Symptoms of a violation of sexual development

Clinical characteristics of the main forms of congenital pathology of sexual development

Distinguishing the clinical form as a specific nosological unit, it should always be borne in mind that between types of pathology closely located on the scale of stages of embryogenesis, intermediate types can exist, in separate features bearing the signs of neighboring forms.

Main clinical signs of congenital pathology.

1. Pathology of gonad formation: complete or unilateral absence, violation of their differentiation, the presence of one individual gonadal structures of both sexes, degenerative changes in gonads, non-admission testicles.
2. Pathology of the formation of internal genitalia: the simultaneous presence of derivatives of Muller and volphic passages, the absence of internal genitalia, inconsistency of the gonad floor with the structure of internal genitalia.
3. Pathology of the formation of external genitalia: a mismatch of their structure with the genetic and gonadal sex, sexually defined structure or underdevelopment of the external genitalia.
4. Violation of the development of secondary sexual characteristics: the development of secondary sexual characteristics that do not correspond to the genetic, gonadal or civil sex, absence, insufficiency or premature development of secondary sexual characteristics, absence or delay of menarche.

In clinical practice, the following main nosological forms of intrauterine disruption of sexual development are distinguished.

Agonizing gonads is the lack of development of gonads. According to the laws of embryogenesis, patients with initially absent gonads retain Muller structures (uterus, tubes, vagina) and female ("neutral") type of external genital structure. The cause of gonadal agenesis can be either chromosomal abnormalities (absence or disruption of the structure of one of the sex chromosomes), and any damaging factors (intoxication, irradiation) that prevent the migration of gonocytes to the primary kidney and the formation of a gonad in a normal karyotype. If we analyze the main components of the sex of gonadal agenesis, then the genetic floor can be either indeterminate or masculine or feminine; gonadal sex and hormonal sex absent; somatic, civil and psychological gender of women.

Clinically, there are two forms of gonads agenesis: "pure" agenesis without obvious chromosomal abnormalities and somatic malformations and Shereshevsky-Turner syndrome, genetically determined pathology with defects of sex chromosomes and multiple somatic malformations.

"Pure" gonad agenesis. All sick groups, regardless of genetic, have a female gender from birth, determined in accordance with the structure of the external genitalia. Sexual chromatin happens to be both negative and positive (with a normal or low number of Barr's bodies). Karyotype - 46, XY; 46, XX; mosaic variants. Gonads are absent, in their place connective tissue strands are found. The internal genitalia are the rudimentary uterus and the tubes, the infantile vagina. External genitalia are female, infantile. Secondary sexual characteristics do not spontaneously develop. Growth - normal or high, without somatic malformations - hence the term "clean". At puberty, untreated, euchinodal traits are formed. Somatic anomalies are absent. Patients consult a doctor only in late pubertal age due to the absence of secondary sexual characteristics and menstruation. There is an irreversible primary infertility. The differentiation of the skeleton lags behind the age norm slightly. In untreated patients, manifestations of hypothalamic regulation disorders can be expressed both in obesity and in exhaustion. The first occurs more often without trophic disturbances. There are signs of acromegaloidization, transient arterial hypertension.

Treatment is carried out by female sex hormones (estrogens or estrogens and progestins) with imitation of female sexual cycles, for a long time, starting with pubertal age (11-12 years) and throughout the childbearing age. In connection with the duration, oral therapy is preferred (the schemes are given below). Treatment prevents the development of eunuchoid body proportions, leads to pronounced feminization, the development of sexual and secondary sexual characteristics, the onset of induced menstruation, provides an opportunity for sexual life, prevents the development of hypothalamic disorders.

Syndrome Shereshevsky-Turner (CST) - agenesis or dysgenesis of gonads with characteristic defects of somatic development and stunted. Genital chromatin is more often negative or with a low content of Barra bodies, sometimes with reduced or enlarged sizes. Karyotype - 45, X; 45, X / 46, XX; 45, X / 46, XY, structural defect of the X-chromosome, gonads are often absent, in their place - connective tissue strands. In mosaic versions of the syndrome, there are underdeveloped (dysgenetic) gonadal tissue (ovary or testicle). Internal genitals - rudimentary uterus and tubes, vagina. External genitalia are female, infantile, sometimes with hypertrophy of the clitoris.

The latter should always be alarming about the presence of testosterone elements in the gonadal tracts, representing a cancer risk. In a number of cases, there are krauroid-like changes in the vulva. Secondary sexual characteristics in untreated patients are usually absent. The most characteristic malformations of somatic development are in decreasing order in frequency (own data): short stature - 98%; general dysplasticity - 92%; barrel chest - 75%; absence of mammary glands, wide distance between nipples - 74%; Neck shortening - 63%; low hair growth on the neck - 57%; high "gothic" palate - 56%; pterygoid folds in the neck - 46%; deformation of the auricles - 46%; shortening metakarpalnyh and metatarsal bones, aplasia phalanx - 46%; deformation of nails - 37%; valgus deformity of elbow joints - 36%; multiple pigmentary moles - 35%; micrognatism - 27%; lymphostasis - 24%; ptosis - 24%; epicanthus - 23%; heart defects and large vessels - 22%; vitiligo - 8%.

Differentiation of the skeleton at pubertal age lags markedly behind the age norm, then it begins to progress and corresponds to or exceeds the actual age to the pubertal period.

The stimulation of the physical development of patients with the Shereshevsky-Turner syndrome begins at the prepubertal age with the use of anabolic steroids. It should be emphasized that in some of these patients, especially with chromosome mosaicism 45, X / 46, XY and in some patients with karyotype 45, X, often before the beginning of therapy there are features of virilization of the external genitalia. The sensitivity of patients with Shereshevsky-Turner syndrome and to estrogens, and to androgens is high. The use of anabolic steroids, which possess certain androgenic activity, may lead to an intensification or appearance of signs of virilization.

This feature determines the need for the use of anabolic steroids in strictly physiological doses: methandrostenolone (nerobol, dianabol) 0.1-0.15 mg per day per 1 kg of body weight orally, courses for 1 month with interruptions of 15 days; nerobolil - 1 mg per 1 kg of body weight per month intramuscularly (the monthly dose is divided in half and introduced after 15 days); retabolil or silobolin - 1 mg per 1 kg of body weight once a month intramuscularly. During the treatment with anabolic steroids, patients need regular gynecological control. When there are signs of androgenation, breaks between treatment courses are prolonged. If there are persistent signs of virilization, treatment with anabolic steroids is canceled.

Spontaneous development of female secondary sexual characteristics, menarche and fertility in the Shereshevsky-Turner syndrome are rare and only in mosaicism with the prevalence of clone 46, XX. In such cases, the dysgenetic ovaries develop with different degrees of damage to the hormonal and generative functions. With gonad agenesis, naturally, both hormonal and generative functions are absent. Therefore, the main means of help is estrogen replacement therapy, which, with a small growth, is prescribed from pubertal (no earlier than 14-15 years) and is performed throughout the entire childbearing age. In the initial period of treatment, estrogens are prescribed in small doses in order to shake the epiphyseal growth zones. Depending on the degree of lag in sexual development, two treatment options are possible. 1 st - with severe underdevelopment, estrogens are prescribed for a long period (6-18 months) without interruptions in order to increase proliferative processes in myometrium, endometrium, vaginal epithelium, development of secondary sexual characteristics. After such an estrogenic preparation, one can proceed to the usual variant - cyclic estrogen therapy, which simulates a normal sexual cycle. 2 nd - in patients with a moderate delay in sexual development, treatment can begin immediately with cyclic administration of estrogens. With sufficient development of the uterus and mammary glands and the appearance of regular induced menstruation, estrogens can be combined with gestagens. Successfully used in recent years are combined estrogen-progestogen preparations with synthetic progestins (infecondin, bisekurin, non-ovilon, and rigevidon).

Against the background of treatment, feminization of the phenotype is achieved, the development of female secondary sexual characteristics, most often disappear kraurozopodobnye changes in the vulva, there are induced menstruation, provides the possibility of sexual life.

Gonadal dysgenesis. True hermaphroditism (a syndrome of a gonadal two-cavity) - presence at one person of sexual glands of both sexes. Sex chromatin is often positive. Karyotype - prevails 46, XX, sometimes - mosaic variants, less often - 46.XY. Gonads of both sexes, either located separately: on one side ovary, on the other - an egg (the so-called lateral form of true hermaphroditism), or with the presence of tissue and ovary and testicle in one gonad (ovoteistis). Internal and external genitalia are bisexual. Secondary sexual characteristics are often female, often spontaneous onset of menstruation.

Treatment. After the election of the civil sex - surgical and, if necessary, hormonal correction. The functional prevalence of the female part of the gonad is more often observed, therefore it is more expedient to elect a female gender. The male part of the gonad is removed (if the gonads are separated) or the ovotestis is removed (leaving the male gonadal elements in the abdominal cavity is dangerous oncologically) and then the plastic reconstruction of the external genitalia by the female type. Treatment with estrogen while preserving ovarian tissue is not required. It is assigned only in the case of castration according to the usual scheme. When the male is elected, the female part of the gonad and uterus is removed, the penis is straightened and, if possible, the urethra is plasty. If the androgen function of the testicular part is insufficient, the gonads resort to supportive androgen therapy. Authentic cases of fertility in the syndrome of gonadal bipartism are not described.

Treatment depends on the choice of sex and is determined by the characteristics of spontaneous development. With the eunuchoid type of dysgenesis of testicles, the majority of patients at birth are female. Surgical correction consists of removing testicles from the abdominal cavity and, if necessary, feminizing correction of the external genitalia; the issue of removal of testicles occurs only with the increase of their androgenic activity in pubertal or the presence of tumor degeneration (according to our data, tumors in dysgenetic testicles are very frequent and occur in 30% of cases). Patients undergo estrogen replacement therapy throughout the childbearing age to develop secondary female sexual characteristics, to receive induced menstruation, to ensure the possibility of sexual life in the chosen field. The results of prolonged estrogen therapy testify to the high sensitivity of these patients to estrogens. In the android type, some patients are brought up from birth as boys, others as girls. With this form, it is most expedient to elect a male civilian gender. Surgical correction in such cases consists in excretion of testicles from the abdominal cavity, plastic reconstruction of the genitals according to the male type with straightening of the penis and plasty of the urethra.

In the android type of dysgenesis of testicles in adolescence, androgen replacement therapy is generally not required. Patients are sterile due to a deep lesion of the hermetic apparatus of testicles. In adulthood, especially in patients living with a sexual life, there is sometimes a need for additional androgen administration in order to enhance sexual potency. Most of these patients are capable of a normal sexual life. According to the indications, a chorionic gonadotropin can be treated (1000-1500 units 2 times a week intramuscularly 15-20 injections per course). If necessary, the course of therapy is repeated.

With tumor changes in the testicles, you have to go on castration. In such cases it is more profitable to choose a female sex with the appropriate surgical and hormonal correction.

Parts of patients with a "turnaround" form are assigned at birth, female, parts - male. The choice of it depends on the prevalence of certain traits in the structure of the external genitalia, which would provide more favorable opportunities for sexual activity. However, unlike the android form, in borderline cases it is better to lean towards the choice of the female, as the patients are usually low. When choosing the latter, castration, feminizing plasty of the external genitalia and estrogen therapy are necessary, when choosing a male - removing testicles from the abdominal cavity, masculinizing plastic and treatment with a chorionic gonadotropin. The indications, duration and intensity of androgen therapy are individualized depending on the clinical data.

Rokitansky-Küster-Mayer syndrome - congenital aplasia of the vagina and uterus in the genetic and gonadal female field, female external genitalia and female secondary sexual characteristics. The pathogenetic basis of development is the embryonic involution of the Müllerian derivatives. The cause has not yet been elucidated, but it can be assumed that embryonic ovaries can be isolated from a peptide similar to antimulylerovym hormone. Ovaries, despite the confirmation of their ovulatory possibilities, often have the features of Stein-Leventhal syndrome, sometimes tend to migrate to the pelvic wall and even into the inguinal canals, like testicles. Most often this syndrome is diagnosed at pubertal age due to the non-occurrence of menarche with the normal development of female secondary sexual characteristics.

Treatment - the formation of an artificial vagina to ensure the possibility of sexual life. Naturally, menstruation and pregnancy can not have patients with this pathology, since they do not have a uterus.

Klinefelter's syndrome is a form of chromosomal congenital pathology of sexual development, determined during fertilization. Diagnosed usually only in the puberty period. It is characterized by infertility, moderate hypogonadism, and progressive hyalinosis of the seminiferous tubules with age, with degeneration of the germicidal elements of the testicles. Sex chromatin is positive, in some patients there are two or more Burr bodies in one nucleus. Karyotype - 47.XXY; 46, XY / 47, XXY; 48.XXXY. Gonads reduced in size, compacted testicles, usually located in the scrotum. Histologically - hyalinosis of the seminiferous tubules of various degrees, degeneration or absence (in adult patients) of germinal elements. Internal genitalia of male type, prostate gland of normal size or slightly reduced. External genitalia are male. The penis is of normal size or slightly behind in development. The scrotum is formed correctly. The testicles are located in the scrotum, less often in the inguinal canals, reduced in size. Secondary sexual characteristics are not developed enough, hairiness is meager, more often female. More than half of the patients have true gynecomastia. The growth of patients is above average. The differentiation of the skeleton corresponds to the age or slightly behind the age norm. The intellect of patients is often reduced, and the degree of its violation increases in proportion to the number of additional X chromosomes in the karyotype.

Treatment of patients with Klinefelter's syndrome is necessary only in cases of pronounced androgen deficiency accompanied by impotence. In most cases, you can do without hormonal therapy. Given the decrease in these patients tissue sensitivity to androgens, these drugs should, according to indications, be used in sufficient doses. According to some reports, in order to increase the sensitivity of tissues to androgens, it is advisable to combine them with chorionic gonadotropin. It should be remembered that an increased endogenous level of gonadotropins is considered as one of the reasons for the progression of the hyalinosis of the seminiferous tubules in these patients, therefore, the courses of treatment with the chorionic gonadotropin should be short, and the applied doses - small.

The incomplete masculinization syndrome is characterized by the presence of both testicles, anatomically correctly formed, located extra-abdominally: in the inguinal canals, often at their outer holes or in a split scrotum (large labia). Sexual chromatin is negative. Karyotype - 46.XY. Internal genitalia are male (epididymis, vas deferens, seminal vesicles). The prostate gland and Müllerian derivatives are absent (the antimuller activity of testicles in embryogenesis is preserved). External genitalia bisexual with variants from similar with female to more close to masculine. The penis is underdeveloped, the urethra opens in the urogenital sinus, there is a more or less pronounced "blind" vaginal process. Incomplete masculinization in this syndrome depends on the insufficient androgenic activity of testicles in both embryogenesis and puberty. There are also data on the inadequate sensitivity of target tissues to androgens of varying severity.

The syndrome of testicular feminization (STF) is characterized by the insensitivity of the target tissues of patients with the genetic and gonadal male sex to androgens with good sensitivity to estrogens. The pathogenetic nature of the syndrome is the absence or disruption of the receptor response of target organs to androgens, as well as a defect of the tissue enzyme 5a-reductase, which converts testosterone into the active form-5a-dihydrotestosterone. In the pathogenesis of the syndrome, absolute androgen deficiency also matters. It differs from the syndrome of incomplete masculinization by manifestations of feminization of the phenotype in puberty. Sexual chromatin is negative. Karyotype - 46, XY. Gonads - anatomically correctly formed testicles, located more often extra-abdominal: in the inguinal canals or in the "large labia", but sometimes in the abdominal cavity. The internal genitalia are represented by the epididymis, the vas deferens. The prostate gland is absent. External genitalia of the female structure, sometimes with the "clitoris" hypotrophy and deepening of the vaginal vestibule by the type of urogenital sinus. There is a more or less pronounced "blind" vaginal process. All patients with testicular feminization syndrome have a female civil gender since birth.

Clinically, this group, depending on the severity of feminization can be divided into 2 forms.   

1. Full (classical), which is characterized by a good development of female secondary sexual characteristics (physique, mammary glands, voice), lack of secondary hairiness ("hairless women"), female external genitalia, rather deep "blind" vagina.
2. Incomplete - with intersexual physique, female type of hair, underdevelopment of the mammary glands, with moderate masculinization of the external genitalia, short vagina.

With the full form (STFp), there is no sensitivity to androgens, so in embryonic development, despite the presence of androgenic testicles, the external genitalia remain female ("neutral") structure. Antimyuller activity of testicles is preserved, therefore the Mueller tubules are reduced and the derivatives of the volcanic tubules are formed - the epididymis, the vas deferens, the seminal vesicles. At birth, the female sex of a child with STF is not in doubt, only in a number of cases, the detection of testicles in the inguinal hernia or split "large labia" is prompted by the diagnosis. In the pubertal, despite the normal activity of the adrenal glands, pubarche does not come, sexual hair is completely absent. At the same time, the mammary glands develop very well, the figure acquires pronounced feminine features. If the testicles are in the abdominal cavity, the thought of the pathology of development arises only in puberty due to the lack of menstruation and sexual hair loss. The tactics of corrective therapy for STFs consists in biopsy and ventrophication of both testes (they are removed only in case of oncological findings during biopsy, in order to avoid the development of post-stroke syndrome and the need for hormone replacement therapy), and with the shortest available vagina in operative colpopoiesis.

Incomplete form (STFN) to puberty is clinically indistinguishable from the syndrome of incomplete masculinization: the sexually defined structure of the external genitalia, absence of the uterus, truncated vagina, testicles in the inguinal canals (less often in the abdominal cavity and large labia). However, in the puberty, along with the development of sexual embrace (feminine type, sometimes slightly strengthened) feminization of the figure appears, the formation of mammary glands. As in all cases of hermaphroditism, establishing a sex at birth is difficult, but usually with STF, the masculinization of the external genitalia is small, so it is difficult to assume a functional realization in adulthood. Therefore, in most cases a female correction direction is chosen. The testicles are ventrofixed to pubertal. If puberty shows undesirable androgenic activity, causing a roughening of the voice and excessive hairiness, they are removed from under the skin of the abdomen, where they were previously fixed.

Congenital virilizing dysfunction of the adrenal cortex (adrenogenital syndrome) in girls

Idiopathic congenital extrafetal virilization of the external genitalia in girls is a peculiar pathology, the etiology of which is not clear, however, it is possible to assume pathogenetically the effect of androgens (the source is unclear) on the formation of external genitalia between the 12th and 20th week of fetal life. Genetic and gonadal sex are feminine, there is a normally developed uterus, only external genitalia are sexually vague.

In the puberty, women develop secondary sexual characteristics in a timely manner, menarche attack, women are fertile. Rehabilitation consists in the feminizing plastic of the external genitalia. Hormonal correction is not necessary.

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