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Adrenocortical hormones
Physiology
Adrenocortical hormones
Structure of the adrenal gland
Iain Campbell
Zona reticularis (androgens)
Cortex
Zona fasciculata (glucocorticoids e.g. cortisol)
Medulla (catecholamines)
Zona glomerulosa (mineralocorticoids e.g. aldosterone)
Abstract The adrenal glands lie on top of the kidneys. The adrenal medulla produces catecholamines and the adrenal cortex produces three types of steroid hormone (mineralocorticoids (aldosterone), glucocorticoids (cortisol) and androgens (dehydroepiandrosterone, DHEA)). All are syn thesized from cholesterol. Cortisol secretion is controlled by adreno corticotrophic hormone from the pituitary. It rises in response to stress and is essential for life. It stimulates gluconeogenesis, breaking down lean tissue, and is anti-inflammatory. Aldosterone secretion is controlled by angiotensin II and extracellular potassium concentrations, so is influenced by renal perfusion. It provides the fine tuning for sodium and potassium, and thus water, balance via its action on the distal renal tubule. DHEA is a weak androgen. In the male it is unimportant; in the female DHEA produced by the adrenal gland accounts for most of the androgen in the blood.
Hormones produced by different layers given in parentheses
Figure 1
Control of adrenocorticotrophic activity The control of adrenocorticotrophic activity (Figure 2) is primarily under the influence of adrenocorticotrophic hormone (ACTH) secreted by the pituitary gland. ACTH is controlled by corticotrophic releasing hormone (CRH) from the hypothalamus. The hypothalamus in turn is influenced by inputs such as ‘stress’
Keywords adrenal cortex; endocrinology; fasciculata; glomerulosa; gluconeogenesis
The two adrenal glands sit on top of the two kidneys. They are shaped like pyramids, and measure 5 cm across. The cortex constitutes 80% of the mass of the gland and the medulla 20%. The two regions are histologically distinct and function independently in terms of the hormones secreted and their control. The cortex produces and secretes several types of steroid hormone, and the medulla produces and secretes catecholamines. The adrenal cortex is divided into three histological zones (Figure 1), each producing a different type of steroid hormone. In the outer zone (zona glomerulosa) the cells are arranged in whorls (glomeruli); they produce mineralocorticoids, which control the renal secretion of sodium and potassium, and so indirectly affect fluid balance. In the middle zone (zona fasciculata) the cells are arranged in fascicles or cords separated by venous sinuses; they produce glucocorticoids. The innermost zone (zona reticularis) is arranged in a network or reticulum and produces androgens. Throughout the adrenal cortex, but particularly in the zona fasciculata, the cells contain lipid droplets. These contain cholesterol from which the various steroid hormones are synthesized.
Control of adrenocortical activity Higher centres
–ve
Corticotrophic-releasing hormone (CRH)
–ve
Pituitary
Adrenocorticotrophic hormone (ACTH)
Adrenal cortex
Cortisol
Iain Campbell MD, FRCA, is a Consultant Anaesthetist at the University Hospitals of South Manchester and Visiting Professor of Human Physiology at Liverpool John Moores University, UK. He qualified from Guy’s Hospital Medical School, London, and trained in anaesthesia in Zimbabwe, Southend, Montreal, and Leeds.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
–ve Hypothalamus
Blood cortisol concentrations exert negative feedback on the pituitary and hypothalamus
Figure 2
420
© 2008 Elsevier Ltd. All rights reserved.
Physiology
from higher centres. ACTH stimulates growth of the cells in the adrenal cortex and synthesis of the various steroid hormones. It stimulates growth of all three zones, but its steroidogenic effects are principally on the cells of the zona fasciculata, which produce glucocorticoids. In the absence of ACTH, glucocorticoid secretion is dramatically reduced but mineralocorticoid production is reduced by only 50%. The concentration of cortisol in the blood is controlled by negative feedback to the anterior pituitary and the hypothalamus. In addition, ACTH feeds back directly to the hypothalamus, affecting CRH secretion (Figure 2).
and in general this is the rate-limiting step. The three synthetic pathways then diverge to produce the three different hormones in the three different areas of the cortex. Steroid hormones are not stored but are synthesized and secreted on demand from the store of cholesterol in the cells. Cholesterol is taken up from the blood where it is carried in the low-density lipoproteins and an increased supply of cholesterol enhances hormone synthesis. Beyond the synthesis of pregnenolone, the three zones of the adrenal cortex carry the enzymes specific to the synthesis of each hormone so that each region can synthesize only its own specific hormone.
Hormonal types
Glucocorticoids Cortisol is the principal glucocorticoid. Its secretion is predominantly under the control of ACTH from the anterior pituitary. However, there is a background level of secretion, which follows a circadian rhythm, repeating every 24 hours and related to the individual’s sleep/wake cycle. Peak concentrations in the blood occur around the time of waking, and in normal circumstances the lowest concentrations are seen around midnight. The pattern alters with shifts in the individual’s sleep/wake cycle, though with a sudden shift in activity patterns it takes several days to adjust. Cortisol also rises in response to almost any type of stress (physical or psychological), including trauma, sepsis, heavy exercise, hypoglycaemia and acute anxiety. This occurs in response to ACTH secreted by the anterior pituitary, which in
Numerous steroids are produced by the adrenal cortex but only three in significant quantities: • aldosterone (a mineralocorticoid) from the zona glomerulosa • cortisol (a glucocorticoid) from the zona fasciculata • dehydroepiandrosterone (DHEA, an androgen) from the zona reticularis. The two principal hormones are aldosterone and cortisol. DHEA is a weak androgen and is converted to testosterone in the tissues. In the male, this is relatively unimportant; however, in the female, DHEA produced by the adrenal gland accounts for most of the androgens in the blood. The hormones are all synthesized from cholesterol. Their different chemical structures are given in Figure 3. Common to all of them is the conversion of cholesterol to pregnenolone,
Structure and synthetic pathways of adrenocortical hormones Zona glomerulosa
Zona fasciculata
Zona reticularis
Cholesterol
Cholesterol
Cholesterol
Pregnenolone
Pregnenolone
Pregnenolone
Corticosterone
17-OH progesterone
17-OH pregnenolone
Aldosterone
Cortisol
Dehydroepiandrosterone
CH2OH C
CH2OH O
O
CH
HO
O
O
C
O
O
HO
The rate-limiting step for all three hormones is conversion of cholesterol to pregnenolone
Figure 3
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
421
© 2008 Elsevier Ltd. All rights reserved.
Physiology
turn is under the control of the hypothalamus and higher centres (Figure 2). ACTH is synthesized as part of a much larger molecule (pro-opiomelanocortin), so that when ACTH is released other active peptides, including β-endorphin, are released at the same time. β-Endorphin is an endogenous opioid; it increases the pain threshold and elevates the mood, which is appropriate in injury, and in the psychological response to this or any other form of ‘stress’. Cortisol has a negative feedback effect on CRH and ACTH production and decreases the sensitivity of the ACTH response to CRH (Figure 2). Cortisol is bound predominantly to the protein corticosteroid binding globulin in the blood, but also to albumin; about 5% is free in solution.
Renin–aldosterone–angiotensin relationship Liver
Kidney
Angiotensinogen
Angiotensin I
Physiological effects of glucocorticoids: glucocorticoids have a major role in responding to environmental stimuli and are essential for life. They elevate blood glucose. They stimulate gluconeogenesis via actions at a variety of sites, stimulating the enzymes involved in gluconeogenesis in the liver and increasing the activity of the urea cycle, also in the liver. Unchecked, this results in the erosion of lean tissue as amino acids are released for glucose synthesis. In addition to elevating blood glucose, the storage of glucose is enhanced, stimulating the enzymes involved in glycogen synthesis. Skeletal muscle is broken down both via suppression of muscle synthesis (from amino acids in the blood) and through an increase in the breakdown of muscle to amino acids. This results in a net transfer of amino acids into the bloodstream for hepatic and renal gluconeogenesis. Cardiac muscle is not affected. Cortisol also has an anti-insulin effect in opposing muscle glucose uptake. Glucocorticoids have a similar effect on fat stores, promoting lipid mobilization to free fatty acids and glycerol. This fat mobilization occurs predominantly in the limbs. In the presence of excess glucocorticoids, due to therapeutic steroid ingestion or Cushing’s syndrome, the limbs are typically very thin and fat is redistributed to the trunk, particularly the abdomen and the shoulders. Glucocorticoids also have a ‘permissive’ role in conjunction with the catecholamines in promoting the breakdown of fat stores and increasing the reactivity (constriction) of blood vessels to sympathetic or catecholamine stimulation. They also suppress lymphoid tissue; they are potent anti-inflammatory agents and are used therapeutically for this purpose.
Lungs
Angiotensin-converting enzyme
Angiotensin II
Zona glomerulosa
Figure 4
glomerulosa in the adrenal cortex stimulates the synthesis and release of aldosterone (Figure 4). Aldosterone release is thus ultimately dependent on renal blood flow and all the factors affecting it (e.g. sympathetic stimulation, volaemic status). In addition, the sympathetic nervous system innervates the juxtaglomerular apparatus directly and this can also affect renin secretion. Potassium: one of the actions of aldosterone on the kidney is to promote the excretion of potassium in exchange for sodium reabsorption. The cells of the zona glomerulosa are directly affected by the potassium ion. Aldosterone and the kidney are thus intimately concerned with the regulation of plasma sodium and potassium concentrations and ultimately with fluid balance (see below).
Mineralocorticoids The principal mineralocorticoid is aldosterone and the two major influences on its secretion are angiotensin II and potassium. All three are intimately bound up with the physiology of the kidney and the renin–angiotensin system. Angiotensinogen is a large protein molecule secreted by the liver (Figure 4). Renin is produced by the juxtaglomerular apparatus in the kidney in response to changes (i.e. decreases) in renal perfusion. A decrease in renal blood pressure or perfusion stimulates renin production, whereas an increase in renal perfusion inhibits it. Renin in the blood acts on angiotensinogen, resulting in the formation of angiotensin I, a ten amino acid polypeptide. This passes to the lungs, where angiotensin-converting enzyme (ACE) cleaves off two amino acids to form angiotensin II, a polypeptide with eight amino acids, which is carried to all the tissues in the body. Binding of angiotensin II to the cells of the zona
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
Renin
Physiological effects: aldosterone acts on a variety of epithelial tissues (e.g. sweat and salivary glands) and the intestine, where it promotes the excretion of potassium and the absorption of sodium. However, in terms of its effects on whole-body physiology its principal effect sites are the distal convoluted tubules and the collecting ducts of the kidney, where it fine-tunes sodium and potassium balance. In the absence of aldosterone, urinary sodium concentrations are high and urinary volumes large. In absolute terms, the amount of sodium resorption controlled by aldosterone is less than 2% of the total sodium filtered, but with 25,000 mmol passing into the renal tubule each day, a difference of 1–2% in reabsorption has a huge effect on urinary sodium excretion, on urinary volume and eventually on extracellular fluid volume. A loss of sodium of 300–400 mmol/day would lead 422
© 2008 Elsevier Ltd. All rights reserved.
Physiology
to a severe and, over a few days, a rapidly fatal depletion of the extracellular fluid volume. In addition to its effects on aldosterone, angiotensin II has a number of other physiological effects in relation to blood pressure and extracellular fluid volume. It stimulates smooth muscle contraction in blood vessels, activates thirst centres in the brain and stimulates antidiuretic hormone (ADH) release from the posterior pituitary. With its effects on sodium, potassium and fluid
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
balance this all contributes to the maintenance of fluid balance and blood pressure. ◆
Further reading Ganong WF. Review of medical physiology, 21st edn. New York: Lange Medical Books/McGraw Hill, 2003. Gard PR. Human endocrinology. London: Taylor & Francis, 1998.
423
© 2008 Elsevier Ltd. All rights reserved.
Adrenocortical hormones
Structure of the adrenal gland
Iain Campbell
Zona reticularis (androgens)
Cortex
Zona fasciculata (glucocorticoids e.g. cortisol)
Medulla (catecholamines)
Zona glomerulosa (mineralocorticoids e.g. aldosterone)
Abstract The adrenal glands lie on top of the kidneys. The adrenal medulla produces catecholamines and the adrenal cortex produces three types of steroid hormone (mineralocorticoids (aldosterone), glucocorticoids (cortisol) and androgens (dehydroepiandrosterone, DHEA)). All are syn thesized from cholesterol. Cortisol secretion is controlled by adreno corticotrophic hormone from the pituitary. It rises in response to stress and is essential for life. It stimulates gluconeogenesis, breaking down lean tissue, and is anti-inflammatory. Aldosterone secretion is controlled by angiotensin II and extracellular potassium concentrations, so is influenced by renal perfusion. It provides the fine tuning for sodium and potassium, and thus water, balance via its action on the distal renal tubule. DHEA is a weak androgen. In the male it is unimportant; in the female DHEA produced by the adrenal gland accounts for most of the androgen in the blood.
Hormones produced by different layers given in parentheses
Figure 1
Control of adrenocorticotrophic activity The control of adrenocorticotrophic activity (Figure 2) is primarily under the influence of adrenocorticotrophic hormone (ACTH) secreted by the pituitary gland. ACTH is controlled by corticotrophic releasing hormone (CRH) from the hypothalamus. The hypothalamus in turn is influenced by inputs such as ‘stress’
Keywords adrenal cortex; endocrinology; fasciculata; glomerulosa; gluconeogenesis
The two adrenal glands sit on top of the two kidneys. They are shaped like pyramids, and measure 5 cm across. The cortex constitutes 80% of the mass of the gland and the medulla 20%. The two regions are histologically distinct and function independently in terms of the hormones secreted and their control. The cortex produces and secretes several types of steroid hormone, and the medulla produces and secretes catecholamines. The adrenal cortex is divided into three histological zones (Figure 1), each producing a different type of steroid hormone. In the outer zone (zona glomerulosa) the cells are arranged in whorls (glomeruli); they produce mineralocorticoids, which control the renal secretion of sodium and potassium, and so indirectly affect fluid balance. In the middle zone (zona fasciculata) the cells are arranged in fascicles or cords separated by venous sinuses; they produce glucocorticoids. The innermost zone (zona reticularis) is arranged in a network or reticulum and produces androgens. Throughout the adrenal cortex, but particularly in the zona fasciculata, the cells contain lipid droplets. These contain cholesterol from which the various steroid hormones are synthesized.
Control of adrenocortical activity Higher centres
–ve
Corticotrophic-releasing hormone (CRH)
–ve
Pituitary
Adrenocorticotrophic hormone (ACTH)
Adrenal cortex
Cortisol
Iain Campbell MD, FRCA, is a Consultant Anaesthetist at the University Hospitals of South Manchester and Visiting Professor of Human Physiology at Liverpool John Moores University, UK. He qualified from Guy’s Hospital Medical School, London, and trained in anaesthesia in Zimbabwe, Southend, Montreal, and Leeds.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
–ve Hypothalamus
Blood cortisol concentrations exert negative feedback on the pituitary and hypothalamus
Figure 2
420
© 2008 Elsevier Ltd. All rights reserved.
Physiology
from higher centres. ACTH stimulates growth of the cells in the adrenal cortex and synthesis of the various steroid hormones. It stimulates growth of all three zones, but its steroidogenic effects are principally on the cells of the zona fasciculata, which produce glucocorticoids. In the absence of ACTH, glucocorticoid secretion is dramatically reduced but mineralocorticoid production is reduced by only 50%. The concentration of cortisol in the blood is controlled by negative feedback to the anterior pituitary and the hypothalamus. In addition, ACTH feeds back directly to the hypothalamus, affecting CRH secretion (Figure 2).
and in general this is the rate-limiting step. The three synthetic pathways then diverge to produce the three different hormones in the three different areas of the cortex. Steroid hormones are not stored but are synthesized and secreted on demand from the store of cholesterol in the cells. Cholesterol is taken up from the blood where it is carried in the low-density lipoproteins and an increased supply of cholesterol enhances hormone synthesis. Beyond the synthesis of pregnenolone, the three zones of the adrenal cortex carry the enzymes specific to the synthesis of each hormone so that each region can synthesize only its own specific hormone.
Hormonal types
Glucocorticoids Cortisol is the principal glucocorticoid. Its secretion is predominantly under the control of ACTH from the anterior pituitary. However, there is a background level of secretion, which follows a circadian rhythm, repeating every 24 hours and related to the individual’s sleep/wake cycle. Peak concentrations in the blood occur around the time of waking, and in normal circumstances the lowest concentrations are seen around midnight. The pattern alters with shifts in the individual’s sleep/wake cycle, though with a sudden shift in activity patterns it takes several days to adjust. Cortisol also rises in response to almost any type of stress (physical or psychological), including trauma, sepsis, heavy exercise, hypoglycaemia and acute anxiety. This occurs in response to ACTH secreted by the anterior pituitary, which in
Numerous steroids are produced by the adrenal cortex but only three in significant quantities: • aldosterone (a mineralocorticoid) from the zona glomerulosa • cortisol (a glucocorticoid) from the zona fasciculata • dehydroepiandrosterone (DHEA, an androgen) from the zona reticularis. The two principal hormones are aldosterone and cortisol. DHEA is a weak androgen and is converted to testosterone in the tissues. In the male, this is relatively unimportant; however, in the female, DHEA produced by the adrenal gland accounts for most of the androgens in the blood. The hormones are all synthesized from cholesterol. Their different chemical structures are given in Figure 3. Common to all of them is the conversion of cholesterol to pregnenolone,
Structure and synthetic pathways of adrenocortical hormones Zona glomerulosa
Zona fasciculata
Zona reticularis
Cholesterol
Cholesterol
Cholesterol
Pregnenolone
Pregnenolone
Pregnenolone
Corticosterone
17-OH progesterone
17-OH pregnenolone
Aldosterone
Cortisol
Dehydroepiandrosterone
CH2OH C
CH2OH O
O
CH
HO
O
O
C
O
O
HO
The rate-limiting step for all three hormones is conversion of cholesterol to pregnenolone
Figure 3
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
421
© 2008 Elsevier Ltd. All rights reserved.
Physiology
turn is under the control of the hypothalamus and higher centres (Figure 2). ACTH is synthesized as part of a much larger molecule (pro-opiomelanocortin), so that when ACTH is released other active peptides, including β-endorphin, are released at the same time. β-Endorphin is an endogenous opioid; it increases the pain threshold and elevates the mood, which is appropriate in injury, and in the psychological response to this or any other form of ‘stress’. Cortisol has a negative feedback effect on CRH and ACTH production and decreases the sensitivity of the ACTH response to CRH (Figure 2). Cortisol is bound predominantly to the protein corticosteroid binding globulin in the blood, but also to albumin; about 5% is free in solution.
Renin–aldosterone–angiotensin relationship Liver
Kidney
Angiotensinogen
Angiotensin I
Physiological effects of glucocorticoids: glucocorticoids have a major role in responding to environmental stimuli and are essential for life. They elevate blood glucose. They stimulate gluconeogenesis via actions at a variety of sites, stimulating the enzymes involved in gluconeogenesis in the liver and increasing the activity of the urea cycle, also in the liver. Unchecked, this results in the erosion of lean tissue as amino acids are released for glucose synthesis. In addition to elevating blood glucose, the storage of glucose is enhanced, stimulating the enzymes involved in glycogen synthesis. Skeletal muscle is broken down both via suppression of muscle synthesis (from amino acids in the blood) and through an increase in the breakdown of muscle to amino acids. This results in a net transfer of amino acids into the bloodstream for hepatic and renal gluconeogenesis. Cardiac muscle is not affected. Cortisol also has an anti-insulin effect in opposing muscle glucose uptake. Glucocorticoids have a similar effect on fat stores, promoting lipid mobilization to free fatty acids and glycerol. This fat mobilization occurs predominantly in the limbs. In the presence of excess glucocorticoids, due to therapeutic steroid ingestion or Cushing’s syndrome, the limbs are typically very thin and fat is redistributed to the trunk, particularly the abdomen and the shoulders. Glucocorticoids also have a ‘permissive’ role in conjunction with the catecholamines in promoting the breakdown of fat stores and increasing the reactivity (constriction) of blood vessels to sympathetic or catecholamine stimulation. They also suppress lymphoid tissue; they are potent anti-inflammatory agents and are used therapeutically for this purpose.
Lungs
Angiotensin-converting enzyme
Angiotensin II
Zona glomerulosa
Figure 4
glomerulosa in the adrenal cortex stimulates the synthesis and release of aldosterone (Figure 4). Aldosterone release is thus ultimately dependent on renal blood flow and all the factors affecting it (e.g. sympathetic stimulation, volaemic status). In addition, the sympathetic nervous system innervates the juxtaglomerular apparatus directly and this can also affect renin secretion. Potassium: one of the actions of aldosterone on the kidney is to promote the excretion of potassium in exchange for sodium reabsorption. The cells of the zona glomerulosa are directly affected by the potassium ion. Aldosterone and the kidney are thus intimately concerned with the regulation of plasma sodium and potassium concentrations and ultimately with fluid balance (see below).
Mineralocorticoids The principal mineralocorticoid is aldosterone and the two major influences on its secretion are angiotensin II and potassium. All three are intimately bound up with the physiology of the kidney and the renin–angiotensin system. Angiotensinogen is a large protein molecule secreted by the liver (Figure 4). Renin is produced by the juxtaglomerular apparatus in the kidney in response to changes (i.e. decreases) in renal perfusion. A decrease in renal blood pressure or perfusion stimulates renin production, whereas an increase in renal perfusion inhibits it. Renin in the blood acts on angiotensinogen, resulting in the formation of angiotensin I, a ten amino acid polypeptide. This passes to the lungs, where angiotensin-converting enzyme (ACE) cleaves off two amino acids to form angiotensin II, a polypeptide with eight amino acids, which is carried to all the tissues in the body. Binding of angiotensin II to the cells of the zona
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
Renin
Physiological effects: aldosterone acts on a variety of epithelial tissues (e.g. sweat and salivary glands) and the intestine, where it promotes the excretion of potassium and the absorption of sodium. However, in terms of its effects on whole-body physiology its principal effect sites are the distal convoluted tubules and the collecting ducts of the kidney, where it fine-tunes sodium and potassium balance. In the absence of aldosterone, urinary sodium concentrations are high and urinary volumes large. In absolute terms, the amount of sodium resorption controlled by aldosterone is less than 2% of the total sodium filtered, but with 25,000 mmol passing into the renal tubule each day, a difference of 1–2% in reabsorption has a huge effect on urinary sodium excretion, on urinary volume and eventually on extracellular fluid volume. A loss of sodium of 300–400 mmol/day would lead 422
© 2008 Elsevier Ltd. All rights reserved.
Physiology
to a severe and, over a few days, a rapidly fatal depletion of the extracellular fluid volume. In addition to its effects on aldosterone, angiotensin II has a number of other physiological effects in relation to blood pressure and extracellular fluid volume. It stimulates smooth muscle contraction in blood vessels, activates thirst centres in the brain and stimulates antidiuretic hormone (ADH) release from the posterior pituitary. With its effects on sodium, potassium and fluid
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
balance this all contributes to the maintenance of fluid balance and blood pressure. ◆
Further reading Ganong WF. Review of medical physiology, 21st edn. New York: Lange Medical Books/McGraw Hill, 2003. Gard PR. Human endocrinology. London: Taylor & Francis, 1998.
423
© 2008 Elsevier Ltd. All rights reserved.