The adrenal glands are important for our energy, health, and mood.

The adrenal glands are small glands located on top of the kidneys and play a large role in hormone production. The hormones that are produced and released from the adrenal glands regulate multiple processes in the body including metabolism, the immune system, blood pressure, and stress response. Thus these small glands have big impact on our health.

Adrenal Gland Structure and Function

The adrenal glands consist of two regions: an outer region called the cortex and an inner region called the medulla. The cortex is further divided into three regions; zona glomerulosa, zona fasciculata and zona reticularis. Each zone releases different hormones. The whole gland is covered by a protective adipose capsule.

The adrenal cortex release three types of hormones:

• Mineralocorticoids (aldosterone to preserve salt in the body)
• Glucocorticoids (cortisol the stress hormone which has impact on glucose and illness)
• Androgens (male sex hormones dehydroepiandrosterone DHEA and testosterone)

The adrenal medulla produces the stress hormones

• Epinephrine (adrenaline and the fight-or-flight body response)
• Norepinephrine (noradrenaline and the fight-or-flight body response)

Cortisol

Cortisol is a steroid hormone belonging to the corticosteroid class known as glucocorticoids. It is produced and secreted by the adrenal gland and is involved in a variety of functions including the stress response, immune response, inflammation and carbohydrate metabolism. Although cortisol is involved in a variety of functions, it is best known as the stress hormone.

Cortisol is synthesized by the zona fasciculata and helps regulate:

• Metabolism of fat, proteins and carbs
• Suppresses immune system inflammation
• Regulates blood pressure and heart function
• Increase blood sugar through balancing of insulin effects
• Decrease bone formation
• Sleep cycle

Aldosterone

Aldosterone is a mineralocorticoid produced by the zona glomerulosa. This hormone regulates blood pressure and blood pH by altering levels of electrolytes sodium and potassium. Aldosterone signals the kidneys to alter uptake of sodium from the bloodstream and release of potassium into the urine.

DHEA and Androgenic Steroids

DHEA and Androgenic steroids are male hormones that can be converted into stronger female hormones (estrogen) in the ovaries or male hormones (androgens) in the testes.

Adrenaline and Noradrenaline

Adrenaline (also known as epinephrine) and Noradrenaline (also called norepinephrine) are the hormones that regulate the fight or flight response. These hormones regulate changes in heart rate and contraction, blood flow to the brain and muscles, airway muscle contraction, blood vessel restriction and blood pressure in response to stressful situations.

How the adrenal glands produce hormones

The adrenal gland is part of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is a system that regulates several bodily responses and processes such as stress response, digestion, and energy expenditure. The cycle often begins with a region in the brain called the hypothalamus.

The hypothalamus produces and releases hormones vasopressin and corticotropin-releasing hormone (CRH) into the bloodstream. These hormones then stimulate the pituitary gland, a gland in the brain that produces and releases hormones to regulate other hormone producing glands. CRH promotes the production and release of the adrenocorticotropic hormone (ACTH) in the pituitary gland. ACTH then stimulates production of glucocorticoid hormones like cortisol in the adrenal glands. The glucocorticoids then act on the hypothalamus and the pituitary gland to reduce production of CRH and ACTH.

What is Adrenal Fatigue?

Adrenal fatigue is a controversial condition in which several symptoms arise in response to insufficient functioning of the adrenal gland caused by intense stress, usually after a severe infection, excessive exercise, or emotional stress. Adrenal fatigue was coined by naturopath James Wilson, PhD in 1998.

Adrenal fatigue is thought to occur when the adrenal gland becomes overworked due to prolonged stress on in the gland. In this case the adrenals are no longer able to produce the hormones, specifically norepinephrine, DHEA, and cortisol, needed to fight against the stress and these hormones will show low on blood tests.

Testing for Adrenal Fatigue

While there is no specific protocol for testing for adrenal fatigue, many will measure cortisol levels first. In this case, lower than normal levels of cortisol indicate adrenal fatigue.

Hormones continuously fluctuate depending on multiple factors such as time of day and month and levels of other interacting hormones. Cortisol levels can be tested through blood, urine or saliva. The urine test being the most accurate. Because the level of other hormones can impact cortisol levels, the level of other hormones may also be measured. Such interacting hormones include the thyroid stimulating hormone (TSH), Free triiodothyronineT3 (FT3) and T4 (FT4), ACTH and DHEA.

Adrenal Fatigue Symptoms

Symptoms of adrenal fatigue can vary greatly, symptoms often include:

• Chronic fatigue
• Muscle weakness
• Loss of appetite
• Weight loss
• Low blood pressure (hypertension0
• Abdominal pain
• Nausea
• Diarrhea
• Autoimmune complications
• Body aches
• Lightheadedness
• Loss of body hair
• Depression
• Irritability
• Salt cravings
• Low blood sugar
• Dry skin
• Trouble falling asleep
• Difficulty waking up
• Craving sugar
• Dependence on caffeine and/or other stimulants
• Digestive issues
• Mood swings
• Brain fog
• Lack of motivation

Treatment of adrenal fatigue

Those thought to have adrenal fatigue are often recommended treatment with a diet low in sugar, caffeine, and processed food. It is also recommended that individuals take supplemental vitamins and minerals such as vitamins B5, B6, B12, C and magnesium. Many will be advised to reduce the amount and intensity of their exercise program if they are chronic cardio advocates, marathon runners, or extreme sport participants. This does not mean to stop working out, it just means switching to walking, swimming, or light cardio with moderate weight training. Taking it easy is the key here.

Probiotics, which are bacteria similar to that naturally occurring in the digestive system are also recommended as they are associated wit improvements in health and immune system functioning. Some will recommend taking hormones, but in most cases this would be ill advised.

Is adrenal fatigue real?

There is no scientific research available to support adrenal fatigue as a disease. The Endocrine Society, the world’s largest organization of researchers and clinicians focused on treating diseases related to glands and hormones, do not recognize adrenal fatigue as a disease.

The society argues that the symptoms are so nonspecific that they can be applied to several conditions or be the result of everyday life. It is argued that any improvements in diet will likely result in feeling better regardless of the condition one may have. There is also a danger associated with the diagnosis of this condition as it may encourage those with health issues from continuing to determine the true cause of their symptoms.

A recent systemic review of the scientific literature on adrenal fatigue reviewed 58 studies. The review concluded that there was no scientific evidence supporting the existence of adrenal fatigue. The studies reviewed had conflicting results, regardless of the quality of the studies. Many of the studies were descriptive rather than quantitative in nature. Study quality and assessment of fatigue was often low or used invalidated methods not endorsed by endocrinologists to assess cortisol levels.

Conditions like adrenal fatigue

Symptoms of adrenal fatigue can be attributed to several other conditions such as

• Depression or Stress
• Fibromyalgia
• Chronic fatigue syndrome
• Vitamin D deficiency
• Sleep apnea
• Sleep disorders
• Hypothyroidism
• Anemia
• Irritable bowel syndrome (IBS)Fibromyalgia
• Adrenal insufficiency
• Overtraining

What is adrenal insufficiency?

Adrenal insufficiency, also known as chronic adrenal insufficiency or hypercortisolism, is a medically recognized, diagnosable disease. Adrenal insufficiency is a rare disorder, impacting 1 in 100,000 people. The disease is not specific to a certain age or sex. There are three forms: primary adrenal insufficiency (Addison’s disease), secondary adrenal insufficiency and tertiary adrenal insufficiency.

Symptoms of adrenal insufficiency include:

• Chronic fatigue
• Reduced strengthen
• Gastric pain
• Myalgia or joint pain
• Dizziness
• Dry skin (in women)
• Loss of libido (in women)
• Loss of appetite
• Muscle weakness
• Weight loss
• Stomach pain
• Craving salt (primary adrenal insufficiency only)
• Nausea
• Vomiting
• Low blood pressure
• Diarrhea
• Depression
• Darkening of the skin (hyperpigmentation only in primary adrenal insufficiency)
• Pale skin (Secondary adrenal insufficiency only)
• Fever
• Dehydration
• Loss of pubic hair (in women)
• Abdominal pain

Other changes resulting from the disease include

• Increased level of serum creatinine (only in primary adrenal insufficiency)
• Hyponatraemia (low sodium levels)
• Hyperkalaemia (high potassium levels)
• Anaemia (iron deficiency), lymphocytosis and eosinophilia (high amount of lymphocytes and eosinophils in the blood, respectively)
• Increased thyrotropin (primary adrenal insufficiency only)
• Hypercalcaemia (high calcium levels; only in primary adrenal insufficiency)
• Hypoglycamia

Causes

Adrenal insufficiency typically develops over a long period of time. However, sudden causes of acute adrenal failure (adrenal crisis) may occur. In sudden cases, the symptoms can be more severe like shock, seizures or coma.

One of the most common causes is decrease in the breakdown of the adrenal cortex by the host immune system (autoimmune disorder). The immune system attacks the body’s own tissues and organs resulting in a gradual destruction. Other glands can also be targeted causing polyendocrine deficiency syndrome. Metastatic cancer cells can spread to the adrenal glands and promote disintegration. Amyloidosis, the buildup of amyloids in the organs, and surgical removal of the glands can also cause adrenal insufficiency.

Primary Adrenal Insufficiency

Primary adrenal insufficiency occurs when the adrenal glands do not produce enough cortisol and sometimes aldosterone due to disease or damage to the adrenal glands. Damage to the adrenal glands in the primary disease can be the result of:

• Autoimmune adrenalitis
• Genetic disorders (Congenital adrenal hyperplasia, sSmith-Lemli-Optiz syndrome, Adrenal hypoplasia congenita)
• Drugs that inhibit steroidogenesis or the production of steroids (anticoagulants, aminoglutethimide, trilostane, ketoconazole, fluconazole, etomidate, phenobarbital, rheytoin, rifampicin, troglitazone)
• Fungal and other infections
• Adrenal hemorrhage
• Adrenal metastases
• Adrenal infiltration
• Adrenalectomy
• IMAGe syndrome
• Kearns-Sayre syndrome
• Wolman’s disease
• Sitosterolaemia (accumulation of fat in the blood and tissues)
• Familiarl glucocorticoid deficiency
• Primary generalized glucocorticoid resistance
• Triple A syndrome

Adrenal insufficiency can result from a genetic condition known as congenital adrenal hyperplasia. Individuals with this disease lack an enzyme needed to produce cortisol, aldosterone or both. In addition to low cortisol and/or aldosterone, these individuals tend to have high levels of androgen which can cause the development of male features in female children and early puberty in males. Severe forms can cause infants to experience ambiguous genitalia, dehydration, vomiting or death.

ALD is an X-linked recessive disorder, meaning that it occurs on the X-chromosome and only occurs when both X chromosomes have a specific mutation. The mutation occurs in gene ABCD1 which results in spastic paralysis and primary adrenal insuffiency.

HIV-associated immunosuppression has opened up opportunities for AI caused by infections such as tuberculous and cytomegaloviral (CMV) adrenalitis.

Drugs that suppress steroid production include anti-fungal agents, tyrosine kinase targeting drugs and etomidate (an anesthetic).

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency results from disease of the pituitary gland and causes include:

• Lesions
• Pituitary tumors
• Pituitary surgery or irradiation for tumors
• Infection or infiltrative process
• Pituitary apoplexy (incapacity)
• Sheehan’s syndrome (decrease in pituitary glad function due to blood loss)
• Genetic disorders
• Mutations in transcription factors involved in pituitary development 9HESX homeobox 1, Orthodentical homeobox 2, LIM homeobox 4, PROP paired-like homeobox 1, sex-determine region Y, Box3, and T-box 19)
• Congenital pro-opiomelanocortin deficiencyPrader-Will syndrome (disorder caused by the loss of function of specific genes)

Tertiary adrenal insufficiency

Tertiary adrenal insufficiency results from interference with hypothalamic processes and secretion of CRH, vasopressin or both. Causes include:

• Lesions
• Hypothalamuc tuors
• Hypothalamic surgery or irradiation to treat tumors
• Infections or infilrative processes
• Injury
• Drug induced
• Glucocorticoid therapy
• Glucocorticoid hypersecretion (Cushion’s syndrome)
• Mifepristone
• Antipsychotics
• Antidepressants

Diagnosis

Adrenal insufficiency is commonly diagnosed through ACTH stimulation testing. Levels of cortisol are measured before, 30, 45 and 60 minutes after intravenous administration of CTH. A normal response is any concentration at or above 18 µg/dl. While there is no specific definition for adrenal insufficiency, many intensive care units consider a cortisol increase of less than 9 µg/dl after ACTH stimulation as diagnostic. To distinguish between the different forms of adrenal insufficiency there are different tests and test result ranges.

To determine if someone has primary adrenal insufficiency the following tests can be performed:

• 0800 h basal serum cortisol (serum levels below 165nmol/L)
• 0800 h basal plasma corticotropin (Plasma corticotropin higher than 22pmol/L)
• 24 h urinary free cortisol (typically not helpful in diagnosis)
• Standard-dose corticotrophin test (Peak cortisol level lower than 500nmol/L)

Most of the above tests can be used to diagnose secondary and tertiary adrenal insufficiency. However, the diagnostic ranges differ from those for primary adrenal insufficiency

• 0800 h basal serum cortisol (serum levels below 100nmol/L)
• 0800 h basal plasma corticotropin (Plasma corticotropin lower than 12pmol/L)
• Standard-dose corticotrophin test (Peak cortisol level lower than 500nmol/L)
• Low-dose corticotropin test (Peak cortisol level less than 500nmol/L)
• Prolonged corticotropin test (Peak cortisol level less than 500nmol/L)
• Insulin tolerance test (Peak cortisol level less than 500nmol/L)

Congenital adrenal hyperplasia caused by 21-hydrozylase deficiency can be identified using the standard-dos corticotropin test. Peak 17-hydroxyprogesterone greater than 300nmol/L indicate the classic disease.

Treatments

One method of treatment involves oral replacement doss of hydrocortisone. It is recommended to use lower doses as decreases in bone mineral density has been observed with higher levels of treatment. While treatment with glucocorticoids improves adrenal insufficiency, many people have reported worse quality of life with this treatment possibly because accompanying mineralocorticoid replacement is not available. A limitation of replacement therapy is that the circadian rhythms of cortisol levels can not be replicated through medication. Administration of multiple doses throughout the day and long acting doses have shown to have no impact on patient quality of life.

However, administration of hydrocortisone using a subcutaneous pump was shown to successfully replicate the circadian rhythms of cortisol. However, one study found that infusion did not improve quality of life or cognition. Thus, this treatment method may still need some refinement.

A novel hydrocortisone treatment that modifies the release of hydrocortisone is in development. This formula has the potential to alter cortisol levels in a way similar to endogenous cortisol (high during waking hours).

Standard treatment of acute adrenal insufficiency is with glucocorticoid replacement. Patients receive 100 mg od hydrocortisone intravenously followed by an additional 100 to 200 mg in 5% glucose by intravenous infusion.

Mineralocorticoid replacement may also be added if it is primary adrenal insufficiency and hydrocortisone dose is greater than 50mg per 24hr.

In the case of chronic adrenal insufficiency, glucocorticoid replacement is also provided. Primary adrenal insufficiency is treated with 20 to 25 mg of hydrocortisone every day. Secondary is treated with a smaller daily dose of 15 to 20 mg. In some cases, 10 mg may be provided. Treatment is given in 3 doses throughout the day.

Treatment also involves monitoring changes in symptoms. Chronic primary adrenal insufficiency may also require mineralocorticoid replacement. It is only given if the daily amount of hydrocortisone provided is less than 50 mg. 100 mg of fludrocortisone is given as one dose in the morning with the morning dose of hydrocortisone. Treatment with mineralocorticoid replacement should also be closely monitored.

Another treatment option for chronic adrenal insufficiency is adrenal androgen replacement. This option is only considered when patients do not feel an improvement in mood or quality of life with the previously mentioned treatments. This option involves a single dose of dehydroepiandrosterone (20 to 50 mg) in the morning.

In general, chronic adrenal insufficiency should be monitored with regular 6-month visits to the doctor, a detailed history of the symptoms and origin of the disease, and familial education on treatment.

Adrenal Crisis

Adrenal crisis is a life-threatening emergency resulting from treatment of patients with adrenal insufficiency with standard therapy. Adrenal crisis requires immediate medical attention. To prevent an adrenal crisis patient should wear a medical alert bracelet at all times and carry a card that lists the long-term steroid treatments they are using. Patient should also not stop ay long-term glucocorticoid replacement treatments that have been taken for longer than 2 to 3 weeks. Patients should also have and know how and when to use an emergency hydrocortisone self-injection kit. Patients may be advised to increase their therapy during times of illness.

It should be noted that many drugs can interact with treatment such as anticonvulsants (phenytoin, phenobarbital and carbamazepine), which can increase metabolism of glucocorticoids leading to a reduced therapeutic effect. Antiretoviral drugs (ritonavir) can slow down glucocorticoid metabolism resulting in an increase in glucocorticoid levels.

Other treatments under consideration

Use of DHEA replacement therapy is still under debate. There are conflicting results related to quality of life after treatment with this therapy. DHEA replacement is recommended since some postulate that DHEA insufficiency may be responsible for the low quality of life in adrenal insufficiency, especially for women. A daily dose of 50mg of DHEA adequately replaces physiological DHEA. A small improvement in quality of life is observed. However, treatment had no major effects on anxiety or sexual well-being in a recent study. There is evidence that DHEA replacement therapy may be more effective among pubescent females and middle-aged men.

Statin therapies could be effective against ALD. However, more research is still needed to determine whether statin therapies could be used to treat ALD, let alone adrenal insufficiency.

Another approach for consideration if adrenal transplantation. One study found that transplantation of a kidney and adrenal gland improved adrenal insufficiency in a 5-year-old girl. The transplantation resulted in normal ACTH levels.