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УДК 616.45-008.64-053.1-078.839-039


IS CONGENITAL ADRENAL HYPERPLASIA DUE TO 21- HYDRO- XYLASE DEFICIENCY DECEPTIVE DISEASE? MANAGEMENT AND DIFFERENTIATION OF SYNDROME IN ADULTS


Anna Nowak,


Medical University of Warsaw, Poland, abazylevych@gmail.com


Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most com- mon autosomal recessive hereditary diseases.

The lack of cortisol synthesis leads to excessive stimulation of the adrenal glands by adrenocorticotropic hormone (ACTH). Moreover the impairment of cortisol synthesis results in adrenal hyperplasia and excessive androgen synthesis. Congenital adrenal hyperplasia is characterised by a considerable correlation between the genotype and the phenotype with the type of CYP21A2 gene mutation affecting the severity of 21-hydroxylase deficiency.

The clinical manifestations of congenital adrenal hyperplasia in adults result from adrenocortical insufficiency, hyperandrogenism, and the adverse effects of glucocorticosteroids, which are used for the treatment of the syndrome. Non-classic congenital adrenal hyperplasia may sometimes be asymptomatic. Patients with classic congenital adrenal experience a wide variety of symptoms, including obesity, hyperinsulinaemia, insulin resistance, and hyperleptinaemia. These abnormalities promote the development of metabolic syndrome and its sequelae, including endothelial dysfunction, and cardiovascular disease. The symptoms are more often seen in patients suffering from congenital adrenal hyperplasia syndrome than in the general population.

Long-term glucocorticosteroid treatment is also a known risk factor for many diseases, for instance osteoporosis.

Patients with congenital adrenal hyperplasia require constant monitoring of biochemical parameters (17a-hydroxyprogesterone [17-OHP] and androstenedione), clinical parameters (Body Mass Index, waist circumference, blood pressure, glucose, and lipids), and bone mineral density by densitometry. Appropriate treatment of congenital adrenal hyperplasia is extremely important. The principal goal of treatment in adults with CAH is to improve quality of life, ensure that they remain fertile, reduce the manifestations of hyperandrogenisation in females. Furthermore it is key to reduce the adverse effects of medicaments used for therapy of the CAH syndrome.

Patients with classic congenital adrenal hyperplasia require treatment with glucocorticosteroids and, in cases of salt wasting, also with a mineralocorticosteroid.

Radical measures, such as bilateral adrenalectomy, are very rarely needed.

Asymptomatic patients with non-classic congenital adrenal hyperplasia require monitoring; treatment is not always necessary.

Medical care for patients suffering from congenital adrenal hyperplasia should be provided by reference centres, as the management of such patients requires collaboration between an endocrinologist, diabetologist, gynaecologist, andrologist, urologist, and psychologist.


Key words: congenital adrenal hyperplasia, 21- hydroxylase, glucocorticosteroids

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ЧИ Є ВРОДЖЕНА ГІПЕРПЛАЗІЯ НАДНИРНИКІВ ЧЕРЕЗ

21-ГИДРОКСИЛАЗНУ НЕДОСТАТНІСТЬ ОМАНЛИВОГО ЗАХВОРЮВАННЯ? УПРАВЛІННЯ ТА ДИФЕРЕНЦІЮВАННЯ СИНДРОМУ У ДОРОСЛИХ


Анна Новак,


Варшавський медичний університет, Польща, abazylevych@gmail.com


Вроджена гіперплазія надниркових залоз (CAH), зумовлена дефіцитом 21-гідроксилази, є однією з найбільш поширених аутосомно-рецесивних спадкових захворювань. Відсутність синтезу кортизолу призводить до надмірної стимуляції наднирників за допомогою адрено- кортикотропного гормону (АКТГ). Крім того, погіршення синтезу кортизолу призводить до гіперплазії наднирників та надмірного синтезу андрогену. Вроджена гіперплазія наднирників характеризується значною кореляцією між генотипом і фенотипом з типом мутації гена CY- P21A2, що впливає на тяжкість дефіциту 21-гідроксилази.

Клінічні прояви вродженої гіперплазії надниркових залоз у дорослих спричинені адрено- кортикальною недостатністю, гіперандрогенізмом та несприятливими ефектами глюкокор- тикостероїдів, які використовуються для лікування синдрому. Некрасована вроджена гіпер- плазія наднирників іноді може бути асимптоматичною. Пацієнти з класичними вродженими наднирниками мають широкий спектр симптомів, включаючи ожиріння, гіперінсулінемію, резистентність до інсуліну та гіперлептінемію. Ці аномалії сприяють розвитку метаболічного синдрому та його наслідків, включаючи дисфункцію ендотелію та серцево-судинні захворю- вання. Симптоми частіше спостерігаються у пацієнтів із вродженим синдромом гіперплазії надниркових залоз, ніж в загальній популяції. Довготривале лікування глюкокортикосте- роїдами також є відомим фактором ризику багатьох захворювань, наприклад, остеопорозу. Пацієнти з вродженою гіперплазією наднирників потребують постійного моніторингу біохіміч- них показників (17а-гідроксипрогестерон [17-OHP] та андростендіону), клінічних показників (індекс маси тіла, коліна талії, артеріального тиску, глюкози та ліпідів) та мінеральної щіль- ності кісткової тканини за допомогою денситометрії.

Відповідне лікування вродженої гіперплазії наднирників надзвичайно важливе. Основна мета лікування у дорослих з САН полягає у поліпшенні якості життя, забезпеченні їхньої родючості, зниженні проявів гіперандрогенації у жінок. Крім того, ключовим є зменшення несприятливого впливу лікарських засобів, що застосовуються для терапії синдрому CAH. Пацієнти з класичною вродженою гіперплазією надниркових залоз вимагають лікування глюкокортикостероїдами, а в разі втрати солі - також з мінералокортикостероїдами. Радикальні заходи, такі як двостороння адреналектомія, дуже рідко потрібні. Безсимптомні пацієнти з некатегоричною вродженою гіперплазією надниркових залоз вимагають моніто- рингу; лікування не завжди є необхідним. Медичне обслуговування пацієнтів, що страждають на вроджену гіперплазію наднирників, повинно забезпечувати відправні центри, оскільки для управління такими пацієнтами необхідна співпраця між ендокринологом, діабетологом, гінекологом, андрологом, урологом та психологом.


Ключові слова: вроджена гіперплазія наднирників, 21-гідроксилаза, глюкокортикостероїди.

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Etiology:


Congenital adrenal hyperplasia (CAH) is one of the most common autosomal re- cessive hereditary disease. 95 percent of cases of CAH is a result of 21-hydroxylase deficiency, the enzyme encoded by the CY- P21A2 gene. The role of 21-hydroxylase is to converse 17-hydroxyprogesterone to 11-deoxycortisol. Mutations in the CYP21A2 gene cause the cortisol deficiency and, in more progressive form, aldosterone defi- ciency. Moreover, a higher amount of ACTH is released, leading to excessive production of 17-hydroxyprogesterone (17-OHP). This steroid undergoes inordinate conversion to androgens.


Depending on the severity of 21-hydroxylase deficiency three main types of CAH are iden- tified:


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Figure 1. Pathway of adrenal and gonadal steroidogenesis in 21-hydroxylase deficiency. Pediatrics Clerkship, The University of Chicago

Epidemiology:


The frequency of occurrence of congenital adrenal hyperplasia was based on neonatal screening. Data from approximately 6.5 million newborn infants screened worldwide to show the mean prevalence of classic CAH approx. 1 in 15,000 live births. Spread differs according to ethnicity and geographic area. This number varies from as low as 1 in 28,000 in the Chinese population, 1 in 5000 to 23,000 live births in Caucasian, to as high as 1 in 280 in Yupik Eskimos in Alaska and 1 in 2100 in the French island of La Reunion. In the United States, the prevalence is lower in African Americans than in Caucasians (1 in 42,000 versus 1 in 15,500, respectively) [1-4].


Approximately 67 percent of classic congeni- tal adrenal hyperplasia patients are classified as “salt-losing,” (SW CAH), while 33 percent of classic adrenal hyperplasia patients have “non-salt-losing” or the “simple virilizing” form (SV CAH) reflecting the degree of aldosterone deficiency.


The non-classic CAH is more common and the frequency depends on the ethnicity. Among Caucasians, the prevalence of NC CAH may be as high as 1 in 1000 to 1 in 100, with the spread being significantly higher among Med- iterranean, Hispanics, Yugoslavs, and East- ern European Jews. Most patients with the non-classic form are based upon detection of very high levels of 17-hydroxyprogesterone [5-7].


Clinical manifestation:

The clinical spectrum of classic forms of con- genital adrenal hyperplasia ranges from the mild to the most severe forms, depending on such factors as adrenocortical and adre- nomedullary insufficiency, androgen excess, individual sensitivity to androgens and the ad- verse effects of medicines used for the treat- ment of CAH.


Manifestations of adrenocortical insuffi- ciency:

Adrenocortical insufficiency is diagnosed in pa- tients with classic congenital adrenal hyperpla- sia. Patients with classic-salt wasting CAH (SW CAH) may be apathetic and show general mal- aise, easy fatigability, loss of appetite, weight loss. Symptoms such as abdominal pain, nau- sea, vomiting, diarrhoea, myalgia and low

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blood pressure indicate an early adrenal crisis, which is a potentially life-threatening situation requiring immediate emergency treatment. Moreover, some patients suffering from classic- salt-wasting CAH (SW CAH) present with skin lesions, for instance, hyperpigmentation [8, 9].


Patients with classic congenital adrenal hy- perplasia also present insufficient level of hor- mones produced in adrenal glands medulla. It is associated with the abnormal formation of the adrenal medulla during the prenatal pe- riod. Patients with CAH have lower levels of plasma adrenaline, methoxy adrenaline and urinary adrenaline compared to control group. Adrenaline and cortisol deficiency increases the risk of severe hypoglycemia, especially in situations of growth requirement for adrenal cortex hormones [10].


Reproductive system manifestations: Women suffering from CAH present with var- ious gynaecological endocrinology symptoms. Higher androgens levels (hyperandrogenism) may cause hirsutism, acne, insufficient de- velopment of the breasts and menstrual dis- orders. About 40% of women with classic salt-wasting congenital adrenal hyperplasia (SW CAH ) and 20% of women with classic simple virilizing congenital adrenal hyperpla- sia (SV CAH) suffer from fertility problems.


Causes of decreased fertility are complex. Ex- posure of the fetus to the high concentrations of androgens during prenatal period may in- terfere with the development of the hypotha- lamic-pituitary-gonadal axis. Elevated levels of progesterone, 17-hydroxyprogesterone and androgens have a negative impact on the re- productive system [11].


Furthermore, women with congenital adrenal hyperplasia often suffer from polycystic ova- ry syndrome (PCOS) and insulin resistance, which increase the risk of anovulation cycles.


In addition, women diagnosed with classic CAH have sex life problems. Abnormal anatomical structure of the external genitals causes pain in the pelvis and bleeding during sexual in- tercourse, frequently resulting in post-inter- course dissatisfaction and subsequently lose their interest in sex life.


Men suffering from congenital adrenal hyper- plasia, similarly to women, are at higher risk

of infertility. It is caused by testicular adrenal rest tumour (ART), LH suppression and co-ex- istence of metabolic syndrome and insulin re- sistance.


Manifestations of non-classic congenital adrenal hyperplasia:

Manifestations of NC CAH in adult women in- clude hirsutism, acne, frontal alopecia, oligo- menorrhoea, infertility and virilisations symp- toms (clitoromegaly, male pattern hair growth, deepening of the choice). The causes of infer- tility are similar to those in the classic forms of congenital adrenal hyperplasia and affect about 13 % of women with NC CAH [12].


Adrenal tumours:

Patients suffering from classic forms of CAH and non-classic CAH are at higher risk of appear- ance of unilateral or bilateral focal changes in the structure of adrenal glands. Treatment with glucocorticoids may decrease in size the adre- nal tumours. It is important to examine the pa- tients with congenital adrenal hyperplasia for adrenal tumours. Likewise, patients diagnosed with adrenal tumours should be examined for congenital adrenal hyperplasia [13, 14].


Height and bone mineral density:

Early exposure to androgens and accelerat- ed growth rate in childhood cause the lower growth in adult life in patients with congenital adrenal hyperplasia [15].


Moreover, treatment of CAH with glucocorti- coids can lead to reduced bone mineral density (BMD) resulting in osteoporosis thus increas- ing the risk of bone fracture. In order to reduce the risk of osteoporosis development physician should apply low doses of glucocorticoids. Fur- thermore, nutrition has also a significant im- pact on reducing the frequency of osteoporosis. In this setting, Calcium and Vitamin D3 rich diet and/or supplementation in combination with appropriate physical activity are recommended [16-18].


Metabolic syndrome:

Classic congenital adrenal hyperplasia signifi- cantly increases the risk of metabolic syndrome. The patients diagnosed with CAH present in- creased body fat, increased incidence of over- weight or obesity, insulin resistance and higher insulin levels. As a result, these patients suf- fer from dyslipidemia, abnormalities of carbo- hydrate metabolism (impaired fasting glucose,

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impaired glucose tolerance, diabetes mellitus) hypertension and increased risk of cardiovascu- lar diseases (for instance myocardial infarction). Combination of healthy, well-balanced diet and physical activity may also reduce cardiovascu- lar risk in this group of patients [19, 20].


Psychosocial problems

Patients suffering from congenital adrenal hy- perplasia have the considerably lower quality of life in comparison to healthy individuals. Psychosocial problems in women with CAH re- sult from hyperandrogenism, especially from the effects of androgens on central nervous system functions. These patients often live a solitary life, have low self-esteem and are less sexually active. It results in lack of satisfac- tion during sexual intercourse and lowers their interest in this aspect of life. Sexual orienta- tion also varies from controls. Studies show that women suffering from congenital adrenal hyperplasia present more often homosexual and bisexual behaviour than healthy women.


Diagnostic approach in congenital adrenal hyperplasia

Appropriate diagnosis of congenital adrenal hyperplasia should firstly aim to determine the form of the disease that concerns the giv- en patient. This is based on a clinical picture with correlation to laboratory findings.


Diagnosis of classic forms of congenital adrenal hyperplasia

The diagnosis of classic forms of congenital adrenal hyperplasia to 21-hydroxylase de- ficiency (21OHD) is based on very high se- rum concentration of 17-hydroxyprogesterone (17OHP), which is the normal substrate for 21-hydroxylase.


Most of the affected neonates have random concentrations greater than 3500 ng/dL (105 nmol/L). The diagnosis of classic salt-wast- ing congenital adrenal hyperplasia (SW CAH) is mostly made in neonates (75 percent are salt-losing). Routine neonatal screening is obligatory in many countries and it is per- formed in 3-5 days after childbirth. It is es- sential to note that the setting of preterm babies, birth weight below 2500g and/or dis- tressed neonates, may lead to false positive results. Therefore diagnosis of CAH should include ACTH stimulation test, especially in ambiguous cases. During this test, a synthet- ic adrenocorticotropic hormone (Synacthen™)

at a dose of 250 μg is injected intravenously. Then serum 17-hydroxyprogesterone concen- trations are marked at baseline, 30 and 60 minutes after dosing.


The post-stimulation levels of 17-hydroxypro- gesterone are increased in classic-salt wasting congenital adrenal hyperplasia (300-1000 ng/ ml) while in classic-simple virilizing congen- ital adrenal hyperplasia those are decreased (100-300 ng/ml).


Other tests used in the diagnosis of CAH in- clude urinary steroid profiling, which allows accurate assessment of steroidogenesis ab- normalities, such as mineralocorticoids and glucocorticoids.


Complete Blood Count in patients with clas- sic-salt wasting congenital adrenal hyper- plasia present with reduced blood levels of aldosterone and 11-deoxycorticosterone, however plasma renin activity (PRA) is el- evated. Moreover, patients present with hy- pernatremia, hypercalcemia and metabolic acidosis.


Last but not least, genetic testing with the as- sessment for CYP21A2 mutation may provide a diagnosis in up to 90–95% of patients.


Classic simple virilizing congenital adrenal hy- perplasia (SV CAH) in boys and girls may be undiagnosed until early childhood when the signs of precocious maturation develop. Mild clinical forms of SV CAH are sometimes un- diagnosed until adult age. The test of choice is measuring the serum levels of 17-hydroxy- progesterone (with the normal values equal- ing < 1-2 ng/ml).


Diagnosis of non-classic congenital adrenal hyperplasia

NC-CAH diagnosis is similar to the diagnosis of classic forms of congenital adrenal hyperpla- sia. Diagnostic criteria involve the determina- tion of serum 17-hydroxyprogesterone, ACTH stimulation test, urinary steroid profiling, ge- netic testing for CYP21A2 mutations.


The ACTH stimulation test is a test of choice and usually is decisive in the diagnosis of non-classic congenital adrenal hyperplasia.


The 17-OHP concentrations following ACTH stimulation that are typical of NC CAH are most

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commonly in the range of 15–100 ng/ml.


The biochemical findings are less severe in pa- tients with the non-classic form of the disor- der in comparison to classic forms of congeni- tal adrenal hyperplasia.


Differential diagnosis:

Polycystic ovary syndrome (PCOS) may pres- ent similar clinical picture to CAH due to hy- perandrogenic symptoms thus it has always should to be considered in differential diagno- sis. Adrenal tumours is another condition that may mimic CAH – in this case, imaging studies are sufficient in differentiation between those two entities [11-14, 18, 19].


Treatment

The management of CAH depends on the age of onset, sex, and the severity of enzyme defi- ciency. Treatment aims to improve the patient’s quality of life by correction of hormone defi- ciency as well as alleviation of the symptoms of hyperandrogenism. This is done by application of glucocorticoids (this allows to reduce hyper- plasia and overproduction of androgens) in as- sociation with mineralocorticoids.


Glucocorticoid therapy in patients with con- genital adrenal hyperplasia is very compli- cated and thus it has to be planned carefully. The substitutive doses of GCS are sufficient

in the management of adrenocortical insuffi- ciency but in the majority of the cases it fails to provide sufficient suppression of ACTH se- cretion or to prevent hyperandrogenism and therefore doses should be always adjusted upon correlation with the clinical picture and laboratory findings [8, 17].


Combined contraceptive pills are effective in reducing the signs of hyperandrogenism and should be always considered in management planning [20, 21].


Last but not least, treatment of congenital ad- renal hyperplasia may involve surgery. Bilat- eral adrenalectomy is seldom used a surgical technique that has limited indications.


The principal indication is drug-resistant hy- perandrogenism, in which case adrenalectomy allows to limit doses of glucocorticoids.


Summary:

Congenital adrenal hyperplasia due to 21-hy- droxylase deficiency is a disorder that requires complex treatment and systematic monitoring. The main task in the care of CAH patients is to establish appropriate medication doses, im- prove sexuality and fertility, provide psycho- logical support and to prevent other diseases, especially those of cardiovascular system.


References


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  11. Baron JJ, Baron J. Differential diagnosis of hirsutism in girls between 15-19 years old. Ginekologia pol- ska. 1993 May;64(5):267-9.

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Стаття надійшла 27.10.17


Після допрацювання 17.11.17


Підписана до друку 20.12.17