Adrenal Gland Physiology Flashcards
Anatomy of Adrenal Cortex
(and physiology
a. The adrenal glands are located at the upper poles of the kidney and have two major divisions, the medulla and the cortex.
b. The cortex secretes steroid hormones that are referred to as mineralocorticoids, glucocorticoids and sex steroids.
i. We will focus on the steroid hormones that are glucocorticoids—>essential for life and necessary for responding to both acute and chronic stress.
ii. Mineralocorticoids, mainly aldosterone, act in the maintenance of salt balance.
iii. The most important sex steroids secreted by the adrenals are weak androgens (e.g., dehydroepiandrosterone-sulfate, DHEA-S).
c. The cortex is organized anatomically in three distinct zones but functionally as two.
i. The outer most is the Zona glomerulosa, which produces aldosterone.
ii. The middle one is the Zona fasciculata, which is the major producer of cortisol (the most important glucocorticoid made by the adrenals in humans).
iii. The inner most one is the Zona reticularis which is the major producer of adrenal androgens.
* The latter two zones function more as a unit.
The adrenal cortex is organized anatomically in three distinct zones but functionally as two.
a. The outer most is the Zona glomerulosa, which produces aldosterone.
b. The middle one is the Zona fasciculata, which is the major producer of cortisol (the most important glucocorticoid made by the adrenals in humans).
c. The inner most one is the Zona reticularis which is the major producer of adrenal androgens.
* The latter two zones function more as a unit.
Steroidogenesis
Large Summary
a. Cholesterol is the precursor of the adrenal hormones.
i. It is derived from circulating LDL (low-density lipoproteins)
ii. LDLs are rich in cholesterol.
b. Once inside the cell the cholesterol is removed, esterified and stored in this form in lipid droplets.
i. The cortex also has the ability to synthesize cholesterol from acetyl-CoA, but this is not the major source of cholesterol.
c. Thus, the most common first step in steroid hormone synthesis is the release of cholesterol from lipid droplets by removal of the esters.
d. The subsequent steps in steroid hormone synthesis occur within either the mitochondria or endoplasmic reticulum.
i. The rate-limiting step requires mitochondrial enzymes - the cytochrome P-450 enzymes or 20, 22 desmolase.
ii. Pregnenolone is the product of this reaction.
e. Why are the primary hormones secreted by each zone of the cortex different? After all, the rate-limiting reaction is the formation of pregnenolone, which occurs throughout the cortex.
i. However, other biosynthetic enzymes involved in steroid hormone synthesis have different activities in each zone.
ii. For example, the Zona glomerulosa lacks the enzyme 17α-hydroxylase and hence cannot make glucocorticoids or the sex steroids.
iii. Likewise, in the inner zone, critical enzymes (e.g., 11β-hydroxylase) required for cortisol synthesis have high activity.
Why are the primary hormones secreted by each zone of the cortex different? After all, the rate-limiting reaction is the formation of pregnenolone, which occurs throughout the cortex.
a. However, other biosynthetic enzymes involved in steroid hormone synthesis have different activities in each zone.
b. For example, the Zona glomerulosa lacks the enzyme 17α-hydroxylase and hence cannot make glucocorticoids or the sex steroids.
c. Likewise, in the inner zone, critical enzymes (e.g., 11β-hydroxylase) required for cortisol synthesis have high activity.
Steroidogenesis steps for Hormone production in the Adrenal Cortex
- the most common first step in steroid hormone synthesis is the release of cholesterol from lipid droplets by removal of the esters.
i. Get cholesterol from LDL–> Once inside the cell the cholesterol is removed, esterified and stored in this form in lipid droplets. - The subsequent steps in steroid hormone synthesis occur within either the mitochondria or endoplasmic reticulum. Will create Pregnenolone, which can become different hormones based on the adrenal cortex region
i. The rate-limiting step requires mitochondrial enzymes - the cytochrome P-450 enzymes or 20, 22 desmolase.
ii. Pregnenolone is the product of this reaction. - Other biosynthetic enzymes involved in steroid hormone synthesis have different activities in each zone.
ii. For example, the Zona glomerulosa lacks the enzyme 17α-hydroxylase and hence cannot make glucocorticoids or the sex steroids.
iii. Likewise, in the inner zone, critical enzymes (e.g., 11β-hydroxylase) required for cortisol synthesis have high activity.
Congenital deficiencies (complete and partial) of several adrenal enzymes exist.
a. Normal biosynthetic pathways are suppressed and precursors build up or other products are produced in excess.
b. The most common defect involves the enzyme, 21-hydroxylase, which is required for the conversion of 17-hydroxyprogesterone and progesterone to the precursors of cortisol and aldosterone, 11-deoxycortisol and 11-deoxycorticosterone, respectively.
i. Defects in other biosynthetic enzymes exist but are less common.
c. When 21-hydroxylase is defective, neither cortisol nor ALDO are synthesized; levels of adrenal androgens are increased.
i. Some of the consequences of this deficiency are due to effects of ACTH regulation of cortical function as well as to ACTH itself, which we will discuss later in this lecture.
Gluococorticoid- Cortisol
a. The most important glucocorticoid, Cortisol, has ketones at carbons 3 and 20 and hydroxyls on carbons 11, 17 and 21
i. Cortisol is secreted at a rate of 8-25 mg/day and has a plasma concentration of 40-180 µg/100 ml.
b. Just as with most hormones, the plasma levels of cortisol vary with the time of day and in response to various stimuli.
c. Cortisol circulates primarily (90%) bound to proteins.
i. Only 10% circulates in a free form
ii. Of the 90% that is bound, 75% is bound to cortisol binding globulin (CBG) and 15% is bound to albumin.
d. As discussed previously, the free form of hormones is the active form, although it is in equilibrium with the bound form.
e. Protein binding increases the plasma concentration of hormone, prevents its excretion by the kidney, prolongs its half-life and serves as a reservoir of extra hormone.
i. If the binding protein is elevated, the total concentration of hormone in the plasma is elevated but the biological activity of the hormone is unchanged, because it is the concentration of free hormone (set point) that is regulated.
Actions of Glucocorticoids
Large summary
a. At physiological levels, important actions of glucocorticoids involve glucose mobilization.
b. Two mechanisms are involved: a stimulation of gluconeogenesis in the liver and increased proteolysis in muscle and other soft tissues providing amino acid substrates for gluconeogenesis.
c. Cortisol is of great significance in maintaining or elevating blood glucose in times of stress.
i. However, its strong catabolic actions mean that glucocorticoids have severe detrimental effects in situations where they are maintained at high levels for prolonged periods.
ii. Muscle weakness is a hallmark of this condition.
iii. Other consequences of cortisol’s catabolic actions include thinning of the skin and increased capillary fragility leading to easy bruising.
iv. High concentrations of cortisol appear to interfere with calcium absorption and/or bone formation, so that osteoporosis and bone fractures are a common side effect of cortisol excess.
d. Although the direct actions of glucocorticoids seem to facilitate lipolysis, their overall effects on lipid metabolism are complex.
i. High doses lead to deposition of adipose tissue on the trunk, abdomen, face, and mobilization from the extremities.
e. Other effects of glucocorticoids are facilitation of excretion of a water load (this occurs due to cortisol’s ability to inhibit ADH function) and increased gastric acid secretion.
f. In addition, cortisol has a paracrine effect on the adrenal medulla and stimulates the synthesis and activity of phenyl-N-methyl Transferase (PNMT) thus increasing the production of epinephrine from norepinephrine.
g. High doses of glucocorticoids have significant anti-inflammatory effects and they are used as treatment when the inflammatory process is life threatening.
i. At these doses, they also act as immunosuppressants and induce all of the phenotypic, metabolic sequelae of hypercortisolism (Cushing’s disease).
High Cortisol (high glucocorticoid)
How the body is affected
a. Cortisol is of great significance in maintaining or elevating blood glucose in times of stress.
b. Two mechanisms are involved: a stimulation of gluconeogenesis in the liver and increased proteolysis in muscle and other soft tissues providing amino acid substrates for gluconeogenesis.
c. Cortisol is of great significance in maintaining or elevating blood glucose in times of stress.
d. However, its strong catabolic actions mean that glucocorticoids have severe detrimental effects in situations where they are maintained at high levels for prolonged periods.
1) Muscle weakness is a hallmark of this condition.
2) Other consequences of cortisol’s catabolic actions include thinning of the skin and increased capillary fragility leading to easy bruising.
3) High concentrations of cortisol appear to interfere with calcium absorption and/or bone formation, so that osteoporosis and bone fractures are a common side effect of cortisol excess.
Negative componenets of high Cortisol
However, its strong catabolic actions mean that glucocorticoids have severe detrimental effects in situations where they are maintained at high levels for prolonged periods.
1) Muscle weakness is a hallmark of this condition.
2) Other consequences of cortisol’s catabolic actions include thinning of the skin and increased capillary fragility leading to easy bruising.
3) High concentrations of cortisol appear to interfere with calcium absorption and/or bone formation, so that osteoporosis and bone fractures are a common side effect of cortisol excess.
Glucocorticoids as Anti-inflammatory
Cortisol as an example
a. High doses of glucocorticoids have significant anti-inflammatory effects and they are used as treatment when the inflammatory process is life threatening.
b. At these doses, they also act as immunosuppressants and induce all of the phenotypic, metabolic sequelae of hypercortisolism (Cushing’s disease).
c. Synthetic glucocorticoids used clinically include the powerful dexamethasone, and milder prednisone and triamcinolone.
i. Hydrocortisone and prednisone also have considerable mineralocorticoid potency and can be used in cases of
d. Addison’s disease where both gluococorticoid and mineralocorticoid secretions are compromised.
Summary of Glucocorticoid (Cortisol) effect on the body system
a. At physiological levels, important actions of glucocorticoids involve glucose mobilization.
i. Two mechanisms are involved: a stimulation of gluconeogenesis in the liver and increased proteolysis in muscle and other soft tissues providing amino acid substrates for gluconeogenesis.
b. Although the direct actions of glucocorticoids seem to facilitate lipolysis, their overall effects on lipid metabolism are complex.
i. High doses lead to deposition of adipose tissue on the trunk, abdomen, face, and mobilization from the extremities.
c. Other effects of glucocorticoids are facilitation of excretion of a water load (this occurs due to cortisol’s ability to inhibit ADH function) and increased gastric acid secretion.
d. In addition, cortisol has a paracrine effect on the adrenal medulla and stimulates the synthesis and activity of phenyl-N-methyl Transferase (PNMT) thus increasing the production of epinephrine from norepinephrine.
e. High doses of glucocorticoids have significant anti-inflammatory effects and they are used as treatment when the inflammatory process is life threatening.
i. At these doses, they also act as
Glucocorticoid (Cortisol) effect on lipids, water, and Ne/Epi
a. Although the direct actions of glucocorticoids seem to facilitate lipolysis, their overall effects on lipid metabolism are complex.
i. High doses lead to deposition of adipose tissue on the trunk, abdomen, face, and mobilization from the extremities.
b. Other effects of glucocorticoids are facilitation of excretion of a water load (this occurs due to cortisol’s ability to inhibit ADH function) and increased gastric acid secretion.
c. In addition, cortisol has a paracrine effect on the adrenal medulla and stimulates the synthesis and activity of phenyl-N-methyl Transferase (PNMT) thus increasing the production of epinephrine from norepinephrine.
Regulation of cortisol secretion
Large Summary
a. Cortisol secretion is regulated by a negative feedback loop through the hypothalamo-pituitary axis.
b. The hypothalamus secretes CRH, which acts on the anterior pituitary to stimulate the release of ACTH.
i. CRH binds to receptors on corticotrophs, thereby activating adenylate cyclase.
ii. Secretion of ACTH occurs in a calcium-dependent manner; POMC gene transcription is also activated.
c. ACTH in turn interacts with receptors on the cells of the Zona fasciculata and reticularis to promote secretion of cortisol.
c. ACTH has several actions, which lead to increased cortisol secretion.
i. In the cortex, ACTH leads to elevated cAMP levels, which in turn increase the rate of synthesis of pregnenolone.
ii. LDL uptake is also enhanced, as is hydrolysis of stored cholesterol esters and transport of cholesterol into mitochondria.
d. Plasma free cortisol feeds back on the hypothalamus and the pituitary to inhibit CRH and ACTH secretion, completing the negative feedback loop.
i. The negative feed-back can be overridden by the effects of stress, which can produce up to a 40-fold increase in cortisol secretion.
Negative Feedback Loop of Cortisol
a. Plasma free cortisol feeds back on the hypothalamus and the pituitary to inhibit CRH and ACTH secretion, completing the negative feedback loop.
b. There is also evidence that ACTH can inhibit its own secretion. This entire mechanism is subject to considerable variation.
c. In particular, there is a daily rhythm or diurnal variation in cortisol secretion that results in cortisol being elevated about the time of waking in the morning and falling to a low level at about the onset of sleep.
i. This rhythm may be entrained by light and dark cycles, but tends to vary in individuals who habitually work at night and sleep during the day.
ii. It takes some time to alter the cycles, which may explain the sensation of “jet lag”.
d. The negative feed-back can be overridden by the effects of stress, which can produce up to a 40-fold increase in cortisol secretion.
i. Individuals who are not able to respond to stress with increased cortisol secretion have increased morbidity.
e. Stress of various forms stimulates secretion of CRH and thus ACTH and cortisol.
i. Stress can be physical in nature such as pain, trauma or cold exposure.
ii. Emotional stress is another stimulant.
iii. Stress due to exposure to specific chemicals is also effective.
Adrenal Androgens
Handout summary
a. Adrenal androgens generally vary with the secretion of cortisol and appear to be stimulated by ACTH.
b. However, there is a large increase in adrenal androgen secretion at puberty (adrenarche).
i. This increase occurs in both females and males.
c. Adrenal androgens are less potent than ones made in the male gonads.
d. However, in females, adrenal secretion of androgens is the major source of hormone with androgen like activity.
i. Thus, in females, they are important for libido and growth of pubertal hair, processes that require androgens
Mineralcorticoid Summary
Regulation of aldosterone secretion:
a. Aldosterone is regulated by the renin-angiotensin system.
i. It is only minimally influenced by ACTH.
b. Renin is secreted by the juxtaglomerular apparatus of the kidney in response to a decrease in plasma volume or sodium.
i. It also responds to diminished blood pressure, receiving signals from the sympathetic nervous system.
c. Renin converts circulating angiotensinogen to angiotensin I, which in turn is degraded to angiotensin II.
i. Angiotensin II is the major stimulus for aldosterone secretion.
d. Angiotensin II is also a powerful pressor agent. The adrenal also responds to high plasma potassium with an increase in aldosterone secretion.
i. Long-term elevation of angiotensin may lead to hypertrophy of the glomerulosa region of the adrenal cortex.
e. Aldosterone actions:
i. The major action of aldosterone is to stimulate sodium absorption, potassium, and hydrogen ion excretion in the renal tubule.
ii. It has similar effects on sweat glands, sparing sodium in chronically hot, humid environments. These actions maintain or increase blood volume.
Angiotensin II and Aldosterone Actions
a. Angiotensin II is the major stimulus for aldosterone secretion.
b. Angiotensin II is also a powerful pressor agent. The adrenal also responds to high plasma potassium with an increase in aldosterone secretion.
i. Long-term elevation of angiotensin may lead to hypertrophy of the glomerulosa region of the adrenal cortex.
c. Aldosterone actions:
i. The major action of aldosterone is to stimulate sodium absorption, potassium, and hydrogen ion excretion in the renal tubule.
ii. It has similar effects on sweat glands, sparing sodium in chronically hot, humid environments.
iii. These actions maintain or increase blood volume.
Regulation of aldosterone secretion:
a. Aldosterone is regulated by the renin-angiotensin system.
i. It is only minimally influenced by ACTH.
b. Renin is secreted by the juxtaglomerular apparatus of the kidney in response to a decrease in plasma volume or sodium.
i. It also responds to diminished blood pressure, receiving signals from the sympathetic nervous system.
c. Renin converts circulating angiotensinogen to angiotensin I, which in turn is degraded to angiotensin II.
i. Angiotensin II is the major stimulus for aldosterone secretion.
Metabolism of Steroid Hormones
a. Cortisol has a plasma half-life of 60-70 minutes, while aldosterone is metabolized more quickly, having a half-life of ~ 20 minutes.
b. Important points about degradation of steroid hormones include that they undergo reactions in the liver that tend to both reduce their activity and increase their water solubility.
c. The metabolites are then excreted in the urine providing a convenient medium for assessing their secretion.
Primary adrenal insufficiency, Addison’s disease:
a. This rare condition results from an infectious process (e.g., tuberculosis, fungal disorders, autoimmune response) that wipes out the entire adrenal cortex.
b. It is life threatening and both mineralocorticoid and glucocorticoid secretion is deficient.
c. Symptoms include weakness, weight loss, hyponatremia, hyperkalemia, GI problems.
d. ACTH is not subjected to negative feedback and it is elevated leading to hyperpigmentation.
e. Glucocorticoid and mineralocorticoid activities must be replaced.
