Treatment of congenital adrenal cortex dysfunction

Treatment of congenital adrenogenital syndrome consists of eliminating the deficiency of glucocorticoids and hyperproduction of corticosteroids, which have an anabolic and virilizing effect.

Glucocorticoid therapy for congenital adrenogenital syndrome is substitution therapy. The feedback of the pituitary-adrenal cortex system is restored, and thus the increased secretion of ACTH by the pituitary is inhibited, which in turn leads to the suppression of the secretion of androgens by the adrenal cortex. As a result, the formation of intermediate products of biosynthesis - 17-hydroxyprogesterone and progesterone - decreases, and, consequently, both the biosynthesis and secretion of androgens. With prolonged use of glucocorticoids (prednisolone, etc.), virilization of the body decreases. As a result of the removal of the "androgen brake" from the "target" organs, feminization occurs in girls and women, mammary glands develop under the influence of their own ovarian hormones, and the menstrual cycle is restored. Additional administration of sex hormones is usually not required. In boys, true sexual development occurs, spermatogenesis appears, and sometimes tumor-like formations in the testicles disappear.

To quickly suppress adrenocorticotropic activity and androgenic hyperfunction of the adrenal cortex, it is recommended to begin treatment with high doses of dexamethasone used to perform differential diagnostic tests: 4 tablets (2 mg) of dexamethasone are given every 6 hours for 2 days, followed by a decrease to 0.5-1 mg (1-2 tablets). Then patients are usually transferred to prednisolone. If the diagnosis of congenital adrenogenital syndrome is not in doubt, then prednisolone is prescribed at 10 mg / day for 7-10 days, after which the excretion of 17-KS in urine or the level of 17-hydroxyprogesterone in the blood is determined again. Depending on the results obtained, the dose of prednisolone is increased or decreased. In some cases, a combination of different steroid drugs is necessary. For example, if a patient shows signs of adrenal insufficiency, it is necessary to use glucocorticoids that are close in action to the natural hormone cortisol. At the same time, deoxycorticosterone acetate (DOXA) is also administered, and table salt is added to food to taste, usually 6-10 g per day. The same treatment is prescribed for the salt-wasting form of the disease.

The table shows the half-life, i.e. the half-action period, of some synthetic steroid analogues in relation to their glucocorticoid and mineralocorticoid activity. The data on this activity are given in relation to corticosol, the indicator of which is taken as one.

Activity of various glucocorticoid drugs

Preparation	Biological half-life, min	Protein binding, %	Activity
			Glucocorticoid	Mineral corticoid
Cortisol Cortisone Prednisolone Prednisone Dexamethasone Aldosterone	80 30 200 60 240 50	79 75 73.5 72 61.5 67	1 0.8 4.0 3.5 30 0.3	1 0.6 0.4 0.4 0 500-1000

A comparative analysis of various drugs used by us to treat congenital adrenogenital syndrome showed that the most suitable drugs are dexamethasone and prednisolone. In addition, prednisolone has some sodium-retaining properties, which is positive in the treatment of patients with relative mineralocorticoid deficiency. In some cases, a combination of drugs is necessary. Thus, if prednisolone at a dose of 15 mg does not reduce the excretion of 17-KS to normal values, then a drug should be prescribed that more vigorously suppresses the secretion of ACTH, for example, dexamethasone at 0.25-0.5-1 mg / day, more often in combination with 5-10 mg of prednisolone. The dosage of the drug is determined by the patient's condition, his blood pressure, excretion of 17-KS and 17-OCS with urine and the level of 17-hydroxyprogesterone in the blood.

Given the difficulties in selecting the optimal dose of the drug, it is advisable to begin treatment in a hospital setting under the control of 17-KS excretion in urine and the level of 17-hydroxyprogesterone in the blood. Subsequently, it is continued on an outpatient basis under constant dispensary observation.

Treatment of patients with congenital adrenogenital syndrome should be continuous and lifelong. Average doses of prednisolone are usually 5-15 mg/day. If the patient develops an intercurrent disease, the dose is increased depending on the course of the disease, usually by 5-10 mg. Side effects of glucocorticoids are extremely rare, observed only in cases of exceeding physiological doses of the drug and can manifest as a complex of symptoms of Itsenko-Cushing's disease (weight gain, appearance of bright stretch marks on the body, matronism, hypertension). Excessive doses of glucocorticoids sometimes lead to osteoporosis, decreased immunity, formation of gastric ulcer and duodenal ulcer. To get rid of these phenomena, it is necessary to gradually reduce the doses under the control of excretion of 17-KS in urine or the level of 17-hydroxyprogesterone in the blood. In no case should the treatment be canceled or interrupted.

Sometimes patients with congenital adrenogenital syndrome are treated incorrectly, by prescribing large doses of glucocorticoids, using intermittent treatment, and discontinuing glucocorticoids in intercurrent diseases (instead of increasing the dose). Refusal of the drug, even for a short time, causes a relapse of the disease, which is manifested by an increase in the excretion of 17-KS in the urine. In addition, with a long break in treatment and in untreated patients, adenomatosis or tumor of the adrenal cortex, microcystic degeneration of the ovaries in girls and women, and tumor-like formations of the testicles in males may develop. In some cases, in the absence of treatment, patients gradually experience depletion of the adrenal cortex with the manifestation of chronic adrenal insufficiency as a result of prolonged hyperstimulation of ACTH.

In the treatment of the hypertensive form of the disease, hypotensive agents are used along with glucocorticoids. The use of hypotensive agents alone is ineffective. In this form, intermittent treatment with glucocorticoids is especially dangerous, as it contributes to complications in the cardiovascular system and kidneys, which in turn lead to persistent hypertension.

Unlike the virile (uncomplicated) form of the disease, when treating patients with congenital adrenogenital syndrome with the hypertensive form, one should focus not only on the data of 17-CS excretion in urine, which sometimes may not be very high even with high hypertension. In addition to clinical data, the correctness of adequate therapy is determined by the results of a fractional study of 17-OCS excretion in urine, especially deoxycortisol. Unlike other forms, the result of treating patients with the hypertensive form of congenital adrenogenital syndrome depends on the timely initiation of therapy and the severity of hypertension at its onset.

Patients with the salt-wasting form of congenital adrenogenital syndrome die in early childhood without treatment. Doses of glucocorticoid drugs are selected in the same way as for the virile (uncomplicated) form of the disease. Treatment should begin with parenteral (due to frequent vomiting and diarrhea) {administration of glucocorticoid drugs. Along with glucocorticoids, mineralocorticoid substances are prescribed: table salt is added to food (for children - 3-5 g, for adults - 6-10 g per day).

In the first months of treatment, it is recommended to administer a 0.5% oil solution of deoxycorticosterone acetate (DOXA) 1-2 ml intramuscularly daily, depending on the patient's condition, for 10-15 days with a gradual decrease in the daily dose (but not less than 1 ml) or an increase in the intervals between injections (every 1-2 days, 1 ml).

Currently, instead of the oil solution of DOXA, the tablet preparation Cortinef (Florinef) is used, which has a predominantly mineralocorticoid effect. One tablet contains 0.0001 or 0.001 g of the preparation. Treatment should be started with a % tablet in the morning with a gradual increase in the dose in accordance with clinical and biochemical data. The approximate maximum daily dose of the preparation is 0.2 mg. A side effect of Cortinef is fluid retention (edema). If the daily requirement for the preparation is more than 0.05 mg, it is necessary to reduce the dose of glucocorticoid drugs (prednisolone) to avoid an overdose. The dose is selected for each patient individually. The disappearance of dyspeptic symptoms, weight gain, elimination of dehydration, normalization of electrolyte balance are indicators of a positive effect of the preparations.

Surgical treatment of patients with congenital adrenogenital syndrome is used to eliminate pronounced virilization of the external genitalia in individuals with genetic and gonadal female sex. This is dictated not only by cosmetic necessity. Heterosexual structure of the external genitalia sometimes leads to pathological formation of personality and can become a cause of suicide. In addition, abnormal structure of the external genitalia interferes with normal sexual life.

Treatment with glucocorticoids in post-pubertal age causes rapid feminization of the body of patients with female genetic and gonadal sex, development of mammary glands, uterus, vagina, and onset of menstruation. Therefore, it is desirable to perform plastic reconstruction of the external genitalia as soon as possible after the start of treatment (not earlier than 1 year). Under the influence of glucocorticoid therapy, the entrance to the vagina significantly widens, clitoral tension decreases, which technically facilitates the operation. When performing reconstructive surgeries of the external genitalia in girls and women with congenital adrenogenital syndrome, it is necessary to adhere to the principle of maximum approximation to the normal configuration of the female external genitalia, ensuring the appropriate cosmetic effect and the possibility of sexual activity, and subsequently the performance of the reproductive function. Even with severe virilization of the external genitalia (penis-shaped clitoris with penile urethra) with compensatory therapy with glucocorticoids, the question of the formation of an artificial vagina never arises; it develops during the treatment to its normal size.

Treatment of patients with congenital adrenogenital syndrome during pregnancy

With proper treatment, even when started in adulthood, normal sexual development, pregnancy and childbirth are possible. During pregnancy, it is necessary to take into account that these are patients with glucocorticoid insufficiency of the adrenal cortex. Consequently, under any stressful condition, they require additional administration of glucocorticoids. In most of them, prolonged exposure to androgens leads to underdevelopment of the endometrium and myometrium. A slight increase in androgen levels with an insufficient dosage of prednisolone prevents the normal course of pregnancy and often leads to its spontaneous termination.

Some researchers have established that patients with congenital adrenogenital syndrome have estriol deficiency during pregnancy. This also creates a risk of miscarriage. With a high level of androgens in the body of a pregnant woman due to an insufficient dose of prednisolone, intrauterine virilization of the external genitalia is possible for a female fetus. Due to these features, treatment of patients with congenital adrenogenital syndrome during pregnancy should be carried out under strict control of 17-KS excretion in urine or 17-hydroxyprogesterone levels in the blood, which should remain within normal limits. In the last month of pregnancy or in case of threatened miscarriage, the patient should be placed in a maternity hospital and, if necessary, the dose of prednisolone should be increased or estrogens and gestagens should be administered additionally. In case of threatened miscarriage due to isthmic-cervical insufficiency, it is sometimes necessary to apply sutures to the cervix. Early ossification of the skeleton results in a narrow pelvis, which usually requires delivery by cesarean section.

Gender selection in patients with congenital adrenogenital syndrome

Sometimes at birth, a child with genetic and gonadal sex is mistakenly assigned male sex due to pronounced masculinization of the external genitalia. In case of pronounced pubertal virilization, adolescents with true female sex are offered to change their sex to male. Treatment with glucocorticoids quickly leads to feminization, development of mammary glands, appearance of menstruation, up to restoration of reproductive function. In case of congenital adrenogenital syndrome in individuals with genetic and gonadal female sex, the only appropriate choice is female civil sex.

Changing gender in case of its erroneous determination is a very complex issue. It should be resolved at the earliest possible age of the patient after a comprehensive examination in a specialized hospital, consultation with a sexologist, psychiatrist, urologist and gynecologist. In addition to endocrine-somatic factors, the doctor should take into account the patient's age, the strength of his psychosocial and psychosexual attitudes, the type of his nervous system. Persistent and purposeful psychological preparation is necessary when changing gender. Preliminary preparation and subsequent adaptation sometimes require 2-3 years. Patients who retained the erroneously assigned male gender are doomed to infertility, often complete impossibility of life due to a developmental defect of the "penis", constant use of androgens against the background of glucocorticoid therapy. In some cases, it is necessary to resort to the removal of internal genital organs (uterus with appendages), which often leads to the development of severe post-castration syndrome. Preservation of the male sex in patients with genetic and gonadal female sex can be considered a medical error or a consequence of insufficiently serious psychological preparation of the patient.

The prognosis for life and work activity with timely treatment is favorable. With irregular treatment, especially hypertensive and salt-wasting forms of congenital adrenogenital syndrome, patients may develop complications (for example, persistent hypertension), which lead to disability.

Clinical examination of patients with congenital adrenogenital syndrome

To maintain the therapeutic effect obtained in all forms of congenital adrenogenital syndrome, lifelong use of glucocorticoids is necessary, which requires constant dispensary observation of patients by an endocrinologist. At least 2 times a year, he examines them and organizes examinations by a gynecologist and urologist. A study of the excretion of 17-KS with urine or the level of 17-hydroxyprogesterone in the blood should also be carried out at least 2 times a year.

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