Adrenogenital syndrome — a hereditary disease of adrenal glands at which owing to functional insolvency of enzymes it is broken . It is shown by a virilization of genitals, a maskulinopodobny constitution, a breast underdevelopment, a girsutizm, an acne, amenorey or oligomenorey, infertility. During diagnostics determine levels 17 of hydroxyprogesterone, 17 ketosteroids, an androstendion, by AKTG, carry out ultrasonography of ovaries. To patients appoint replaceable hormonal therapy glucocorticoids and mineralokortikoida, estrogen in a combination with androgens or progestins of new generation. If necessary carry out plasticity of genitals.
Adrenogenital syndrome, or congenital dysfunction (giperplaziya) of bark of adrenal glands — the most frequent of the inherited diseases. Prevalence of pathology differs at representatives of different nationalities. Classical options of AGS at persons of Caucasian race meet the frequency of 1:14 000 babies while at Eskimos of Alaska this indicator makes 1:282. Significantly higher incidence at Jews. So, the nonclassical form of adrenogenital frustration is revealed at 19% of Jewish people of group of Ashkenazi. Pathology is transmitted on autosomno-recessive type. The probability of the birth of the child with such syndrome at a carriage of a pathological gene at both parents reaches 25%, in marriage of the carrier and the patient — 75%. If one of parents has full-fledged DNA, clinical manifestations of a syndrome at children do not develop. In the presence of ADS at the father and mother the child will also be sick.
Reasons of an adrenogenital syndrome
At patients with the inherited giperplaziya of adrenal glands genetic defect is shown by insolvency of the fermental systems participating in secretion of steroid hormones. In 90-95% of cases pathology arises at damage of a gene which is responsible for synthesis of 21 hydroxylases — the enzyme influencing formation of cortisol. In other clinical cases owing to defect of DNA production of other enzymes providing — StAR/20,22-desmolaza, 3-β--, 17-α-/17,20-, 11-β-, P450 oxidoreductase and sintetaza of an aldosteron is broken.
At patients with signs of a viriliziruyushchy syndrome instead of an active gene of CYP21-B in a short shoulder of the 6th autosome functionally insolvent pseudo-gene of CYP21-A is located. The structure of these sites of a DNA chain is in many respects homologous that increases probability of conversion of genes in meiosis with movement of the site of a normal gene of a pseudo-gene or a deletion of CYP21-B. Apparently, existence of the latent forms of a disease debuting in a puberty or the postpubertatny period is explained by these mechanisms. In such cases clinical symptoms of pathology become noticeable after the loadings exhausting bark of adrenal glands: serious illnesses, injuries, poisonings, radiative effects, long period of hard work, psychologically intense situations etc.
With defect of a CYP21-B-gene the principle of feedback is the cornerstone of the mechanism of development of the most widespread option of an adrenogenital syndrome. Deficiency of steroids — cortisol and an aldosteron becomes its initial link. Insolvency of processes of a hydroxylation is followed by incomplete transition 17 hydroxyprogesterone and progesterone in 11-dezoksikortizol and . As a result secretion of cortisol decreases, and for compensation of this process in a hypophysis synthesis of AKTG — the hormone causing a compensatory giperplaziya of bark of adrenal glands for stimulation of development of corticosteroids amplifies.
In parallel synthesis of androgens increases and visible signs of their influence on sensitive fabrics and bodies appear. At moderate decrease of the activity of enzyme mineralokortikoidny insufficiency does not develop as the need of an organism for the aldosterena is nearly 200 times lower in comparison with cortisol. Only deep defect of a gene causes heavy clinical symptomatology which is shown from early age. The pathogenesis of development of a disease at violation of structure of other sites of DNA is similar, however the starting moment are violations in other links of a steroidogenez.
Systematization of various forms of a viriliziruyushchy giperplaziya of adrenal glands is based on features of a clinical picture of a disease, expressiveness of genetic defect and time of manifestation of the first pathological signs. Weight of frustration is directly connected with DNA damage rate. Experts in the sphere of endocrinology distinguish the following types of an adrenogenital syndrome:
- Solteryayushchy. The heaviest option of pathology which is shown in the first year of life of the child gross violations of a structure of genitalia at girls and their increase at boys. Activity of 21 hydroxylases makes no more than 1%. Considerable violation of a steroidogenez leads to the expressed somatic violations — vomiting, a diarrhea, spasms, excessive pigmentation of skin. Without treatment such children die at early age.
- Idle time virilny. The course of a disease less heavy, than at solteryayushchy option. Manifestations of the wrong development of genitals in female babies, increase in their sizes at boys prevail. Signs of nadpochechnikovy insufficiency are absent. Level of activity of 21 hydroxylases is reduced to 1-5%. With age at patients virilization signs owing to the stimulating action of androgens accrue.
- Nonclassical (postpubertatny). The AGS optimum form which strong indications arise during puberty and at reproductive age. Genitalia have a normal structure, the clitoris at women and a penis at men can be increased. Functionality of 21 hydroxylases is reduced to 20-30%. The disease comes to light incidentally at inspection in connection with infertility or violations of menstrual function.
Solteryayushchy and simple virilny types of adrenogenital frustration refer to category of the antenatalny pathology which is formed vnutriutrobno and shown from the moment of the birth. At defect of a structure of other genes more rare options of a disease are observed: gipertenzivny — classical (congenital) and nonclassical (late), hyper thermal, lipidic, with the leading manifestations of a girsutizm.
Symptoms of an adrenogenital syndrome
At antenatalny forms of a disease (simple virilny and solteryayushchy) the main clinical symptom is the visible virilization of genitals. Signs of a female pseudo-hermaphroditism are found in newborn girls. The clitoris big by the sizes or has the penisoobrazny form, the threshold of a vagina is deepened, the urogenital sine is created, big and small vulvar lips are increased, a crotch high. Internal genitals are developed normally. At babies boys the penis and a giperpigmentirovana a scrotum is increased. Besides, at solteryayushchy adrenogenital frustration the symptomatology of nadpochechnikovy insufficiency with heavy, often somatic violations incompatible with life (a diarrhea, vomiting, spasms, dehydration, etc.) which are shown from 2-3 weeks age is expressed.
At girls with simple virilny AGS in process of a growing signs of a virilization amplify, the displastichesky constitution is formed. Because of acceleration of processes of ossification of the patient differ in the low growth, big shoulders, a narrow basin, short extremities. Tubular bones massive. Puberty begins early (up to 7 years) and proceeds with development of secondary male sexual characters. Increase in a clitoris, decrease in a timbre of a voice, increase of muscular force, formation of a shape of a cricoid cartilage of a thyroid gland, typical for men, is noted. The breast does not grow, menarche is absent.
The clinical symptoms at nonclassical forms of a viriliziruyushchy syndrome which arose in a puberty and after stress loads are less specific (an abortion on early terms of pregnancy, medical abortion, operation, etc.). Usually patients remember that they at younger school age had a small pilosis in axillary hollows and on a pubis. In the subsequent girsutizm signs with growth of rod hair over an upper lip, on the white line of a stomach, in a breast, developed in a mamillar areolyarnoy to a zone. Women with AGS show complaints to persistent acne rash, porosity and the increased fat content of skin.
Menarche comes late — by 15-16 years. The menstrual cycle is unstable, intervals between periods reach 35-45 days and more. Bloody allocations during monthly poor. Mammary glands small. The clitoris is a little increased. Such girls and women can have the high growth, a narrow basin, big shoulders. On observations of experts in the sphere of obstetrics and gynecology, the adrenogenital frustration develop later, the external signs characteristic of men are less noticeable, and the violation of a monthly cycle becomes more often the leading symptom. At more rare genetic defects of the patient can complain of increase in arterial pressure or, on the contrary, hypotonia with low working capacity and frequent headaches, a skin hyperpegmentation with the minimum symptoms of a virilization.
The main complication of an adrenogenital syndrome concerning which patients address obstetricians-gynecologists is persistent infertility. The earlier the disease was shown, the probability to become pregnant is less. At considerable fermental insufficiency and clinical manifestations of a simple viriliziruyushchy syndrome pregnancy does not occur at all. The become pregnant patients with pubertatny and postpubertatny forms of a disease have spontaneous abortions on early term. In labor functional istmiko-tservikalny insufficiency is possible. Such women are more inclined to emergence of psychoemotional frustration — tendencies to a depression, suicide behavior, aggression manifestations.
Diagnosis at the AGS antenatalny types with characteristic changes of genitals does not represent complexity and is carried out right after childbirth. In doubtful cases apply a kariotipirovaniye to confirmation of a female karyotype (46XX). Bigger value gets diagnostic search at a late clinical debut or the hidden current with the minimum external manifestations of a virilization. In similar situations for identification of an adrenogenital syndrome use the following laboratory and tool methods:
- 17-IT-progesterone level. High concentration 17 hydroxyprogesterone who is a predecessor of cortisol — a key sign of insufficiency of 21 hydroxylases. Its contents is increased by 3-9 times (from the 15th nmol/l and above).
- Steroid profile (17-KC). Increase in level 17 of ketosteroids in urine at women by 6-8 times testifies to the high content of the androgens made by bark of adrenal glands. When performing prednizolonovy test concentration 17-KC decreases by 50-75%.
- The maintenance of an androstendion in blood serum. The raised indicators of this highly specific method of laboratory diagnostics confirm the strengthened secretion of predecessors of male sex hormones.
- The AKTG level in blood. Compensatory hyper secretion of adrenokortikotropny hormone a forward share of a hypophysis is characteristic of classical forms of a disease. Therefore at a syndrome of viriliziruyushchy dysfunction the indicator is raised.
- Ultrasonography of ovaries. In cortical substance the follicles at different stages of maturing which are not reaching the preovulyatorny sizes are defined. Ovaries can be a little increased, however growth of a stroma is not observed.
- Measurement of basal temperature. The temperature curve is typical for an anovulyatorny cycle: the first phase is stretched, the second is shortened that is caused by insufficiency of a yellow body which is not formed due to the lack of an ovulation.
The increased concentration of a renin in blood plasma is also characteristic of solteryayushchy option of AGS. Differential diagnostics of the adrenogenital frustration which arose in pubertatny and childbearing age is carried out with a syndrome of polycystous ovaries, ovarialny androblastoma, androsteroma of adrenal glands, a virilny syndrome of a hypothalamic origin and a constitutional girsutizm. In difficult cases involve endocrinologists, urologists, doctors geneticists in diagnostics.
Treatment of an adrenogenital syndrome
The main way of correction of virilny dysfunction of adrenal glands is the replacement hormonal therapy filling shortage of glucocorticoids. If the woman with the hidden AGS has no reproductive plans, skin manifestations of a giperandrogeniya are insignificant and monthly are rhythmical, hormones do not apply. In other cases the choice of the scheme of treatment depends on a form of the endocrine pathology conducting symptoms and degrees of its expressiveness. Often purpose of glucocorticoid medicines is supplemented with other medicamentous and surgical methods which are picked up according to the specific therapeutic goal:
- Treatment of infertility. In the presence of plans for a child-bearing the woman under control of androgens of blood accepts glucocorticoids to a complete recovery of an ovulyatorny monthly cycle and approach of pregnancy. In resistant cases in addition appoint ovulation stimulators. In order to avoid an abortion hormonal therapy is continued till 13th week of gestational term. In the I trimester estrogen, in II-III — the progesterone analogs which do not have androgenic effect is also recommended.
- Correction irregular monthly and virilization. If the patient does not plan pregnancy, but complains of frustration of a menstrual cycle, a girsutizm, eels, are preferable means with estrogenic and anti-androgenic effect, the oral contraceptives containing gestagena of the last generation. The therapeutic effect is reached in 3-6 months, however upon termination of treatment in the absence of replaceable hormonal therapy signs of a giperandrogeniya are restored.
- Treatment of the AGS congenital forms. To girls with signs of a false hermaphroditism carry out adequate hormonal therapy and carry out surgical correction of a shape of genitals — a kliterotomiya, an introitoplastika (opening of an urogenital sine). At solteryayushchy adrenogenital frustration except glucocorticoids under control of reninovy activity appoint mineralokortikoida with increase in therapeutic doses when developing interkurrentny diseases.
Certain difficulties under the authority of the patient arise when the disease is not diagnosed in an obstetric hospital, and the girl with the expressed virilization of genitals is registered and brought up as the boy. At the decision on restoration of female gender identity surgical plasticity and hormonal therapy are supplemented with psychotherapeutic support. The decision on preservation of a civil male and removal of a uterus with appendages is accepted in exceptional cases at insistance of patients, however such approach is considered wrong.
Forecast and prevention
The forecast at timely detection of an adrenogenital syndrome and adequately picked up therapy favorable. Even at patients with a considerable virilization of genitals after plastic surgery normal sex life and natural childbirth is possible. Replaceable hormonal therapy at any AGS form promotes bystry feminization — development of chest glands, emergence monthly, to normalization of an ovarialny cycle, restoration of generative function. Prevention of a disease is performed at a pregnancy planning stage.
If in a sort cases of similar pathology were observed, consultation of the geneticist is shown. Conducting test with AKTG to both spouses allows to diagnose a heterozygotic carriage or the latent forms of adrenogenital frustration. At pregnancy the syndrome can be found by results of the genetic analysis of cages horionichesky or contents of the amniotic waters received by amniocentesis method. The neonatal screening which is carried out for the 5th days after the delivery is directed to detection of the increased concentration 17 hydroprogesterone for the bystry choice of therapeutic tactics.