Adrenogenital syndrome is a hereditary disease of the adrenal glands, in which steroidogenesis is disrupted due to the functional failure of enzymes. It is manifested by virilization of the genitals, masculine physique, breast underdevelopment, hirsutism, acne, amenorrhea or oligomenorrhea, infertility. During the diagnosis, the levels of 17-hydroxyprogesterone, 17-ketosteroids, androstenedione, ACTH are determined, ultrasound of the ovaries is performed. Patients are prescribed hormone replacement therapy with glucocorticoids and mineralocorticoids, estrogens in combination with androgens or progestins of a new generation. If necessary, plastic surgery of the genitals is performed.
ICD 10
E25.0 E25.8 E25.9
Meaning
Adrenogenital syndrome, or congenital dysfunction (hyperplasia) of the adrenal cortex, is the most common of inherited diseases. The prevalence of pathology differs among representatives of different nationalities. Classical variants of AGS in persons of the Caucasian race occur with a frequency of 1:14,000 infants, while in Alaska Eskimos this indicator is 1:282.
The incidence among Jews is significantly higher. Thus, a non-classical form of adrenogenital disorder is detected in 19% of persons of Ashkenazi Jewish nationality. Pathology is transmitted by autosomal recessive type. The probability of having a child with such a syndrome with the carrier of a pathological gene in both parents reaches 25%, in the marriage of the carrier and the patient — 75%. If one of the parents has full-fledged DNA, clinical manifestations of the syndrome do not develop in children. If the father and mother have adrenogenital syndrome, the child will also be sick.
Causes
In patients with inherited adrenal hyperplasia, the genetic defect is manifested by the failure of enzyme systems involved in the secretion of steroid hormones. In 90-95% of cases, pathology occurs when the gene responsible for the synthesis of 21-hydroxylase, an enzyme that affects the formation of cortisol, is damaged. In other clinical cases, due to a DNA defect, the production of other enzymes providing steroidogenesis is disrupted — StAR/20,22-desmolase, 3-β-hydroxy-steroid dehydrogenase, 17-α-hydroxylase/17,20-lyase, 11-β-hydroxylase, P450-oxidoreductase and aldosterone synthetase.
In patients with signs of virilizing syndrome, instead of the active CYP21-B gene, a functionally incompetent CYP21-A pseudogene is located in the short arm of the 6th autosome. The structure of these sections of the DNA chain is largely homologous, which increases the likelihood of gene conversion in meiosis with the transfer of a section of a normal gene to a pseudogene or deletion of CYP21-B.
Apparently, these mechanisms explain the existence of hidden forms of the disease, debuting in puberty or post-puberty. In such cases, clinical signs of pathology become noticeable after loads that deplete the adrenal cortex: severe diseases, injuries, poisoning, radiation exposure, a long period of intensive work, psychologically stressful situations, etc.
Pathogenesis
The mechanism of development of the most common variant of adrenogenital syndrome with a defect of the CYP21-B gene is based on the principle of feedback. Its initial link is the deficiency of steroids — cortisol and aldosterone. The failure of the hydroxylation processes is accompanied by an incomplete transition of 17-hydroxyprogesterone and progesterone to 11-deoxycortisol and deoxycorticosterone. As a result, the secretion of cortisol decreases, and to compensate for this process, the synthesis of ACTH in the pituitary gland increases, which causes compensatory hyperplasia of the adrenal cortex to stimulate the production of corticosteroids.
In parallel, the synthesis of androgens increases and visible signs of their influence on sensitive tissues and organs appear. With a moderate decrease in the activity of the enzyme, mineralocorticoid insufficiency does not develop, since the body’s need for aldosterone is almost 200 times lower compared to cortisol. Only a deep gene defect causes severe clinical symptoms, which manifests itself from an early age. The pathogenesis of the development of the disease in violation of the structure of other DNA sites is similar, but the starting point is violations in other links of steroidogenesis.
Classification
The systematization of various forms of virilizing adrenal hyperplasia is based on the features of the clinical picture of the disease, the severity of the genetic defect and the time of manifestation of the first pathological signs. The severity of the disorder is directly related to the degree of DNA damage. Specialists in the field of endocrinology distinguish the following types of adrenogenital syndrome:
- The solter. The most severe variant of pathology, manifested in the first year of a child’s life by gross violations of the structure of the external genitalia in girls and their increase in boys. The activity of 21-hydroxylase is no more than 1%. A significant violation of steroidogenesis leads to severe somatic disorders — vomiting, diarrhea, convulsions, excessive skin pigmentation. Without treatment, such children die at an early age.
- Simple virile. The course of the disease is less severe than with the salting variant. Manifestations of abnormal development of the genitals in female infants predominate, and an increase in their size in boys. There are no signs of adrenal insufficiency. The activity level of 21-hydroxylase was reduced to 1-5%. With age, the signs of virilization increase in patients due to the stimulating effect of androgens.
- Non-classical (post-pubertal). The most favorable form of AGS, the obvious signs of which occur during puberty and at reproductive age. The external genitalia have a normal structure, the clitoris in women and the penis in men can be enlarged. The functionality of 21-hydroxylase is reduced to 20-30%. The disease is detected accidentally during examination due to infertility or menstrual function disorders.
Salting and simple virile types of adrenogenital disorders are classified as antenatal pathology, which is formed in utero and manifests itself from the moment of birth. With a defect in the structure of other genes, rarer variants of the disease are observed: hypertensive — classical (congenital) and non-classical (late), hyperthermic, lipid, with leading manifestations of hirsutism.
Symptoms
Salting and simple virile
In the antenatal forms of the disease, the main clinical symptom is visible virilization of the genitals. Newborn girls show signs of female pseudohermaphroditism. The clitoris is large in size or has a penile shape, the vestibule of the vagina is deepened, the urogenital sinus is formed, the labia majora and labia minora are enlarged, the perineum is high. The internal genitalia are normally developed.
Male infants have enlarged penis and hyperpigmented scrotum. In addition, with a losing adrenogenital disorder, symptoms of adrenal insufficiency with severe, often incompatible with life somatic disorders (diarrhea, vomiting, convulsions, dehydration, etc.) are expressed, which manifest themselves from 2-3 weeks of age. In girls with simple virile adrenogenital syndrome, as they grow older, the signs of virilization increase, a dysplastic physique is formed.
Due to the acceleration of ossification processes, the patients are distinguished by their short stature, broad shoulders, narrow pelvis, and short limbs. The tubular bones are massive. Puberty begins early (up to 7 years) and proceeds with the development of secondary male sexual characteristics. There is an increase in the clitoris, a decrease in the timbre of the voice, an increase in muscle strength, the formation of a typical male form of cricoid cartilage of the thyroid gland. The breast does not grow, there is no menarche.
Non – classical
Less specific are the clinical symptoms in non-classical forms of virilizing syndrome that occurred at puberty and after stressful loads (miscarriage in early pregnancy, medical abortion, surgery, etc.). Usually, patients remember that they had a slight hair loss in the armpits and on the pubis even in elementary school age. Subsequently, signs of hirsutism developed with the growth of rod hairs above the upper lip, along the white line of the abdomen, in the sternum, in the nipple-areolar zone.
Women with AGS complain of acne, porosity and increased oiliness of the skin. Menarche comes late — by the age of 15-16. The menstrual cycle is unstable, the intervals between menstruation reach 35-45 days or more. Spotting during menstruation is scanty. The mammary glands are small. The clitoris is slightly enlarged. Such girls and women can have a tall stature, a narrow pelvis, wide shoulders.
According to the observations of specialists in the field of obstetrics and gynecology, the later adrenogenital disorders develop, the less noticeable the external signs characteristic of men, and the more often the leading symptom becomes a violation of the monthly cycle. With rarer genetic defects, patients may complain of increased blood pressure or, conversely, hypotension with low performance and frequent headaches, hyperpigmentation of the skin with minimal symptoms of virilization.
Complications
The main complication of adrenogenital syndrome, about which patients turn to obstetricians and gynecologists, is persistent infertility. The earlier the disease appeared, the less likely it is to get pregnant. With significant enzyme deficiency and clinical manifestations of a simple virilizing syndrome, pregnancy does not occur at all.
In pregnant patients with pubertal and post-pubertal forms of the disease, miscarriage occur at an early stage. Functional cervical insufficiency is possible in childbirth. Such women are more prone to the occurrence of psychoemotional disorders — a tendency to depression, suicidal behavior, manifestations of aggression.
Diagnostics
The diagnosis of antenatal types of AGS with characteristic changes in the genitals is not difficult and is carried out immediately after childbirth. In doubtful cases, karyotyping is used to confirm the female karyotype (46XX), molecular genetic tests. Diagnostic search becomes more important with a late clinical debut or latent course with minimal external manifestations of virilization. In such situations, the following laboratory and instrumental methods are used to detect adrenogenital syndrome:
- The level of 17-OH-progesterone. A high concentration of 17-hydroxyprogesterone, which is a precursor of cortisol, is a key sign of 21-hydroxylase deficiency. Its content is increased by 3-9 times (from 15 nmol/l and above).
- Steroid profile (17-CS). An increase in the level of 17-ketosteroids in the urine of women by 6-8 times indicates a high content of androgens produced by the adrenal cortex. When performing a prednisolone test, the concentration of 17-CS decreases by 50-75%.
- The content of androstenedione in blood serum. The increased indicators of this highly specific method of laboratory diagnostics confirm the increased secretion of male sex hormone precursors.
- The level of ACTH in the blood. The classical forms of the disease are characterized by compensatory hypersecretion of adrenocorticotropic hormone by the anterior pituitary lobe. Therefore, with virilizing dysfunction syndrome, the indicator is increased.
- Ovaries ultrasound. In the cortical substance, follicles are determined at different stages of maturation that do not reach preovulatory sizes. The ovaries may be slightly enlarged, but there is no growth of the stroma.
- Measurement of basal temperature. The temperature curve is typical for the anovulatory cycle: the first phase is stretched, the second is shortened, which is due to the insufficiency of the corpus luteum, which is not formed due to the lack of ovulation.
The salting variant of AGS is also characterized by an increased concentration of renin in blood plasma. Differential diagnosis of adrenogenital disorders that occurred at puberty and childbearing age is carried out with polycystic ovary syndrome, ovarian androblastoma, adrenal androsteromas, virile syndrome of hypothalamic origin and constitutional hirsutism. In difficult cases, endocrinologists, urologists, and geneticists are involved in the diagnosis.
Treatment
The main way to correct the virile dysfunction of the adrenal glands is hormone replacement therapy, which makes up for the deficiency of glucocorticoids. If a woman with latent AHS has no reproductive plans, skin manifestations of hyperandrogenism are insignificant and menstruation is rhythmic, hormones are not used. In other cases, the choice of treatment regimen depends on the form of endocrine pathology, the leading symptoms and the degree of its severity. Often, the appointment of glucocorticoid drugs is supplemented with other medicinal and surgical methods selected in accordance with a specific therapeutic purpose:
- Infertility treatment. If there are plans for childbirth, a woman under the control of blood androgens takes glucocorticoids until the ovulatory monthly cycle is fully restored and pregnancy begins. In resistant cases, ovulation stimulants are additionally prescribed. In order to avoid miscarriage, hormone therapy is continued until the 13th week of gestational age. Estrogens are also recommended in the first trimester, and progesterone analogues that do not have an androgenic effect are recommended in the II-III trimester.
- Correction of irregular periods and virilization. If the patient is not planning a pregnancy, but complains of menstrual cycle disorder, hirsutism, acne, means with estrogenic and antiandrogenic effects, oral contraceptives containing the latest generation of progestogens are preferred. The therapeutic effect is achieved in 3-6 months, however, at the end of treatment in the absence of hormone replacement therapy, signs of hyperandrogenism are restored.
- Treatment of congenital forms of AGS. Girls with signs of false hermaphroditism undergo adequate hormone therapy and perform surgical correction of the shape of the genitals — cliterotomy, introitoplasty (opening of the urogenital sinus). In case of losing adrenogenital disorders, in addition to glucocorticoids, mineralocorticoids are prescribed under the control of renin activity with an increase in therapeutic doses in the event of intercurrent diseases.
Certain difficulties in the management of the patient arise in cases when the disease is not diagnosed in an obstetric hospital, and a girl with pronounced virilization of the genitals is registered and brought up as a boy. When deciding on the restoration of female sexual identity, surgical plastic surgery and hormone therapy are supplemented with psychotherapeutic support. The decision to preserve the civilian male sex and remove the uterus with appendages is made in exceptional cases at the insistence of patients, but this approach is considered erroneous.
Prognosis and prevention
The prognosis with timely detection of adrenogenital syndrome and adequately selected therapy is favorable. Even in patients with significant genital virilization after plastic surgery, normal sexual life and natural childbirth are possible. Hormone replacement therapy in any form of AGS promotes rapid feminization — the development of the mammary glands, the appearance of menstruation, normalization of the ovarian cycle, restoration of generative function. Prevention of the disease is carried out at the stage of pregnancy planning.
If there have been cases of such pathology in the genus, a geneticist’s consultation is indicated. Conducting a test with ACTH for both spouses allows you to diagnose heterozygous carrier or latent forms of adrenogenital disorder. During pregnancy, the syndrome can be detected by the results of genetic analysis of chorionic villi cells or the contents of amniotic fluid obtained by amniocentesis. Neonatal screening conducted on the 5th day after delivery is aimed at detecting an increased concentration of 17-hydrogesterone for a quick choice of therapeutic tactics.
