian rhythm facilitates evaluating its disruption in patients with endogenous Cushing’s syndrome. Salivary cortisol is in equilibrium with the free (bioactive) cortisol in plasma; salivary cortisol is an excellent, non-invasive surrogate for plasma free cortisol. Finding increased late-night salivary cortisol (when cortisol should be at its lowest) allows a very useful screening test for endogenous Cushing’s syndrome of any etiology.

 

Figure 4. Teaching Points: Once Cushing’s syndrome (endogenous hypercortisolism) is established, the next step is to determine the cause. This follows classic physiological principles. If the cause of Cushing’s syndrome is a primary adrenal source due to autonomous steroidogenesis, glucocorticoid negative feedback suppresses pituitary ACTH release, hence plasma ACTH is low. If the cause of Cushing’s syndrome is due to an ACTH-secreting tumor, then ACTH is not suppressed. Once ACTH-dependent Cushing’s syndrome is established, one has to differentiate a pituitary source from a non-pituitary (ectopic) source of ACTH. Since pituitary tumors are often very small and both small ACTH-secreting pituitary adenomas and ectopic ACTH-secreting tumors are often radiologically occult, the best test (again based on physiological principles) is that there will be a large gradient of ACTH between the pituitary venous drainage (inferior petrosal sinuses) and a peripheral vein, if the pituitary is the source of ACTH.

 

Figure 5. Teaching Points: This is a logical follow-up to Figure 4. Let’s start with ectopic ACTH which is usually due to relatively unregulated ACTH secretion from a neuroendocrine tumor; plasma ACTH is increased as shown. With an adrenal (autonomous steroidogenic) tumor, plasma ACTH is suppressed due to glucocorticoid negative feedback. With Cushing’s disease (usually a small, ACTH-secreting benign adenoma), some sensitivity to glucocorticoid negative feedback can be retained so the plasma ACTH is often within the reference range, albeit inappropriately increased in the face of glucocorticoid negative feedback (increased plasma cortisol).

 

Figure 6. Teaching Points: Once ACTH-dependent Cushing’s syndrome is established, one has to differentiate a pituitary source from a non-pituitary (ectopic) source of ACTH. Since pituitary tumors are often very small and not visible on pituitary MRI, and ectopic tumors are also often radiologically occult, the best test (again based on physiological principles) is that there will be a large gradient of plasma ACTH between the pituitary venous drainage (inferior petrosal sinuses) and a peripheral vein in patients with Cushing’s disease (pituitary source of ACTH).

 

Figure 7. Teaching Points: Understanding adrenal insufficiency also hinges on understanding physiological control. In primary adrenal insufficiency, the adrenal gland is destroyed and cortisol secretion is low; ACTH secretion increases dramatically in response to the loss of glucocorticoid negative feedback. In secondary adrenal insufficiency, the pituitary is not producing adequate ACTH to maintain adrenocortical function and the adrenal slowly atrophies. As cortisol decreases, the remaining healthy ACTH-secreting pituitary cells (corticotrophs) secrete ACTH maximally, so plasma ACTH is often measurable but inappropriately not elevated in the face of the loss of glucocorticoid negative feedback.

 

Figure 8. Teaching Points: Insulin injection decreases plasma glucose (blood sugar) because insulin stimulates glucose uptake in target tissue (e.g. skeletal muscle). This is a classic "stressor" that results in a large increase in ACTH (and hence) cortisol secretion. The decrease in plasma glucose is probably sensed by a "glucostat" in the hypothalamus. In a patient with decreased pituitary function (i.e. secondary adrenal insufficiency), there is a greatly attenuated ACTH and cortisol response. This used to be used as a clinical test of pituitary function, but is rarely done these days because the hypoglycemia induced with insulin injection can be dangerous.

 

Figure 9. Teaching Points: Plasma ACTH in patients with primary adrenal insufficiency (adrenal destruction), secondary adrenal insufficiency (decrease in pituitary ACTH secretion), and pharmacological glucocorticoid therapy (e.g. prednisone used as an anti-inflammatory or immunosuppressive drug). In primary adrenal insufficiency, the adrenal gland has been destroyed and plasma ACTH is increased due to the loss of glucocorticoid negative feedback. In secondary adrenal insufficiency, the adrenal gland has atrophied due to inadequate ACTH secretion. Notice that plasma ACTH is measurable and often at the low end of the reference range because the few remaining normal corticotrophs are secreting ACTH maximally due to the loss of glucocorticoid negative feedback. With a glucocorticoid receptor agonist like prednisone (pharmacological glucocorticoid therapy), the hypothalamus and pituitary "thinks" there is too much cortisol and shuts off ACTH release due to glucocorticoid negative feedback.

 

Figure 10. Teaching Points: Post-translational processing of POMC to ACTH and other products. Notice that there is no gene for ACTH. It is produced in the pituitary corticotrophs by processing of POMC.

 

Figure 11. Teaching Points: Weaning patients from long-term glucocorticoid therapy is an art that also requires knowledge of physiological principles. Because of glucocorticoid negative feedback, ACTH has been suppressed leading to adrenal atrophy. As the dose of glucocorticoid therapy is decreased, plasma ACTH slowly increases which ‘wakes up’ the adrenal cortex and it starts to grow back. As a result, cortisol secretion is restored to normal. Notice that plasma ACTH normally overshoots in the process; this helps hasten the restoration of adrenal function. Weaning must be done very carefully and can take a long time depending on the duration and magnitude of the dose of glucocorticoid therapy. Abrupt cessation of glucocorticoid therapy in this scenario can lead to devastating secondary adrenal insufficiency.

 

Figure 12. Teaching Points: The steroidogenic pathway. This is primarily biochemistry but there are a few physiological principles to expound on. The transfer of cholesterol from the cytoplasm to the inner mitochondrial membrane (where P450scc is located) is mediated by steroidogenic acute regulatory (StAR) protein; this is the rate limiting step of steroidogenesis that is stimulated by increases in ACTH (see Figure 1). Mutations in the different steroidogenic enzymes lead to a variety of clinical syndromes grouped under the term "congenital adrenal hyperplasia". The classic example is P450c21 deficiency in which the production of both aldosterone (leading to salt wasting) and cortisol are decreased (but are not zero). The loss of adequate cortisol negative feedback in the fetus leads to a large increase in ACTH secretion and an increase in precursor production and adrenal hyperplasia. If this occurs in an XX fetus, the increased adrenal androgen production can lead to virilization and ambiguous genitalia recognized at birth.

 

Figure 13. Teaching Points: Congenital adrenal hyperplasia is a very useful syndrome to teach the physiology of the hypothalamic-pituitary-adrenal axis. The decrease in function in a specific adrenal steroidogenic enzyme leads to a decrease in cortisol production. The loss of negative feedback results in an increase in plasma ACTH which induces adrenal hyperplasia as well as a shifting of steroidogenic precursors into the adrenal androgen pathway. This can result in virilization of an XX fetus.

 


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Article Title: Physiological Basis for the Etiology, Diagnosis, and Treatment of Adrenal Disorders: Cushing's Syndrome, Adrenal Insufficiency, and Congenital Adrenal Hyperplasia
 

How to Cite

Hershel Raff, Susmeeta T. Sharma, Lynnette K. Nieman. Physiological Basis for the Etiology, Diagnosis, and Treatment of Adrenal Disorders: Cushing's Syndrome, Adrenal Insufficiency, and Congenital Adrenal Hyperplasia. Compr Physiol 2014, 4: 739-769. doi: 10.1002/cphy.c130035