Which of the following is the primary hormone for the long term regulation of sodium balance?

The endocrine system comprises glands and tissues that produce hormones for regulating and coordinating vital bodily functions. This article, the fourth in an eight-part series, looks at the adrenal glands. This article comes with a self-assessment enabling you to test your knowledge after reading it

The endocrine system consists of glands and tissues that produce and secrete hormones to regulate and coordinate vital bodily functions. This article, the fourth in an eight-part series on the endocrine system, explores the anatomy and physiology of the adrenal glands, and describes how they regulate and coordinate vital physiological processes in the body through hormonal action.

Citation: Andrade M et al (2021) Endocrine system 4: adrenal glands. Nursing Times [online]; 117: 8, 54-58.

Authors: Maria Andrade is honorary associate professor in biomedical science; Zubeyde-Bayram Weston is senior lecturer in biomedical science; John Knight is associate professor in biomedical science; all at College of Human and Health Sciences, Swansea University.

This eight-part series on the endocrine system opened with an overview of endocrine glands and the role of hormones as chemical signals that help maintain the homeostatic balance that is essential to good health. This fourth article examines the anatomy and physiology of the adrenal glands.

Anatomy

There are two adrenal (suprarenal) glands: one located immediately above each kidney (Fig 1). They are yellow to orange in colour and are positioned retroperitoneally (behind the peritoneal membrane lining the abdominal cavity). The right adrenal gland is at, approximately, the level of the 12th rib, while the left is located slightly higher between the 11th and 12th ribs (Perrier and Boger, 2005).

Normal, healthy adult adrenal glands are relatively small – they each weigh 4-6g, and are around 3cm wide, 5cm high and 1cm thick; changes in size are often indicative of underlying pathology (Lack and Paal, 2019; Westphalen and Bonnie, 2006). The right adrenal gland is usually distinctly triangular in appearance, resembling a witch’s hat, while the left is more flattened and typically crescent shaped.

The adrenals are highly vascularised, and each gland is supplied with oxygenated blood through superior, middle and inferior suprarenal arteries; deoxygenated blood is carried away from each gland via an adrenal vein (Perrier and Boger, 2005).

Internal structure

Each adrenal gland is protected by a thick collagen-rich outer capsule, with glandular tissues located beneath. The largest portion is the outer region, called the adrenal cortex, accounting for around 90% of total adrenal volume (Gorman, 2013). The adrenal cortex produces a diverse range of steroid hormones, using cholesterol as a substrate. These include the long-term stress hormone cortisol, aldosterone (regulating levels of sodium and potassium in the blood) and a group of testosterone-like hormones called androgens.

The adrenal medulla is the inner region of the adrenal gland, accounting for around 10% of adrenal volume (Gorman, 2013), and produces adrenaline (epinephrine) and noradrenaline (norepinephrine). These have diverse physiological effects, but function primarily to activate the sympathetic branch of the autonomic nervous system (ANS) and prepare the body for immediate action (VanPutte et al, 2017).

Adrenal medulla

The major cells of the adrenal medulla are called chromaffin cells because they take up stains containing chromium salts (Mubarik and Aeddula, 2021). Chromaffin cells produce amino acid-derived hormones called catecholamines.

Adrenaline and noradrenaline

The two major catecholamines are adrenaline (epinephrine) and noradrenaline (norepinephrine), which are enzymatically derived from the amino acid tyrosine. These are commonly referred to as the ‘fight-or-flight' hormones, and will be explored later in this article.

Tyrosine is a non-essential amino acid that can be obtained through diet or derived from the essential amino acid phenylalanine. Chromaffin cells continually take up tyrosine and, through the sequential actions of several enzymes, convert it into the active catecholamines L-dopa, dopamine, noradrenaline and adrenaline. Tyrosine is also taken up by the neurons in the ANS to generate noradrenaline, which functions as a key neurotransmitter in the sympathetic branch of the ANS.

In the adrenal medulla, adrenaline is the major product of catecholamine biosynthesis, accounting for around 95% of the medullary hormones released into the blood (Berends et al, 2019).

Fight-or-flight response

When we perceive a threat (for example, by a predator) or are in a potentially dangerous or exciting situation (for example, at the top of a bungee jump), adrenaline and smaller amounts of noradrenaline are usually released. The bulk of noradrenaline in the circulation is derived from the sympathetic nerve endings because the sympathetic branch of the ANS is activated in acutely stressful situations. The adrenal medulla itself is innervated with sympathetic nerve endings that, when activated, initiate the release of more adrenaline, further amplifying the fight-or-flight response (Verberne et al, 2016).

Adrenaline and noradrenaline have multiple and diverse physiological effects that prepare the body for immediate action. The most-obvious effects of the sudden release of catecholamines (adrenaline rush) primarily centre on the cardiovascular system. Adrenaline binds to beta-adrenergic receptors associated with the sinoatrial node (SAN) of the heart (Macdonald et al, 2020). The SAN functions as the heart’s natural pacemaker and adrenaline dramatically accelerates the heart rate, often way beyond the upper limit for normal resting heart rate of 100 beats per minute (bpm). This is often perceived as a notable thumping in the chest and, as cardiac output and blood pressure increase, the pulse may be perceived (without palpation) in other areas of the body, such as the neck and temples.

Adrenaline also further increases blood pressure by promoting vasoconstriction in the skin and gastrointestinal tract, hence the expression of skin turning ‘ashen with fear’ and the common sensation of ‘butterflies in the stomach’. Simultaneously, adrenaline promotes vasodilation of the arteries in the skeletal muscles and coronary circulation, diverting oxygenated blood to the major muscle groups and myocardium of the heart. Adrenaline improves oxygen uptake by dilating the airways and increasing the breathing rate, increasing blood glucose, and improving sensory perception and response times while decreasing the perception of pain (VanPutte et al, 2017). Cumulatively, this enhances musculoskeletal function, so an individual can put up an effective fight or escape any potential threat (Table 1).

The effects of adrenaline and noradrenaline are rapid and usually observed within a few seconds of release; the primary effect of adrenaline in accelerating heart rate ensures its rapid distribution throughout the body. Adrenaline is a short-acting hormone with a half life of around 2-3 minutes; it is rapidly metabolised by the liver and excreted in the urine (Electronic Medicines Compendium, 2020).

Adrenal cortex

The adrenal cortex lies immediately below the protective collagenous adrenal capsule and continually takes up cholesterol as the substrate to generate a diverse range of steroid hormones. Histologically, the cortex consists of three distinct layers of tissue, each producing its own class of steroid hormones:

• Zona glomerulosa (outer layer) – synthesises mineralocorticoids that help regulate electrolyte concentrations;
• Zona fasciculata (middle layer) – synthesises glucocorticoids that primarily function as long-term stress hormones;
• Zona reticularis (inner layer) – marks the boundary between the cortex and the medulla, producing a class of testosterone-like hormones called androgens.

Aldosterone

As their name suggests, the mineralocorticoid hormones produced by the zona glomerulosa regulate plasma concentrations of minerals/salts (electrolytes). The most important mineralocorticoid in humans is aldosterone, which regulates blood concentrations of ionic sodium (Na+) and ionic potassium (K+).

Na+ and K+ ions are essential for maintaining membrane potentials and generating nerve impulses (action potentials), so need tight regulation in the extracellular and intracellular fluids. To help this balance, many cells have an active transport mechanism called the sodium-potassium pump, which uses membrane transporter proteins to pump K+ ions into cells while pumping out Na+ ions (VanPutte et al, 2017). This ensures most Na+ ions are found in the extracellular fluids, with large amounts accumulating in the blood plasma, while most K+ ions are concentrated in the intracellular fluid.

Although this mechanism ensures the correct distribution of Na+ and K+ between the intracellular and extracellular compartments of the body, it is aldosterone that fine tunes the plasma concentration of Na+ and K+. In health, the normal plasma concentration of Na+ is maintained at 135-145mmol/l, while the activity of the sodium potassium pump keeps plasma concentration of K+ much lower at 3.5-5.0mmol/l (Justice et al, 2019).

Aldosterone is released in response to hyponatraemia (low blood sodium), most commonly due to a lack of Na+ in the diet or Na+ loss through sweating. Aldosterone increases and normalises plasma Na+ concentrations by several mechanisms:

• Enhancing the reabsorption of Na+ into the blood from the renal filtrate at the distal convoluted tubule and collecting duct of kidney nephrons;
• Promoting salt cravings to encourage the intake of sodium-rich foods;
• Enhancing Na+ reabsorption into the colon;
• Reducing loss of Na+ in sweat, saliva and pancreatic juice (Byrd et al, 2018; VanPutte et al, 2017).

Conversely, aldosterone secretion reduces in response to hypernatriemia (high blood sodium), such as following a salty meal, allowing elimination of excess Na+ in the urine, sweat and faeces.

Blood pressure regulation
The primary stimulus for aldosterone release is the activation of the renin angiotensin aldosterone system (RAAS) (Byrd et al, 2018). The RAAS is the most important physiological mechanism for medium to long-term control of blood pressure and is centred around a plasma protein called angiotensinogen, produced by the liver (Atlas, 2007).

When the kidneys detect a drop in blood pressure, they produce the enzyme renin, which converts angiotensinogen into an inactive protein called angiotensin I. This circulates in the plasma until it reaches the lung tissue, where angiotensin-converting enzymes (ACE) convert it into biologically active angiotensin II. This primarily functions as a vasoconstrictor, helping to restore blood pressure while simultaneously stimulating the release of aldosterone from the adrenal cortex.

Aldosterone promotes the reabsorption of Na+ in the kidney, thereby increasing plasma Na+ concentration (Fig 2). This encourages the movement of water from the tissues into the blood vessels by osmosis, thereby increasing blood volume and blood pressure.

Hyperkalaemia and hypokalaemia
Aldosterone also regulates concentration of plasma K+ ions and is released in response to hyperkalaemia (high blood potassium), most commonly following consumption of potassium-rich foods or food supplements, such as bananas or low-sodium salt replacements containing potassium chloride. Hyperkalaemia can also follow major physical injury causing disruption of cell membranes (for example, a burn), leading to the release of large amounts of intracellular potassium that have accumulated via the Na+ K+ pump (Ookuma et al, 2015).

Severe hyperkalaemia requires urgent assessment, as it can interfere with the electrical conductive tissues of the heart, leading to dangerous ventricular arrhythmias and, potentially, cardiac arrest (Weiss et al, 2017). Aldosterone reduces and normalises the blood–potassium concentration, primarily by promoting the excretion of K+ ions into the kidney nephrons for elimination in the urine.

Hypokalaemia (low blood potassium) can result from a lack of potassium in the diet or a side-effect of some diuretic medications. Diuretics such as furosemide are used to reduce oedema and treat high blood pressure by eliminating excess fluids and blood volume through increasing urine output; however, this can lead to significant flushing out of K+. Hypokalaemia inhibits aldosterone secretion, reducing the secretion of K+ in the renal filtrate and causing the retention of K+ in the blood.

Newer forms of potassium-sparing diuretics are available, such as amiloride or triamterene, which increase urine output with minimal loss of K+.

Primary aldosteronism
Primary aldosteronism (PA, also known as Conn’s syndrome) is a condition that is most often caused by benign enlargement (hyperplasia) of the adrenal glands or by tumours in the adrenal cortex. It leads to excess secretion of aldosterone, causing hypernatraemia, which increases blood volume and blood pressure. Around 5-10% of cases of hypertension are thought to be caused by PA (Young, 2019).

Patients with PA also usually show hypokalaemia as increased aldosterone promotes the rapid secretion of potassium in the urine. Other signs and symptoms include water retention and neurological/psychological symptoms, including anxiety, demoralisation, stress, depression and nervousness. When PA is caused by tumours, surgery is usually the treatment of choice; excess aldosterone secretion caused by adrenal hyperplasia is usually treated using aldosterone-blocking drugs (Young, 2019).

Androgens

The zona reticularis secretes small amounts of hormones called androgens, which are structurally similar to the male sex hormone, testosterone. Like testosterone, these hormones function as anabolic steroids of varying potency and promote the development of male physical characteristics such as increased muscle mass, growth of body and facial hair, and deepening of the voice. In females, androgens play key roles in the functioning of the musculoskeletal system, heighten libido and form intermediates for the biosynthesis of oestrogens (Handelsman, 2020).

Androgens, including synthetically produced testosterone, are of clinical use in people physically transitioning from female to trans male, as they help ensure a match between gender identity and physical body (gender congruence). Such masculinising hormone therapy, also known as gender-affirming hormone therapy, helps to block the activity of female sex hormones, such as oestrogens, and suppress the normal menstrual cycle.

Adrenal androgens are secreted by both males and females, but their physiological effects in males tend to be diluted by the presence of testosterone produced by the testes. Hypersecretion of androgens is termed hyperandrogenism and, in early life, can lead to premature (precocious) puberty in boys; in cisgender females, it can lead to potentially unwanted masculine patterns of hair growth and a disrupted menstrual cycle (Utriainen et al, 2015).

Glucocorticoids

The zona fasciculata secretes the glucocorticoid hormones. The most important glucocorticoid in humans is cortisol, which functions as a long-term stress hormone. Long-term stressors, such as physical injury, starvation or emotional stress, activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of cortisol. As implied by their name, glucocorticoid hormones influence the blood–glucose concentration; they work with many other hormones, including insulin and glucagon, to maintain glucose homeostasis (Kuo et al, 2015).

Cortisol release promotes a rise in blood–glucose concentration. This occurs because cortisol stimulates the breakdown of fat and protein, converting amino acid residues and the glycerol portion of fat into glucose; this biochemical process is called gluconeogenesis (literally: the creation of new glucose). Gluconeogenesis allows for blood–glucose concentrations to be maintained when food supplies are limited and increased blood glucose provides a valuable energy resource for tissue repair after physical injury.

Cortisol also influences the sleep/wake cycle, mood and behaviour, and has a variety of immunosupressant properties (Kandhalu, 2013). In terms of immune modulation, it is a powerful natural anti-inflammatory molecule that helps limit and control the inflammatory response. Powerful steroidal anti-inflammatory medications, such as hydrocortisone creams commonly used to treat inflammatory skin conditions, mimic the effects of cortisol (Fleischer et al, 2017). Recently dexamethasone (another cortisol-like drug) has been shown to improve survival in patients with severe Covid-19 infection, primarily by reducing inflammation and preventing over-reaction of the immune system (Johnson and Vinetz, 2020).

HPA axis

Cortisol release is tightly regulated by homeostatic mechanisms that rely on negative feedback. As seen in part 2 of this series, the hypothalamus is a vital region of the brain that acts as a crossover point between the nervous system and the endocrine system. During periods of chronic stress (both physical and emotional), the hypothalamus releases corticotropin-releasing hormone (CRH). CRH is delivered to the anteror pituitary in the hypothalamic-pituitary portal circulation, where it initiates the release of adrenocorticotropic hormone (ACTH).

ACTH circulates systemically and stimulates the release of cortisol from the adrenal cortex. As cortisol is important in regulating metabolism and influences a variety of immune and behavioural responses, the hypothalamus continually monitors the plasma–cortisol concentration. When levels of cortisol rise, the hypothalamus responds by reducing CRH secretion; this decreases the release of ACTH and, ultimately, cortisol secretion (Fig 3).

The HPA axis also influences the release of aldosterone and androgens, although the exact mechanisms are poorly understood (Gallo-Payet, 2016).

Cushing’s syndrome

Cushing’s syndrome (CS) or hypercortisolism is characterised by increased secretion of cortisol. It is more prevalent in women than men and, although it can occur at any age, is most commonly detected at 30-40 years. It is relatively rare, with a reported incidence of around 1 in 200,000, but appears to be becoming more common. Most cases of CS are caused by benign pituitary tumours leading to excess secretion of ACTH, which increases secretion of cortisol from the zona fasiculata. More rarely, hypersecretion of cortisol may be caused by adrenal tumours, this uncommon form is referred to as adrenal Cushing’s (Pappachan et al, 2017).

An excess of cortisol results in major physiological changes that are characteristic of CS. As cortisol is a glucocorticoid that promotes gluconeogenesis, glucose concentration typically increases, leading to hyperglycaemia; this is associated with lipolysis (breakdown of fats) and increased protein catabolism (breakdown), which can lead to muscle wastage and thin, stick-like arms and legs.

A major characteristic of CS is abnormal fat distribution, with increased central-trunk obesity leading to large accumulations of abdominal fat, increased fat around the face (moon face) and possible prominent fat between the shoulder blades (buffalo hump). Excess cortisol is also associated with a thinning of the skin, causing it to bruise easily, and prominent striae (stretch marks), particularly in areas of rapid fat deposition, such as the abdomen. Other common symptoms are fatigue, poor concentration and memory, decreased libido and loss of bone density, potentially leading to osteoporosis (Nieman et al, 2008). How to treat CS depends on the cause but surgical excision of tumours at the pituitary or adrenal glands is usually the treatment of choice.

Addison’s disease

Addison’s disease (AD) affects around 1 in 10,000 people and is characterised by the reduced secretion of hormones from the adrenal cortex. It is usually associated with depletion in all three categories of adrenal steroid hormones (mineralocorticoids, glucocorticoids and androgens). There are many known causes of AD, with autoimmune destruction of the tissues of the adrenal cortex the most common in developed countries (Michels and Michels, 2014). The depletion of aldosterone and cortisol after damage to the zona glomerulosa and zona fasiculata precipitates many of the symptoms associated with AD.

AD onset is usually insidious and often goes unrecognised for long periods. Symptoms are incredibly diverse, hindering diagnosis, particularly in the disease’s early stages. As the reduced secretion of the hormones of the adrenal cortex will activate the HPA axis, AD is usually associated with increased levels of ACTH. Part 2 of this series highlighted that ACTH is structurally similar to melanocyte-stimulating hormone, which can lead to hyperpigmentation in areas of skin – a common feature of AD. The most common symptoms can usually be traced back to a lack of aldosterone, cortisol or both as highlighted below:

• Lethargy, drowsiness and overwhelming exhaustion – lack of cortisol and aldosterone;
• Loss of appetite, nausea and unintentional weight loss – lack of cortisol and aldosterone;
• Hypotension and postural hypotension – lack of aldosterone;
• Hyperpigmentation, leading to dark patches of skin – increased ACTH;
• Hypoglycaemia – lack of cortisol;
• Hyponatraemia and hyperkalaemia – lack of aldosterone;
• Muscle weakness and cramping – lack of aldosterone;
• Poluria and increased thirst – lack of aldosterone;
• Low mood or irritability – lack of cortisol and aldosterone;
• Increased thirst – lack of aldosterone.

Treatment and management of AD is usually achieved through life-long synthetic hormone replacement therapy with glucocorticoids (cortisone or hydrocortisone) and mineralocorticoids (fludrocortisone) (Bornstein et al, 2016).

Severe deficiency of aldosterone and cortisol can be life-threatening and lead to a medical emergency termed an adrenal crisis. This is characterised by some or all of the following symptoms:

• Rapid shallow breathing;
• Severe dehydration;
• Sweating;
• Pale, cold, clammy skin;
• Dizziness;
• Hypotension;
• Severe vomiting and diarrhoea;
• Abdominal pain or pain in the side;
• Fatigue and severe muscle weakness;
• Headache;
• Severe drowsiness or loss of consciousness.

Unless treated quickly, adrenal crisis can lead to convulsions, coma and death; it is usually treated with intravenous hydrocortisone (Bornstein et al, 2016).

Conclusion

This article has explored the anatomy, physiology and function of the adrenal glands. Part 5 will focus on the pineal and thymus glands.

Key points

• There are two adrenal glands: one located above each kidney
• Adrenal glands consist of two parts, the cortex and the medulla, which each produce different hormones
• The adrenal cortex produces a diverse range of steroid hormones, using cholesterol as a substrate
• The main hormones produced by the medulla are the ‘flight or fight’ hormones adrenaline and noradrenaline

Also in this series

• Test your knowledge with Nursing Times Self-assessment after reading this article. If you score 80% or more, you will receive a personalised certificate that you can download and store in your NT Portfolio as CPD or revalidation evidence.
• Take the Nursing Times Self-assessment for this article

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