Patients may present with rather non-specific symptoms or be admitted for emergency care because of an adrenal crisis. With regards to the former, symptoms develop gradually and comprise fatigue, lethargy, generalized weakness, gastrointestinal complaints, loss of appetite and weight, and hypotension. Depending on its severity, the latter may manifest in form of orthostatic hypotension or prolonged dizziness and syncopes. Patients may experience mood swings and behavioral disorders. Hyperpigmentation is common in patients suffering from primary AI, is of great diagnostic value, and is primarily noted in sun-exposed areas. Additional symptoms may result from mineralocorticoid deficiency - affected individuals frequently report to crave salt - and lack of androgens in females, which may cause delayed pubarche and reduced libido. Secondary AI may be accompanied by other endocrine disorders resulting from panhypopituitarism or more extensive lesions of the hypothalamus.

The adrenal or Addisonian crisis is a life-threatening condition most commonly observed in individuals affected by primary AI. Patients may present with severe hypotension leading to reduced levels of consciousness and shock, with acute-onset high fever, nausea, vomiting and abdominal pain. Myalgia and arthralgia may also be experienced.

• Fatigue

  However, his appetite and fatigue did not improve over time and he was readmitted for an examination. [ncbi.nlm.nih.gov]

  Adopting the adrenal fatigue diet, adrenal fatigue natural supplements, and adrenal fatigue lifestyle including positive thoughts can help heal your adrenal glands. [drlam.com]

  Unexplained weight loss, anorexia, weakness, nausea, abdominal pain, arthralgias, fatigue, and malaise should be observed in most patients with adrenal insufficiency. [ime.acponline.org]

• Weakness

  Depends on the course of the disease: acute stage: the patient presents with fever, back pain, hypotension, weakness chronic stage: progressive lethargy, weakness, cutaneous pigmentation, weight loss Laboratory data chemistry: hyponatremia, hyperkalemia [radiopaedia.org]

  The presenting symptoms can be non-specific (as in this patient) and easily confused with other common sequelae of ASCI such as orthostasis and diffuse weakness. [ncbi.nlm.nih.gov]

• Weight Loss

  Adequacy of GC replacement is assessed by looking for signs and symptoms of cortisol insufficiency (under-replacement), such as afternoon fatigue, weight loss, or malaise, or Cushing syndrome (over-replacement), such as weight gain, hyperglycemia, or [ime.acponline.org]

  We present the case of a 68-year-old Caucasian male who underwent a thymoma resection and suffered from preoperative weight loss and lack of strength. [ncbi.nlm.nih.gov]

  ADRENAL CRISIS concurrent illness, surgery, failure to take medications GI: abdominal pain, vomiting and diarrhoea CVS: dehydration, hypotension, refractory shock, poor response to inotropes/pressors fever confusion CHRONIC ADRENAL INSUFFICIENCY GENERAL: weight [lifeinthefastlane.com]

  Symptoms are the same as for Addison disease and include fatigue, weakness, weight loss, nausea, vomiting, and diarrhea, but there is usually less hypovolemia. [merck.com]

• Collapse

  Late-onset transient adrenal insufficiency with circulatory collapse is a rare condition that occurs in preterm infants. [ncbi.nlm.nih.gov]

  Symptoms Adrenal insufficiency can present either as an acute crisis with vascular collapse or as a chronic insufficiency, which has much more obscure symptomology. [endocrinologyadvisor.com]

• Infertility

  In 46, XY individuals with mutation of SF-1 gene, adrenal failure, testis dysgenesis, androgen synthesis defects, hypospadias and anorchia with microphallus, infertility can occur from severe to mild. [ncbi.nlm.nih.gov]

  FSH and LH deficiency: In women, symptoms include irregular or stopped menstrual periods and infertility. In men, symptoms include loss of body and facial hair, weakness, lack of interest in sexual activity, erectile dysfunction, and infertility. [webmd.com]

  […] continuous subcutaneous hydrocortisone infusion, as well as ACTH stimulation and immunomodulatory therapies. 39 Despite improved outcomes following these changes, patients with AI continue to suffer from poor metabolic profiles, low quality of sleep, infertility [endocrinefacts.org]

• Pneumonia

  A 52-year-old male was admitted to the Intensive Care Unit for severe sepsis due to bacterial pneumonia and heart failure associated with atrial fibrillation in November 2015. [bloodjournal.org]

  Contrasting inflammatory responses in severe and non-severe community-acquired pneumonia. Inflammation 2014;37:1158-1166. Yende S, D’Angelo G, Kellum JA, et al. [reliasmedia.com]

  Severe pneumonia. Adult respiratory stress syndrome (ARDS). Trauma. HIV infection. After treatment with etomidate. The pathophysiology of this is not yet clear. It involves reduction in the production of glucocorticoids as well as reduced effect. [patient.info]

  During critical illness (such as septic shock, severe communityacquired pneumonia, trauma, head injury, burns) AI is frequent, and is associated with a worse prognosis [ 3 ]. [omicsonline.org]

  Diagnoses included septicaemia as a result of Neisseria meningitidis (n = 16); Staphylococcus aureus (n = 4); group B streptococcus (n = 2); Streptococcus pneumoniae (n = 1); and Escherichia coli (n = 2), secondary to appendicitis and sickle cell disease [adc.bmj.com]

• Vomiting

  If vomiting or diarrhoea treat as below. [pch.health.wa.gov.au]

  CASE PRESENTATION: A 52-year-old Caucasian woman presented with abdominal pain, vomiting and weakness nine days after arthroplasty and heparin use. [ncbi.nlm.nih.gov]

  Relative suppression of HPA axis over time most common cause: administration of exogenous glucocorticoids mechanism: chronic ACTH suppression -> adrenal atrophy ADRENAL CRISIS concurrent illness, surgery, failure to take medications GI: abdominal pain, vomiting [lifeinthefastlane.com]

  Symptoms are the same as for Addison disease and include fatigue, weakness, weight loss, nausea, vomiting, and diarrhea, but there is usually less hypovolemia. [merck.com]

  Immediate medical attention is needed when severe infections or vomiting or diarrhea occur. These conditions can precipitate an addisonian crisis. A patient who is vomiting may require injections of hydrocortisone. [pituitary.org]

• Nausea

  We describe the case of an 83-year-old woman admitted to the emergency department due to a month's history of asthenia, weight loss, anorexia and nausea. [ncbi.nlm.nih.gov]

  Symptoms are the same as for Addison disease and include fatigue, weakness, weight loss, nausea, vomiting, and diarrhea, but there is usually less hypovolemia. [merck.com]

• Diarrhea

  Diarrhea following organ transplantation is usually associated with infection and immunosuppression therapy. We describe two patients with diarrhea following orthotopic heart transplantation due to tertiary adrenal insufficiency. [ncbi.nlm.nih.gov]

  Discuss with your doctor the need for adequate glucocorticoid replacement if you are having surgery, major dental work, or other invasive procedures or if you are sick with a fever, vomiting, or diarrhea. [jama.ama-assn.org]

  Symptoms are the same as for Addison disease and include fatigue, weakness, weight loss, nausea, vomiting, and diarrhea, but there is usually less hypovolemia. [merck.com]

• Abdominal Pain

  CASE PRESENTATION: A 52-year-old Caucasian woman presented with abdominal pain, vomiting and weakness nine days after arthroplasty and heparin use. [ncbi.nlm.nih.gov]

  pain, vomiting and diarrhoea CVS: dehydration, hypotension, refractory shock, poor response to inotropes/pressors fever confusion CHRONIC ADRENAL INSUFFICIENCY GENERAL: weight loss, arthralgia, myalgia CNS: fatigue, anorexia, mood change CVS: postural [lifeinthefastlane.com]

  Seek emergency medical treatment if you experience the following signs and symptoms: Severe weakness Confusion Pain in your lower back or legs Severe abdominal pain, vomiting and diarrhea, leading to dehydration Reduced consciousness or delirium In an [mayoclinic.org]

  He denies fever, symptoms of upper respiratory infection, chest pain, palpitations, abdominal pain, or urinary symptoms. A physical examination demonstrates hyperpigmentation of his oral mucosa. [medbullets.com]

• Hypotension

  Unexplained hypotension may be a manifestation of an adrenal insufficient state in patients with a history of corticosteroid therapy on hemodialysis. [ncbi.nlm.nih.gov]

  refractory shock, poor response to inotropes/pressors fever confusion CHRONIC ADRENAL INSUFFICIENCY GENERAL: weight loss, arthralgia, myalgia CNS: fatigue, anorexia, mood change CVS: postural hypotension, syncope, salt craving SKIN: pigmentation, vitiligo [lifeinthefastlane.com]

  Patients with long-standing adrenal insufficiency can present with postural hypotension, nausea, vomiting, weight loss, anorexia, lethargy, depression, and/or chronic hyponatremia. [amboss.com]

• Orthostatic Hypotension

  Orthostatic hypotension and salt craving can be prominent in primary insufficiency due to aldosterone deficiency leading to profound volume depletion. [ime.acponline.org]

  Clinical ManifestationsUnexplained hypotension, weight loss, fatigue.Primary and Sec AI Fatigue, weakness, anorexia, weight loss N/V/D, dizziness, orthostatic hypotension Hyponatremia, hypoglycemia, EosinophiliaPrimary AI and associated conditions. [slideshare.net]

  Although there are classic clinical signs (eg, fatigue, orthostatic hypotension, hyperpigmentation, hyponatremia, hyperkalemia, and hypoglycemia) of adrenal insufficiency, its early clinical presentation is most commonly vague and undefined, requiring [pedsinreview.aappublications.org]

  hypotension ) darkening (hyperpigmentation) of the skin, in most cases, including areas not exposed to the sun (characteristic sites are skin creases (e.g. of the hands), nipples, and the inside of the cheek (buccal mucosa), also old scars may darken [web.archive.org]

  Orthostatic hypotension, fever, and hypoglycemia characterize acute AC; whereas chronic primary AI presents with a more insidious history of malaise, anorexia, diarrhea, weight loss, joint, and back pain. [endocrinefacts.org]

• Myalgia

  A 69-year-old Japanese man with a history of suprasellar surgery and irradiation developed bradykinesia and mild fatigue without muscle weakness, myalgia, pyramidal or extrapyramidal signs, parkinsonian symptoms, or ataxia. [ncbi.nlm.nih.gov]

  […] illness, surgery, failure to take medications GI: abdominal pain, vomiting and diarrhoea CVS: dehydration, hypotension, refractory shock, poor response to inotropes/pressors fever confusion CHRONIC ADRENAL INSUFFICIENCY GENERAL: weight loss, arthralgia, myalgia [lifeinthefastlane.com]

  Symptoms: Symptoms may include: Weakness Lethargy, fatigue Nausea and vomiting Arthralgias, myalgias (muscle pains) Low blood pressure (hypotension) that may cause light-headedness or fainting when the affected person stands after sitting or lying down [uclahealth.org]

  Early signs of this medical emergency include malaise, weakness, and myalgias. As cortisol levels remain low, patients may develop severe hypotension, vascular collapse, acute renal failure, and hypothermia. [pharmacytimes.com]

  Other symptoms may include weight loss, anorexia, myalgia, dizziness, fainting. There may also be low self-esteem and depression. [almostadoctor.co.uk]

• Arthralgia

  […] concurrent illness, surgery, failure to take medications GI: abdominal pain, vomiting and diarrhoea CVS: dehydration, hypotension, refractory shock, poor response to inotropes/pressors fever confusion CHRONIC ADRENAL INSUFFICIENCY GENERAL: weight loss, arthralgia [lifeinthefastlane.com]

  Unexplained weight loss, anorexia, weakness, nausea, abdominal pain, arthralgias, fatigue, and malaise should be observed in most patients with adrenal insufficiency. [ime.acponline.org]

  ESSENTIALS OF DIAGNOSIS Weakness, vomiting, diarrhea; abdominal pain, arthralgias; amenorrhea. Sparse axillary hair; increased skin pigmentation, especially of creases, pressure areas, and nipples. Hypotension, small heart. [accessmedicine.mhmedical.com]

  Symptoms: Symptoms may include: Weakness Lethargy, fatigue Nausea and vomiting Arthralgias, myalgias (muscle pains) Low blood pressure (hypotension) that may cause light-headedness or fainting when the affected person stands after sitting or lying down [uclahealth.org]

  Myalgia and arthralgia may also be experienced. [symptoma.com]

• Hyperpigmentation

  PATIENT AND METHODS: The patient was born with hyperpigmentation, micropenis, penoscrotal hypospadias, and mild cryptorchidism. Biochemical and hormonal findings were normal except for low testosterone and low-borderline cortisol. [ncbi.nlm.nih.gov]

  Unlike in Addison disease, hyperpigmentation does not occur and serum sodium and potassium levels are relatively normal. ACTH and cortisol levels both are low. [merck.com]

  A physical examination demonstrates hyperpigmentation of his oral mucosa. A basic metabolic panel reveals hyponatremia and hyperkalemia. [medbullets.com]

• Ulcer

  People take these medicines regularly to treat diseases such as rheumatoid arthritis, ulcerative colitis, or asthma. The drugs act like cortisol in your body. [webmd.com]

  Common adverse drug reactions associated with glucocorticoids include sodium retention, which can lead to edema, hyperglycemia, increased susceptibility to infections, osteoporosis, cataracts, seizures, peptic ulcer disease, and hypokalemia. [pharmacytimes.com]

  Chronic adrenal insufficiency can masquerade as a number of conditions related to weight loss including malignancy, anorexia nervosa, gastric ulcer, tuberculosis or other granulomatous diseases, HIV and hematologic disorders other than malignancy. [endocrinologyadvisor.com]

  Glucocorticoid hormones, which are often used to treat inflammatory illnesses like rheumatoid arthritis, asthma, or ulcerative colitis, block the release of both corticotropin-releasing hormone (CRH) and ACTH. [pituitary.org]

• Freckles

  Symptoms of Adrenal Insufficiency Progressive fatigue and muscle weakness Nausea and vomiting Decreased appetite and weight loss Increased pigmentation of skin and mucous membranes (dark freckles, uneven patches of darkened skin, or unusually persistent [healthcommunities.com]

  Black freckles may develop over the forehead, face, and shoulders, and a bluish black discoloration may develop around the nipples, lips, mouth, rectum, scrotum, or vagina. [merck.com]

• Thin Skin

  Signs of over-replacement include raised blood pressure, thin skin, striae, easy bruising, glucose intolerance, hyperglycaemia and electrolyte abnormalities. [patient.info]

• Stroke

  To our knowledge, the constellation of APS2, stroke and acute mental status change has not been previously reported. We review the literature with regard to the presentation of AI as well as the association between vasculitis and APS2. [ncbi.nlm.nih.gov]

  Those superior centers are located within or close to the brain and may be affected by stroke, trauma, tumors and other pathologies. [symptoma.com]

  Acute adrenal insufficiency can be superimposed on any of these other vascular events, as well as myocardial infarction, stroke or sepsis. [endocrinologyadvisor.com]

• Vertigo

  Other symptoms include vertigo, hypotension, depression, salt craving, and vitiligo (depigmented patches of skin). [pharmacytimes.com]

  […] onset Autoimmune disease, TB, adrenomyeloneuropathy, systemic fungal infection, metastatic cancer, AIDS-related-eg Kaposi sarcoma, CMV Clinical Symptoms shared with 2 0 adrenal insufficiency Tiredness, weakness, mental depression, anorexia, weight loss, vertigo [medical-dictionary.thefreedictionary.com]

Laboratory analyses of blood samples typically yield the following results:

• Hypoglycemia due to corticosteroid deficiency
• Metabolic acidosis due to mineralocorticoid deficiency, furthermore
• Hyponatremia
• Hypochloremia
• Hyperkalemia

Further, workup aims at identifying the cause of hypoglycemia and electrolyte imbalances and may comprise these measures [5]:

• Conduction of an ACTH stimulation test, i.e., determination of serum cortisol levels before and after intravenous administration of synthetic ACTH. Observation of an inadequate cortisol response is consistent with AI but does not allow for a distinction between primary AI and AI due to lesions of superior centers.
• Assessment of serum ACTH concentrations. Enhanced levels of ACTH are observed in primary AI, while secondary or tertiary AI is associated with ACTH deficiency.
• Screening for autoantibodies directed against the adrenal tissue.
• Diagnostic imaging to visualize neoplasms infiltrating the adrenal glands, the pituitary gland or the hypothalamus (computed tomography scans and magnetic resonance imaging).
• Screening for gene defects known to be associated with AI.

• Hypoglycemia

  Hypoglycemia occurred in three patients (10%) during the fasting day but not during the nonfasting day (P = 0.23). Hypoglycemia was asymptomatic in two cases. Male sex was significantly associated with the occurrence of hypoglycemia. [ncbi.nlm.nih.gov]

  Hypoglycemia may be a presenting symptom; therefore, laboratory investigation for hypoglycemia should include serum cortisol, drawn at the time of hypoglycemia. [hindawi.com]

  […] when there is more than 90% destruction of the adrenal gland Clinical features Often insidious in onset, patients may present in shock due to increased stress Malaise, lassitude, fatigue, weakness, anorexia, weight loss, nausea, vomiting, hypotension, hypoglycemia [pathologyoutlines.com]

  An insulin stress test to induce hypoglycemia and a rise in cortisol is the standard for testing integrity of the hypothalamic-pituitary-adrenal axis in many centers but careful monitoring is required to avoid severe prolonged hypoglycemia. [merckmanuals.com]

Hormone replacement is the mainstay of long-term AI therapy. A thorough workup is required to assess the degree of mineralocorticoid and glucocorticoid deficiency in individual patients, who should undergo regular follow-ups to allow for a precise adjustment of doses. In general, medication should be dosed as high as necessary and as low as possible [11].

• Prescription of fludrocortisone is indicated in patients suffering from aldosterone deficiency. Children should receive daily doses of 0.025 to 0.2 mg per day, adults are prescribed 0.05 to 0.2 mg per day [9].
• To compensate for glucocorticoid deficiency, adult patients are generally administered 15-25 mg hydrocortisone daily [9]. Lower doses are indicated in pediatric patients and should be based on height, weight and body surface [Park]. Under physiological conditions, glucocorticoid secretion is highest in the morning and thus, about half of the total daily dose should be administered at this time of the day. The remaining dose of hydrocortisone may be given in another two applications. Because AI patients show an inadequate cortisol response to environmental factors, it may be necessary to augment hydrocortisone dosage in periods of stress, e.g., during sickness and prior to surgery.
• While the lack of adrenal sex steroids is compensated by testicular hormone synthesis in men, females may benefit from dehydroepiandrosterone treatment to prevent mood swings and depression, and to improve their health-related quality of life [12].

Treatment of Addisonian crisis should be initiated immediately and comprises of high-dosed intravenous application of hydrocortisone, glucose, and saline solution. Detailed recommendations are also available [2].

Patients suffering from AI require life-long therapy unless the underlying condition is curable. In the case of non-compliance with therapeutic regimens or if left untreated, an acute metabolic decompensation may result in fatal adrenal crisis. Despite optimum therapy, the annual incidence of adrenal crisis in patients suffering from primary AI has been estimated to be about 8%, while this life-threatening complication is less frequently observed in secondary or tertiary AI [9]. Recently, Norwegian researchers found young AI patients to have an increased mortality due to adrenal failure, infection, and sudden death [10]. Otherwise, AI patients have an excellent prognosis.

AI is a general term that may refer to distinct entities.

Patients may suffer from primary AI, i.e., dysfunction of the adrenal glands results in a decreased production of adrenal hormones. Generally, this form of AI comprises all zones of the adrenal cortex and the adrenal medulla and thus, patients suffer from both mineralocorticoid and glucocorticoid deficiencies. Possible causes of primary AI are adrenal dysgenesis, congenital adrenal hyperplasia due to hereditary enzyme deficiencies, ACTH resistance syndromes, metabolic disorders interfering with cholesterol synthesis or peroxisomal function, isolated autoimmune adrenalitis, autoimmune polyendocrinopathy, infectious diseases like tuberculosis, adrenal infarction, adrenal hemorrhage, trauma, neoplasms, drug-induced AI and surgical resection [1]. Of note, clinical symptoms may only manifest after the destruction of the vast majority of adrenal tissue [2].

Secondary and tertiary AI are provoked by lesions of superior centers. Both glucocorticoid- and androgen-producing cells form part of the hypothalamic-pituitary-adrenal hormone axis, i.e., the corresponding subpopulations of adrenal cells depend on the release of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by the hypothalamus and the anterior pituitary gland, respectively. The hypothalamic and pituitary function may be impaired by ischemia or stroke, inflammation, and/or infection, trauma, benign and malignant neoplasms, long-term administration of glucocorticoids and irradiation of the brain, among others. In contrast, mineralocorticoid release is not affected by CRH and ACTH levels but is regulated by the renin-angiotensin system. Thus, individuals affected by secondary or tertiary AI don't develop mineralocorticoid deficiency.

Of note, partial dysfunction of the adrenal glands is also observed in pathologies that are usually not considered forms of AI. For instance, the adrenogenital syndrome is caused by a gene defect resulting in reduced adrenal glucocorticoid synthesis, consequently increased ACTH levels, and an excess stimulation of adrenal androgen production [3]. Isolated hypoaldosteronism is rare but may occur in patients suffering from chronic idiopathic hypoaldosteronism, familial corticosterone methyl oxidase deficiencies, persistent hypotension or conditions associated with reduced renin secretion [4].

Autoimmune-mediated AI is the most common form of the disease and its prevalence has been estimated to 1 in 10,000 people. Congenital adrenal hyperplasia is diagnosed in 1 per 15,000 life births, and about 1 in 20,000 men suffers from X-linked adrenoleukodystrophy [5]. The annual incidence of primary AI has been stated to be <1 in 100,000 inhabitants of western Norway[6], and this condition is most frequently diagnosed during the fourth decade of life. Of note, symptom onset of congenital adrenal hyperplasia and X-linked adrenoleukodystrophy typically occurs in infancy or childhood [7].

AI due to disturbances of the hypothalamic-pituitary-adrenal hormone axis is more common than primary AI affects up to 28 per 100,000 people and is most commonly a side effect of prolonged glucocorticoid therapy [8]. Women are affected more often than men. Contrary to primary AI, it is usually diagnosed in the elderly.

The adrenal cortex encapsulates the adrenal medulla and consists of three layers denominated zona glomerulosa, zona fasciculata, and zona reticularis. Distinct subpopulations of adrenal cells produce hormones that affect electrolyte balance, carbohydrate metabolism, growth and sexual characteristics, as well as autonomous functions. In detail, the following hormones originate from the adrenal glands:

• Zona glomerulosa: aldosterone
• Zona fasciculata: glucocorticoids like cortisol and corticosterone
• Zona reticularis: sex steroids, e.g., dehydroepiandrosterone which is subsequently converted to androgens and estrogens
  
• Adrenal medulla: epinephrine and norepinephrine

AI is primarily associated with disturbances of electrolyte balance and carbohydrate metabolism, since deficiencies in adrenal androgen and catecholamine production are largely compensated by the testes, chromaffin paraganglia, and the sympathetic nervous system, respectively.

Aldosterone acts on renal tubular epithelial cells, mucous membranes of the intestinal tract, salivary and sweat glands. It favors the excretion of potassium and protons and stimulates the reabsorption of sodium, chloride, and water in distal tubules of the kidneys by inducing an up-regulation of ion channel and Na+-K+-ATPase expression. Consequently, patients suffering from AI with mineralocorticoid deficiency develop hyperkalemia, metabolic acidosis, hyponatremia, hypochloremia, and hypovolemia.

Glucocorticoid release provokes an increase of serum glucose levels by enhancing hepatic gluconeogenesis and induction of peripheral insulin resistance. At the same time, glucocorticoids favor protein and lipid catabolism. Lack of glucocorticoids thus leads to hypoglycemia, insulin sensitivity, and weight loss. Of note, ACTH secretion is physiologically reduced by glucocorticoids, but this negative feedback loop is interrupted in AI. Thus, pituitary ACTH synthesis is permanently elevated and this condition results in increased levels of the melanocyte-stimulating hormone, which originates from the same precursor (proopiomelanocortin; POMC). Therefore, AI patients develop hyperpigmentation of the skin.

Long-term administration of glucocorticoids should be avoided; if required, doses should be maintained as low as possible. Further measures can be undertaken to avoid traumatic lesions of the adrenal glands, pituitary gland, and hypothalamus; excision during retroperitoneal and head surgery; and infectious diseases that may affect these endocrine organs. No specific measures can be recommended to prevent autoimmune-mediated AI.

Healthy adrenal glands release a variety of hormones, namely mineralocorticoids, glucocorticoids, estrogen, progesterone, and catecholamines. Adrenal insufficiency (AI) may refer to a reduced production of either or all of those hormones, and this condition may be provoked by distinct diseases. On the one hand, pathologies may directly affect adrenal tissues and thus interfere with hormone synthesis. This form of AI is deemed primary AI and may also be referred to as Addison's disease. Most cases of primary AI are the result of an autoimmune disease. On the other hand, the adrenal glands form part of the complex endocrine network and are subjected to regulatory mechanisms. Thus, functional impairment of superior centers may be associated with an inadequate stimulation of adrenal hormone synthesis. In detail, lesions of the pituitary gland may cause secondary AI, lesions of the hypothalamus may trigger tertiary AI. Therapy is mainly symptomatic and consists in life-long supplementation of mineralocorticoids and glucocorticoids. If the underlying disease is curable, the patient's prognosis improves.

The adrenal glands are endocrine organs located in close proximity to the kidneys. They are composed of distinct subpopulations of cells which release hormones that affect electrolyte balance, carbohydrate metabolism, growth and sexual characteristics, as well as autonomous function. If an individual suffers from adrenal insufficiency (AI), adrenal hormone production is partially or completely impaired. Since the adrenal glands form part of the complex endocrine network, they are subjected to regulatory mechanisms. Therefore, AI may not only result from a dysfunction of adrenal tissue (e.g., due to developmental or gene defects, or owing to destruction of the adrenal glands in an immune reaction directed against endogenous tissues), but also from lesions of superior centers. Those superior centers are located within or close to the brain and may be affected by stroke, trauma, tumors and other pathologies. Furthermore, regulatory mechanisms may be overridden if certain drugs, mainly glucocorticoids, are administered over long periods of time.

AI patients typically experience fatigue, lethargy, generalized weakness, hypotension, postural dizziness, nausea, vomiting and diarrhea, loss of appetite and weight, and hyperpigmentation. Laboratory analyses of blood samples typically reveal hyponatremia, hypochloremia, hyperkalemia, and metabolic acidosis. In order to prevent so-called adrenal crisis, which are life-threatening events resulting from an acute metabolic decompensation, missing hormones have to be supplemented. Accordingly, affected individuals require life-long therapy with fludrocortisone and/or hydrocortisone. Compliance with therapeutic regimens provided, AI patients have an excellent prognosis.

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