Symptoms of impaired sexual development

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

When identifying a clinical form as a specific nosological unit, it should always be taken into account that between types of pathology that are closely located on the scale of stages of embryogenesis, there may be intermediate types that in some features carry the characteristics of neighboring forms.

The main clinical signs of congenital pathology.

1. Pathology of the formation of the gonads: complete or unilateral absence, disruption of their differentiation, the presence of gonadal structures of both sexes in one individual, degenerative changes in the gonads, undescended testicles.
2. Pathology of the formation of internal genitalia: simultaneous presence of derivatives of the Müllerian and Wolffian ducts, absence of internal genitalia, discrepancy between the sex of the gonads and the structure of the internal genitalia.
3. Pathology of the formation of external genitalia: discrepancy between their structure and the genetic and gonadal sex, gender-indeterminate structure or underdevelopment of the external genitalia.
4. Disorder of development of secondary sexual characteristics: development of secondary sexual characteristics that does not correspond to the genetic, gonadal or civil sex; absence, insufficiency or prematurity of development of secondary sexual characteristics; absence or delay of menarche.

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

Gonadal agenesis is the absence of gonad development. According to the laws of embryogenesis, patients with initially absent gonads retain Müllerian structures (uterus, tubes, vagina) and a female ("neutral") type of external genitalia structure. Gonadal agenesis can be caused by both chromosomal abnormalities (absence or abnormal structure of one of the sex chromosomes) and any damaging factors (intoxication, irradiation) that prevent gonocyte migration to the primary kidney area and gonad formation with a normal karyotype. If we analyze the main components of gonadal agenesis sex, the genetic sex can be either indeterminate, or male or female; gonadal sex and hormonal sex are absent; somatic, civil and mental sex are female.

Clinically, two forms of gonadal agenesis are distinguished: “pure” agenesis without obvious chromosomal abnormalities and somatic deformities, and Shereshevsky-Turner syndrome, a genetically determined pathology with defects in sex chromosomes and multiple somatic deformities.

"Pure" agenesis of the gonads. All patients in the group, regardless of genetic background, have civil female sex from birth, determined in accordance with the structure of the external genitalia. Sex chromatin can be both negative and positive (with a normal or low number of Barr bodies). Karyotype - 46,XY; 46,XX; mosaic variants. Gonads are absent, connective tissue strands are found in their place. Internal genitalia - rudimentary uterus and tubes, infantile vagina. External genitalia are female, infantile. Secondary sexual characteristics do not develop spontaneously. Height is normal or tall, without somatic malformations - hence the term "pure". At puberty, eunuchoid features are formed without treatment. Somatic anomalies are absent. Patients seek medical attention only in late puberty due to the absence of secondary sexual characteristics and menstruation. There is irreversible primary infertility. Skeletal differentiation lags behind the age norm only slightly. In untreated patients, manifestations of hypothalamic regulation disorders may be expressed both in obesity and in exhaustion. The former often occurs without trophic disorders. Signs of acromegaloidization and transient arterial hypertension are encountered.

Treatment is carried out with female sex hormones (estrogens or estrogens and progestins) with imitation of female sexual cycles, for a long time, starting from puberty (11-12 years) and throughout the childbearing years. Due to the duration, therapy with oral drugs is preferable (schemes are given below). Treatment prevents the development of eunuchoid body proportions, leads to pronounced feminization, development of sexual and secondary sexual characteristics, the onset of induced menstruation, ensures the possibility of sexual life, prevents the development of hypothalamic disorders.

Turner-Shereshevsky syndrome (TS) is agenesis or dysgenesis of the gonads with characteristic somatic developmental defects and short stature. Sex chromatin is often negative or with a low content of Barr bodies, sometimes with reduced or increased 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 variants of the syndrome, underdeveloped (dysgenetic) gonadal tissues (ovary or testicle) are encountered. Internal genitalia - rudimentary uterus and tubes, vagina. External genitalia are female, infantile, sometimes with clitoral hypertrophy.

The latter should always raise concern regarding the presence of testicular elements in the gonadal cords, which pose an oncological risk. In some cases, kraurosis-like changes in the vulva are observed. Secondary sexual characteristics are usually absent in untreated patients. The most typical somatic developmental defects in descending order of frequency (our own data): short stature - 98%; general dysplasticity - 92%; barrel-shaped chest - 75%; absence of mammary glands, wide distance between the nipples - 74%; shortened neck - 63%; low hair growth on the neck - 57%; high "Gothic" palate - 56%; pterygoid folds in the neck area - 46%; deformation of the auricles - 46%; shortening of the metacarpal and metatarsal bones, aplasia of the phalanges - 46%; deformation of the nails - 37%. valgus deformity of the elbow joints - 36%; multiple pigmented birthmarks - 35%; micrognathism - 27%; lymphostasis - 24%; ptosis - 24%; epicanthus - 23%; heart defects and large vessels - 22%; vitiligo - 8%.

Differentiation of the skeleton in puberty noticeably lags behind the age norm, then begins to progress and by the pubertal period corresponds to the actual age or is ahead of it.

Stimulation of physical development of patients with Shereshevsky-Turner syndrome begins in prepubertal age with the use of anabolic steroids. It should be emphasized that some of these patients, especially those with chromosomal mosaicism 45,X/46,XY and some patients with the karyotype 45,X, often have features of virilization of the external genitalia even before the start of therapy. The sensitivity of patients with Shereshevsky-Turner syndrome to both estrogens and androgens is high. The use of anabolic steroids with a certain androgenic activity can lead to an increase or the appearance of signs of virilization.

This feature determines the need to use anabolic steroids in strictly physiological doses: methandrostenolone (nerobol, dianabol) - 0.1-0.15 mg per day per 1 kg of body weight orally, in courses of 1 month with breaks of 15 days; nerobolil - 1 mg per 1 kg of body weight per month intramuscularly (the monthly dose is divided in half and administered after 15 days); retabolil or silabolin - 1 mg per 1 kg of body weight once a month intramuscularly. During treatment with anabolic steroids, patients need regular gynecological monitoring. If signs of androgenization appear, breaks between courses of treatment are extended. In the presence of persistent signs of virilization, treatment with anabolic steroids is canceled.

Spontaneous development of female secondary sexual characteristics, menarche and fertility in Shereshevsky-Turner syndrome are rare and only in mosaicism with prevalence of clone 46,XX. In such cases, dysgenetic ovaries develop with varying degrees of damage to hormonal and generative functions. In gonadal agenesis, both hormonal and generative functions are naturally absent. Therefore, the main means of assistance is estrogen replacement therapy, which in case of short stature is prescribed from puberty (not earlier than 14-15 years) and is carried out throughout the childbearing age. In the initial period of treatment, estrogens are prescribed in small doses to spare the epiphyseal growth zones. Depending on the degree of delay in sexual development, two treatment regimens are possible. 1st - in case of severe underdevelopment, estrogens are prescribed for a long period (6-18 months) without interruption in order to increase proliferative processes in the myometrium, endometrium, vaginal epithelium, and development of secondary sexual characteristics. After such estrogen preparation, one can switch to the usual option - cyclic estrogen therapy that imitates a normal sexual cycle. 2nd - in patients with moderate delay in sexual development, treatment can be started immediately with cyclic administration of estrogens. When sufficient development of the uterus and mammary glands is achieved and regular induced menstruation occurs, estrogens can be combined with gestagens. Combined estrogen-progestogen drugs with synthetic progestins (infecundin, bisecurin, non-ovlon, rigevidon) have been successfully used in recent years.

During treatment, feminization of the phenotype is achieved, female secondary sexual characteristics develop, kraurosis-like changes in the vulva most often disappear, induced menstruation appears, and the possibility of sexual activity is ensured.

Gonadal dysgenesis. True hermaphroditism (gonadal bisexuality syndrome) is the presence of the sex glands of both sexes in one person. Sex chromatin is usually positive. Karyotype - 46.XX predominates, sometimes - mosaic variants, less often - 46.XY. Gonads of both sexes, either located separately: on one side - the ovary, on the other - the testicle (the so-called lateral form of true hermaphroditism), or with the presence of tissue and ovary and testicle in one gonad (ovotestis). Internal and external genitalia are bisexual. Secondary sexual characteristics - more often female, spontaneous onset of menstruation is not uncommon.

Treatment. After choosing the civil sex - surgical and, if necessary, hormonal correction. More often, there is a functional prevalence of the female part of the gonad, so it is more advisable to choose the female sex. The male part of the gonad is removed (if the gonads are located separately) or the ovotestis is removed (leaving the male elements of the gonad in the abdominal cavity is dangerous in terms of oncology), followed by plastic reconstruction of the external genitalia according to the female type. Estrogen treatment is not required if the ovarian tissue is preserved. It is prescribed only in case of castration according to the usual scheme. When choosing the male sex, the female part of the gonad and the uterus are removed, the penis is straightened and, if possible, urethral plastic surgery is performed. In case of insufficiency of the androgenic function of the testicular part of the gonad, supportive androgen therapy is used. Reliable cases of fertility in gonadal bisexuality syndrome have not been described.

Treatment depends on the choice of gender and is determined by the characteristics of spontaneous development. In the eunuchoid type of testicular dysgenesis, most patients are assigned female gender at birth. Surgical correction consists of removing the testicles from the abdominal cavity and, if necessary, feminizing correction of the external genitalia; the question of removing the testicles arises only with an increase in their androgenic activity during puberty or the presence of tumor degeneration (according to our data, tumors in dysgenetic testicles are very common and occur in 30% of cases). Patients undergo estrogen replacement therapy throughout their childbearing years in order to develop secondary female sexual characteristics, obtain induced menstruation, and ensure the possibility of sexual activity in the chosen gender. The results of long-term estrogen therapy indicate a fairly high sensitivity of these patients to estrogens. In the android type, some patients are raised as boys from birth, others as girls. In this form, it is most appropriate to choose a male civil sex. Surgical correction in such cases consists of removing the testicles from the abdominal cavity, plastic reconstruction of the genitals according to the male type with straightening of the penis and plastic surgery of the urethra.

In the android type of testicular dysgenesis in adolescence, androgen replacement therapy is usually not required. Patients are sterile due to deep damage to the germinal apparatus of the testicles. In adulthood, especially in patients who are sexually active, there is sometimes a need for additional administration of androgens to enhance sexual potency. Most of these patients are capable of normal sexual activity. According to indications, treatment with chorionic gonadotropin can be carried out (1000-1500 IU 2 times a week intramuscularly, 15-20 injections per course). If necessary, courses of therapy are repeated.

In case of tumor changes in the testicles, castration is required. In such cases, it is more advantageous to choose the female sex with appropriate surgical and hormonal correction.

Some patients with the "turnoid" form are assigned female at birth, some - male. The choice depends on the prevalence of certain features in the structure of the external genitalia, which would provide more favorable opportunities for sexual life. However, unlike the android form, in borderline cases it is better to lean towards choosing the female sex, since patients are usually short. When choosing the latter, castration, feminizing plastic surgery of the external genitalia and estrogen therapy are necessary, when choosing the male sex - removal of the testicles from the abdominal cavity, masculinizing plastic surgery and treatment with chorionic gonadotropin. Indications, duration and intensity of androgen therapy are individualized depending on the clinical data.

Rokitansky-Küster-Meyer syndrome is a congenital aplasia of the vagina and uterus with genetic and gonadal female sex, female external genitalia and female secondary sexual characteristics. The pathogenetic basis for development is embryonic involution of Müllerian derivatives. The cause has not yet been determined, but it can be assumed that embryonic ovaries secrete a peptide similar to anti-Müllerian hormone. The ovaries, despite confirmation of their ovulatory capabilities, often have features of Stein-Leventhal syndrome, sometimes have a tendency to migrate to the pelvic walls and even to the inguinal canals, like the testicles. Most often, this syndrome is diagnosed in puberty due to the failure of menarche with normal development of female secondary sexual characteristics.

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

Klinefelter syndrome is a form of chromosomal congenital pathology of sexual development, determined at fertilization. It is usually diagnosed only in puberty. It is characterized by infertility, moderate hypogonadism and progressive hyalinosis of the seminiferous tubules with degeneration of the germinal elements of the testicles with age. Sex chromatin is positive, some patients have two or more Barr bodies in one nucleus. Karyotype - 47.XXY; 46,XY/47,XXY; 48.XXXY. Gonads are reduced in size, testicles are compacted, usually located in the scrotum. Histologically - hyalinosis of the seminiferous tubules of varying severity, degeneration or absence (in adult patients) of the germinal elements. Internal genitalia are of the male type, the prostate gland is of normal size or slightly reduced. External genitalia are male. The penis is of normal size or slightly underdeveloped. The scrotum is formed correctly. The testicles are located in the scrotum, less often in the inguinal canals, and are reduced in size. Secondary sexual characteristics are underdeveloped, hair growth is sparse, more often of the female type. More than half of the patients have true gynecomastia. The height of patients is above average. Differentiation of the skeleton corresponds to age or slightly lags behind the age norm. The intellect of patients is often reduced, and the degree of its impairment increases proportionally to the number of additional X chromosomes in the karyotype.

Treatment of patients with Klinefelter syndrome is necessary only in cases of severe androgen deficiency accompanied by impotence. In most cases, hormonal therapy can be avoided. Given the decreased tissue sensitivity to androgens in these patients, these drugs should be used in sufficient doses, as indicated. According to some data, in order to increase tissue sensitivity to androgens, it is advisable to combine them with chorionic gonadotropin. It should be remembered that increased endogenous levels of gonadotropins are considered one of the causes of progression of seminiferous tubule hyalinosis in these patients, so courses of treatment with chorionic gonadotropin should be short, and the doses used should be small.

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

Testicular feminization syndrome (TFS) is characterized by insensitivity of target tissues of patients with genetic and gonadal male sex to androgens with good sensitivity to estrogens. The pathogenetic essence of the syndrome is the absence or impairment of the reaction of target organ receptors to androgens, as well as a defect in the tissue enzyme 5a-reductase, which converts testosterone into its active form - 5a-dihydrotestosterone. Absolute androgen deficiency is also important in the pathogenesis of the syndrome. It differs from incomplete masculinization syndrome by manifestations of phenotype feminization in puberty. Sex chromatin is negative. Karyotype is 46,XY. Gonads are anatomically correctly formed testicles, located most often extra-abdominally: in the inguinal canals or in the "labia majora", but sometimes in the abdominal cavity. The internal genitalia are represented by the epididymis and the vas deferens. The prostate gland is absent. The external genitalia are of female structure, sometimes with hypotrophy of the "clitoris" and a deepening of the vaginal vestibule like the urogenital sinus. There is a more or less pronounced "blind" vaginal process. All patients with testicular feminization syndrome have female civil sex from birth.

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

1. Complete (classical), which is characterized by good development of female secondary sexual characteristics (physique, mammary glands, voice), absence of secondary hair growth (“hairless women”), female external genitalia, and a fairly deep “blind” vagina.
2. Incomplete - with an intersexual body type, female type of hair growth, underdeveloped mammary glands, with moderate masculinization of the external genitalia, and a short vagina.

In the complete form (STFP), sensitivity to androgens is absent, therefore, in embryonic development, despite the presence of androgen-active testicles, the external genitalia remain of female ("neutral") structure. Anti-Müllerian activity of the testicles is preserved, therefore, the Müllerian tubules are reduced and derivatives of the Wolffian tubules are formed - the epididymis, the vas deferens, the seminal vesicles. At birth, the female sex of a child with STFP does not raise any doubts, only in some cases the detection of testicles in inguinal hernias or split "labia majora" suggests the diagnosis. In puberty, despite the normal activity of the adrenal glands, pubarche does not occur, sexual hair growth is completely absent. At the same time, the mammary glands develop beautifully, the figure acquires pronounced feminine features. If the testicles are in the abdominal cavity, the thought of developmental pathology arises only in puberty due to the absence of menstruation and genital hair. The tactics of corrective therapy for STFP consists of biopsy and ventrofixation of both testicles (they are removed only in case of oncological findings during biopsy, to avoid the development of postcastration syndrome and the need for hormone replacement therapy), and in the case of a shortened vagina, which is present in most cases, in surgical colpopoiesis.

The incomplete form (STFn) before puberty is clinically indistinguishable from the syndrome of incomplete masculinization: gender-ambiguous structure of the external genitalia, absence of the uterus, shortened vagina, testicles in the inguinal canals (less often - in the abdominal cavity and labia majora). However, during puberty, along with the development of genital hair (female type, sometimes slightly increased), feminization of the figure and formation of mammary glands appear. As in all cases of hermaphroditism, establishing sex at birth can be difficult, but usually with STFn, masculinization of the external genitalia is small, so it is difficult to assume functional implementation in adulthood. Therefore, in most cases, the female direction of correction is chosen. The testicles are ventrofixed before puberty. If during puberty their unwanted androgenic activity manifests itself, causing a coarsening of the voice and excessive hairiness, they are removed from under the abdominal skin 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, but pathogenetically it is possible to assume the effect of androgens (source unclear) on the formation of the external genitalia in the period between the 12th and 20th week of intrauterine life of the fetus. Genetic and gonadal sex are female, there is a normally developed uterus, only the external genitalia are sexually indeterminate.

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

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