Primary adrenal insufficiency: clinical guidelines

List of Abbreviations

1-PANI — primary adrenal insufficiency

2-PANI — secondary adrenal insufficiency

A — aldosterone

AH — arterial hypertension

BP — blood pressure

AITD — autoimmune thyroid disease

AID — autoimmune disease

AC — addisonian crisis

ACTH — adrenocorticotropic hormone

ALD — adrenoleukodystrophy

PAI — primary autoimmune adrenal insufficiency

APS — autoimmune polyglandular syndrome

APS1 — autoimmune polyglandular syndrome type 1

APS2 — autoimmune polyglandular syndrome type 2

APS3 — autoimmune polyglandular syndrome type 3

APS4 — autoimmune polyglandular syndrome type 4

Ab — antibodies

IV — intravenous

IM — intramuscular

CAH — congenital adrenal hyperplasia

HIV — human immunodeficiency virus

HPA axis — hypothalamic-pituitary-adrenal axis

GC — glucocorticoids

DHEA — dehydroepiandrosterone

DHEA-S — dehydroepiandrosterone sulfate

VLCFA — very long-chain fatty acids

GI — gastrointestinal tract

ITT — insulin tolerance test

CBG — cortisol-binding globulin

CMC — chronic mucocutaneous candidiasis

CT — computed tomography

MAS — multiple autoimmune syndrome

MC — mineralocorticoids

MRI — magnetic resonance imaging

AI — adrenal insufficiency

ARF — acute respiratory failure

AAI — acute adrenal insufficiency

ARF – acute renal failure

AHF — acute heart failure

PAP — polyautoimmunity

SC — subcutaneous

R — renin

DM — diabetes mellitus

T1D — type 1 diabetes mellitus

eGFR — estimated glomerular filtration rate

TSH — thyroid-stimulating hormone

LoE — level of evidence

LeR — level of recommendation validity

CAI — chronic adrenal insufficiency

eAID — endocrine autoimmune disease

CTLA-4 — cytotoxic T-lymphocyte-associated protein 4

CYP — cytochrome P

CYP11A1 — cholesterol side-chain cleavage enzyme

CYP21A2 — 21-hydroxylase enzyme

HRQoL — Health-Related Quality of Life questionnaire

IMAGe — intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, genital abnormalities

LADA — latent autoimmune diabetes in adults

LC-MS/MS — liquid chromatography-tandem mass spectrometry

P450c21 — 21-hydroxylase enzyme

PD1 — programmed cell death protein 1

PD-L1 — programmed cell death ligand 1

QR code — Quick Response code

t — temperature

Terms and Definitions

21-hydroxylase (P450c21, CYP21A2) is an enzyme of adrenal steroidogenesis. Antibodies (Ab) to this enzyme are specific immunological markers of the autoimmune form of primary adrenal insufficiency.

Addisonian (adrenal) crisis (AC; acute hypocortisolemia; acute adrenal insufficiency (AAI)) is a life-threatening complication of adrenal insufficiency (AI) that occurs when cortisol levels fail to meet an increased physiological demand.

Adrenocorticotropic hormone (ACTH) is a hormone synthesized by pituitary corticotrophs that stimulates the synthesis of glucocorticoids and androgens in the adrenal cortex.

Autoimmune polyglandular syndrome (APS) is an autoimmune condition affecting 2 or more endocrine glands. An exception is autoimmune polyglandular syndrome type 1 (APS1), which can be diagnosed in the presence of just 1 endocrine autoimmune disease (eAID) (provided there is either an AIRE mutation or an association with mucocutaneous candidiasis), which may be accompanied by non-endocrine autoimmune diseases (AIDs).

Secondary adrenal insufficiency (2-PANI) is a pituitary or hypothalamic disorder of various etiologies characterized by the inability to produce sufficient amounts of GCs and androgens.

Glucocorticoids (GCs) are hormones synthesized by the zona fasciculata of the adrenal cortex that ensure the body's adaptation to environmental stressors. Cortisol is the primary GC.

Adrenal cortex is the outer part of the adrenal gland located above its medulla (inner layer), which differentiates from interrenal tissue and consists of three zones: zona glomerulosa, zona fasciculata, and zona reticularis.

Mineralocorticoids (MCs) are hormones synthesized by the zona glomerulosa of the adrenal cortex that regulate water-electrolyte balance and systemic blood pressure (BP). Aldosterone (A) is the primary MC.

Multiple autoimmune syndrome (MAS) is the coexistence of three or more AIDs (not necessarily endocrine).

Adrenal gland is a paired endocrine gland located in the retroperitoneal space above the upper pole of the kidney, consisting of the medulla and cortex.

Adrenal androgens are sex hormones synthesized by the zona reticularis of the adrenal cortex. The main adrenal androgens include dehydroepiandrosterone (DHEA, which is sulfated to dehydroepiandrosterone sulfate (DHEA-S) prior to secretion) and androstenedione.

Primary adrenal insufficiency (1-AI, primary hypocortisolemia, Addison's disease) is an adrenal disorder of various etiologies, characterized by the inability to produce sufficient amounts of glucocorticoids, mineralocorticoids, and androgens.

Polyautoimmunity (PAI) is a combination of two autoimmune diseases (not necessarily endocrine).

Renin (R) is an enzyme (acting as a hormone) synthesized by the juxtaglomerular cells of the kidneys, which catalyses the formation of angiotensin I. In turn, angiotensin I is converted into angiotensin II, which stimulates aldosterone synthesis.

Chronic adrenal insufficiency (CAI) is adrenal insufficiency outside of an exacerbation. With an increased need for cortisol against the background of untreated CAI or inadequate adjustment of replacement therapy, it can progress to acute adrenal insufficiency (AAI).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

1-AI is a severe, life-threatening condition characterized by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids, mineralocorticoids, and androgens. 1-AI was first described by Thomas Addison and is therefore called Addison's disease [1].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The most common cause of 1-AI is autoimmune (>90%). Specific immunological markers of autoimmune destruction of the adrenal cortex are autoantibodies against the adrenal steroidogenesis enzyme 21-hydroxylase (P450c21). Autoimmune 1-AI can be isolated (i.e., not combined with other endocrine autoimmune diseases) or be a component of APS type 1, 2, or 4 [1,2] (Table 1). Formally, APS can be designated as PAI [3] or, under appropriate conditions, as MAS [4]. If only one endocrine autoimmune disease is combined with one or more non-endocrine autoimmune diseases, the diagnosis of APS is not established, and the patient's condition is regarded as PAI or MAS.

Table 1. Main endocrine autoimmune diseases included in APS (modified by the authors).

Abbreviations: MCC – mucocutaneous candidiasis; AITD – autoimmune thyroid diseases; T1D – type 1 diabetes mellitus; LADA – latent autoimmune diabetes in adults.

* pathognomonic diseases, penetrance <100%.

^{^} other endocrine autoimmune diseases: hypergonadotropic hypogonadism, hypophysitis, Hirata's disease.

As new components appear in APS-3 and APS-4, the diagnosis can be reclassified to APS-2 (for example, if a patient with APS-4 develops AITD, or a patient with APS-3 develops adrenal insufficiency) [10]. Thus, since APS-2, APS-3, and APS-4 share a common disease pathogenesis, polygenic inheritance, and manifestation of autoimmune diseases mostly in adulthood, in our opinion, it is advisable to distinguish a single type of APS (APS-2 or adult-onset APS). At the same time, type 2 APS should include at least any two endocrine autoimmune diseases. Some experts share this position [11], but at the same time, many specialists still use the expanded classification; therefore, it is important to eliminate discrepancies and define uniform criteria for all.

Other causes of 1-AI (Table 2) include infectious diseases (e.g., tuberculosis), various hereditary pathologies that are diagnosed mostly in childhood, total adrenalectomy, metastatic lesions, and adrenal lymphoma [12-14]. In addition, due to the increasing number of critically ill chronic patients requiring multiple, multi-component drug treatments, the impact of additional iatrogenic factors is growing: adrenal hemorrhage during anticoagulant therapy, blockade of cortisol synthesis by certain aromatase inhibitors and general anesthesia drugs, and acceleration of glucocorticoid metabolism due to antiepileptic drugs (phenytoin** and phenobarbital**) and antibiotics (rifampicin**) [12].

Table 2. Other causes of primary adrenal insufficiency [1, 15, 16].

Abbreviations: CAH – congenital adrenal hyperplasia; HIV – human immunodeficiency virus; CTLA-4 – cytotoxic T-lymphocyte-associated protein 4; PD1 – programmed cell death protein 1, PD-L1 – PD1 ligand, CYP – cytochrome P; IMAGe – intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, genital abnormalities.

Primary adrenal insufficiency is based on an absolute deficiency of corticosteroids. Corticosteroid deficiency leads to the loss of sodium and water via the kidneys and gastrointestinal tract (GIT), resulting in dehydration, hypovolemia, hypotension, and progressive hyperkalemia. Deficiency of cortisol—the main adaptogenic hormone of the human body—leads to decreased resistance to various endogenous and exogenous stressors, against the background of which (in most cases, infections) manifestation/decompensation of adrenal insufficiency occurs. Thus, circulatory failure and dehydration play the primary and main role in the pathogenesis of hypocortisolemia [17].

Cortisol deficiency acts via a feedback mechanism on the hypothalamic-pituitary axis, leading to elevated ACTH levels. In mineralocorticoid deficiency, the level of renin, synthesized by the juxtaglomerular cells of the kidneys, increases. This is of significant clinical importance because in secondary adrenal insufficiency, where ACTH secretion is absent, mineralocorticoid function regulated by the renin-angiotensin-aldosterone system is not impaired.

Due to the fact that ACTH only affects the zona fasciculata and zona reticularis, while aldosterone secretion is controlled by other mechanisms, hypovolemia in secondary adrenal insufficiency is less pronounced, since cortisol accounts for about half of the mineralocorticoid response responsible for maintaining water homeostasis.

Acute adrenal insufficiency is based on a sharp and pronounced deficiency of glucocorticoids and mineralocorticoids. A patient with acute adrenal insufficiency exhibits changes similar to those in chronic adrenal insufficiency, but the rate and severity of these disorders are significantly higher: dehydration develops, sodium is lost, renal excretion of potassium and hydrogen ions decreases, resulting in hyperkalemia and metabolic acidosis; an increase in blood calcium levels is also possible. Dehydration and the loss of sodium and chloride ions are exacerbated by a decrease in their intestinal absorption rate, and later by vomiting and diarrhea. Progressive loss of extracellular fluid and a decrease in circulating blood volume lead to a drop in blood pressure, prolonged reduction in glomerular filtration rate (GFR) and renal blood flow, and hypotonicity of smooth muscle and myocardium. Vascular collapse develops. At the same time, increasing glucocorticoid deficiency reduces the sensitivity of arterioles to norepinephrine. It must also be taken into account that glucocorticoid deficiency causes delayed protein catabolism, reduced deamination, and consequently a significant restriction of nitrogen and amino acid excretion, inhibition of gluconeogenesis, and a drop in blood glucose levels, up to the development of hypoglycemic coma. Severe, rapidly progressive metabolic disorders manifest as profound asthenia, acute cardiovascular disorders, gastrointestinal disturbances, and neuropsychiatric status abnormalities (Fig. 1) [1].

Figure 1. Pathogenesis of primary adrenal insufficiency [18].

Abbreviations: ARI – acute renal injury; AHFE – acute heart failure; ARF – acute respiratory failure.

Acute adrenal insufficiency should be suspected in a patient with severe hypotension or shock who is unresponsive to adrenergic and dopaminergic agents, since glucocorticoid deficiency reduces vascular reactivity to angiotensin, norepinephrine, and other vasoconstrictor influences, and decreases the synthesis of the renin substrate while increasing the production and effects of prostacyclin and other vasodilatory metabolites [18, 19].

[1] Cases of primary adrenal insufficiency in patients receiving this drug must be interpreted with caution, as tuberculosis may be an independent cause of adrenal damage.

[2] Certain aromatase inhibitors, mitotane**, and ketoconazole are prescribed, among other things, in the treatment of endogenous hypercortisolism.

[3] Which may be used in the diagnosis of secondary adrenal insufficiency.

1.3 Epidemiology of the Disease or Condition

Primary adrenal insufficiency is a relatively rare disease with a global prevalence of approximately 100–144 cases per million population [20] (according to Martina M. Erichsen et al. [20]), and an incidence of 4.4–6 cases per million population per year [22]. However, in recent years, new data have emerged indicating an increase in prevalence, especially among women [23].

1.4 Features of Coding the Disease or Condition

Other disorders of adrenal glands (E27):

E27.1 – Primary adrenocortical insufficiency;

E27.2 – Addisonian crisis;

E27.3 – Drug-induced adrenocortical insufficiency;

E27.4 – Other and unspecified adrenocortical insufficiency;

E27.8 – Other specified disorders of adrenal glands.

Disorders of endocrine glands in diseases classified elsewhere (E35*):

E35.1 – Disorders of adrenal glands in diseases classified elsewhere.

Postprocedural endocrine and metabolic disorders, not elsewhere classified (E89):

E89.6 – Postprocedural adrenocortical (medullary) hypofunction.

1.5 Classification of the disease or condition

Depending on the clinical course, chronic and acute primary adrenal insufficiency are distinguished [24].

Depending on the cause, hereditary and acquired primary adrenal insufficiency are distinguished [1].

Depending on the adequacy of replacement therapy, pharmacological compensation, subcompensation, and decompensation (addisonian crisis) of glucocorticoid and mineralocorticoid deficiency are distinguished.

Autoimmune primary adrenal insufficiency can be isolated or occur as a component of autoimmune polyglandular syndrome (APS).

1.6 Clinical presentation of the disease or condition

The symptoms of adrenal insufficiency are presented in Table 3. In primary adrenal insufficiency, the following are frequently observed: weight loss, orthostatic hypotension due to dehydration, salt craving, hyponatremia, hyperkalemia (usually after the manifestation of hyponatremia), complete blood count changes (anemia, eosinophilia, lymphocytosis), and hypoglycemia. Increased secretion of ACTH and other pro-opiomelanocortin peptides often leads to hyperpigmentation of the skin and mucous membranes. However, this sign varies in severity and may sometimes be entirely unnoticeable (it is advisable to compare the skin color with that of the patient's sibling). In women, axillary and pubic hair is lost due to decreased adrenal androgen levels. All other symptoms of primary adrenal insufficiency are non-specific: weakness, fatigue, musculoskeletal and abdominal pain, depression, and increased anxiety. As a result, the disease is quite frequently diagnosed only at the stage of addisonian crisis, an extremely life-threatening condition [25].

Table 3. Clinical manifestations of primary adrenal insufficiency [26] (modified by the authors).

It should also be noted that diagnosing adrenal insufficiency in pregnant women is challenging, as nonspecific symptoms such as fatigue, nausea, and vomiting often do not differ from those associated with a normal pregnancy [1]

2. Diagnostics, medical indications and contraindications for diagnostic methods

Laboratory evaluation results are fundamental for establishing the diagnosis of adrenal insufficiency. Importantly, in severe patients with clinical signs of adrenal insufficiency, blood should ideally be drawn for diagnostic purposes beforehand, if possible, and treatment with glucocorticoids should be initiated without waiting for the results. Confirmatory testing can be performed after treatment, during temporary cessation of therapy, once the patient's condition has stabilized [27,28].

2.1 Complaints and Anamnesis

• Screening to rule out primary adrenal insufficiency is recommended in patients with symptoms unexplained by other pathologies that are suspicious for primary adrenal insufficiency: weight loss, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, hypoglycemia [12,25,29].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Primary adrenal insufficiency is often diagnosed late due to the predominance of nonspecific symptoms over several months or even years. Therefore, a thorough, multi-faceted assessment of the patient's condition and complaints is necessary. Most suspicious is the combination of several symptoms of adrenal insufficiency, as well as symptoms of primary adrenal insufficiency in patients with autoimmune disorders (e.g., type 1 diabetes mellitus, autoimmune gastritis, pernicious anemia, vitiligo), infectious diseases (tuberculosis, HIV infection, cytomegalovirus, candidiasis, histoplasmosis), or those taking relevant medications (Tables 1, 2). Such patients are at risk and require closer monitoring.

2.2 Physical Examination

Signs of primary adrenal insufficiency that can be detected during physical examination are presented in Table 3.

2.3 Laboratory Diagnostics

• In patients with clinical symptoms suspicious for adrenal insufficiency, it is recommended to measure morning blood levels of total cortisol and ACTH to clarify the diagnosis [30,31].

LE RLoE 4Level of Evidence / Recommendation Grade: C (Level of Evidence – 4)

• In patients with clinical symptoms suspicious for adrenal insufficiency, it is recommended to measure morning blood levels of aldosterone and renin to clarify the diagnosis [32,33].

GCR CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Since 80% of plasma cortisol is bound to cortisol-binding globulin (CBG) and 10–15% to albumin, plasma cortisol levels must be interpreted in the context of conditions that decrease (inflammation, rare genetic disorders) or increase CBG levels (estrogens, pregnancy, mitotane**) [34].

In rare cases (less than 1 per million population [35]), the cause of decreased CBG may be an inherited disorder—familial CBG deficiency. The cause of the disease is a mutation in the SERPINA6 (CBG) gene (semi-dominant inheritance pattern [35]). Clinically, patients present with hypotension and weakness. Laboratory evaluation in homozygous mutations may reveal a significant decrease in total blood cortisol (1.9 mcg/dL and below) against the background of normal ACTH levels, as well as normal urinary free cortisol and blood free cortisol, but the free cortisol fraction (%) significantly exceeds normal values. In heterozygous mutations, the total cortisol level may be normal (up to 17 mcg/dL), while the free cortisol fraction (%) is comparable to or exceeds that of healthy individuals. It is hypothesized that glucocorticoid activity is mediated precisely by the free cortisol fraction. Furthermore, it cannot be excluded that receptor sensitivity to glucocorticoids is increased in such patients, which could explain the absence of an ACTH rise via negative feedback mechanisms [36]. Thus, the question of whether replacement therapy is necessary in such patients remains open.

Measurement of blood renin and aldosterone levels is important at the onset of the disease, when mineralocorticoid deficiency may either predominate in the clinical picture or be the sole initial sign of the disease [32,33]. Measurement of blood sodium and potassium levels is not independently useful for confirming or excluding a diagnosis of primary adrenal insufficiency; however, it must be performed to laboratory-assess the severity of the patient's condition and the effectiveness of therapy.

For the initial diagnosis of primary adrenal insufficiency, blood levels of free (unconjugated) DHEA or DHEA-S may additionally be measured, which will be decreased. However, because the levels of these hormones can also be low in healthy individuals, especially older adults, monitoring and isolated testing of these parameters is impractical [26].

• In patients with suspected adrenal insufficiency, it is recommended to rule out the diagnosis if the morning blood cortisol level is above 500 nmol/L [39].

GCR CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Blood collection is recommended between 6:00 and 10:00 AM. Unfortunately, most studies establishing the diagnostic cortisol threshold were performed on patients without primary adrenal insufficiency. Moreover, morning blood cortisol in adrenal insufficiency is generally below or near the lower limit of normal (113–131 nmol/L [4.1–4.7 mcg/dL]) [40]. Variations among cortisol assay methods significantly impact the actual cut-off point used in clinical practice.

An ACTH level exceeding 300 ng/L (66 pmol/L) represents the maximum stimulation of glucocorticoid synthesis [26], and accordingly, a low cortisol level (140 nmol/L [5 mcg/dL]) combined with an elevated ACTH concentration indicates the inability of the adrenal cortex to respond to ACTH stimulation, leading to a diagnosis of primary adrenal insufficiency [30,31,41,42]. An elevated ACTH concentration with normal cortisol levels may be an early sign of primary adrenal insufficiency [43]. Due to the significant dependence of ACTH levels on laboratory assay kits, it is impossible to derive a universal diagnostic threshold for ACTH [44,45]. Only two studies have defined a diagnostic threshold for ACTH in primary adrenal insufficiency compared to a control group, and in those studies, ACTH was typically markedly elevated. Therefore, a 2-fold elevation of ACTH above the upper limit of the reference interval is proposed for diagnosing primary adrenal insufficiency. It should be kept in mind that in rare cases of proven primary adrenal insufficiency, ACTH levels may be only slightly above the upper limit of the reference range and not exceed a 2-fold increase [30,31].

Different researchers propose various threshold values for morning cortisol concentration to rule out adrenal insufficiency: from >285 nmol/L (10.3 mcg/dL) to >480 nmol/L (17 mcg/dL) [46]. The diagnostic value of cortisol measured at other times of the day (not in the morning) for ruling out adrenal insufficiency has not been sufficiently investigated to date.

Many questions remain regarding laboratory methods for investigating blood A and P levels (or determining plasma renin activity); therefore, currently, diagnosis should be based on the reference ranges of the specific laboratory [47]. In some cases, such as familial glucocorticoid deficiency or in patients with milder mutations in CAH, mineralocorticoid deficiency is not observed during 1-HD.

• In patients with symptoms of AD whose laboratory results do not meet the laboratory criteria for 1-HD, but do not rule it out, it is recommended to perform a pharmacological stimulation test in the absence of contraindications [46,48].

GCR CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• In patients with suspected AD, it is recommended to rule out the diagnosis if the peak cortisol level during pharmacological stimulation tests is greater than 500 nmol/L [49].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: For the diagnosis of 1-HD, most experts recommend a stimulation test using drugs from the ACTH ATC group [18,26,40,50-59]. Factors that may affect the result must be taken into account, such as the binding of cortisol to CBG [52] and, to a lesser extent, to albumin [53]. The use of estrogen preparations leads to an increase in CBG with a corresponding increase in cortisol levels [40,54]. In patients with nephrotic syndrome [54] and liver disease [55], as well as in postoperative patients [56] or critically ill patients [57], CBG and albumin levels may be reduced, and consequently, lower cortisol concentrations will be determined.

Also, the insulin tolerance test (ITT) is used for the diagnosis of 1-HD. This is one of the oldest tests, yet it has not lost its significance in the diagnosis of AD to this day; it allows for the investigation of the integrative integrity of the entire hypothalamic-pituitary-adrenal axis (HPA axis) at once. Hypoglycemic stress is a potent indirect stimulator of cortisol secretion, which is mediated through the activation of hypothalamic centers and the corticotropic function of the pituitary gland. During the ITT, at any time of day, a single IV administration of the drug (#insulin soluble [human genetically engineered]**) is performed at a dose of 0.1–0.15 IU/kg (if the patient has insulin resistance, the dose of #insulin soluble [human genetically engineered]** can be increased) [60-62], and initially and at 30, 45, 60, 90, and 120 minutes, peripheral venous blood is drawn to study total cortisol and blood glucose levels. The test is considered informative if glycemia at any point is less than 2.2 mmol/L and/or if the cortisol level is greater than 500 nmol/L at any point. AD is excluded if the cortisol level at any point is greater than 500 nmol/L. If serum glucose does not decrease below 2.2 mmol/L, the test should be repeated. The main disadvantage of the ITT is the potential risk of developing severe hypoglycemia in the presence of AD, which can trigger an addisonian crisis. Therefore, the test should be stopped immediately if the patient's condition worsens, after first performing the final peripheral venous blood draw. In elderly patients, patients with epilepsy, as well as in the presence of cardiovascular and other severe pathologies, the ITT is contraindicated [63]. To rule out contraindications to the ITT, it is recommended to conduct an initial primary and, if necessary, a repeated consultation (appointment) with a cardiologist. Factors that may influence the results of the ITT are described above.

In addition, the #glucagon** test can be used: at any time of day, a single IM administration of the drug (#glucagon**) at a dose of 1 mg is performed [61,64], and peripheral venous blood is drawn initially and at 90, 120, 150, 180, 210, 240 minutes to study the level of total cortisol in the blood. The test can be used if there are contraindications to the ITT [60]. However, the #glucagon** test is characterized by low specificity (39% [65]). According to Karaca Z et al. [66], false-positive results occurred in 10-20% of cases (it should be noted that in these studies [65,66] the diagnosis of AD was excluded at a cortisol level greater than 599 nmol/l). Therefore, based on the results of the #glucagon** test, the diagnosis of AD can be established only in conjunction with other indicators pointing to the presence of AD. For example, it is possible to study the level of free cortisol in the urine. Thus, in the presence of a full-blown clinical picture of primary hypocortisolemia, the detection of a significant decrease in the daily urinary excretion of free cortisol allows for the confirmation of the diagnosis [18]. The lower limit of the reference interval of a specific laboratory can be adopted as the diagnostic threshold.

An isolated study of the urinary free cortisol level for the diagnosis of 1-HD is not recommended, as it is characterized by low sensitivity (approximately 20% of patients have this indicator within reference values) [67].

• In all patients with 1-HD, it is recommended to determine the etiology of the disease [26].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: When 1-HD is confirmed at the laboratory stage, it is then important to identify the cause of the disease (Tables 1, 2, Fig. 2). Autoimmune adrenalitis is the most common cause of 1-HD in adult patients, and screening for anti-CYP21A2 autoantibodies and other autoimmune diseases is very important, considering that laboratory assays for anti-CYP21A2 antibodies in the Russian Federation are not standardized. Anti-CYP21A2 antibodies may circulate for several years before the manifestation of 1-HD. It has been determined that approximately 30% of healthy patients positive for anti-CYP21A2 antibodies manifest 1-HD within 5 years [33].

In men with negative anti-CYP21A2 antibodies, a battery of tests for the diagnosis of X-linked ALD must be performed [68]. AD may be the only manifestation of ALD, which is most commonly found in boys aged 2 to 10 years. In bilateral adrenal lesions, it is necessary to consider evaluation for infiltrative diseases, infections, hemorrhage, metastases, tumors, and in some cases, genetic disorders [12,69]. Non-autoimmune cases of 1-HD are most commonly detected in children and elderly patients.

Figure 2. Algorithm for determining the etiology of primary adrenal insufficiency.

Abbreviations: CT – computed tomography, MRI – magnetic resonance imaging.

2.4 Instrumental Diagnostics

• In all patients with 1-HD during the workup to determine the etiology of the disease, if blood tests for anti-P450c21 antibodies are negative and, if necessary, ABCD1, or if they cannot be performed, imaging is recommended [26].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: If tests for anti-CYP21A2 and ABCD1 are negative, CT or MRI of the adrenal glands is necessary to identify infectious diseases (e.g., tuberculosis) or tumors. However, CT/MRI in the case of infiltrative processes in the adrenal glands, including tuberculosis, are not always informative [26].

Given the lack of availability of a full laboratory workup to determine the etiology of 1-HD, adrenal imaging is indicated for all patients.

In cases where the cause of the disease is not identified, it is referred to as idiopathic 1-HD.

2.5 Other Procedures

• To rule out monogenic diseases in patients with 1-HD, it is recommended to consider genetic testing [26].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Several forms of 1-HD are familial. Thus, it has been determined that 10% of Norwegian patients with 1-HD have a genetic etiology. It is known that 1-HD combined with ALD is inherited in an X-linked manner, whereas CAH and APS1 are inherited in an autosomal recessive manner [22].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 GC Replacement Therapy

• In all patients with AD, it is recommended to prescribe GC therapy [70-91,96].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: The characteristics of drugs that can be used for the replacement therapy of glucocorticoid deficiency are given in Table 4. The calculation of the equivalent dose of drugs can be performed using the online calculator: https://clincalc.com/Corticosteroids/?example.

Table 4. Characteristics of tablet preparations that can be used for the replacement therapy of glucocorticoid deficiency [1,60].

• In patients with 1-HD, compensation for GC deficiency is recommended to be assessed solely on the basis of clinical signs: changes in body weight and blood pressure, presence/absence of weakness, and symptoms of hypercortisolism. Serial hormone level testing is not recommended [26].

URG CLoE 5Level of recommendation validity C (level of evidence – 5)

Comments: Symptoms of drug overdosage include weight gain, insomnia, and edema. Deficiency is characterized by nausea, decreased appetite and weight, somnolence, and hyperpigmentation. To determine the timing, dose, and frequency of medication administration, it is necessary to take a detailed history from the patient regarding their usual work and rest routine, presence of weakness, decreased concentration, daytime sleepiness, and other changes in condition throughout the day. Measuring blood ACTH levels to monitor therapy is not recommended, as ACTH levels may increase even with adequate treatment. Measurement of total blood cortisol levels during treatment may only be used when malabsorption syndrome is suspected (e.g., when taking medications that affect the half-life) in order to adequately select the dose [26].

Measurement of free urinary cortisol levels to monitor the adequacy of GC replacement therapy is also not recommended [60,93]. This indicator reflects the breakdown of the GC-CBG complex, which depends on numerous factors. At the same time, high 24-hour urinary cortisol levels can occur even when serum levels of this hormone are low.

• For the treatment of primary adrenal insufficiency, it is recommended to prescribe hydrocortisone** (15-25 mg daily) or #cortisone (20-35 mg daily) orally in two or three divided doses per day: it is recommended to administer the highest dose in the morning upon waking, the second in the evening (around 16:00) for a twice-daily regimen, or at noon and in the afternoon (closer to evening) for a three-times-daily regimen. In individual cases, an increase in the frequency of administration and dosage of the drug is possible [60,70-90,94-96].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: GCs are secreted in a pulsatile and circadian rhythm, with the highest peak in the morning and the lowest around midnight. In adults, cortisol secretion depends on age and body composition and averages 5–8 mg/m²/day [71-74], which is equivalent to 15-25 mg/day of hydrocortisone** or 20-35 mg/day of #cortisone for oral formulations (with a trend toward a lower threshold).

Hydrocortisone** and prednisolone** are active GCs, whereas the activation of #cortisone requires type 1 11-beta-hydroxysteroid dehydrogenase (a liver enzyme). Therefore, replacement therapy with inactive GCs can lead to significant pharmacokinetic variability in patients, but this has not yet been studied in detail [78].

Due to the short plasma half-life of hydrocortisone** (approximately 90 minutes), multiple administrations are recommended to closely approximate physiological conditions. The first and largest dose should be taken upon waking, the second in the afternoon, and, in the case of a three-dose regimen, the third, last, and smallest dose no later than 4–6 hours before bedtime. This regimen is closer to the circadian rhythm, and a lower final dose will help avoid sleep disorders and insulin sensitivity issues [76-77].

All studies comparing dosing regimens were performed on small patient cohorts, making it difficult to determine the most adequate one. Taking into account the normal fluctuating range of cortisol throughout the day, Peacey et al. and Howlett et al., independently of each other, recommended hydrocortisone** 10 mg upon waking, 5 mg around noon, and 5 mg in the early evening [79-80]. Some patients require a higher GC dose, which should be approached with caution. In a study where a single morning dose of hydrocortisone** in patients with adrenal insufficiency was calculated based on body surface area (5.5 mg/m²) or weight (0.12 mg/kg), cortisol levels remained within the normal range for more than 6 hours, almost like the healthy control group, unlike a fixed morning dose of 10 mg [81]. Consequently, dose titration based on weight or body surface area is more physiological than a fixed regimen. Laureti et al. [82] and Barbetta et al. [83] determined that administering #cortisone 3 times a day reduced ACTH levels to a greater extent, and the diurnal cortisol fluctuations corresponded more closely to the endogenous cortisol rhythm compared to a twice-daily regimen. One double-blind, randomized, crossover study evaluated twice-daily and four-times-daily hydrocortisone** regimens [84] and concluded that cortisol pharmacokinetics were more physiological with the four-times-daily regimen, which was unexpectedly better tolerated by the participating patients. Alonso et al. [85], conversely, determined that health-related quality of life (HRQoL) questionnaire scores were either similar or, in some parameters, worse on the three-times-daily regimen compared to the twice-daily hydrocortisone** regimen. Thus, based on prevailing research results and clinical experience, 3- and 4-times-daily dosing regimens are more physiological and preferred for primary adrenal insufficiency replacement therapy. A weight-based dose is highly likely to keep cortisol levels within the reference range. However, studies confirming this recommendation are insufficient, and less frequent dosing may be associated with better patient compliance [86].

Major pharmacokinetic comparative studies in adrenal insufficiency have only been conducted for hydrocortisone** and #cortisone. The pharmacokinetic curve of #cortisone is less steep and has a later onset than that of hydrocortisone** [78,87], which may be more preferable given the short half-life of hydrocortisone**.

• As an alternative to hydrocortisone**, especially for non-compliant patients with primary adrenal insufficiency, it is recommended to prescribe #prednisolone** (3-5 mg/day), orally once or twice daily [92].

GGR ALEL 3Grade of Recommendation A (Level of Evidence – 3)

Comments: In cases where the patient shows no improvement in terms of quality of life and performance, or finds it difficult to adhere to a multi-dose regimen, a 1-2 times daily administration of #prednisolone** at a dose of 3-5 mg per day can be offered. Retrospective studies of patients taking higher doses of GCs, including #prednisolone** or dexamethasone**, showed an unfavorable prognosis regarding metabolic disorders, including weight gain, dyslipidemia, and diabetes mellitus (DM) [88]. According to a systematic review [92], #prednisolone** is a safe and effective alternative to hydrocortisone**, although an increase in the drug dose is associated with the risk of dyslipidemia and cardiovascular disease. In a 10.0 ± 4.9-month follow-up of patients receiving #prednisolone** at 3-6 mg/day and hydrocortisone** at 15-30 mg/day, a significant increase in total cholesterol and low-density lipoproteins was detected in the first group [97]. However, prospective studies comparing the safety and efficacy of #prednisolone** and hydrocortisone** over a longer period have not yet been conducted.

• The administration of dexamethasone** to patients with primary adrenal insufficiency is not recommended due to the high risk of overdosage [98].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Cushingoid side effects are most frequently manifested during dexamethasone** therapy [98].

3.2 Mineralocorticoid Replacement Therapy

• All patients with primary adrenal insufficiency are recommended mineralocorticoid therapy with #fludrocortisone** (starting daily dose of 50-100 mcg), without restricting salt intake [27,90-91,99-108].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: The synthetic mineralocorticoid #fludrocortisone** is used in replacement therapy, but its use in primary adrenal insufficiency has not been sufficiently studied. #Fludrocortisone** is usually prescribed once in the morning, since the level of endogenous aldosterone is normally highest at this time, by analogy with the circadian rhythm of cortisol [99]. The daily dose of #fludrocortisone** depends on fluid and electrolyte intake/loss and is usually 0.05-0.2 mg. During excessive sweating, for example, in a hot climate, a temporary dose increase of 50-100% or an increase in the intake of salty foods may be required. During therapy with #prednisolone**, a higher dose of #fludrocortisone** may be required than during treatment with hydrocortisone** and, even more so, during treatment with dexamethasone**, which lacks mineralocorticoid activity [26].

#Fludrocortisone** therapy in primary adrenal insufficiency may be omitted in exceptional cases (familial glucocorticoid deficiency and certain forms of congenital adrenal hyperplasia).

• Compensation for mineralocorticoid deficiency in patients with primary adrenal insufficiency is recommended to be assessed by clinical signs (salt craving, orthostatic hypotension, edema, arterial hypertension) and the results of blood sodium and potassium levels and, in complex cases, blood renin levels [26,101,102].

GCR CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Patients should be asked about cravings for salty foods and presyncopal states, blood pressure should be measured in the sitting and standing positions, and patients should be examined for peripheral edema (which has low sensitivity). General well-being, normal electrolyte and blood pressure levels, and the absence of orthostatic hypotension are signs of adequate compensation for mineralocorticoid deficiency. In addition, a renin level in the upper reference range is also a useful marker of compensation [26,101,102]. It must be taken into account that licorice and grapefruit juice enhance the mineralocorticoid effect of hydrocortisone** and should be avoided [103]. Phenytoin** enhances the metabolism of #fludrocortisone**, necessitating an increase in its dose [104].

Comments: Primary adrenal insufficiency can be combined with essential arterial hypertension (AH) [105]. In a patient with primary adrenal insufficiency and hypertension, the adequacy of both mineralocorticoid and glucocorticoid therapy must be assessed, as an overdose of either drug can raise blood pressure. In addition, the patient may be advised to limit excessive intake of salty foods and fluids [60].

If blood pressure does not normalize after adjusting replacement therapy (reducing the #fludrocortisone** dose), antihypertensive agents should be prescribed, predominantly those acting on the renin-angiotensin system: angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors [105]. Second-line drugs are selective calcium channel blockers with a predominantly vascular effect (dihydropyridine derivatives). Diuretics are prescribed in exceptional cases, and aldosterone antagonists are contraindicated in patients with primary adrenal insufficiency [26].

3.3 Management during pregnancy

• For all pregnant women with primary adrenal insufficiency, it is recommended to consider increasing the dose of hydrocortisone**, especially in the third trimester [26].

Level of Evidence CGrade of Recommendation 5Level of Evidence C (reliability of evidence – 5)

Comments: During normal pregnancy, cortisol levels gradually increase (2–3 fold) starting from the first trimester due to elevated corticosteroid-binding globulin (CBG) levels [59,109]. From the 22nd week of pregnancy, free cortisol levels begin to increase significantly [109,110]. Cortisol levels return to baseline immediately after delivery [59]. Inadequate replacement therapy during pregnancy may lead to an adrenal crisis [106]. Currently, there is limited evidence for optimizing primary adrenal insufficiency replacement therapy in pregnant women; however, most specialists recommend a 20–40% increase in the hydrocortisone** dose starting from the 24th week of pregnancy in accordance with physiological changes [26].

Mineralocorticoid requirements during pregnancy are difficult to assess due to the similarity of symptoms (e.g., edema or postural hypotension). Blood or urine sodium and potassium levels can be tested, but blood renin levels, which physiologically increase during pregnancy, cannot be used for monitoring. It is known that renin during normal pregnancy increases [58] as progesterone levels also rise, exerting some antimineralocorticoid effect. Consequently, pregnant patients with primary adrenal insufficiency may require an increased mineralocorticoid dose [111]. In practice, however, this is rarely necessary, as the increased dose of hydrocortisone** covers the additional mineralocorticoid requirement [26].

• During pregnancy, it is recommended to prescribe hydrocortisone** to patients with primary adrenal insufficiency for glucocorticoid replacement therapy [26].

URG CLoE 5Level of recommendation validity C (level of evidence – 5)

Comments: #Cortisone and #prednisolone** may also be used.

• During pregnancy, the prescription of dexamethasone** for glucocorticoid replacement therapy is not recommended in patients with primary adrenal insufficiency [26].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Dexamethasone** is contraindicated during pregnancy because it is not inactivated by placental 11-beta-hydroxysteroid dehydrogenase type 2 and can cross the placenta to the fetus [26].

• During labor, it is recommended to administer a stress dose of hydrocortisone** to patients with primary adrenal insufficiency, similar to surgical interventions [59,112].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: Administration of the stress dose of hydrocortisone** should be performed at the onset of active labor (cervical dilation of 4 cm and/or contractions every 5 minutes for an hour): 100 mg of hydrocortisone** is administered IV bolus, followed by a continuous IV infusion of 200 mg of hydrocortisone** over 24 hours [59,112]. After delivery, the hydrocortisone** dose is gradually tapered down to the pre-pregnancy dose. During lactation, the excretion of glucocorticoids into breast milk is minimal, so physiological-dose therapy cannot cause potential harm to the infant [113].

1.4 Management of Addisonian crisis

In a retrospective analysis of 444 patients with adrenal insufficiency, the incidence of adrenal crises averaged 6.6 episodes per 100 patient-years [114]. The most common causes of crises are infections: gastrointestinal tract in 32.6% and other localizations in 24.3%. In another observation of more than 1,000 patients with primary adrenal insufficiency, 8% of patients were diagnosed with a crisis annually, with gastrointestinal and acute respiratory viral infections being the most common triggers [115]. A prospective study comprising 768 patient-years reported 8.3 crises per 100 patient-years [116]. Thus, approximately every 12th patient will experience a life-threatening crisis in the coming year, and the mortality rate from crises may be approximately 0.5 episodes per 100 patient-years.

In a cross-sectional study based on a questionnaire of 122 patients with 1-OHD and classic CAH (including children), 5.8 adrenal crises per 100 patient-years were recorded [117]. In children, the most common cause of crises was respiratory infections, and in adults, gastrointestinal infections. The average time from the onset of initial symptoms to an overt adrenal crisis is 1 day.

• In severely ill patients with symptoms of AC, it is recommended to initiate therapy immediately without waiting for laboratory test results [27,28].

URG CLoE 5Level of recommendation validity C (level of evidence – 5)

Comments: Untimely treatment significantly increases mortality and therefore must not be delayed until test results are available. In severe patients with clinical signs of AI, blood should be drawn first for diagnostic purposes and, without waiting for the results, GC treatment should be initiated. Before prescribing GCs, ACTH and cortisol levels are primarily investigated. Confirmatory testing can be performed after treatment, against the background of temporary discontinuation of therapy, once the patient's condition is stabilized [27,28].

• In patients with AC, it is recommended to administer hydrocortisone** therapy. As an alternative, equivalent doses of #prednisolone** and, in exceptional cases, dexamethasone** may be prescribed [17,34,60].

GCR CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: Currently, 3 main GCs are used for IV administration: hydrocortisone**, #prednisolone**, and dexamethasone**. Synthetic corticosteroids, compared with hydrocortisone**, bind less actively to plasma proteins, undergo slower hepatic degradation, and therefore possess a more pronounced effect. An important difference between the drugs is their mineralocorticoid effect (Table 5). Hydrocortisone** has the greatest sodium-retaining effect, making its use preferable for patients with acute adrenal insufficiency (AAI). At a dosage of more than 40-50 mg per day, which is equivalent to 100 mcg of #fludrocortisone**, hydrocortisone** is able to fully provide the body with mineralocorticoid action [26]. #Fludrocortisone** is prescribed after the hydrocortisone** dose reaches less than 40-50 mg per day, the #prednisolone** dose – less than 12.5 mg per day, and the dexamethasone** dose – regardless of the dose from the first day of AK treatment [118].

Table 5. Glucocorticoid and mineralocorticoid effects of main glucocorticoid drugs [119].

In the absence of water-soluble drugs for IV administration, treatment is carried out with drugs intended for IM administration.

It is important to remember that in adrenal crisis, the administration of adrenergic and dopaminergic agents is ineffective because glucocorticoid deficiency reduces vascular reactivity to norepinephrine and other vasoconstrictor influences.

• In patients with suspected adrenal crisis, it is recommended to parenterally administer 100 mg of hydrocortisone**, perform hydration, and subsequently administer 200 mg of hydrocortisone** during the first 24 hours (continuously via infusion pump or divided into injections every 6 hours) [17,26] (Tab. 6).

GCR CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: An inadequate increase in GC dose during a crisis is potentially life-threatening. However, currently, no systematic studies have been conducted to determine the adequate dose in adrenal crisis, so the recommended therapy is largely chosen empirically [26].

The volume of glucocorticoid therapy proposed in Tab. 6 for the treatment of adrenal crisis is undoubtedly of much higher value than the potential side effects of short-term overdose.

Table 6. Adjustment of replacement therapy in primary adrenal insufficiency [17,64,120-122].

The principles of analgesic therapy in patients with primary adrenal insufficiency do not differ from those in the general population.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

In the majority of patients against the background of adequate treatment, health-related quality of life is reduced [122]. Moreover, health-related quality of life is inversely proportional to the duration of diagnostic delay (sometimes spanning several years) [123].

Comments: Most studies confirm that, overall, mortality in patients with primary adrenal insufficiency is higher than in the general population [26]. In all these studies, the primary cause of death is adrenal crisis. Therefore, patient education on crisis prevention and emergency glucocorticoid administration is extremely necessary [124]. It has been shown that a significant proportion of patients (46%) were not adequately educated on corticosteroid administration in stress situations [26]. Thus, repeated patient training is required during each outpatient visit.

A large review determined that approximately one-third of all urgent conditions in patients with primary adrenal insufficiency occurred outside the home. Only 12% of patients with adrenal crisis self-administered glucocorticoids, while 2/3 of patients waited for medical personnel to provide treatment. In another study (in the UK) out of 26 patients with primary adrenal insufficiency, only two patients were able to independently administer an intramuscular hydrocortisone** solution, and 10 patients stated they had never been trained to perform injections. In a survey of 254 patients with primary adrenal insufficiency from Germany, only 63% considered themselves well-informed about actions to take in urgent/stress situations [26].

Specific medical rehabilitation is not required for patients with primary adrenal insufficiency. Rehabilitation measures may include clinical and psychological counseling.

5. Prevention and Dispensary Observation

• To prevent adrenal crisis in patients with primary adrenal insufficiency, it is recommended to adequately adjust the glucocorticoid dose depending on the severity of the intercurrent illness and the degree of stress (Table 6) [125-136].

URG CLoE 5Level of recommendation validity C (level of evidence – 5)

Comments: Numerous studies have proven an increase (to varying degrees) in endogenous cortisol levels during anesthesia, surgical interventions, trauma, and critical illnesses [125-129]. Currently, randomized trials to determine the exact glucocorticoid dose under conditions of increased demand have not yet been conducted. The dose is usually calculated based on the severity and duration of the stress factor. It is believed that under physiological conditions, the adrenal glands secrete 75-100 mg of cortisol per day in response to complex surgery and 50 mg per day for minor invasive procedures. Thus, the glucocorticoid dose during surgical interventions should be no less than the secretion of healthy adrenal glands during surgery, and must be sufficient to cover sudden additional demands in case of complications. Furthermore, there is no evidence that such doses lead to adverse consequences (complications), and at the same time, there are no studies indicating that lower doses are safer. One review showed that cortisol secretion in the first 24 hours after surgery rarely exceeded 200 mg, and the level of secretion correlated with the duration and complexity of the intervention [132]. It has been proven that cortisol metabolism slows down during critical illnesses [134]. In a study of 158 intensive care unit patients and 64 controls, it was determined that total and free cortisol levels are higher in ICU patients than in control subjects due to a reduction in cortisol clearance by more than 50% and decreased inactivation of cortisol to cortisone. The causes of slowed cortisol metabolism during critical illness in patients with primary adrenal insufficiency have not yet been studied.

In case of fever, the daily oral glucocorticoid dose is increased two- or threefold until condition normalizes, usually within two to three days. If the patient is unable to take oral medication due to vomiting or trauma, parenteral administration (IV, IM, or SC) of glucocorticoids is indicated during this period. Mineralocorticoid supplementation is not required if the daily dose of hydrocortisone** exceeds 40-50 mg [26].

A single-center, open-label, randomized, crossover study in 12 patients with primary adrenal insufficiency showed that both subcutaneous and intramuscular administration of #hydrocortisone** yield nearly identical pharmacokinetic results. However, subcutaneous administration requires two injections rather than one as in intramuscular administration, and it took longer to reach a cortisol level of 1000 nmol/L (36 mcg/dL) (22 and 11 minutes, respectively) [135-136].

Concomitant therapy that affects cortisol concentration can also trigger a crisis. Therefore, in such cases, the issue of adjusting the glucocorticoid dose should be considered. Initiating levothyroxine sodium** replacement therapy can precipitate an adrenal crisis due to accelerated cortisol metabolism [26]. Clearance of cortisol is increased by medications that activate the CYP3A4 enzyme: carbamazepine**, mitotane**, St. John's wort herb extract [137].

The administration of dexamethasone** without mineralocorticoids may also precipitate an adrenal crisis, as dexamethasone** lacks mineralocorticoid activity [26].

It has been shown that patients with primary adrenal insufficiency (PAI) do not require additional hydrocortisone** intake during high-intensity physical exercise lasting up to 20 minutes [26], but for longer exertion, an additional 5–10 mg of hydrocortisone** is recommended in addition to therapy [96]. However, currently, there is no substantial evidence to support this recommendation.

• All patients with PAI are recommended to carry an identification card (medical bracelet or pendant) indicating their diagnosis and the need for glucocorticoid administration [26].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Patients must always carry a medical bracelet or pendant with basic information about their disease and treatment (which may also be encoded using a QR code) [111]. Furthermore, not all physicians may be aware of the need for immediate treatment of acute adrenal insufficiency (AAI). Therefore, it is advisable for patients to always carry an "emergency card" with simple instructions for treating AAI [138].

• All patients with PAI are recommended to have injectable glucocorticoids available for use in emergency situations [26].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• All patients with PAI are recommended to undergo dispensary follow-up by an endocrinologist at least once a year to rule out signs of inadequate therapy [26].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: The goal of treatment and monitoring is to ensure that patients have a satisfactory general well-being, can pursue their normal professional activities, and maintain a lifestyle as close to normal as possible. Regular examinations allow for the assessment of physical condition—especially regarding overreplacement or underreplacement of hormone therapy—and quality of life. Any episode of acute primary adrenal insufficiency must be thoroughly discussed.

Monitoring of replacement therapy is primarily based on clinical symptoms. With adequate therapy, the patient exhibits no hyperpigmentation, blood pressure and weight remain stable. The presence of orthostatic hypotension indicates insufficient mineralocorticoid therapy or restricted salt intake.

Routine laboratory evaluation should include blood sodium and potassium levels. Blood renin measurement can be used as an additional method for monitoring mineralocorticoid deficiency; this parameter should target the upper reference range or slightly above [26].

Currently, there is no consensus regarding the necessity of regular X-ray densitometry in patients with PAI. Specifically, in the absence of glucocorticoid overreplacement, premenopausal women and men with PAI show no decrease in bone mineral density (BMD) [108]. At the same time, increased glucocorticoid doses are associated with reduced BMD [139]. We suggest that routine X-ray densitometry for all patients with PAI is not indicated; the test is recommended only for those individuals who have experienced prolonged periods of glucocorticoid overreplacement. However, some authors [140] do not exclude the necessity of regular BMD monitoring (every 2–5 years) even for patients receiving low-dose glucocorticoid therapy.

• Patients with autoimmune etiology of PAI are recommended to undergo annual screening for other autoimmune pathologies: autoimmune thyroid disease, diabetes mellitus, hypogonadism, celiac disease, autoimmune gastritis, and vitamin B12 deficiency [141-146].

GCR CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: The elevated risk of other autoimmune disorders necessitates careful monitoring in this regard, particularly for autoimmune thyroid disease (AITD), which is observed in half of women and 25% of men with primary adrenal insufficiency (PAI). Type 1 diabetes mellitus is diagnosed in 10–15% of patients. Therefore, annual testing of blood thyroid-stimulating hormone (TSH), free thyroxine, glucose, and glycated hemoglobin levels is required [141-144]. It should be noted that an elevated TSH level may be recorded in primary adrenal insufficiency (PAI). In such cases, an elevation up to 10 mIU/L inclusive is generally due to the loss of the inhibitory effect of glucocorticoids on TSH secretion and does not require medical correction [147].

To rule out hypoparathyroidism, annual blood testing for total calcium and albumin (with calculation of albumin-corrected calcium) is indicated. Given the high prevalence of 25-OH vitamin D deficiency in the cohort of patients with autoimmune PAI [148], an annual blood test for 25-OH vitamin D is also recommended.

Women should be informed about the risk (8%) of premature ovarian insufficiency [141]. Betterle et al. demonstrated that premature ovarian insufficiency was diagnosed in 20.2% of 258 women with PAI, in 20 of 49 (40.8%) with APS1, in 6 of 18 (33.3%) with APS4, in 26 of 163 (16%) with APS2, but in none of 28 with isolated PAI [149]. Although CYP11A1 is expressed in all steroidogenic tissues, it has been proven that the presence of autoantibodies against this protein correlates with the presence of hypogonadism [150]. However, the predictive value of CYP11A1 is questionable. For instance, Reato et al. [149] determined that only 3 out of 13 seropositive female patients were diagnosed with hypogonadism over 8 years of follow-up. Unlike patients with non-autoimmune hypogonadism, patients with PAI preserve follicular function for several years after diagnosis establishment [151]. This provides an opportunity for oocyte cryopreservation for in vitro fertilization. Furthermore, to assess ovarian reserve (and, accordingly, for early detection of premature ovarian insufficiency), annual blood testing for anti-Müllerian hormone is recommended for female patients with PAI. If hypergonadotropic hypogonadism is suspected, serum follicle-stimulating and luteinizing hormone levels, as well as blood estradiol (E2) levels, must be measured.

Patients with PAI require a comprehensive complete blood count annually. Due to autoimmune gastritis, vitamin B12 deficiency is frequently detected; therefore, annual determination of blood vitamin B12 (cyanocobalamin) levels is additionally performed. If vitamin B12 deficiency is suspected or detected, it is also advisable to test for holotranscobalamin, homocysteine, methylmalonic acid, and antibodies against gastric parietal cells and intrinsic factor of Castle [26].

If clinical symptoms of celiac disease develop, it is necessary to determine the blood levels of antibodies to tissue transglutaminase and total IgA [26,142,145-146].

Vitiligo and alopecia are frequently detected and are considered markers of autoimmune pathology [26].

Given the risk of developing autoimmune liver and kidney diseases, annual determination of aspartate aminotransferase and alanine aminotransferase activities and blood creatinine levels is indicated.

• Pregnant women with adrenal insufficiency are recommended to be monitored by an endocrinologist at least once per trimester to rule out clinical symptoms of inadequate therapy [26].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

6. Organization of Medical Care

Medical care, except for care provided within the framework of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Public Health Protection in the Russian Federation."

Indications for hospitalization in a medical organization (form: emergency, conditions: inpatient):

1) Adrenal crisis;

2) Suspected adrenal crisis;

3) Newly diagnosed primary adrenal insufficiency (in the absence of suspected adrenal crisis);

4) Severe glucocorticoid or mineralocorticoid overdose.

Indications for hospitalization in a medical organization (form: planned, conditions: inpatient):

1) Presence of mild signs of inadequate glucocorticoid or mineralocorticoid therapy (in cases where outpatient therapy adjustment is ineffective).

Indications for discharging a patient from a medical organization:

1) Persistent improvement in condition (satisfactory general well-being, absence of signs of inadequate therapy) and normal electrolyte panel values, when the patient can continue treatment in an outpatient clinic or at home without detriment to health;

2) If there is a necessity to transfer the patient to another healthcare organization;

3) gross violation of the hospital regime;

4) Upon the written request of the patient or their legal representative, provided that discharge does not threaten the patient's life and is not dangerous to others. In this case, discharge may be carried out only with the permission of the chief physician of the hospital or their deputy for medical work.

7. Additional Information

7.1 Classification of autoimmune adrenal insufficiency

Betterle et al. [152], based on clinical and laboratory data, proposed a classification of autoimmune adrenal insufficiency (AAI), identifying 3 main stages of the disease. At the initial stage (so-called potential adrenal insufficiency), in individuals with genetic predisposition exposed to environmental trigger factors [21,153], autoimmune aggression reactions are initiated with the formation of antibodies to P450c21. Clinical manifestations and hormonal changes are absent at this stage.

At the next subclinical (latent) stage of adrenal insufficiency, destruction of the cells of the zona glomerulosa and subsequently the zona fasciculata of the adrenal cortex occurs [152]. At the same time, the disease remains subclinical for a long time: symptoms are mostly episodic, mild, and nonspecific. However, upon exposure to significant triggering factors, in particular during surgical interventions, labor and delivery, acute illnesses, trauma, etc., latent primary adrenal insufficiency may manifest with the development of an adrenal crisis [154-155]. Depending on the results of hormonal studies, 3 substages of subclinical adrenal insufficiency are distinguished:

1 – impairment of mineralocorticoid function (elevation of plasma renin concentration/renin activity combined with normal or decreased aldosterone level);

2 – additional impairment of glucocorticoid function is detected (decreased cortisol during stimulation testing with ACTH preparations/insulin tolerance test; ACTH level is normal or elevated);

3 – progression of glucocorticoid function impairment (decreased basal cortisol; ACTH level is normal or elevated) [152].

Upon destruction of 90% of adrenocortical cells [153], manifest adrenal insufficiency develops, which is manifested by a more pronounced clinical picture and characteristic laboratory changes [152]. In the vast majority of cases, the disease is diagnosed only at this stage, frequently during the development of an adrenal crisis (Table 7, Fig. 3).

Figure 3. Stages of autoimmune adrenal insufficiency [150] (modified by the authors).

Table 7. Classification of autoimmune adrenal insufficiency [150] (modified by the authors).

Abbreviations: N – normal; ↓ – decreased; ↑ – increased.

Currently, the presented classification is not generally accepted. Most likely, this is due to the lack of clear diagnostic criteria (primarily hormone levels reflecting hypothalamic-pituitary-adrenal axis function) for defining each stage and substage of AAI. Thus, a modification of the classification by Betterle et al. is required.

However, undoubtedly, the introduction of the AAI classification into clinical practice is extremely necessary, as it will significantly reduce patient mortality through active screening for potential and latent forms of the disease (primarily in risk groups—individuals with other autoimmune diseases) and timely treatment. In addition, it is advisable to conduct epidemiological studies dedicated to studying potential and latent forms of adrenal insufficiency in order to assess the true prevalence of the disease and determine the risk of developing this pathology in a cohort of patients with other autoimmune diseases.

Furthermore, at present, the diagnosis and treatment of primary adrenal insufficiency still require more optimal approaches.

7.2 Diagnosis of primary adrenal insufficiency

There are many unresolved issues regarding the assessment of adrenal function. In particular, there is no consensus on the need for glucocorticoid monitoring during intercurrent illnesses and the use of various medications, nor on the determination of adrenal dysfunction during critical illness.

Specifically, some authors hypothesize a key role of HPA axis dysfunction (or "relative AI") in the pathophysiology of multiple organ failure. For instance, it was hypothesized that cortisol levels are lower in critically ill patients with an unfavorable outcome compared to those with a favorable outcome. However, comparative studies have refuted this hypothesis: cortisol levels in patients with an unfavorable outcome were even higher than in the control group. It has also been suggested that the development of "relative AI" is a consequence of tissue resistance to GCs in critically ill patients. However, there are currently no standard methods for assessing GC activity in tissues. Thus, the existence of "relative AI" or "critical illness-related corticosteroid insufficiency (CIRCI)" remains controversial, and some authors do not recommend routine assessment of adrenal function in this category of patients [156].

Clinicians need a more reliable biochemical marker of AI. Currently, two avenues show promise. The first is the measurement of salivary free cortisol [26]. Assessing morning salivary free cortisol can be used as a second-line method or as an additional test in complex cases. However, further studies are needed to confirm these findings.

The second avenue involves the widespread adoption of specific diagnostic testing: liquid chromatography-tandem mass spectrometry (LC-MS/MS), which should provide better standardization in cortisol measurement. Such methods are relatively free from analytical interferences associated with cross-reactivity inherent in immunoassays [157].

7.3 Perspectives on Replacement Therapy for Primary Adrenal Insufficiency

7.3.1 Androgen Replacement Therapy

In women, the adrenal gland is the sole source of androgen secretion (DHEA and androstenedione). Consequently, adrenal insufficiency also manifests as androgen deficiency. DHEA is activated to DHEA-S in peripheral tissues and gonads with the participation of the sulfotransferase enzyme. The physiological serum concentration of DHEA-S peaks between the ages of 20 and 30, with a gradual decline regardless of the onset of menopause. DHEA is a precursor to sex hormones (estrogens and androgens). In addition, this hormone binds directly to sex steroid receptors, activates them, and increases their number. Furthermore, studies suggest that in tissues containing both estrogen and androgen receptors, DHEA predominantly activates estrogen receptors [158]. DHEA is also activated in the brain, where its metabolite is classified as a neurosteroid because it affects γ-aminobutyric acid receptors and exerts an antidepressant effect. In rodent studies, DHEA restored memory impairment induced by perinatal cocaine exposure or transient perinatal ligation of the common carotid arteries by activating brain σ1-receptors.

According to experimental animal data, DHEA has a positive effect on maintaining muscle mass and reduces the risk of obesity, diabetes mellitus, systemic lupus erythematosus, and chemical-induced cancers (colon cancer, lung cancer, skin papilloma). These effects of DHEA are hypothesized to be mediated by influencing the number of receptors (hepatic nuclear receptors, PPARα, etc.) that regulate CYP gene transcription. Additionally, by acting on PPARs, DHEA enhances fatty acid metabolism. DHEA-S levels are known to be inversely proportional to cardiovascular risk, morbidity, and mortality. This effect is presumably due to the activation of NO synthase [158].

Furthermore, DHEA reduces the production of reactive oxygen species in rat aortic smooth muscle cells, thereby inhibiting angiotensin II-induced inflammation. DHEA also promotes an increase in bone mineral density by stimulating osteoblast differentiation (via enhanced transcription of the insulin-like growth factor 1 gene) and inhibiting osteolysis (via reduced interleukin-6 secretion) [158].

Thus, the physiological significance of DHEA is not limited exclusively to its conversion into sex steroids. This hormone is presumably a signaling molecule, as it can act directly on cells.

Daily single oral administration of DHEA in primary AI restores androgen and precursor levels to normal values. Studies have shown that DHEA therapy in primary AI can improve quality of life and mood, and reduce levels of depression and anxiety. A systematic review and meta-analysis of randomized placebo-controlled trials showed no significant clinical benefit of such therapy for all women with primary AI, but a considerable number of scientific papers have reported positive effects on libido and the restoration of pubarche in young girls undergoing DHEA therapy for primary AI [25, 159]. However, long-term studies of women with primary AI taking DHEA are currently extremely scarce.

DHEA administration (as a dietary supplement) at a dose of 25–50 mg once orally in the morning is considered only for women of reproductive age with primary AI who experience decreased/absent libido, depression, anxiety, and pronounced fatigue despite optimized glucocorticoid and mineralocorticoid therapy. If the patient does not report a sustained, beneficial effect of DHEA therapy within 6 months, discontinuation of the drug is recommended. In addition to monitoring clinical efficacy and potential side effects, individual dose titration is performed by measuring morning blood levels of DHEA-S prior to medication intake. The goal of therapy is to achieve a level in the middle of the reference range for the reproductive period [26].

7.3.2 Modified-Release Glucocorticoids

Despite optimal replacement therapy, a significant number of patients continue to report objective and subjective complaints: symptoms of overdose and decompensation, reduced work capacity and physical activity (especially in women), deterioration in general health, and metabolic and cardiovascular complications, including hypertension. New modified-release hydrocortisone** preparations mimic the circadian rhythm of endogenous cortisol secretion to some extent [25, 160]. Dual-release and delayed-release preparations come closest to this [161].

Thus, dual-release hydrocortisone** has been approved for use in several European countries since late 2012. The drug is available in 5 mg and 20 mg doses and consists of an outer coat containing immediate-release hydrocortisone** and an inner core with delayed-release hydrocortisone**. The drug is taken once daily in the morning [162].

According to a phase 2 clinical trial, the cortisol profile in patients with congenital adrenal hyperplasia (CAH) taking delayed-release hydrocortisone** (at an initial dose of 10 mg at 07:00 and 20 mg at 23:00 with subsequent titration) was close to physiological. Moreover, this therapy was associated with a reduction in the required daily dose of hydrocortisone**. In the study, the drug was administered to patients in 5, 10, or 20 mg capsules [160].

In 2019, a multicenter open-label randomized phase 3 trial of this drug was completed (including 122 patients with CAH receiving delayed-release hydrocortisone** or standard therapy with various GC preparations for 6 months). Notably, standard therapy led to adrenal crisis in 4.92% of cases, whereas delayed-release therapy did not result in an adrenal crisis in any patient [163].

However, dual- and delayed-release preparations do not mimic the physiological pulsatile secretion of cortisol. Although there is evidence of a slight reduction in blood pressure and glycated hemoglobin with dual-release hydrocortisone** [161], such results may not always be reproducible in patients with primary AI.

Additionally, a modified-release prednisolone analogue is available on the pharmaceutical market in some countries. Administration of the drug is recommended at 22:00 (its action begins at approximately 03:00) [162]. According to Langenheim et al. [164], treatment with the modified-release prednisolone analogue (compared to standard prednisolone**) resulted in reduced fatigue and improved several quality-of-life parameters.

To fully assess the potential benefits of delayed-release preparations, additional, preferably double-blind, studies compared with hydrocortisone** and #cortisone are required.

7.3.3 Continuous Subcutaneous Glucocorticoid Infusion via Insulin Pumps

Continuous subcutaneous glucocorticoid infusion via insulin pumps better replicates the pulsatile and circadian rhythm [25, 165]. In an open-label crossover study, such administration of #hydrocortisone** was associated with improved health-related quality of life [165]. However, another double-blind study observed no effect on health-related quality of life [166]. Pump therapy is more labor-intensive than traditional therapy and should be offered only to patients who fail conventional treatment. Because this method of #hydrocortisone** delivery closely mimics the endogenous cortisol rhythm, blood ACTH levels can be used as a biochemical marker for optimal dosing [165]. Large randomized clinical trials are needed to strengthen the evidence base regarding the efficacy and safety of various replacement regimens for primary adrenal insufficiency [167].

7.3.4 Other Treatment Prospects

At disease onset, the majority of patients with primary adrenal insufficiency still retain some degree of endogenous cortisol secretion. It has been demonstrated that in such patients, stimulation with ATC group ACTH preparations [168] or the administration of the immunosuppressant #rituximab** [169] can restore endogenous cortisol production for a certain period. However, in a recent study [170], the combination of these drugs was ineffective in restoring adrenal cortex function. In addition, the risk of side effects from #rituximab** must be taken into account: acute renal failure, neutropenia, infusion reactions (including fatal ones), and others.

Furthermore, modern regenerative medicine technologies may be applied to treat primary adrenal insufficiency. Specifically, the literature describes a single case of successful adrenal transplantation from mother to daughter, as well as adrenal-kidney and adrenal-kidney-pancreas allotransplantation [171].

Cell therapy also holds enormous potential, enabling stem cells to differentiate into adrenocortical phenotype cells. Moreover, differentiated specialized cells (e.g., fibroblasts) can also acquire an adrenocortical phenotype (either directly or via a pluripotent cell stage). In monogenic hereditary forms of primary adrenal insufficiency, gene editing is also considered at this stage. For cell transplantation, highly biocompatible encapsulation devices are proposed to prevent rejection [171].

It should be noted that currently none of the described treatments for primary adrenal insufficiency have been introduced into clinical practice; there is no other additional information influencing outcomes in primary adrenal insufficiency.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

LEADERS:

Dedov I.I., MD, PhD, Professor, Academician of the RAS, Moscow, President of the Russian Association of Endocrinologists.

Mokrysheva N.G., MD, PhD, Professor, Corresponding Member of the RAS, Moscow, member of the Russian Association of Endocrinologists.

Melnichenko G.A., MD, PhD, Professor, Academician of the RAS, Moscow, Vice-President of the Russian Association of Endocrinologists.

TEXT AUTHORS:

Troshina E.A., MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Moscow.

Yukina M.Yu., PhD, Moscow.

Nuralieva N.F., PhD, Moscow.

EXPERTS INVOLVED IN THE DISCUSSION AND APPROVAL OF THE CLINICAL GUIDELINES:

1. Fadeev V.V., MD, PhD, Professor, Corresponding Member of the RAS, Moscow.

2. Beltsevich D.G., MD, PhD, Professor, Moscow.

3. Platonova N.M., MD, PhD, Moscow.

Conflict of interest:

The authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. endocrinologist;

2. internist;

3. district general practitioner;

4. district general practitioner of an occupational medical district;

5. general practitioner (family physician);

6. health station physician;

7. emergency physician;

8. senior physician of the ambulance station (department);

9. anesthesiologist-intensivist;

10. obstetrician-gynecologist;

11. occupational district obstetrician-gynecologist;

12. surgeon;

13. diabetologist;

14. medical geneticist;

15. infectious disease physician;

16. cardiologist;

17. phthisiatrician;

18. district phthisiatrician;

19. endoscopist;

20. oncologist.

Table A2.1. Scale for assessing the levels of evidence certainty (LEC) for diagnostic methods (diagnostic interventions)

Table A2.2. Levels of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table A2.3. Grades of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Current instructions for medicinal products mentioned in these clinical guidelines can be found on the website http://grls.rosminzdrav.ru.

1. Instructions for the use of hydrocortisone** http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=c1e77d64-929d-43b9-bd72-ef9b1be5ff72&t=; http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=5d9fe173-3760-410d-a134-8f95191f133d&t=; http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=fbcbdf31-9c97-4650-8356-e8fc336729a3&t=.

2. Instructions for the use of #cortisone http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=0520e9e1-c416-4083-bd98-78a453141c12&t=.

3. Instructions for the use of #prednisolone** http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=0bae57ed-f795-4cab-ba98-0efa31cdac0b&t=; http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=5bb36449-e307-43d1-ad5a-7171d992c66a&t=.

4. Instructions for the use of dexamethasone** http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=750062c9-62ff-45c8-aa44-98d2dba6d6f8&t=; http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=e5a54a56-22c9-4336-8e19-2e521f8a29cd&t=.

5. Instructions for the use of #fludrocortisone** https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=12b63a34-d085-4f85-bd99-14a9f47b969c.

6. Instructions for the use of #glucagon** http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=5b735c6c-6854-4f5b-81fd-cdffb0eaa2c7&t=.

7. Instructions for the use of #insulin soluble [human recombinant]** http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=992ee31f-d426-48e1-b9cb-2e4cbd7b02fc&t=.

8. Procedure for the provision of medical care to the adult population in the specialty "endocrinology" (Order of the Ministry of Health of the Russian Federation No. 899n dated November 12, 2012) https://base.garant.ru/70293326/

9. Nomenclature of Positions of Medical and Pharmaceutical Workers (Order of the Russian Ministry of Health No. 1183n dated December 20, 2012 (as amended on August 1, 2014)) https://legalacts.ru/doc/prikaz-minzdrava-rossii-ot-20122012-n-1183n/.

10. Nomenclature of Medical Services (Order of the Russian Ministry of Health No. 804n dated October 13, 2017) https://minjust.consultant.ru/documents/37309?items=1&page=1.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

The adrenal gland is a paired organ that synthesizes hormones: glucocorticoids (GC), mineralocorticoids (MC), adrenal androgens, and catecholamines. GCs and MCs perform the most vital functions: ensuring the body's survival in stressful situations and maintaining normal levels of sodium, potassium, water, and blood pressure (BP). In primary adrenal insufficiency (PAI), the synthesis of adrenal hormones is impaired. In most cases, the cause of the disease is the destruction of the adrenal glands due to autoimmune damage (when the immune system malfunctions), and PAI may be associated with other autoimmune pathologies. Chronic and acute PAI are distinguished. Acute PAI, or Addisonian crisis (AC), is a critical condition with markedly pronounced symptoms. AC can be fatal!

Once the diagnosis is confirmed, the physician prescribes GC and MC medications and determines the dose, regimen, and frequency of administration. Individualized therapy selection is based on information regarding your well-being throughout the day, blood pressure readings, weight dynamics, craving for salty foods, presence of edema, and dizziness upon sudden changes in body position.

The physician will explain the specifics of temporarily self-adjusting your treatment under certain circumstances: infectious diseases, trauma, or diagnostic procedures to prevent AC. Furthermore, the physician will train you and your loved ones in providing first aid should an AC develop: the immediate administration of medication (intramuscularly) before the ambulance crew arrives. It is essential that you always carry these medications with you, along with an identification card (bracelet or pendant) containing information about your PAI and first aid instructions in the event of an AC.

The diet for patients with PAI should correspond to that of healthy individuals (balanced in caloric intake and essential nutrient content). It is recommended not to restrict salt intake (especially during hot weather) and to exclude licorice and grapefruit juice from the diet.

With adequate therapy, there are no additional restrictions regarding sports, cosmetic, or wellness procedures associated with PAI. Follow-up with an endocrinologist is mandatory for all patients with PAI.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.