Congenital adrenal hyperplasia (adrenogenital syndrome): clinical guidelines

List of Abbreviations

17-OHP - 17-hydroxyprogesterone

HLA complex - Human Leukocyte Antigens

TART - Testicular Adrenal Rest Tumors

AH - Arterial hypertension

ACTH - Adrenocorticotropic hormone

PRA - Plasma renin activity

CAH - Congenital adrenal hyperplasia

GC - Glucocorticoids

H-CAH - Hypertensive form of congenital adrenal hyperplasia

DOC - Desoxycorticosterone

GI - Gastrointestinal tract

BMI - Body mass index

CHCC - Combined hormonal contraceptives

HDL - High-density lipoproteins

MC - Mineralocorticoids

NC-CAH - Non-classic congenital adrenal hyperplasia

GIA - External genitalia

IGT - Impaired glucose tolerance

OGTT – Oral glucose tolerance test

TC – Total cholesterol

DM – Diabetes mellitus

Terms and Definitions

Sequencing is the determination of the nucleotide sequence in a DNA molecule or the amino acid sequence in a protein molecule.

Compound heterozygosity is a state of the organism in which the same locus on homologous chromosomes is represented by different mutant alleles.

Mutation (pathogenic variant) is an alteration in hereditary structures (DNA, gene, chromosome, genome):

• frameshift – leading to disruption of the normal reading frame of coding triplets (deletions or insertions of DNA segments whose sizes are not multiples of three bases); usually leads to a change in the amino acid sequence of the protein;

• splicing – affecting a splice site and leading to aberrant excision of an intron or deletion of a functionally significant exonic sequence from the RNA molecule.

Neonatal screening for 17OHP enables the diagnosis of classic forms of 21-hydroxylase deficiency. At the second stage of screening (retesting), the determination of the multisteroid profile by tandem mass spectrometry is preferred.

In the Russian Federation, neonatal screening for 21-hydroxylase deficiency is carried out in accordance with the Order of the Russian Ministry of Health and Social Development No. 185 dated March 22, 2006. Screening begins in the maternity hospital: a few drops of blood are taken from each newborn onto a special filter paper card, which is sent to a specialized laboratory for testing. In full-term infants, blood is collected on the 4th day of life, and in premature infants on the 7th day of life. Different threshold levels of 17OHP are used depending on birth weight, defined for each laboratory. Information about a positive screening result is communicated to the child's local outpatient clinic, after which a repeat blood sample is taken for retesting.

Introitoplasty – creation of the vaginal introitus vestibule.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by a defect in one of the enzymes or transport proteins involved in cortisol synthesis in the adrenal cortex.

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

The cause of any form of CAH is pathogenic variants in genes responsible for the synthesis of enzymes or transport proteins involved in cortisol biosynthesis.

CAH due to 21-hydroxylase deficiency is caused by pathogenic variants in the CYP21 (CYP21A2) gene, located in the HLA complex on the short arm of the 6th chromosome (6p21.3). More than 200 pathogenic variants of CYP21A2 have been described. The majority (75–80%) of these are point microconversions between the CYP21 gene and its homologous pseudogene CYP21P (CYP21A1P, CYP21A), while only 20–25% are major mutations—deletions and conversions leading to more severe forms of CAH. In addition, rarer sporadic pathogenic variants exist.

In most cases of 21-hydroxylase deficiency, a phenotype-genotype correlation is observed. Thus, pathogenic variants accompanied by the preservation of more than 5% of enzyme activity lead to the non-classic form of the disease; large deletions and splicing mutations, in which enzyme activity is reduced to 0–2%, lead to the classic forms. However, it must be remembered that the same pathogenic variants can lead to different phenotypic manifestations (Table 1) [1,2,3,4].

Table 1. Phenotypic correlation of the most frequent CYP21 gene pathogenic variants in various forms of CAH.

In cases of compound heterozygous states, the clinical presentation is most often determined by the "lighter" pathogenic variant. Unlike in childhood, mineralocorticoid receptor sensitivity is somewhat higher in adults, so those pathogenic variants that in childhood typically caused a clinical picture characteristic of the salt-wasting form may manifest in adults as the simple virilizing form (Table 2).

Table 2. Phenotypic manifestations of various genotypes in adult patients with 21-hydroxylase deficiency in the Russian Federation [4].

Hypertensive CAH develops due to pathogenic variants of the CYP11B gene located on chromosome 8 (8q21-q22). There are 2 isoforms of the enzyme functioning in the human body, sharing 93% identity. Type 1 11β-hydroxylase (CYP11B1) is produced in the zona fasciculata of the adrenal cortex, is responsible for cortisol biosynthesis, and is regulated by ACTH via negative feedback. It is precisely the deficiency of type 1 11β-hydroxylase that leads to the development of the hypertensive form of CAH. The most frequent pathogenic variant in the CYP11B1 gene is R448H.

An isolated defect of the second isoform of 11β-hydroxylase (aldosterone synthase) is not classified as CAH.

Impaired cortisol synthesis due to 21-hydroxylase deficiency leads to ACTH hypersecretion via negative feedback, which stimulates the adrenal cortex and causes its hyperplasia. Concurrently, due to the existing enzymatic block in the steroidogenesis pathway, precursors of cortisol and androgens whose synthesis pathways are not blocked accumulate (Fig. 1a, 1b, 1c) [1,2,4].

Notes. P450scc (CYP11A1) – 20,22-desmolase, or cholesterol side-chain cleavage enzyme; StAR – steroidogenic acute regulatory protein; P450c17 (CYP17A1) – 17α-hydroxylase;

P450c17 + b5 – 17,20-lyase (CYP17A1) + cytochrome b5; 3βHSD2 – 3-beta-hydroxysteroid dehydrogenase type 2; 17βHSD5 – 17-beta-hydroxysteroid dehydrogenase type 5; P450c21 (CYP21A2) – 21-hydroxylase; P450c11β (CYP11B1) – 11β-hydroxylase; 11βHSD2 – 11-beta-hydroxysteroid dehydrogenase type 2; P450c11AS (CYP11B2) – aldosterone synthase; DHEA – dehydroepiandrosterone; 5αR2 – 5-alpha-reductase 2.

Notes. P450scc (CYP11A1) – 20,22-desmolase, or cholesterol side-chain cleavage enzyme; StAR – steroidogenic acute regulatory protein; P450c17 (CYP17A1) – 17α-hydroxylase; P450c17 + b5 – 17,20-lyase (CYP17A1) + cytochrome b5; 3βHSD2 – 3-beta-hydroxysteroid dehydrogenase type 2; 3αHSD – 3-alpha-hydroxysteroid dehydrogenase; 17βHSD5 – 17-beta-hydroxysteroid dehydrogenase type 5; P450c21 (CYP21A2) – 21-hydroxylase; P450c11β (CYP11B1) – 11β-hydroxylase; 11βHSD2 – 11-beta-hydroxysteroid dehydrogenase type 2; P450c11AS (CYP11B2) – aldosterone synthase; DHEA – dehydroepiandrosterone; 5αR1 – 5-alpha-reductase 1; 5αR2 – 5-alpha-reductase 2.

Figure 1c. Pathogenesis of CAH due to 21-hydroxylase deficiency (abbreviated version).

In the hypertensive form of CAH (11β-hydroxylase deficiency, P450c11β), the pathogenesis is similar to that of 21-hydroxylase deficiency. The main difference is that in the hypertensive form, the block is located further downstream, disrupting the conversion of deoxycorticosterone (DOC) to corticosterone. It is precisely the excess of DOC, which possesses mineralocorticoid activity, that is considered the primary cause of blood pressure elevation in CAH (Fig. 2). The potential role of 18-hydroxy and 19-oxo metabolites of DOC, which also possess mineralocorticoid properties, is also being discussed.

Figure 2. Pathogenesis of CAH due to 11β-hydroxylase deficiency.

1.3 Epidemiology of the Disease or Condition

The prevalence of classic forms of 21-hydroxylase deficiency ranges from 1:14,000 to 1:18,000 live births worldwide. According to neonatal screening data in the Russian Federation, the prevalence of the disease in individual regions ranges from 1:5,000 to 1:12,000, and nationwide is 1:9,638 live births. The non-classic form of CAH is more common, occurring in 1:500 to 1:1,000 of the general population, and in certain isolated ethnic groups characterized by a high percentage of consanguineous marriages (e.g., Ashkenazi Jews), the prevalence can reach 1:50 to 1:100 [2,3,5].

Ranking second is the hypertensive form of CAH (hypertensive CAH) — 11β-hydroxylase deficiency, which according to literature occurs in approximately 1 per 100,000 newborns, and among Moroccan Jews, 1 in 5,000–7,000 newborns. In Russia, the prevalence of hypertensive CAH has not been studied.

Other forms have been described only as individual clinical case reports and cannot be systematized for the development of clinical guidelines.

1.4 Features of Coding the Disease or Condition

Adrenogenital disorders (E25):

E25.0 - Congenital adrenogenital disorders associated with enzyme deficiencies;

E25.8 - Other adrenogenital disorders;

E25.9 - Adrenogenital disorder, unspecified.

1.5 Classification of the disease or condition

Currently, 7 forms of CAH have been described:

• lipoid adrenal hyperplasia (StAR protein deficiency);

• 20,22-desmolase deficiency;

• 17α-hydroxylase / 17,20-lyase deficiency;

• 3β-hydroxysteroid dehydrogenase deficiency;

• 21-hydroxylase deficiency;

• 11β-hydroxylase deficiency;

• oxidoreductase deficiency.

The most common form of CAH, accounting for more than 90% of cases, is caused by 21-hydroxylase deficiency. In turn, CAH due to 21-hydroxylase deficiency is subdivided into non-classic and classic (simple virilizing and salt-wasting) forms.

1.6 Clinical presentation of the disease or condition

The clinical presentation of 21-hydroxylase deficiency consists of two main components: adrenal insufficiency, resulting from impaired synthesis of cortisol and aldosterone, and hyperandrogenism, caused by excessive production of unblocked sex steroids. Depending on the residual activity of the 21-hydroxylase enzyme, two classic forms of CAH are distinguished: salt-wasting and simple virilizing.

The salt-wasting form is characterized by a deficiency of both mineralocorticoids and glucocorticoids. Furthermore, deficiency of the latter, in the absence of replacement therapy, leads to a life-threatening condition—a salt-wasting crisis, caused by decreased sodium reabsorption in the renal tubules, reduced circulating blood volume, lowered blood pressure, and severe dehydration. Adrenal crises are most severe in childhood; their frequency decreases with age, although in stressful situations—such as surgery, trauma, or intercurrent illnesses—they may complicate the course of the disease in adults as well.

The simple virilizing form is characterized solely by cortisol deficiency, which, if untreated, manifests as muscle weakness, fatigue, and skin hyperpigmentation against the background of hyperandrogenism symptoms.

In the non-classic form of the disease, the primary complaints of female patients are excessive hair growth, menstrual irregularities, infertility, or recurrent pregnancy loss [1,2,4,6].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for diagnosing classic forms of 21-hydroxylase deficiency: the diagnosis is established from birth based on laboratory findings: neonatal screening (measurement of 17-hydroxyprogesterone (17OHP) in newborns), subsequently confirmed by a repeat laboratory evaluation demonstrating elevated blood levels of 17OHP, as well as additional testing for testosterone and androstenedione; in the salt-wasting form, by elevated levels of renin and plasma renin activity, hyperkalemia, and hyponatremia; genetic testing results (detection of mutations in the CYP21A2 gene); and physical examination findings: atypical external genitalia in female newborns, or signs of precocious puberty in children of both sexes. In undiagnosed cases of classic CAH, female karyotype patients present with a male phenotype; the principles of laboratory and genetic diagnosis in adults are the same as in childhood [1,2,4-16].

Criteria for diagnosing the non-classic form of 21-hydroxylase deficiency: the diagnosis is established based on anamnesis: patients report menstrual irregularities, recurrent pregnancy loss or infertility, and excessive hair growth in androgen-dependent areas; physical examination findings: signs of hirsutism and acne in women; laboratory and genetic evaluations: elevated 17OHP levels, and detection of mutations in the CYP21A2 gene. Targeted diagnosis is not performed in men due to the absence of clinical manifestations. Exceptions include patients with infertility, TART, adrenal tumors, and genetic test results that fall intermediate between classic and non-classic phenotypes [17,19,21,24-31,53,56,62].

Criteria for diagnosing the hypertensive form of CAH due to 11β-hydroxylase deficiency: the diagnosis is established from birth based on the measurement of 11-deoxycortisol and genetic testing for mutations in the CYP11B1 gene. Typically, this form of the disease presents with elevated 17OHP levels; therefore, based on neonatal screening and subsequent laboratory workup, patients are initially diagnosed with the simple virilizing form of 21-hydroxylase deficiency. However, given the subsequent clinical picture—arterial hypertension, low potassium levels, and low plasma renin activity (PRA) off mineralocorticoid (MC) therapy or during glucocorticoid (GC) overreplacement—a more in-depth evaluation with the aforementioned laboratory parameters is performed, and a diagnosis of the hypertensive form of CAH is established [1,4,6,119-121].

2.1 Complaints and Anamnesis

Patient complaints are determined by the form of the disease (simple virilizing, salt-wasting, non-classic) [1,2,4,6].

Patient complaints are determined by the clinical presentation of 21-hydroxylase deficiency (see section 1.5).

2.2 Physical Examination

• Physical examination of patients is recommended to be performed according to standard propaedeutics principles. It is necessary to evaluate anthropometric parameters, the degree of hirsutism in women, and the presence of clinical signs of adrenal insufficiency [1,2,4,6].

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

Comments: signs of hyperandrogenism in women with classic forms of 21-hydroxylase deficiency are usually pronounced and, in the absence of treatment, manifest as virilization of the external genitalia, amenorrhea, severe alopecia, and hirsutism. In undiagnosed cases of CAH, female karyotype patients present with a male phenotype. In men, signs of adrenal hyperandrogenism are less pronounced than in childhood, and may include acne and infertility.

Patients frequently exhibit short final stature, which may be a consequence of either inadequate treatment (due to androgen excess) or excessive treatment (due to glucocorticoid excess) during childhood.

The non-classic form of CAH is not accompanied by signs of adrenal insufficiency and manifests relatively late—usually after puberty. In men, this condition is almost never diagnosed and does not require treatment due to the absence of characteristic features. In women, signs of mild hyperandrogenism are observed: acne, hirsutism, alopecia; menstrual irregularities, infertility, and pregnancy loss are frequent.

Patients with 11β-hydroxylase deficiency, similarly to those with the simple virilizing form of 21-hydroxylase deficiency, develop clinical signs related to the effects of androgen excess and cortisol deficiency. Therefore, in childhood, patients are frequently misdiagnosed with 21-hydroxylase deficiency, especially since their 17OHP levels are typically elevated, as in the virilizing form. The hypertensive form should be suspected in cases of elevated blood pressure in patients receiving glucocorticoid therapy in the absence of signs of treatment overreplacement. Hypertension, which occurs in 2/3 of patients with 11β-hydroxylase deficiency, begins to manifest at various ages, most commonly in childhood, and can range from mild to severe with the development of complications such as left ventricular hypertrophy, retinopathy, and macrovascular complications [1,2,4,6].

2.3 Laboratory Diagnostics

Diagnosis of classic forms of 21-hydroxylase deficiency

• As the primary method for detecting classic forms of 21-hydroxylase deficiency, neonatal screening with blood 17OHP testing (A09.05.139) is recommended for all newborns [5,7-15].

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

Comments: because CAH is a genetic, potentially lethal disease with a clear diagnostic marker, neonatal screening is currently considered the optimal method for detecting CAH worldwide. Since mid-2006, it has also been implemented in Russia, making it possible to establish a diagnosis and initiate treatment in early childhood. Therefore, diagnosing classic forms in adulthood is usually no longer required. However, sometimes the disease is not diagnosed in a timely manner, and establishing the diagnosis becomes necessary at an older age. This situation typically arises in adults presenting with a discrepancy between legal and genetic sex or with long-standing, severe virilization [5,7-15].

Comments: Diagnosis of 21-hydroxylase deficiency is based on measuring the level of 17-hydroxyprogesterone (17-OHP), a cortisol precursor located immediately proximal to the enzymatic block. In classical forms, its level is typically significantly elevated—above 300 nmol/L or over 100 ng/mL. In addition, there is a marked increase in the levels of testosterone, androstenedione, and other sex steroid precursors. With such values, the diagnosis is unquestionable, and no additional confirmation is required. Liquid chromatography-tandem mass spectrometry is the preferred laboratory method for hormonal assays, whereas ELISA yields a higher rate of false-positive results [16–28].

Diagnosis of the Non-Classical Form of 21-Hydroxylase Deficiency

• It is recommended to diagnose non-classical congenital adrenal hyperplasia (NCAH) in women presenting with signs of hirsutism, alopecia, acne, menstrual irregularities, infertility, and/or recurrent pregnancy loss [16–21, 29–31].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

Comments: Diagnosing the non-classical form of CAH is a more frequent task and is routinely encountered in the practice of endocrinologists and obstetrician-gynecologists, as its clinical manifestations resemble polycystic ovary syndrome. Differential diagnosis of NCAH is most frequently performed precisely to rule out this condition [16–21, 29–31].

• For the diagnosis of NCAH, it is recommended to measure blood 17-OHP levels (A09.05.139) in women during the early follicular phase in the morning hours. In cases of recurrent doubtful test results, a comprehensive determination of steroid hormone concentrations (multisteroid blood analysis) using tandem mass spectrometry (B03.016.023.001) is recommended [16–21, 29–40].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: To diagnose the non-classical form, blood for 17-OHP is drawn early in the morning during the follicular phase of the cycle (no later than days 5–7), or on any day in cases of amenorrhea, strictly outside of pregnancy. Values below 6 nmol/L or less than 2 ng/mL are considered normal; NCAH is practically non-existent below these levels. However, a number of authors suggest applying stricter criteria (less than 5.1 nmol/L, 1.7 ng/mL) for assessing 17-OHP levels. As a differential criterion between NCAH and PCOS, for instance, it is proposed to use a basal 17-OHP level exceeding 5.4 ng/mL (16.2 nmol/L) [41–43]. It should be borne in =mind that reference ranges provided by various laboratories usually differ and may be significantly lower than the specified cut-off points for diagnosing non-classical CAH. When basal 17-OHP values exceed 30 nmol/L or 10 ng/mL, the diagnosis of CAH is considered confirmed, and no additional diagnostics are required.

In borderline 17-OHP values (6–30 nmol/L or 2–10 ng/mL—the so-called "grey zone"), detected on at least two separate occasions, international guidelines recommend performing an additional stimulation test using ACTH-group drugs according to the ATC classification (H01AA02), which is the gold standard for CAH diagnosis worldwide.

Multisteroid blood analysis may be recommended as an additional diagnostic method for adrenal hyperandrogenism, particularly in cases of repeatedly ambiguous blood 17-OHP results [16, 17, 18, 19, 21, 29–43].

• In cases of inconclusive 17-OHP results, as well as for genetic counseling purposes, it is subsequently recommended to perform genetic testing of the CYP21A2 gene (B03.019.001, B03.019.027.001) [1–4, 44–52].

The algorithm for diagnosing non-classical CAH in the Russian Federation is presented in Table 3.

Table 3. Algorithm for diagnosing NCAH due to 21-hydroxylase deficiency in the Russian Federation

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

Comments: in cases where a tetracosactide stimulation test is not feasible, or for the purpose of genetic counseling, genetic testing for pathogenic variants in the 21-hydroxylase gene (CYP21A2) is performed.

The structural features of the CYP21A2 gene, specifically the presence of the adjacent CYP21A1 pseudogene, mean that approximately 90% of CAH cases are accounted for by the 12 most frequent pathogenic variants resulting from gene recombination. To reduce costs and accelerate testing, allele-specific PCR assays have been developed to detect the most common mutations. However, this method has a number of limitations: it fails to detect sporadic pathogenic variants. Furthermore, it cannot distinguish between homo- and hemizygous variants, which can be of critical importance during genetic counseling for pregnancy planning. Sequencing of the CYP21A2 gene is a more accurate and preferred method of genetic diagnosis, as it enables the identification of sporadic pathogenic variants. Thus, in non-classical forms of CAH, it is possible to identify both pathogenic variants leading to a minor loss of protein function and those responsible for complete protein inactivation.

However, similar to allele-specific PCR, when 2 or more mutations are detected, sequencing does not determine whether they reside in compound heterozygosity or at the same locus within the gene. In addition, determining gene copy numbers, large deletions, and rearrangements presents a diagnostic challenge. In suspected cases of this nature, quantitative real-time PCR or multiplex ligation-dependent probe amplification (MLPA) can be utilized.

Due to the aforementioned complexities, discrepancies between laboratory, clinical, and genetic parameters cannot serve as an indication to rule out a CAH diagnosis. In such controversial cases, most researchers recommend performing diagnostics using multiple molecular genetic methods, as well as conducting genetic testing of the patients' parents [1, 2, 4, 5, 46–52].

Diagnosis of 11β-Hydroxylase Deficiency

• In patients with an atypical clinical course of CAH or the development of arterial hypertension, it is recommended to diagnose the hypertensive form of CAH via a comprehensive assessment of steroid hormone concentrations using tandem mass spectrometry, including the measurement of 11-deoxycortisol levels in the blood (B03.016.023.001) [1, 4, 6].

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

Comments: The primary diagnostic marker for the hypertensive form of CAH is the determination of 11-deoxycortisol—the main cortisol precursor located proximal to the enzymatic block—which exceeds the normal range by more than 5–10 times in the classical variant of the disease. However, in routine clinical practice, this can only be achieved through multisteroid profiling. Therefore, when the hypertensive form of CAH is suspected—for example, in the presence of low potassium levels and plasma renin activity (PRA) outside of mineralocorticoid (MC) therapy or glucocorticoid (GC) overdosage, when blood pressure elevates in patients with a previously diagnosed virilizing form of the disease, or in the absence of typical pathogenic variants in the CYP21-hydroxylase gene—the patient must be referred to specialized centers to clarify the diagnosis and optimize treatment.

Mutation analysis of the CYP11B1 gene is performed extremely rarely; therefore, in Russia, genetic diagnostics can only be conducted via gene sequencing. In certain countries (e.g., Israel), testing for one of the most frequent pathogenic variants, His R448H , is employed in routine practice.

Cases of non-classical 11β-hydroxylase deficiency have been described in literature. The clinical picture is dominated by signs of hyperandrogenism and menstrual irregularities in women, whereas arterial hypertension is either absent or mild in this form of the disease. The non-classical form of 11β-hydroxylase deficiency can be diagnosed based on elevated 11-deoxycortisol levels measured via tandem mass spectrometry [1, 4, 6].

2.4 Instrumental Diagnostics

Comments: Instrumental diagnostics in adult patients with CAH is aimed at detecting secondary adrenal masses, especially in patients with a history of prolonged decompensation episodes (adrenal ultrasound, CT). A necessary step is the evaluation of the reproductive system status; screening methods used include pelvic ultrasound in women and scrotal ultrasound in men. During the initial patient visit, an instrumental assessment of bone mineral density is performed (dual-energy X-ray absorptiometry of at least two sites: the lumbar spine and the proximal femur). Instrumental diagnostics in CAH is described in more detail in the section "Dispensary Follow-up" [1,4,53-75].

2.5 Other Procedures

None.

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

3.1 Conservative Treatment

Treatment of patients with classic forms of 21-hydroxylase deficiency

Comments: Treatment of classic forms of CAH boils down to the lifelong use of glucocorticoids and mineralocorticoids (in the salt-wasting form). The main difficulty in treating CAH is that there are currently no drugs that fully mimic endogenous cortisol secretion and are capable of completely suppressing the excessive synthesis of adrenal androgens at physiological doses; therefore, patient management comes down to balancing between the signs of hypercortisolism and hyperandrogenism.

Hydrocortisone** is the most physiological drug for treating any form of adrenal insufficiency, including CAH, as it is an analogue of endogenous cortisol. Given its duration of action (about 8 hours), it is recommended to use it 2 or, preferably, 3 times a day at an average dose of 15-25 mg/day, with a higher dose administered in the morning. In children, hydrocortisone is the only recommended GC given its minimal impact on growth. In adult patients, hydrocortisone is also the preferred GC; however, in some cases (e.g., low compliance, inability to suppress the morning rise in androgens, or for the treatment of adrenal masses/TART), the use of long-acting GCs (prednisolone**, dexamethasone**, methylprednisolone**) is possible. These drugs are most often prescribed with a higher dose at night or in combination with hydrocortisone**. The most common regimen for switching from one glucocorticoid drug to another is: 20 mg of hydrocortisone** ≈ 5 mg of prednisolone** ≈ 4 mg of methylprednisolone** ≈ 0.375-0.5 mg of dexamethasone** [1-6,76-89].

• In the salt-wasting form of 21-hydroxylase deficiency, it is recommended to use mineralocorticoids (fludrocortisone**) in addition to GCs [1-6,76-89].

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

Comments: Fludrocortisone** is used to compensate for mineralocorticoid function. Average dosages and regimens of drugs for the treatment of classic forms of CAH are presented in Table 4 [1-6,76-89].

Table 4. Glucocorticoid and mineralocorticoid drugs used in the treatment of classic forms of CAH in adults, ** - drugs included in the VLDN (Essential Drugs) list

Comments: In patients with classic forms of CAH, the body does not produce adequate cortisol in response to physical stress, for example, during illnesses accompanied by high fever, gastroenteritis with dehydration, surgeries, and trauma. That is why all patients with CAH are recommended to carry identification documents or bracelets indicating that they have this condition and requiring the immediate administration of hydrocortisone in emergency situations. Since the disease is rare and unfamiliar to many primary care specialists, it has been proposed to indicate the presence of chronic adrenal insufficiency in such patients, which facilitates decision-making in these situations.

In the case of intercurrent illnesses where oral GC intake can be continued, it is necessary to increase the glucocorticoid dose by 2-3 times. If ineffective, hydrocortisone** (hydrocortisone sodium succinate) 50-100 mg is administered intramuscularly, followed by repeated administration of 50 mg every 4-6 hours if necessary. If there is no improvement within 24-48 hours, hospitalization is recommended, where intravenous infusion of hydrocortisone** is performed alongside rehydration therapy. When using parenteral hydrocortisone**, the fludrocortisone** dose remains unchanged, or MCs are even discontinued entirely. As soon as the patient's condition stabilizes, one should gradually return to the usual doses of medications. The principles of treating an addisonian crisis are outlined in Appendix A3 [1-6,90-94].

• During emotional and nervous stress, mild viral illnesses, and upcoming physical exertion, increasing the GC dose is not recommended [1-6,90-94].

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

Comments: During physical exertion and psychological stress, there is no need to increase the GC dose [1-6,90-94].

Treatment of patients with non-classic forms of 21-hydroxylase deficiency

• Treatment of female patients with NC-CAH using GCs is recommended when severe hyperandrogenism, infertility, or recurrent pregnancy loss is detected [17,87,95-103].

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

Comments: In women with pronounced symptoms of hyperandrogenism, the prescription of GCs is possible (Table 5). In addition, therapy can be combined with systemic hormonal contraceptives (ATC code G03AA (Progestogens and estrogens (fixed combinations)) and/or antiandrogens (ATC code G03H), and various hair removal methods can also be recommended to women [17,87,95-100].

Table 5. GC drugs used in the treatment of the non-classic form of CAH

Despite the fact that 68% of women with non-classic CAH can achieve spontaneous pregnancy even without the use of glucocorticoids, spontaneous miscarriages in early stages without treatment are quite common. Therefore, the issue of GC therapy must be considered primarily at the stage of pregnancy planning, especially in women with infertility or recurrent pregnancy loss. It should be noted that when the decision is made in favor of GC therapy, it is very important to start it from the pregnancy planning stage, rather than after pregnancy has already occurred, since the implantation stage under GC coverage is most important for improving pregnancy outcomes.

Pregnant women with CAH should be monitored by an endocrinologist experienced in managing patients with this condition, and the prescription of glucocorticoids should be carried out after assessing the likely positive effect of the drug versus the potential risk, with the patient's informed voluntary consent. Treatment can be carried out using any glucocorticoid drug except dexamethasone. Drug doses generally do not change upon the onset of pregnancy; treatment is carried out either in the first and second trimesters with subsequent discontinuation or until delivery depending on the course of pregnancy.

As a rule, in non-classic CAH, cortisol deficiency and salt-wasting crises are absent, so there is no need to increase the GC dose during stressful states, surgical interventions, or acute viral illnesses. The exception is the detection of insufficient cortisol production during a stimulation test (less than 500 nmol/L) [1,101-103].

• In women with moderate hyperandrogenism and ovarian dysfunction outside of pregnancy planning, it is recommended to use symptomatic therapy instead of GCs: progestogens and estrogens (fixed combinations), ATC code G03AA, and/or antiandrogens, ATC code G03H [17,87,97,98,104-118].

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

Comments: although the pathogenetic treatment of the non-classical form of CAH should follow the same principles as that of the classical forms (by replacing cortisol deficiency), the necessity of prescribing GC therapy to absolutely all women with non-classical CAH remains a subject of considerable debate among specialists worldwide. The reason is that the doses of GCs required to suppress excessive androgen production are frequently supraphysiological. Given the mild course of this disease form, this raises certain doubts regarding the necessity of their lifelong intake. Therefore, an increasing number of specialists globally conclude that outside the context of pregnancy planning and pronounced hyperandrogenism, GC use is not mandatory and can be replaced by symptomatic treatment with combined hormonal contraceptives and/or antiandrogens. Combined hormonal contraceptives suppress LH secretion, leading to decreased ovarian androgen production, while ACTH suppression reduces adrenal androgen production. Furthermore, the progestin component can interact with androgen receptors and attenuate 5-alpha-reductase activity. By increasing sex hormone-binding globulin levels, combined hormonal contraceptives reduce free circulating testosterone in the blood. It is preferable to choose preparations containing ethinylestradiol at 20–30 mcg and progestins with antiandrogen activity (chlormadinone, drospirenone, dienogest, cyproterone, nomegestrol acetate) [17,87,97,98,104-118].

Table 6. Combined hormonal contraceptive and antiandrogen preparations used in the treatment of non-classical CAH, including manifestations of hirsutism [87,97,98,104-118]

• Treatment of asymptomatic forms of non-classical CAH in women is not recommended [17,57,95,96].

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

• Treatment of men with non-classical CAH is not recommended [17,57,95,96].

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

Comments: in cases of an asymptomatic course of the disease in women, therapy is not administered. Treatment of non-classical CAH in men is generally not performed. Exceptions include patients with infertility, TART, adrenal tumors, and genetic test results that fall intermediate between classical and non-classical phenotypes [17,57,95,96].

Treatment of 11β-hydroxylase deficiency CAH

• Treatment of 11β-hydroxylase deficiency CAH is recommended to be carried out according to the same principles as the treatment of the virilizing form caused by 21-hydroxylase deficiency. Short- and long-acting GC preparations may be used in therapy [1,4,6,119-121].

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

Comments: patients with the classical form of 11β-hydroxylase deficiency, similarly to other forms of CAH, receive lifelong GC preparations to correct symptoms of adrenal insufficiency, hyperandrogenism, and arterial hypertension. While hydrocortisone is the drug of choice in children, long-acting preparations can also be used in adults. There is no need to prescribe mineralocorticoids in such patients, as aldosterone deficiency is excessively compensated by DOC [1,4,6,119-121].

• It is recommended to prescribe antihypertensive drugs (ATC code C02)—preferably potassium-sparing diuretics (ATC code C03D) and dihydropyridine derivatives of selective calcium channel blockers (ATC code C08CA)—as add-on therapy for patients with 11β-hydroxylase deficiency CAH [1,4,6,119-121].

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

Comments: if arterial hypertension cannot be controlled with GC monotherapy, additional antihypertensive drugs may be used, among which potassium-sparing diuretics (ATC code C03D) and dihydropyridine derivatives of selective calcium channel blockers (ATC code C08CA) are preferred [1,4,6,119-121].

3.2 Surgical Treatment

Comments: to date, no randomized controlled trials have been conducted to standardize approaches to the surgical treatment of female patients with CAH. Special attention must be given to: the timeliness of feminizing external genitalia surgery, the evaluation of surgical outcome adequacy, and the absence of postoperative complications (scars, strictures, etc.). Genital virilization is observed in patients from birth. In cases of high-degree virilization, feminizing surgery is performed in two stages: the first stage, which includes clitoroplasty and urogenital sinus dissection, is performed in the first years of the child's life, while the second stage—introitoplasty—is recommended after menarche and the achievement of adequate genital estrogenization. In clinical practice, it is common to encounter cases where the second stage of surgery is not performed until adulthood. Such women should be referred to federal specialized gynecological centers possessing experience with such procedures, as well as a team of experts in this field: surgeons, anesthesiologists, psychologists, and endocrinologists [122-127].

3.3 Other Treatment

Bilateral adrenalectomy.

• In rare cases, in patients with uncontrolled hyperandrogenism provided with adequate treatment adherence, bilateral adrenalectomy may be recommended [128-131].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: a small percentage of patients with the severe salt-wasting form of CAH and virtually complete absence of 21-hydroxylase activity do not respond to GC treatment: even with high doses of medications, androgen production is not reduced, and signs of virilization persist. This is particularly relevant when addressing fertility restoration. In such instances, several authors propose an alternative treatment method for CAH—bilateral adrenalectomy. However, this treatment approach raises numerous questions. On the one hand, it reduces virilization and allows for lower GC doses. On the other hand, there are intraoperative risks and the risk of postoperative adrenal crises. Bilateral adrenalectomy is contraindicated in non-compliant patients, as irregular intake of replacement GC therapy in the postoperative period can be fatal. Therefore, the decision to perform such radical treatment should not be made routinely in general outpatient practice. When such situations arise, where patients fail to achieve compensation even with supraphysiological GC doses and the development of iatrogenic hypercortisolism, they should be referred to a federal endocrinology center to determine the optimal treatment strategy [128-131].

Prenatal therapy.

Comments: prenatal therapy is off-label dexamethasone treatment in pregnant women who, based on genetic counseling results, are at high risk of giving birth to a child with the classical form of 21-hydroxylase deficiency (for example, in families with previously affected children with CAH and confirmed mutation carrier status in both parents, where the risk of bearing a subsequent affected child is 25%). Since dexamethasone is the only GC preparation that crosses the placenta and can suppress fetal adrenal androgen production, its administration from very early gestation makes it possible to reduce external genitalia virilization in newborn girls with CAH. The doses of dexamethasone recommended in the global literature are 20 mcg/kg of the pregnant woman's weight, up to a maximum of 1.5 mg/day. During treatment, fetal glucocorticoid levels may exceed average values by up to 60-fold.

The main problem is that to achieve an effect, therapy must be started as early as possible—no later than the 6th week of gestation. At the same time, prenatal diagnosis to determine the sex and presence of CAH in the fetus is only possible at 9–10 weeks of pregnancy. Therefore, 7 out of 8 children will uselessly receive high-dose dexamethasone treatment during organogenesis. Currently, a commercial method for determining the Y-chromosome-specific fetal DNA fragment in the blood of a pregnant woman is available from earlier gestation periods, but this technique is not yet widely used in routine practice.

Negative effects of dexamethasone are currently being actively studied. The risk of hypercortisolism-associated maternal complications has been demonstrated: gestational diabetes mellitus, arterial hypertension, edema, sleep disorders, and weight gain. Regarding adverse effects on the fetus, studies are ongoing, but effects on the central nervous system, adipose tissue distribution, adrenal and pancreatic function have already been demonstrated as part of fetal programming and epigenetic changes.

It should be noted that in Russia there is an opinion that dexamethasone can prevent external genitalia virilization in girls by neutralizing the effect of maternal androgens; therefore, dexamethasone is often prescribed to pregnant women with non-classic CAH. However, research data do not confirm the ability of maternal androgens to cross the placenta and exert a negative effect on the fetus. Therefore, dexamethasone** is acceptable for use in pregnant women only in those rare cases where severe classic forms of CAH are suspected in the child itself. For this reason, prenatal therapy with dexamethasone** is currently not recommended in routine practice, and dexamethasone is classified as an undesirable drug for the treatment of any form of CAH during pregnancy [132–143].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• It is recommended that patients with CAH who have psychosocial problems due to disorders of sex development consult experts specializing in this nosology [144–170].

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

Comments: the main issue in the rehabilitation of adult patients with CAH is related to their psychosocial problems, as with any disease associated with disorders of sex development. Ideally, counseling should be performed by specialists experienced in this field.

46,XX patients with CAH and their families may need assistance in addressing problems specific to disorders of sex development, such as: 1) medical education of the family, counseling on psychosocial prognosis; 2) sex assignment in cases of pronounced virilization; 3) decision-making regarding early childhood feminizing genitoplasty; 4) psychosocial evaluation for sex assignment and counseling regarding sex reassignment at any age upon the patient's request, from female to male or male to female, although such situations are extremely rare.

Additional issues specific to disorders of sex development include preparation for surgery, assessment of gender-atypical behavior, social adaptation, bisexuality and homosexuality (which is somewhat higher in women with CAH, but still rare), issues of sexual function and overall quality of life, as well as assisting in patient adaptation when faced with curiosity from relatives, peers, or sexual partners due to atypical body structure.

Patients with CAH may also have psychosocial and psychiatric problems unrelated to the underlying disease, which can be addressed through general psychiatric care [144–170].

5. Prevention and Dispensary Observation

5.1 Prevention and dispensary follow-up in adult patients with classic forms of 21-hydroxylase deficiency.

• To assess the degree of compensation, it is recommended to determine blood levels of androstenedione (A09.05.146), 17-OHP (A09.05.139), testosterone (A09.05.078) in all patients with the virilizing and salt-wasting forms of CAH, as well as plasma renin activity (A09.05.120.001) or direct renin (A09.05.121) (only in patients with the salt-wasting form) [1, 2, 54, 55, 85, 171–174].

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

Comments: to assess the efficacy of glucocorticoid therapy for CAH, three indicators are currently most commonly used worldwide: androstenedione, 17-OHP, and testosterone, which should be tested early in the morning on an empty stomach, before taking medications. Testing 2 hours after taking medications is also acceptable. Liquid chromatography-tandem mass spectrometry is the preferred laboratory method for determining hormonal parameters; the ELISA method yields a higher number of false-positive results. ACTH measurement is not necessary to determine diagnostic or therapeutic tactics in patients with CAH. As a new method for assessing compensation in patients receiving hydrocortisone therapy, 24-hour cortisol monitoring is currently being studied, although it has not yet been introduced into routine practice [174].

In women with a preserved menstrual cycle, testing should preferably be performed in the early follicular phase, while taking combined oral contraceptives (COCs) — on days 3–4 of the cycle (before starting a new COC pack to avoid cross-reactivity), and in case of amenorrhea — on any day [1, 2].

In men, dynamic monitoring is complicated by the fact that testosterone levels mainly reflect gonadal rather than adrenal production and therefore do not allow for an adequate assessment of disease compensation. Men with prolonged decompensation or testicular adrenal rest tumors (TART) may have low testosterone levels due to impaired Leydig cell function. Therefore, the main markers become androstenedione and 17-OHP levels, as well as the androstenedione-to-testosterone ratio. An androstenedione/testosterone ratio of less than 0.5 is characteristic of healthy men, while a ratio greater than 2 indicates poor CAH compensation and hyperproduction of adrenal androgens [54, 55, 171]. Gonadotropin determination serves as an additional diagnostic method. In men, decreased gonadotropin levels may indicate patient infertility, while elevated FSH levels indicate testicular dysfunction, especially in the presence of TART.

According to most specialists, there are currently no clear laboratory criteria for disease compensation. Complete suppression of 17-OHP levels is considered inappropriate because it requires supraphysiological doses of glucocorticoid drugs, which cause adverse effects. Compensated CAH patients usually have 17-OHP levels at the upper limit of normal or moderately elevated. The androstenedione level should be within the reference ranges for sex and age. In individual cases (e.g., when planning pregnancy or in the presence of TART in men), individual target values are chosen. For women with CAH planning pregnancy, achieving a follicular phase progesterone level of less than 0.6 ng/mL (less than 2 nmol/L) against the background of ongoing therapy is advisable [85, 172, 173].

If mineralocorticoids are required for the salt-wasting form of the disease, plasma renin activity (PRA) or renin should be maintained at the upper limit of normal or elevated, but no more than 2-fold. At the same time, blood potassium and sodium levels must be within the reference interval. It should be remembered that mineralocorticoid requirement decreases with age, and the drug dose may be adjusted (Table 7) [85, 173].

• If decompensation or glucocorticoid overdosage is detected, in addition to adjusting therapy, it is recommended to also conduct additional examinations (as part of dynamic monitoring) for complications characteristic of hyperandrogenism or hypercortisolism [18, 85, 86, 175–184].

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

Comments: see the section "Dispensary Follow-up and Monitoring of Complications",

Table 7. Laboratory parameters used for dispensary and dynamic monitoring of patients with CAH

5.2 Follow-up care and complication monitoring

The management of patients with classical 21-hydroxylase deficiency requires maintaining a continuous balance between androgen excess and exogenous glucocorticoid excess, which can be quite challenging to achieve in clinical practice. Therefore, careful monitoring of complications and sequelae of both the disease itself and its treatment is essential.

Comments: the range of metabolic disorders in CAH is quite broad. In addition to the main side effects resulting from glucocorticoid overdose, such as obesity, arterial hypertension, dyslipidemia, insulin resistance, and carbohydrate metabolism disorders, patients with CAH are also affected by additional factors: hyperandrogenism, hypogonadism, and adrenomedullary insufficiency (Fig. 4). Therefore, as part of the annual clinical follow-up, all patients with classical forms of 21-hydroxylase deficiency need education on the principles of healthy nutrition and a healthy lifestyle, as well as blood pressure and body weight monitoring (Fig. 3) [18,85,86,175-179].

Figure 3. Pathogenesis of metabolic disorders in classical forms of 21-hydroxylase deficiency

Comments: international retrospective and cohort studies have shown that adult patients with CAH exhibit decreased bone mineral density on densitometry, mostly to the degree of osteopenia and, less frequently, osteoporosis. Some studies have demonstrated that the degree of bone mass loss depends on the cumulative lifetime dose of glucocorticoids. Data from the Endocrinology Research Centre showed that the development of osteopenic syndrome did not depend on the degree of disease compensation or the doses of glucocorticoids taken; therefore, it is advisable to perform dual-energy X-ray absorptiometry in all patients with classical forms of 21-hydroxylase deficiency regardless of compensation status at the initial visit if it has not been done previously, and subsequently decide on the frequency of bone density monitoring based on the results obtained (at least once every 5–7 years in the absence of bone mineral density reduction and more frequently if osteopenic syndrome is detected) [4,85,86,180-184].

Comments: computed tomography frequently reveals unilateral or bilateral benign adrenal masses in adult patients with classical forms of 21-hydroxylase deficiency. Targeted screening for such masses is usually required only in the presence of prolonged decompensation, as they can reach significant sizes. When adequate glucocorticoid doses are prescribed, tumor regression is observed, and surgical treatment is generally not performed. If compensation is satisfactory, screening is unnecessary, as small masses have no clinical significance [4,185-188].

Comments: testicular adrenal rest tumors (TART) occur in 21–28% of men with classical forms of 21-hydroxylase deficiency. With prolonged disease decompensation, they can reach large sizes, compress the testicular tissue, and lead to hypogonadism and infertility. In clinical practice, these patients may be misdiagnosed with testicular cancer, leading to unjustified surgeries. Unlike testicular cancer, TARTs are typically bilateral lesions that tend to regress with the intensification of glucocorticoid therapy. TARTs are detected either by palpation during physical examination or via ultrasound. Scrotal MRI serves as an additional imaging method. If TART dimensions do not change despite achieving disease compensation, sperm cryopreservation is recommended. Assessment of reproductive function in men is necessary in cases of infertility or prolonged disease compensation. Men with classical forms of CAH require follow-up by a urologist in addition to an endocrinologist [54,56,58,60-64,171,189,190].

Comments: menstrual cycle irregularities are observed in women with classical forms of 21-hydroxylase deficiency regardless of the degree of compensation—in 64–68% of women with the salt-wasting form and 55–75% with the simple virilizing form. Evaluation of such women frequently reveals ultrasound signs of polycystic ovaries. In CAH, the pathogenesis of polycystic ovary formation involves insulin resistance, obesity, and high androgen secretion. In some cases, cycle normalization can be achieved by intensifying glucocorticoid therapy; however, if this proves ineffective or signs of iatrogenic hypercorticism appear, adding progestogens and estrogens (fixed combinations) to the therapy is recommended.

The literature describes cases of ovarian adrenal rest tumors (OART) with a structure similar to TART. Their frequency is less than 0.1% among all ovarian masses. It is hypothesized that OART occurs more frequently in female patients with prolonged CAH decompensation. Pelvic MRI is the gold standard for clarifying the size and localization of pelvic space-occupying lesions. Isolated cases of OART combined with CAH are described in world literature; their early diagnosis in some patients allows for organ-sparing surgeries, which is undoubtedly important for their quality of life and the preservation of menstrual and reproductive function. Women with classical forms of CAH require follow-up by a gynecologist in addition to an endocrinologist [65-69,191-196].

Figure 4 presents a schematic plan for the examination and follow-up of adult patients with classical forms of 21-hydroxylase deficiency depending on the degree of compensation. As seen from this scheme, a number of examinations (adrenal CT or MRI, testicular ultrasound) should be performed only in cases of disease decompensation, whereas active screening for metabolic disorders, assessment of bone mineral density, and evaluation of reproductive function in women are required regardless of the degree of disease compensation.

Figure 4. Follow-up of adult patients with classical forms of 21-hydroxylase deficiency

Prevention and clinical follow-up in adult patients with non-classical forms of 21-hydroxylase deficiency

Comments: unlike classical forms of 21-hydroxylase deficiency, there are no universally accepted guidelines for the follow-up and assessment of disease compensation in the non-classical form.

Outside of pregnancy planning and in cases of moderate hyperandrogenism, when combined hormonal contraceptives and/or anti-androgen therapy are chosen as the primary treatment method, such patients are typically not followed by endocrinologists, and further management and treatment adjustments are carried out by a gynecologist.

In patients with severe hyperandrogenism who opt for long-term glucocorticoid therapy, follow-up should be conducted similarly to classical forms of CAH. Disease control is assessed clinically (target ranges for laboratory parameters such as 17-OHP, testosterone, and androstenedione have not yet been established). If clinical signs of iatrogenic hypercortisolism appear, further diagnostic workup is required to detect metabolic disorders and a decrease in BMD [17, 29, 95, 96, 98–100].

Prevention and clinical follow-up in adult patients with 11β-hydroxylase deficiency

• To assess disease control in patients with 11β-hydroxylase deficiency, it is recommended to perform a comprehensive determination of steroid hormone concentrations by tandem mass spectrometry with the assessment of 11-deoxycorticosterone levels in the blood (A09.05.141) [197–200].

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

Comments: just as in classical forms of 21-hydroxylase deficiency, the monitoring of patients with 11β-hydroxylase deficiency aims to select an adequate glucocorticoid dose, assess disease control, and detect complications of lifelong replacement glucocorticoid therapy. However, due to the rare occurrence of non-classical forms of CAH, dynamic monitoring and control assessment present a significant challenge. According to international guidelines, monitoring should be based on 11-deoxycortisol levels, whereas this marker is not routinely assessed in clinical practice. Therefore, when therapy adjustment and precise assessment of disease control are necessary, it is recommended to refer such patients to federal endocrinology centers where comprehensive determination of steroid hormone concentrations by tandem mass spectrometry is available.

Disease control in non-classical forms of CAH can be inferred from indirect data. When an insufficient glucocorticoid dose is prescribed, there is an increase in androstenedione and testosterone levels (in men, evaluation is based solely on androstenedione levels), while plasma renin activity (PRA) and potassium levels decrease. The clinical picture reveals elevated blood pressure, the development of macrovascular complications, as well as signs of hyperandrogenism and hypocortisolism.

Signs of overtreatment include classic features of hypercortisolism: weight gain, central (abdominal) obesity, striae, and a dorsocervical fat pad ("buffalo hump"). Laboratory tests show decreased testosterone and androstenedione levels, signs of dyslipidemia, and impaired carbohydrate metabolism. Densitometry reveals evidence of decreased BMD. Blood pressure elevation may be absent, although some patients may maintain hypertension as part of iatrogenic hypercortisolism.

Patients with non-classical forms of CAH should be examined by a cardiologist at least annually, with ECG, echocardiography, 24-hour blood pressure monitoring, and ECG monitoring performed as indicated for the timely diagnosis and management of macrovascular complications of hypertension [197–200].

6. Organization of Medical Care

Indications for planned hospitalization:

1) surgical treatment (typically plastic surgery on the external genitalia in women, less frequently surgical treatment of TART in men, removal of secondary adrenal tumors);

2) for therapy adjustment, comprehensive screening for complications, in the event that specialized endocrinological medical care cannot be provided on an outpatient basis.

Indications for emergency hospitalization:

1) adrenal crisis.

Indications for patient discharge from the hospital:

1) achievement of target androgen levels, determination of the management strategy for complications;

2) stable health status of the patient and hemodynamic parameters in case of emergency hospitalization.

7. Additional Information

Pregnancy in CAH.

Monitoring of pregnant women with classical forms of 21-hydroxylase deficiency.

Comments: the rate of pregnancies and live births is low in women with classical forms of 21-hydroxylase deficiency, particularly the salt-wasting form, despite ongoing treatment aimed at restoring fertility. The primary role is played by psychosocial factors, poor disease control, and the consequences of inadequately performed external genitalia plastic surgery. In some cases, even with adequate CAH therapy, assisted reproductive technologies are required to achieve pregnancy. It is essential to remember genetic counseling for couples if one of the partners has CAH and to recommend genetic testing to identify mutations in the CYP21 hydroxylase gene in the second partner.

The main challenge in managing pregnant women with classical forms of CAH is that during pregnancy, androgen levels gradually increase due to elevated levels of sex hormone-binding globulin and corticosteroid-binding globulin, meaning there are no reliable criteria for assessing treatment adequacy.

Treatment adjustments are usually made empirically, based on the clinical picture, blood pressure levels, and blood electrolytes, due to the lack of hormonal criteria for assessing disease control. It is believed that the requirement for glucocorticoids and mineralocorticoids increases sharply during pregnancy, especially in the second and third trimesters, when disease decompensation and orthostatic hypotension may develop. However, a recent study showed that in routine clinical practice, glucocorticoid and mineralocorticoid doses could either increase or decrease. During labor, it is recommended to administer hydrocortisone** (hydrocortisone sodium succinate) parenterally at 50 mg intramuscularly or intravenously, followed by repeated doses of 50 mg every 4–6 hours if necessary, with subsequent transition back to oral medication within 1–2 days. If the woman underwent external genitalia plastic surgery, delivery via Cesarean section is recommended to reduce trauma during childbirth [94, 172, 201–207].

• During pregnancy, it is not recommended to use glucocorticoids that cross the placenta, such as dexamethasone [1, 3, 94, 201].

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

Comments: dexamethasone should not be used during pregnancy because it is not inactivated by the placental enzyme 3β-hydroxysteroid dehydrogenase and crosses unchanged into the fetal circulation. Other glucocorticoids are acceptable for use after assessing potential benefits and risks, in accordance with official product labeling requirements [1, 3, 94, 201].

Monitoring of pregnant women with non-classical forms of 21-hydroxylase deficiency

Comments: female patients with a history of recurrent pregnancy loss, infertility, or ineffective management of hyperandrogenism are switched from combined oral contraceptives to glucocorticoids, with the primary criterion for control being the restoration of spontaneous ovulation and achievement of pregnancy. Just as in classical forms of CAH, dexamethasone is contraindicated. The question of the duration of glucocorticoid therapy during pregnancy in non-classical CAH is debatable; therapy is continued either through the first trimester or throughout the entire pregnancy, based on its clinical course.

In women with non-classical CAH, the use of glucocorticoids is not recommended during pregnancy if conception occurred without their use.

Delivery is performed according to general obstetric indications. On the day of delivery, women who showed an inadequate cortisol response (less than 500 nmol/L) during the tetracosactide test require parenteral hydrocortisone administration. Postpartum, the endocrinologist routinely decides whether the patient requires ongoing glucocorticoid treatment or if gradual discontinuation is possible, provided this was not done earlier [1, 3, 29, 99, 103, 208, 209].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Mokrysheva Natalia Georgievna, Corresponding Member of RAS, DSc, Professor, Director of the National Medical Research Center for Endocrinology of the Russian Ministry of Health, Member of the Russian Association of Endocrinologists.

2. Melnichenko Galina Afanasyevna, Academician of RAS, Professor, DSc, Deputy Director for Research, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Member of the Russian Association of Endocrinologists.

3. Adamyan Leila Vladimirovna, Academician of RAS, DSc, Professor, Deputy Director of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Honored Scientist of Russia, Head of the Department of Reproductive Medicine and Surgery, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health, Chief Obstetrician-Gynecologist of the Russian Ministry of Health, President of the Society for Reproductive Medicine and Surgery of the Russian Association of Endometriosis, Member of the Russian Society of Obstetricians and Gynecologists.

4. Troshina Ekaterina Anatolyevna, Corresponding Member of RAS, DSc, Professor, Director of the Institute of Clinical Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

5. Molashenko Natalya Valeryevna, PhD, Endocrinologist, Department of Therapeutic Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

6. Sazonova Anna Igorevna, PhD, Endocrinologist, Therapeutic Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.

7. Uvarova E.V., Corresponding Member of RAS, Professor, DSc, Chief Freelance Specialist in Pediatric and Adolescent Gynecology of the Russian Ministry of Health, Head of the Department of Pediatric and Adolescent Gynecology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, President of the Interregional Public Organization "Association of Pediatric and Adolescent Gynecologists".

8. Rosa M. Esayan, Cand. of Sci. (Med.), Associate Professor, Head of the Therapeutic Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.

9. Elena N. Andreeva, Doc. of Sci. (Med.), Professor, Director of the Institute of Reproductive Medicine, Head of the Department of Endocrine Gynecology, Professor at the Department of Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, and Department of Reproductive Medicine and Surgery, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health, Member of the Society for Reproductive Medicine and Surgery, Russian Association of Gynecological Endocrinologists, Russian Association for Endometriosis, Russian Society of Obstetricians and Gynecologists, International Federation of Gynecology and Obstetrics / International Association of Obstetricians-Gynecologists and Endocrinologists.

10. Zh.A. Uzhegova, Physician at the Department of Endocrine Gynecology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

11. Natalia Yu. Kalinchenko, Cand. of Sci. (Med.), Leading Researcher at the Department of Thyroidology, Reproductive and Somatic Development, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

12. Ekaterina I. Kim, Endocrinologist, Postgraduate Student at the Institute of Clinical Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

13. Valentin V. Fadeev, Doc. of Sci. (Med.), Professor, Head of the Department of Endocrinology, I.M. Sechenov First Moscow State Medical University.

14. Elena V. Biryukova, Doc. of Sci. (Med.), Professor at the Department of Endocrinology and Diabetology, A.I. Evdokimov Moscow State University of Medicine and Dentistry.

15. Mikhail B. Antsiferov, Doc. of Sci. (Med.), Professor, Chief Physician, Endocrinological Dispensary of the Moscow Healthcare Department, Chief Endocrinologist of Moscow.

16. L.A. Suplotova, Doc. of Sci. (Med.), Professor at the Department of Therapy with Courses in Endocrinology, Functional and Ultrasound Diagnostics, Institute of Continuing Professional Education, Tyumen State Medical University of the Russian Ministry of Health, Chief Endocrinologist of Tyumen Oblast, Tyumen.

17. T.P. Kiseleva, Doc. of Sci. (Med.), Professor at the Department of Internal Diseases and Endocrinology, Ural State Medical University, Chief Endocrinologist of the Ural Federal District, Yekaterinburg.

18. M.I. Yarmolinskaya, Doc. of Sci. (Med.), Professor at the Department of Obstetrics and Gynecology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, Head of the Department of Reproductive Endocrinology, D.O. Ott Research Institute of Obstetrics and Gynecology, Member of the Russian Society of Obstetricians and Gynecologists.

19. L.V. Suturina, Doc. of Sci. (Med.), Professor, Head of the Department of Reproductive Health Protection, Scientific Centre for Family Health and Human Reproduction Problems (Irkutsk), Member of the Association of Gynecological Endocrinologists of Russia, Member of the Russian Society of Obstetricians and Gynecologists.

Conflict of interest:

The authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. endocrinologists;

2. obstetricians-gynecologists;

3. general practitioners / internists.

These clinical guidelines are based on systematic reviews, meta-analyses, and original articles, as well as scientific studies on the subject conducted in the Russian Federation and other countries.

Methods used to assess the quality and strength of evidence:

• Expert consensus.

• Evaluation of significance according to levels of evidence and classes of recommendations (attached).

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Rating scale for levels of evidence (LE) for preventive, therapeutic, and rehabilitation methods (interventions)

Table 3. Rating scale for grades of recommendation (GR) for preventive, diagnostic, therapeutic, and rehabilitation methods (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 at http://grls.rosminzdrav.ru.

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

3. Instructions for 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 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 use of #fludrocortisone** http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=84721278-8107-4f05-afc2-3f24209faae2&t

Related regulatory legal acts:

1. Procedure for the provision of medical care to the adult population in the profile "endocrinology" (Order of the Ministry of Health of the Russian Federation dated March 12, 2023, No. 104).

2. Standard of medical care for adults with congenital adrenal hyperplasia (adrenogenital syndrome) (Appendix to the Order of the Ministry of Health of the Russian Federation dated May 23, 2023, No. 255n).

3. Nomenclature of positions of medical workers and pharmaceutical workers (Appendix to the Order of the Ministry of Health of the Russian Federation dated May 2, 2023, No. 255n No. 205n).

4. Nomenclature of medical services (Order of the Russian Ministry of Health dated October 13, 2017, No. 804n, as amended on September 24, 2020). https://minjust.consultant.ru/documents/37309?items=1&page=1

   https://minjust.consultant.ru/documents/25126

Characteristics of glucocorticoid and mineralocorticoid drugs for the treatment of CAH

Glucocorticoids. Mechanism of action and pharmacological effects.

The mechanism of action of glucocorticoids is based on their binding to intracellular steroid receptors, whereby the hormones regulate the expression of a wide range of genes at the transcriptional and post-transcriptional levels. Glucocorticoids play an important role in the body's adaptation to environmental stress factors, exerting a multifaceted effect on metabolism. They promote the development of hyperglycemia through several mechanisms: they stimulate hepatic gluconeogenesis; enhance protein catabolism by stimulating the release of amino acids, which are substrates for gluconeogenesis; reduce glucose consumption and utilization by adipose tissue; and increase the efficacy of hormones that stimulate key metabolic processes, including gluconeogenesis. Glucocorticoids enhance the lipolytic action of catecholamines and growth hormone (GH) and increase the plasma content of free fatty acids; they exert an anabolic effect on protein metabolism in the liver and a catabolic effect in muscles, adipose and lymphoid tissues, skin, and bones. They inhibit the growth and division of fibroblasts and collagen synthesis, thereby disrupting the reparative phase of inflammation; their excess increases bone resorption and inhibits bone formation, resulting in a decrease in BMD. Glucocorticoids possess potent anti-inflammatory and immunosuppressive effects. In the hypothalamus–pituitary–adrenal axis, the classical principle of "negative feedback" operates: glucocorticoids suppress the production of corticotropin-releasing hormone and ACTH. In endocrinology, the main indication for prescribing glucocorticoids is replacement therapy for adrenocortical insufficiency.

According to their duration of action, glucocorticoid drugs are divided into 3 groups: short-acting (hydrocortisone), intermediate-acting (prednisolone, methylprednisolone), and long-acting (dexamethasone). In addition, the biological activity of the drugs varies (Table A1).

Table A1. Comparative characteristics of glucocorticoid and mineralocorticoid drugs

Pharmacokinetics. When taken orally, glucocorticoids are well absorbed in the gastrointestinal tract, and food intake has little effect on their absorption. Other routes of administration in the treatment of endocrine diseases are practically not used, except for cases of acute adrenal insufficiency (AAI), when hydrocortisone is administered parenterally. Despite the short T_1/2, glucocorticoids persist in tissues much longer, and accordingly their therapeutic effects are quite prolonged (Tables A2, A3).

Table A2. Pharmacokinetics of glucocorticoid drugs

Side effects. The frequency of occurrence and severity of adverse drug reactions (ADRs) of glucocorticoids depend on the dose and duration of their use. Typical side effects from parenteral administration of glucocorticoids are usually reversible and can be eliminated or reduced by lowering the dose.

Endocrine system: suppression of adrenal function, secondary adrenal and pituitary unresponsiveness of various origins, development of Cushing's syndrome, menstrual irregularities, decreased glucose tolerance, manifestation of latent diabetes mellitus (DM), increased need for insulin or oral hypoglycemic agents in patients with DM.

Gastrointestinal tract: peptic ulcer with possible perforation and bleeding, pancreatitis (nausea, vomiting), abdominal distension, erosive/ulcerative esophagitis; increased activity of ALT, AST, and alkaline phosphatase (ALP) in blood serum (usually these changes are insignificant, not associated with any clinical syndromes, and reversible after discontinuation of treatment).

Cardiovascular system: heart failure in patients with appropriate predisposition, increased blood pressure (BP), in patients with acute and subacute myocardial infarction—extension of the necrosis zone, slowed scar tissue formation, which can lead to myocardial rupture.

Nervous system: increased intracranial pressure with papilledema, convulsions, dizziness, headache, delirium, disorientation, euphoria, hallucinations, manic-depressive psychosis, depression, paranoia.

Sense organs: posterior subcapsular cataract, increased intraocular pressure (IOP), glaucoma with possible optic nerve damage, exophthalmos, tendency to develop secondary bacterial, fungal, or viral eye infections.

Metabolism: negative nitrogen balance due to protein catabolism.

Musculoskeletal system: "steroid" myopathy, decreased muscle mass, osteoporosis, tendon ruptures, especially of the Achilles tendon, vertebral compression fractures, aseptic necrosis of the femoral and humeral epiphyses, pathological fractures of long bones.

Skin and integument: delayed wound healing, thinning and reduced skin strength, petechiae, ecchymoses, facial erythema, possible suppression of skin test reactions, hirsutism, increased sweating.

Allergic reactions: generalized (skin rash/urticaria).

Other: increased appetite, hiccups, arrhythmias, hypercoagulation, thrombosis, trophic corneal changes, increased calcium excretion, hypocalcemia, development or exacerbation of infectious diseases.

Withdrawal syndrome: if the dose of the drug is reduced rapidly in a patient receiving long-term glucocorticoid therapy, signs of adrenal insufficiency, arterial hypotension, and death may develop. In addition, a withdrawal syndrome not related to adrenal insufficiency may develop (anorexia, nausea, vomiting, lethargy, headache, fever, arthralgia, epithelial desquamation, myalgia, weight loss, decreased blood pressure).

Table A3. Drug interactions of glucocorticoids

Mineralocorticoids. Mechanism of action and pharmacological effects.

The primary function of mineralocorticoids is sodium retention in the body and maintenance of the physiological osmolarity of the internal environment. The main target organ of these hormones is the kidney, where they enhance active sodium reabsorption in the distal convoluted tubules and collecting ducts by stimulating the expression of the Na⁺-K⁺-ATPase gene. In addition, mineralocorticoids promote renal excretion of potassium, hydrogen, and ammonium ions. Currently, only fludrocortisone is used for the replacement therapy of mineralocorticoid deficiency.

Pharmacokinetics. Following oral administration, fludrocortisone is rapidly and completely absorbed from the gastrointestinal tract. The C_max of fludrocortisone in plasma is reached in approximately 2 hours. Plasma protein binding is 42%. It is metabolized in the liver. It is excreted by the kidneys as inactive metabolites. The plasma T_1/2 is 3.5 hours. It easily crosses blood-tissue barriers. T_1/2 is 18–36 hours. A minor fraction is excreted during lactation.

Administration specifics. The drug is effective orally and possesses potent mineralocorticoid activity comparable to aldosterone. During pregnancy, an increase in the fludrocortisone dose may be required due to a significant elevation in progesterone levels, which acts as a mineralocorticoid receptor antagonist. Sometimes the fludrocortisone dose has to be increased in the summer (especially in hot climates) due to greater sodium and water losses through sweat (Table A4).

Adverse reactions.

Cardiovascular system: hypertension, peripheral edema, left ventricular hypertrophy, circulatory failure, hypernatremia, hypocalcemia, arrhythmias, bradycardia, ECG changes characteristic of hypokalemia, hypercoagulation, thrombosis, thromboangiitis obliterans.

Musculoskeletal system: muscle weakness, steroid-induced muscle wasting, osteoporosis, vertebral compression fracture, aseptic necrosis of the femoral and humeral heads, pathological fractures of long tubular bones.

Gastrointestinal tract. Steroid ulcer with potential perforation and hemorrhage, pancreatitis; flatulence, ulcerative esophagitis, digestive disorders, nausea, increased or decreased appetite, vomiting, hiccups, increased ALT, AST, and ALP activity.

Skin and subcutaneous tissue: acne, delayed wound healing; skin thinning; petechiae and hematomas, erythema, increased sweating, allergic dermatitis, urticaria, angioedema, ecchymoses, hyper- or hypopigmentation, susceptibility to pyoderma and candidiasis.

Central nervous system: increased intracranial pressure, convulsions, dizziness, headache, sleep disorders.

Endocrine system: secondary adrenal and hypothalamic-pituitary insufficiency, Cushing's syndrome, menstrual irregularities; impaired glucose tolerance; manifestation of latent diabetes mellitus and increased demand for insulin or oral hypoglycemic agents in patients with diabetes mellitus; hirsutism.

Special senses (eye): posterior subcapsular cataract, increased intraocular pressure, glaucoma, exophthalmos, susceptibility to secondary bacterial, fungal, or viral eye infections, corneal trophic changes.

Psychiatric disorders: mania or delirious syndrome.

Metabolic disorders: negative nitrogen balance; hyperglycemia; glucosuria, increased Ca²⁺ excretion, hypokalemic syndrome.

Other: anaphylactic reactions; weight gain; masking of symptoms of infectious diseases; syncope; development or exacerbation of infections (concomitant immunosuppressants and vaccination contribute to the appearance of this adverse drug reaction [ADR]); leukocyturia; withdrawal syndrome.

Table A4. Interactions of fludrocortisone with other medicinal products

Table A5. Regimen for adjusting replacement therapy in congenital adrenal hyperplasia (CAH)

*hydrocortisone sodium succinate

Treatment algorithm for acute adrenal insufficiency in CAH [1-6,90-94]

Emergency measures.

• Establishment of intravenous access.

• IV administration of 2–3 L of 0.9% sodium chloride solution (at a rate of 1 L per hour). Monitoring for signs of fluid overload (blood pressure, central venous pressure, urine output, blood electrolytes, pulmonary rales) is mandatory.

• IV administration of hydrocortisone (100–150 mg immediately and then every 6 hours).

Post-stabilization measures.

• Continued IV administration of 0.9% sodium chloride solution with a reduction in infusion volume and rate (over 24–48 hours); after restoration of circulating blood volume, additional administration of 5% dextrose solution (0.5-1 L).

• Gradual reduction of glucocorticoid dose (over 1–3 days).

• Initiation of mineralocorticoid replacement therapy (fludrocortisone 0.1 mg/day) when the parenteral dose of hydrocortisone is less than 100 mg/day, upon discontinuation of 0.9% sodium chloride solution, or when switching to oral hydrocortisone.

• Search for and treatment of the etiological factor (probable infections) that led to acute adrenal insufficiency.

Further management

After patient stabilization and reduction of the daily hydrocortisone dose to less than 100 mg per day, the patient is switched to continuous hormone replacement therapy with oral hydrocortisone preparations.

Table A6. Replacement therapy for acute adrenal insufficiency in CAH

Appendix B. Physician Action Algorithms

General scheme

Appendix C. Patient Information

Congenital adrenal hyperplasia (CAH) is a condition associated with impaired adrenal function. The adrenal glands (AG) are paired, small organs located close to the kidneys. They consist of 2 main parts: the inner part is the medulla, which produces adrenaline, and this function is not impaired in CAH. The outer part is the cortex, which is where the abnormalities leading to CAH occur.

The cortex produces hormones (steroids) that maintain the body's basic vital functions. These hormones are formed from cholesterol through a complex, multi-step process, and ultimately the cortex produces 3 groups of hormones: cortisol, aldosterone, and male sex hormones (androgens).

Cortisol regulates the functioning of almost all body systems: blood circulation, stress response (including to infection, trauma), and much more.

Aldosterone: is responsible for maintaining normal levels of substances such as potassium and sodium in the body.

Androgens: are produced in the adrenal glands in both men and women and affect reproductive health.

Adrenal function is controlled by the brain (pituitary gland, hypothalamus). If the blood cortisol level is insufficient for normal body function, this is "recognized" by the hypothalamus, a signal is transmitted to the pituitary gland, and it begins to produce corticotropin (ACTH), which acts on the adrenal cortex, resulting in a release of cortisol. When a normal cortisol level is reached in the body, pituitary stimulation ceases and ACTH production decreases. If a patient takes glucocorticosteroid medications (synthetic cortisol) in tablets or injections, the hypothalamus, under the influence of these drugs, reduces ACTH production by the pituitary gland; the adrenal glands are not stimulated by ACTH, and the synthesis of cortisol in the human body decreases. If therapy is carried out for a long time in high doses for any reason, the synthesis of "own" cortisol ceases.

As noted above, the hormone production process in the adrenal glands is multi-step, and each step is driven by its own enzyme. If at least 1 enzyme malfunctions, CAH develops. Ultimately, CAH leads to a deficiency in the body's cortisol production and, in some cases, aldosterone, while androgens are synthesized in increased amounts. Due to low cortisol levels, patients with CAH have elevated ACTH levels, which attempt to "stimulate" adrenal cortex function, leading to proliferation (hyperplasia) of the adrenal tissue.

Almost 90% of CAH cases are associated with a dysfunction of an enzyme called 21-hydroxylase. This is due to various mutations in the gene responsible for the enzyme's function. In other words, CAH is a genetically determined condition! When the enzyme function is almost completely disrupted, the classical form of CAH develops. Classical CAH has 2 types (forms) of the disease: the virilizing form (cortisol deficiency with normal aldosterone production, pronounced increase in androgens in the body) and the salt-wasting form (cortisol deficiency + aldosterone deficiency, pronounced increase in androgens). When the enzyme function is partially disrupted, the non-classical form of CAH occurs (excessive androgen production only; cortisol and aldosterone are normal).

The classical form of CAH is diagnosed from birth; newborn screening for this disease has been introduced in the Russian Federation since 2006. Newborns with the salt-wasting form of the disease present without treatment with decreased appetite, weight loss, and vomiting (salt-wasting crises). In newborn females, due to abnormal adrenal function and the production of large amounts of androgens, external genitalia are masculinized, which in some cases requires plastic surgery. The virilizing form does not present with salt-wasting crises; girls show signs of external genital abnormalities, while boys aged 2–4 years exhibit signs of rapid growth and early puberty. Untreated children initially outpace their peers in growth, but androgens promote the rapid closure of bone growth plates, ultimately resulting in short stature.

The non-classical form of CAH is diagnosed in young women or adolescents during evaluations for irregular menstrual cycles or excessive hair growth. In men, this condition causes no clinical signs and is not diagnosed.

The diagnosis of CAH is established based on a comprehensive evaluation, including hormone level testing, in some cases an ACTH stimulation test, genetic analysis, ultrasound, and CT/MRI.

Children and adults with classical forms of CAH require lifelong treatment with pills containing cortisol—glucocorticoids. Continuous treatment normalizes ACTH and adrenal androgen levels, as well as blood cortisol levels. For the salt-wasting form of the disease, aldosterone medications are prescribed in addition. It must be remembered that cortisol is important for the body in any stressful situation: illness, trauma, surgical procedures. In CAH, patients' adrenal glands do not produce normal amounts of cortisol, so in stressful situations, it is necessary to increase the glucocorticoid dose or administer them intramuscularly or intravenously. A clear action algorithm must be provided by the patient's attending physician.

Female patients with the non-classical form of CAH require an individualized approach. For the majority of patients, the main complaint is excessive body hair growth, while the menstrual cycle may be normal and fertility preserved. In such cases, various hair removal methods are recommended. When patients experience problems with conception, maintaining pregnancy, or significant menstrual irregularities, the issue of prescribing glucocorticoids or oral contraceptives is addressed.

It should be noted that drug doses are selected individually by an endocrinologist under the supervision of blood hormone assays. Follow-up evaluations for adult patients are generally performed 1–2 times a year. Examinations to detect complications of the disease or the consequences of improper treatment (gastrointestinal status, ophthalmological evaluation, gynecological and andrological examination) must be carried out.

Adult patients with CAH naturally have questions regarding the possibility of passing the disease on to their children. When a spermatozoon and an egg fuse, the fetal genome is formed. Each fetal cell contains 23 pairs of chromosomes, with one chromosome in each pair coming from the mother and the other from the father. The disease develops if 2 chromosomes contain a damaged gene (2 mutations); if only 1 mutation is detected (the gene on one chromosome is damaged), this condition is called being a "healthy carrier". Now let us consider a situation where one partner in a married couple has CAH. If the other partner is healthy, only 1 mutated gene will be transmitted to the child, and the child will be healthy. If the partner also has CAH or is a healthy carrier, the birth of a child with CAH is possible. Therefore, such couples need a genetic consultation and screening of the partner for mutations in the 21-hydroxylase enzyme gene.

A common situation in CAH is psychological problems. This disease is undoubtedly a stressor for family members and adult patients. Specialized psychological support is an integral part of working with CAH patients in many countries.

In conclusion, we would like to state that CAH is a treatable disease. With adequate therapy and quality patient monitoring, they lead a normal lifestyle, achieve full social adaptation, receive an education, start families, and raise children.

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

G.1. Modified Ferriman-Gallwey scale

Russian name: Ferriman-Gallwey scale.

Original name (if any): Ferriman-Gallwey score.

Source (official developer website, validation publication): Yildiz et al., 2010.

Type: rating scale.

Purpose: assessment of the severity of hirsutism.

Content (template): in each of the depicted androgen-dependent areas, hair growth is scored from 0 to 4.

Key (interpretation): the sum of scores across all areas is called the hirsutism score. A hirsutism score of less than 8 is a variant of normal, 8–15 is moderate hirsutism, and greater than 15 is moderate to severe hirsutism.

Explanations: it is recommended not to use depilation or wax hair removal for at least 4 weeks and to avoid shaving hair for at least 5 days prior to the examination.