Treatment of congenital dysfunction of the adrenal cortex

Treatment of congenital adrenogenital syndrome consists in elimination of glucocorticoids deficiency and hyperproduction of corticosteroids, which have anabolic and virilizing effect.

Therapy with glucocorticoids with congenital adrenogenital syndrome is replaceable. The feedback of the pituitary-adrenal cortex system is restored, and thus, the strengthened secretion of ACTH by the pituitary gland, which in turn leads to suppression of the secretion of androgens by the adrenal cortex. As a result, the formation of intermediate products of biosynthesis, 17-hydroxyprogesterone and progesterone, and, consequently, biosynthesis and androgen secretion is reduced. With prolonged use of glucocorticoids (prednisolone, etc.), the body's virilization decreases. As a result of the removal of the "androgenic brake" from the target organs, feminization occurs in females and females, under the influence of its own ovarian hormones, the mammary glands develop and the menstrual cycle is restored. Additional introduction of sex hormones is usually not required. The boys have a true sexual development, spermatogenesis appears, sometimes the tumor-like formations of the testicles disappear.

For rapid suppression of adrenocorticotropic activity and androgenic hyperfunction of the adrenal cortex, the treatment of patients is recommended to start with large doses of dexamethasone used for differential diagnosis: 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 the patients are usually transferred to prednisolone. If the diagnosis of congenital adrenogenital syndrome is not in doubt, prednisolone is prescribed at 10 mg / day for 7-10 days, after which once again determine the excretion of 17-CS with urine or the level of 17-hydroxyprogesterone in the blood. 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, in the case of the appearance of signs of adrenal insufficiency in the patient, it is necessary to use glucocorticoids, which approach cortisol by the action to the natural hormone. At the same time, deoxycorticosterone acetate (Doxa) is injected, and in the food to taste, sodium chloride is added, usually 6-10 g per day. The same treatment is prescribed and with a salt form of the disease.

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

Activity of various glucocorticoid drugs

A drug	Biological half-life, min	Binding to protein,%	Activity
			Glucococcidoid	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

Comparative analysis of various drugs used by us for the treatment of congenital adrenogenital syndrome showed that the most suitable drugs are dexamethasone and prednisolone. In addition, prednisolone has some sodium-retarding property, which is positive in the treatment of patients with a relative mineralocorticoid insufficiency. In some cases, a combination of drugs is necessary. So, if prednisolone at a dose of 15 mg does not reduce the excretion of 17-CS to normal, then a drug that suppresses secretion of ACTH more vigorously, for example dexamethasone 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-CS and 17-ACS in the urine and the level of 17-hydroxyprogesterone in the blood.

Given the difficulty of selecting the optimal dose of the drug, treatment is advisable to begin in a hospital under the control of excretion of 17-CS in the urine and the level of 17-hydroxyprogesterone in the blood. In the future, it is continued on an outpatient basis under constant dispensary supervision.

Treatment of patients with congenital adrenogenital syndrome should be carried out continuously and for life. The average dose of prednisolone is usually 5-15 mg / day. If a patient develops an intercurrent illness, the dose of the drug is increased depending on the course of the disease, usually 5-10 mg. Side effects of glucocorticoids are extremely rare, are observed only in cases of excess physiological doses of the drug and may manifest as a complex of symptoms of Itenko-Cushing's disease (weight gain, the appearance of bright striae on the body, matronism, hypertension). Excess doses of glucocorticoids sometimes lead to osteoporosis, decreased immunity, the formation of gastric and duodenal ulcers. To get rid of these phenomena, you should gradually reduce the dose by controlling the excretion of 17-CS with urine or the level of 17-hydroxyprogesterone in the blood. To cancel or interrupt treatment in any case it is impossible.

Sometimes patients with congenital adrenogenital syndrome are treated incorrectly, administering large doses of glucocorticoids, applying intermittent treatment, eliminating glucocorticoids in intercurrent diseases (instead of increasing doses). Refusal of the preparation even for a short time causes a relapse of the disease, which is manifested by an increase in the excretion of 17-CS with urine. In addition, with prolonged interruption in treatment and in untreated patients, adenomatosis or adrenal cortex tumors, small-cystic ovarian degeneration in girls and women, and tumor-like formations of testicles in males can develop. In some cases, in the absence of treatment in patients as a result of prolonged hyperstimulation of ACTH, the adrenal cortex gradually depletes with the manifestation of chronic adrenal insufficiency.

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

Unlike the virile (uncomplicated) form of the disease, in treating patients with congenital adrenogenital syndrome with hypertensive form, one should be guided not only by the data of excretion of 17-CS with 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 excretion of 17-ACS in the urine, especially deoxycortisol. Unlike other forms, the result of treatment of patients with hypertensive form of congenital adrenogenital syndrome depends on the timely initiation of therapy and the severity of hypertension to its onset.

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

In the first months of treatment, it is recommended to inject 0.5% oily 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 (after 1-2 days to 1 ml).

At present, instead of the Doxa oil solution, a cortine fructose preparation (florinef) is used, which primarily has a mineralocorticoid effect. One tablet contains 0.0001 or 0.001 g of the drug. Begin the treatment with a pill in the morning with a gradual increase in dose in accordance with clinical and biochemical data. The approximate maximum daily dose of the drug is 0.2 mg. Side effect of cortinef is fluid retention (edema). With a daily requirement for the drug more than 0.05 mg, it is necessary to reduce the dose of glucocorticoid drugs (prednisolone) in order to avoid an overdose. The dose is selected for each patient individually. Disappearance of dyspeptic phenomena, increase in body weight, elimination of dehydration, normalization of electrolyte balance are indicators of the positive effects of drugs.

Surgical treatment of patients with congenital adrenogenital syndrome is used to eliminate pronounced viral manifestations of external genitalia in persons with genetic and gonadal female sex. This is dictated not only by cosmetic necessity. The heterosexual structure of the external genitalia sometimes leads to a pathological formation of the personality and can become a cause of suicide. In addition, the wrong structure of the external genitalia prevents normal sexual life.

Treatment with glucocorticoid drugs in post-pubertal age causes rapid feminization of the body of patients with female genetic and gonadal sex, development of mammary glands, uterus, vagina, the appearance of menstruation. Therefore, the operation of plastic reconstruction of the external genital organs should preferably be carried out as early as possible from the start of treatment (not earlier than 1 year). Under the influence of glucocorticoid therapy, the entrance to the vagina considerably widens, the clitoral tension decreases, which technically facilitates the operation. When performing reconstructive surgeries of external genital organs in girls and women with congenital adrenogenital syndrome, it is necessary to adhere to the principle of closest approximation to the normal configuration of female external genital organs, which provides the corresponding cosmetic effect and the possibility of sexual activity, and in the future, the performance of genital function. Even with severe virilization of the external genitalia (penis-like clitoris with penial urethra) with compensatory therapy with glucocorticoids, one never has to raise the question of the formation of an artificial vagina, it develops during the treatment to normal sizes.

Treatment of patients with congenital adrenogenital syndrome in pregnancy

With proper treatment, begun even in adulthood, it is possible to achieve normal sexual development, the onset of pregnancy and childbirth. During pregnancy it is necessary to take into account that these are patients with glucocorticoid insufficiency of the adrenal cortex. Therefore, for any stress state, they need additional glucocorticoid administration. In most of them, prolonged exposure to androgens leads to underdevelopment of the endometrium and myometrium. A slight increase in the level of androgens with insufficient dosage of prednisolone interferes with the normal course of pregnancy and often leads to its spontaneous interruption.

The work of some researchers found that in patients with congenital adrenogenital syndrome in pregnancy, estriol deficiency is observed. 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 for a female fetus is possible. In connection with these features, treatment of patients with congenital adrenogenital syndrome during pregnancy should be carried out under strict control of 17-CS urinary excretion or 17-hydroxyprogesterone levels in the blood, which should remain within normal limits. In the last month of pregnancy or with a threatening miscarriage the patient should be placed in the maternity hospital and, if necessary, to increase the dose of prednisolone or introduce additional estrogens and gestagens. In case of a threatening miscarriage, due to an ischemic-cervical insufficiency, sometimes you have to put seams on the cervix. Early ossification of the skeleton forms a narrow pelvis, which usually requires delivery by caesarean section.

The choice of sex in patients with congenital adrenogenital syndrome

Sometimes, at birth, a child who has a genetic and gonadal sex, due to the expressed masculinization of the external genitalia, mistakenly install the male sex. With pronounced pubertal virilization, adolescents with a true female sex are offered to change their gender to male. Treatment with glucocorticoids leads quickly to feminization, development of mammary glands, the appearance of menstruation, until the restoration of childbearing function. With congenital adrenogenital syndrome in persons with a genetic and gonadal female sex, it is only expedient to choose a female gender.

Sex change in case of its erroneous definition is a very difficult question. It should be solved at the earliest possible age of the patient after a comprehensive examination in a specialized hospital, a sexopathologist, a psychiatrist, a urologist and a gynecologist. In addition to endocrine-somatic factors, the doctor must take into account the age of the patient, the strength of his psychosocial and psychosexual settings, the type of his nervous system. Persistent and purposeful psychological preparation is necessary when changing sex. Preliminary preparation and subsequent adaptation sometimes take 2-3 years. Patients who have retained the male sex mistakenly assigned to them are doomed to infertility, often the total impossibility of life due to the malformation of the "penis", the 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-stroke syndrome. Preservation of the male sex with 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 forecast for life and work with the timely treatment is favorable. With irregular treatment, especially hypertensive and salt-losing forms of congenital adrenogenital syndrome, patients may experience complications (eg, persistent hypertension) that lead to disability.

Clinical examination of patients with congenital adrenogenital syndrome

To maintain the curative effect obtained with all forms of congenital adrenogenital syndrome, a life-long use of glucocorticoids is required, which requires a regular follow-up of patients with an endocrinologist. At least 2 times a year he examines them and organizes examinations by a gynecologist and urologist. The study of excretion of 17-CS with urine or the level of 17-hydroxyprogesterone in the blood should also be performed at least 2 times a year.

[1], [2], [3], [4], [5], [6], [7]