Violation of sexual differentiation - Medical reference book. Violations of sexual differentiation Violation of sexual differentiation

Jean D. Wilson, James E. Griffin Sh ( Jean D . wilson , James E . Griffin W)

Sexual differentiation is a consistent and ordered process. The chromosomal sex, which is formed at the time of fertilization, determines the gonadal sex, and the gonadal sex, in turn, determines the development of the phenotypic sex, which implies the formation of a male or female genitourinary apparatus (Table 333-1). Changes at any stage of this process during embryogenesis lead to disturbances in sexual differentiation. Known causes of impaired sexual development include environmental changes, for example, when taking virilizing agents during pregnancy, non-familial aberrations of sex chromosomes, for example 45, X-gonadal dysgenesis, congenital malformations of multifactorial genesis. for example, most cases of hypospadias, as well as hereditary defects caused by single gene mutations, such as testicular feminization syndrome.

Limited knowledge allows us to give only an empirical assessment of the nature of physiological disorders in certain defects. Nevertheless, with the help of a combination of methods of genetic, (phenotypic and chromosomal analysis), it is usually possible to establish a specific diagnosis, determine sex and, if necessary, make changes in the phenotype.

Normal sexual differentiation

At the first stage of sexual differentiation, the chromosome sex is established: the sex of the heterogamete (XY) is male, and the homogamete (XX) is female. Then, until about the 40th day of pregnancy, embryos of both sexes develop in the same way. The second stage of sexual differentiation consists in the transformation of undifferentiated gonads into testicles or ovaries. Differentiation of the gonads into testis is mediated by genes on the Y chromosome, one of which is either identical to the gene encoding the HY antigen or closely linked to it. The final process - the translation of the gonadal sex into the phenotypic sex - depends on the type of fetal gonads formed and their endocrine secretion. The development of the phenotypic sex leads to (the formation of the male and female genitourinary apparatus.

The internal genital organs are formed from the wolf and müllerian ducts, which are on early stages embryonic development both sexes are located side by side (333-1, a). In the male fetus, the Wolffian ducts give rise to the epididymis, vas deferens, and seminal vesicles, while the Müllerian ducts disappear. In female embryos, the fallopian tubes, uterus, and upper vagina develop from the Müllerian ducts, while the Wolffian ducts regress. The external genitalia and urethra in fetuses of both sexes develop from a common anlage - the urogenital sinus and genital tubercle, folds and swellings (333-1, b). The urogenital sinus in the male fetus gives rise to the prostate gland and the prostatic part of the urethra, and in the female fetus to the urethra and part of the vagina. The genital tubercle forms the glans penis in male fetuses and the clitoris in female fetuses. The urogenital swellings turn into the scrotum or labia majora, and the genital folds into the labia minora or merge to form the male urethra and penile shaft.

If the testicles are absent, as, for example, in normal female embryos or in male embryos castrated before the onset of phenotypic differentiation, the development of the phenotypic sex occurs in a female direction. In this way. masculinization of the fetus is a positive result of the action of the hormones of the embryonic gonads, while the development of the female type does not require the journey of the gonads. The sexual phenotype normally corresponds to the chromosomal sex. In other words, chromosomal sex determines gonadal sex, and gonadal sex in turn controls phenotypic sex.

Table 333-1. Classification of violations of sexual development in humans

Chromosome sex disorders Klinefelter's syndrome Males with karyotype XX Gonadal dysgenesis Mixed gonadal dysgenesis True hermaphroditism Gonadal sex disorders Pure gonadal dysgenesis No testicle syndrome Phenotypic sex disorders Female pseudohermaphroditism

Congenital adrenal hyperplasia Female pseudohermaphroditism of extraadrenal genesis Developmental disorders of the Mullerian ducts Male pseudohermaphroditism Disorders of androgen synthesis Disorders of androgen action Müllerian duct persistence syndrome Malformation of the male genitalia

The formation of the male phenotype is determined by the action of three hormones. Two of these, the Müllerian duct inhibitor and testosterone, are secretory products of the fetal testicles. The Müllerian duct inhibitory substance is a protein hormone that causes the Müllerian ducts to regress and therefore prevents the formation of the uterus and fallopian tubes in male embryos. Testosterone directly stimulates the differentiation of derivatives of the wolf ducts and serves as a precursor of the third embryonic hormone, dihydrotestosterone (ch. 330). Dihydrotestosterone, which is formed from circulating testosterone, induces the formation of the male urethra, prostate, penis, and scrotum. Thus, during intrauterine life, testosterone and dihydrotestosterone cause the formation of accessory organs of the male reproductive system, acting through the same intracellular mechanism that mediates their effects in differentiated tissues (chap. 330).

333-1. Normal sexual differentiation. a - internal genital organs; b - external genitalia.

The secretion of testosterone by embryonic testicles reaches a maximum by the 8-10th week of pregnancy, and the formation of the sexual phenotype is completed mainly by the end of the first trimester. On the late stages During pregnancy, female fetuses develop ovarian follicles and vaginal maturation, while male fetuses develop testicular descent and external genitalia growth.

Table 333-2. Clinical manifestations chromosomal sex disorders

Chromosomal sex disorders

Chromosomal sex disorders (Table 333-2) occur when the number or structure of X- or Y-chromosomes changes (Ch. 60).

Klinefelter syndrome

Clinical manifestations. Klinefelter's syndrome is characterized by primary hypogonadism (small, hard testicles), azoospermia, gynecomastia, and elevated plasma gonadotropins in men with two or more X chromosomes. Karyotype - more often 47, XXY (classic form) or mosaicism 46, XY / 47, XXY. This syndrome is the most common disorder of sexual differentiation and occurs in about 1 case per 500 men.

In prepubertal age, patients have small testicles, but otherwise they look normal. After puberty, the disease is manifested by infertility, gynecomastia, or sometimes insufficient androgenization (Table 333-3). A constant feature of the 47,XXY karyotype is hyalinization of the seminiferous tubules and azoospermia. The testicles are small, firm, less than 2 cm long (always less than 3.5 cm), corresponding to a volume of 2 ml (12 ml). The increase in average height is determined by the lengthening of the lower part of the body. Gynecomastia usually appears in adolescence and usually on both sides; the mammary glands are painful and can increase to a size that changes the figure (ch. 332). From 30 to 50% of patients suffer from obesity and varicose veins. Mild mental retardation, difficulties in social adaptation, thyroid dysfunction, diabetes mellitus and lung disease are common. to the occurrence of breast cancer is 20 times higher than that among healthy men (but 5 times less than that in women). Most patients are characterized by a male psychosexual orientation, their sexual function is similar to that of healthy men.

According to the results of the study of the chromosomal karyotype in peripheral blood leukocytes, it was found that about 10% of patients suffer from the mosaic variant of the syndrome. The frequency of this variant seems to be underestimated, since chromosomal mosaicism can only occur in the testicles, and the peripheral leukocyte karyotype remains normal. Mosaic 4yurma is usually not as severe as variant 47, XXY, and the testicles may retain normal size (Table 333-3). Endocrine disorders are also less pronounced, and gynecomastia and azoospermia are less common. Moreover, patients with mosaicism can sometimes be fertile. In some of them, due to the insignificance of physical deviations from the norm, one may not suspect the correct diagnosis.

Table 333-3. Characteristics of patients with classic and mosaic variant of Klinefelter syndrome 1

The table is based on the results of a survey of 519 patients with an XX karyotype and 51 patients with an XY/XXY- karyotype. 2 Probability of differences p<0,05 или еще выше. Из Gordon et al.

333-2. Scheme of normal spermatogenesis and fertilization.

The effects of nondisjunction in meiosis and mitosis are shown, which leads to the formation of the classical Klinefelter's syndrome, Turner's syndrome and the mosaic form of Klinefelter's syndrome. The scheme will not change if disturbances occur during oogenesis.

About 30 more karyotype variants have been described in Klinefelter's syndrome, both without mosaicism (XXYY, XXXY and XXXXY) and with mosaicism with or without concomitant structural disorders of the X chromosome. As a rule, the greater the degree of chromosomal abnormalities (and in the case of a mosaic form, the more pathological cell lines), the more severe the clinical manifestations.

Pathophysiology. The classical form is due to the nondisjunction of chromosomes during meiosis during hematogenesis (333-2). In about 40% of cases, nondisjunction in meiosis occurs during spermatogenesis, and in 60% during oogenesis. As the age of the mother increases, the likelihood of nondisjunction increases. The mosaic form is attributed to the non-disjunction of chromosomes in mitosis after fertilization of the egg; this nondisjunction can occur in both the 46,XY zygote and the 47,XXY zygote. A double defect (nondisjunction in both meiosis and mitosis) most often causes the syndrome and thus explains why its mosaic form is diagnosed less frequently than the classical one.

Plasma levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are usually elevated; due to a permanent defect in the seminiferous tubules, the FSH level overlaps less with normal values ​​and is of greater diagnostic value. Plasma testosterone levels are on average half normal, but their fluctuations overlap with normal ones. The average content of estradiol in plasma is increased for reasons that are not entirely clear. In the early stages of the disease, the testicles might secrete large amounts of estradiol due to elevated plasma LH levels, but eventually testicular secretion of estradiol (and testosterone) is reduced. An increase in the content of estradiol in the later stages of the disease can probably be explained by a combination of a decrease in the rate of its metabolic clearance with an acceleration of the conversion of testosterone to estradiol outside the gland. As a result, both in the early and late stages, one or another degree of insufficient androgenization and excessive feminization is manifested. Feminization, including gynecomastia, depends on the relative or absolute predominance of estrogens over androgens in the blood, and individuals with less testosterone and more estradiol are more likely to develop gynecomastia (ch. 332). The increase in plasma gonadotropins after the administration of luteinizing hormone-releasing hormone (LHRH) in postpubertal age is more significant, and the normal inhibitory effect of testosterone on pituitary LH secretion (negative feedback) is weakened. Patients with untreated Klinefelter's syndrome may have "reactive pituitary pathology" in the form of an increase or deformity of the Turkish saddle. This is apparently due to the chronic loss of the influence of the gonads by the negative feedback mechanism and the hypertrophy of gonadotrophs due to their stimulation by LHRH. Whether a true adenoma occurs in such cases is unknown.

Treatment. It is impossible to restore fertility in Klinefelter's syndrome, and the only effective way to correct gynecomastia is the surgical removal of breast tissue. Some patients with insufficient androgenization are helped by androgen therapy, but sometimes it leads to a paradoxical increase in gynecomastia, probably due to the fact that it increases the availability of substrates for the formation of estrogens in peripheral tissues. Androgens should be used in the form of testosterone cypionate or testosterone enanthate. With the introduction of testosterone, the level of LH in plasma, if normal, is only after a few months.

XX-male syndrome

The 46,XX karyotype in phenotypic males occurs at a frequency of approximately 1:20,000 to 1:24,000. In such persons, all female internal genitalia are absent, and psychosexually they feel like men. Indeed, the symptoms of this syndrome are similar to those of Klinefelter's syndrome: the testicles are small and firm (usually less than 2 cm), gynecomastia, azoospermia and hyalinization of the seminiferous tubules are often observed, the penis is either normal or reduced in size. Plasma testosterone concentration is reduced, estradiol is increased, and the content of gonadotropins reaches a high level. Such patients differ from patients with classic Klinefelter's syndrome only in that their height is on average lower than in normal men, mental lag is not more common than in the general population, and the incidence of hypospadias is increased.

The pathogenesis of this disorder is explained as follows: 1) translocation of a part of the Y chromosome to the X chromosome; 2) mosaicism along the Y chromosome in some cell lines or early loss of the Y chromosome; 3) mutation of an autosomal gene; and 4) deletion of the genetic substance of the X chromosome, which normally has a negative regulatory effect on testicular development. However, none of them is able to fully explain this violation. Mosaicism is unlikely to take place in most cases, but all other processes are quite possible. The heterogeneous nature of the syndrome cannot be ruled out. Therapeutic measures in such cases are similar to those in Klinefelter's syndrome.

Gonadal dysgenesis (Turner syndrome)

Clinical manifestations. Gonadal dysgenesis is characterized by primary amenorrhea, sexual infantilism, short stature, multiple congenital anomalies, and the presence of gonadal cords on both sides in phenotypic women with some kind of X-chromosome defect. This condition should be distinguished: 1) from mixed gonadal dysgenesis, in which there is a testicle on one side and a gonadal cord on the other; 2) from pure gonadal dysgenesis: in this case, gonadal cords on both sides occur in individuals with a normal karyotype 46 , XX or 46, XY, normal growth and primary amenorrhea; 3) Noonan syndrome - an autosomal dominant disorder in men and women, characterized by wrinkled skin on the neck, short stature, congenital heart defects, valgus deformity of the forearms and other congenital defects, despite normal karyotype and gonads.

The frequency of gonadal dysgenesis is 1:2500 newborn girls. The diagnosis is made either immediately after birth for concomitant congenital malformations, or, more often, at puberty, when amenorrhea accompanies congenital anomalies. Gonadal dysgenesis is the most common cause of primary amenorrhea (about 30%). Patients do not reach puberty, the external genitalia of the female type, but underdeveloped, as well as the mammary glands (in the event that the patient was not treated with estrogens). The internal genitalia are represented by the infantile fallopian tubes and uterus; in wide ligaments on both sides, gonadal strands travel. In the process of embryogenesis, primordial germ cells appear transiently, but they disappear as a result of accelerated atresia (ch. 331). By the age of expected puberty, these strands no longer contain distinguishable follicles and eggs; they contain fibrous tissue indistinguishable from normal ovarian stroma.

Associated somatic anomalies affect mainly the skeleton and connective tissue. In infancy, the disease is diagnosed by the presence of lymphatic edema of the hands and feet, wrinkling of the neck, low hairline, excessive skin folds at the back of the head, shield chest with widely spaced nipples, and low birth weight. In addition, patients have a characteristic face with a small jaw, epicanthus, low-set or deformed ears, fish horn, and ptosis. In 50% of cases, shortening of the IV metacarpal bones is noted, and in 10-20% - coarctation of the aorta. Growth in adult patients rarely exceeds 150 cm. Associated disorders include kidney malformations, pigmented birthmarks, nail hypoplasia, ketotic tendencies, hearing loss, unexplained hypertension, and autoimmune disorders. About 20% of patients suffer from hypothyroidism.

Pathophysiology. Approximately 50% of patients have a 45.X karyotype, and 25% have mosaicism without structural abnormalities (46,XX/45,X). and the rest have structural para-collapses of the X-chromosome with or without mosaicism (ch. 60). Variant 45, X is caused by the loss of a chromosome during gametogenesis in either parent or by a mitotic error in one of the early divisions of the fertilized zygote (332-2). Short stature and other somatic changes are a consequence of the loss of genetic material from the short arm of the X chromosome. Gonadal cords are formed when genetic material is lost from either the long or short arm of the X chromosome. In patients with mosaicism or structural disorders of the X chromosome, phenotype changes occupy an intermediate position in severity between those observed in the 45,X variant and the norm. In some patients with clitoral hypertrophy, in addition to the X chromosome, a fragment of some other chromosome, presumably an abnormal Y chromosome, is also missing. Rarely, a balanced autosomal X translocation can cause familial transmission of gonadal dysgenesis (Chapter 60).

Previously, sex chromatin was studied to detect X chromosome abnormalities. Sex chromatin (Barr bodies) in healthy women is a product of inactivation of one of the two X chromosomes; women with a chromosome set,45,X, like normal men, were classified as chromatin-negative. However, only about 50% of patients with gonadal dysgenesis are chromate-negative (patients with a 45,X karyotype and with the most pronounced mosaicism and structural disorders). Therefore, to establish the diagnosis and identify patients with Y-chromosome elements and a high lump of malignant tumors in the gonadal cords, analysis of the karyotype is necessary.

During the period of expected puberty, armpit and pubic hair is scanty, the mammary glands are undeveloped, and there is no menstruation. The content of FSH in serum, elevated in infancy, decreases to normal in childhood, and at the age of 9-10 years increases to the level characteristic of castrates. At this time, the content of LH in serum is also increased, and the level of estradiol in plasma is reduced (less than 10 pg / ml). Approximately 2% of patients with variant 45.X and 12% of patients with mosaicism have enough follicles in the ovaries to occasionally menstruate. Furthermore, in lindens with minimal damage, pregnancy is sometimes possible. However, the duration of the childbearing period in such patients is small.

Treatment. At the expected time of puberty, estrogen replacement therapy should be initiated to induce the development of the mammary glands, labia, vagina, uterus, and fallopian tubes (chap. 331). In the first year of treatment with estradiol, the rate of body growth in length and bone maturation approximately doubles, but the final growth of patients rarely reaches the expected (ch. 331). Treatment with growth hormone is not successful. In patients with variant 45, X gonadal tumors are rare, but they occur in some individuals with Y-chromosome mosaicism. Therefore, gonadal cords should be removed in any case if there are signs of virilization or when a cell line containing the Y chromosome is detected.

Mixed gonadal dysgenesis

Clinical manifestations. Mixed gonadal dysgenesis is a condition in which phenotypic males or females have a testis on one side and a gonadal cord on the other. Mosaicism 45, X / 46, XY is found in most patients, but the clinical manifestations go beyond the limits of chromosomes determined by this aberration. The frequency of the syndrome is unknown, but according to most clinics, this is the second most common cause (after congenital adrenal hyperplasia) of genital ambisexuality in newborns.

Approximately 60% of patients are considered girls, and most phenotypic boys are not fully virilized at birth. Most have ambisexual genitalia, including a slightly enlarged penis, urogenital sinus, and labia fused to the scrotum to varying degrees. The testis in most patients is located intra-abdominally; persons with a testicle in the groin or in the scrotum are considered boys. There is almost always a uterus, vagina, and at least one fallopian tube.

Until puberty, the testis appears relatively normal. At postpubertal age, it contains many mature Leydig cells, but the seminiferous tubules are devoid of germinal elements and contain only Sertoln cells. Gonadal cord - a thin pale elongated formation, located either in the broad ligament or on the pelvic wall, consists of the stroma of the ovary. In patients of pubertal age, the testicle secretes androgens and both virilization and an increase in the size of the penis occur. Feminization is rare, but if present, estrogen secretion by a gonadal tumor should be suspected.

Approximately 30% of patients have somatic manifestations of 45, X-gonadal dysgenesis - low posterior hairline, shield-shaped chest, multiple pigmented birthmarks, valgus de4urmation of the forearms, neck folding and short stature (height less than 150 cm).

Almost all patients are chromatin-negative. When examining a group of patients, the 45,X/46.XY karyotype was found in 60%, the 46,XY karyotype was found in the rest, but the frequency of mosaicism could be underestimated or limited to only some cell lines. The cause of 45,X/46,XY mosaicism is best explained by the loss of the Y chromosome early in the mitotic division of the XY zygote, similar to the postulated loss of the X chromosome in 46,XY/47,XXY mosaicism shown at 333-2.

Pathophysiology. It is assumed that the 46, XY cell line stimulates testicular differentiation, while the 45, X line causes the development of a contralateral gonadal cord, but a real comparison of karyotypic and phenotypic manifestations does not confirm such a relationship. Moreover, there is no correlation between the percentage of cultured blood or skin cells containing 45.X or 46.XY and the degree of gonadal development or somatic abnormalities.

Both masculinization and regression of the Müllerian ducts inutero are incomplete. Since Leydig cells function normally during puberty, insufficient intrauterine virilization may be due to a delay in the development of the testis, in which the Leydig cells eventually acquire the ability to function normally. It is also possible that the testicle of the fetus is simply not able to synthesize the required amount of the substance that inhibits the Müllerian ducts and androgens.

Treatment. It should be noted that in older children and adults whose gender was fixed before diagnosis, tumors may appear in the gonads. The overall incidence of such tumors is 25%. Seminomas are more common than gonadoblastomas, and tumors can occur before puberty. Patients with a female phenotype, devoid of somatic signs of typical 45,X-gonadal dysgenesis, are more susceptible to this; intra-abdominal testicles are affected more often than gonadal bands. When the diagnosis is established in patients with a female phenotype, exploratory laparotomy and prophylactic gonadectomy should be performed, both because gonadal tumors can develop in childhood and because the testis at puberty secretes androgens and thereby causes virilization. In order to induce and maintain feminization, such patients, as well as those with gonadal dysgenesis, are then prescribed estrogens.

Treatment of patients with a male phenotype, in whom the diagnosis is established in older childhood or in adulthood, is difficult. Phenotypic males with mixed gonadal dysgenesis are infertile (the testicles lack germinal elements), and they also have an increased risk of developing gonadal tumors. In what cases can you save the testicle without fear? As a rule, the following should be taken into account: tumors develop in the scrotal gonadal cords, but not in the testicles located in the scrotum; tumors appearing in undescended testicles are always associated with structures of the ipsilateral Müllerian duct; tumors in the gonadal cords are always associated with tumors in the contralateral intra-abdominal testes. Therefore, it is recommended that all gonadal cords be removed, that the testicles in the scrotum be preserved, and that the intra-abdominal testes be removed unless they can be brought down into the scrotum and are not associated with structures of the ipsilateral Müllerian duct. When performing reconstructive operations on the penis, it is necessary to take into account the nature of the defect.

If the diagnosis is made in early childhood and the genitals are ambisexual, the female sex is more likely to be chosen. Later, resection of the enlarged penis and gonadectomy can be performed (usually immediately). If they choose the male sex, then when deciding on the removal of the testicle, I use the same criteria in childhood as in adult men.

True hermaphroditism

Clinical manifestations. True hermaphroditism is a condition in which the patient has both ovaries and testicles or gonads with histological features of both sexes (ovotestis). The diagnosis can be confirmed only if the histological examination reveals both types of gonadal epithelium (it is not enough to detect only the ovarian stroma without oocytes). The frequency of occurrence of the syndrome is unknown, but more than 400 cases have been described in the literature. Patients are divided into three groups:

1) in 20%, both testicular and ovarian tissue (ovotestis) travel on both sides;

2) 40% have an ovotestis on one side and either an ovary or a testicle on the other;

3) the rest have a testicle on one side, and an ovary on the other.

The external genital organs of patients are at various stages of transition from male to female. Two-thirds of sufficiently masculinized patients (about 60%) are brought up as boys. However, less than 10% of patients have normal male external genitalia; most have hypospadias and more than 50% have incomplete fusion of the labia into the scrotum. In 60% of individuals with a female phenotype, the clitoris is enlarged, and the majority have a urogenital sinus. The differentiation of the internal ducts usually corresponds to the adjacent gonad. Although the testis usually has an adnexa, the vas deferens is fully formed in only 30% of patients. Among individuals with ovotestis, 75% have an epididymis and 60% have a fallopian tube. The uterus is usually hypoplastic or has one horn. The ovaries are usually in a normal position, but testicles or ovotestis may be found at any level along the path of testicular descent in embryogenesis and are often associated with an inguinal hernia. In 30% of patients, testicular tissue is localized in the scrotum or labioscrotal fold, in 30% - in the inguinal canal, in the rest - in the abdominal cavity.

Puberty is characterized by feminization and virilization of varying degrees; 75% of patients develop gynecomastia and about 50% menstruate. In individuals with a male phenotype, menstruation appears as cyclic hematuria. Ovulation occurs in about 25% of patients - more often than spermatogenesis. In individuals with a male phenotype, ovulation may present with testicular pain. Fertile individuals with a female phenotype have been described who had their ovotestis removed, as well as a "man" who had two children. Congenital defects of other systems are rare.

Pathophysiology. Approximately 60% of patients have a 46,XX karyotype, 10% have a 46,XY karyotype, and the rest have chromosomal mosaicism, in which a cell line with a Y chromosome travels. The mechanism that determines this development of the gonads is unknown. It is believed (although not proven by the available karyotyping methods) that sufficient Y-chromosome genetic material is present in this case (due to translocation, non-disjunction, or mutation) to induce the development of testicular tissue. Rarely, many sibs with a 46,XX karyotype are affected, probably due to autosomal recessive gene traversal or a common translocation.

Since the ovaries of more than 25% of patients contain corpus luteum, it can be concluded that the female neuroendocrine system functions normally in such individuals. Feminization (gynecomastia and menstruation) is due to the secretion of estradiol by the existing ovarian tissue. In masculinized individuals, androgen secretion predominates over estrogen secretion, and some of them produce spermatozoa.

Treatment. If the diagnosis is made in a newborn or a young child, the choice of sex depends on the anatomical features. In older children and adults, gonads and their internal ducts that are contrary to the predominant phenotype (and gender of upbringing) should be removed, and, if necessary, the external genitalia should be modified accordingly. Although gonadal tumors are rare in true hermaphroditism, individuals with the XY cell line have been diagnosed with gonadoblastomas. Therefore, when deciding whether to preserve the tissue of the gonads, it is necessary to take into account the possibility of the appearance of a tumor in them.

Gonadal sex disorders

A violation of the gonadal sex is said when the differentiation of the gonads does not correspond to the chromosomal sex, i.e., the chromosome sex does not correspond to the gonadal ifenotypic sex.

Pure gonadal dysgenesis

Clinical manifestations. Pure gonadal dysgenesis is a disorder in which individuals with a female phenotype whose reproductive organs, including the gonads, are identical to those of individuals with gonadal dysgenesis (bilateral gonadal cords, infantile uterus and fallopian tubes, and sexual intimacy) have normal height , a normal karyotype (46, XX or 46, XY), while they have practically no congenital anomalies. This condition is 10 times less common than gonadal dysgenesis. From a genetic point of view, it is distinct from gonadal dysgenesis, but clinically it is not possible to differentiate pure gonadal dysgenesis from gonadal dysgenesis with minimal somatic abnormalities. Patients are usually tall (sometimes more than 170 cm). Estrogen deficiency varies from pronounced, characteristic of typical 45, X-gonadal dysgenesis, to insignificant. In the latter case, the mammary glands are developed to some extent in patients, menstruation occurs, although menopause occurs quite early. Approximately 40% of patients note a certain degree of feminization. Axillary and pubic hair growth is scanty, and the internal genital organs are represented only by derivatives of the Mullerian ducts.

Tumors may develop in the gonadal cords, especially dysgerminomas or goiadoblastomas (46,XY karyotype). Such tumors are often accompanied by signs of virilization or the appearance of plus tissue in the pelvic region.

Pathophysiology. Although the term "pure gonadal dysgenesis" has also been used to describe cases of chromosomal mosaicism, we refer only to non-mosaic cases of the 46,XX or 46,XY karyotype. (Mosaicism is a variant of gonadal dysgenesis or mixed gonadal dysgenesis discussed above.) The rationale for this distinction is that both XX and XY variants of this syndrome can result from single gene mutations. Families are described in which the 46,XX karyotype was detected in several snbs; this was often observed in marriages between blood relatives, indicating an autosomal recessive pattern of inheritance. Familial cases of variant 46, XY were also noted; sometimes the mutation seems to be transmitted as an X-linked recessive trait, while in other families the prevalence of this syndrome corresponds to an autosomal recessive inheritance of a trait that appears only in men. In both forms (46,XX and 46,XY), the mutation prevents differentiation of the ovaries or testicles, respectively; the mechanism for this is unclear. If the gonads do not develop, a female phenotype is formed. As in all persons with non-functioning gonads, the secretion of gonadotropins is increased, and estrogens are reduced.

Treatment. Treatment of patients with estrogen deficiency is similar to that for gonadal dysgenesis. Estrogen replacement therapy begins at the time of expected puberty and continues throughout the entire period of maturity (ch. 331). Patients with a 46,XY karyotype should undergo an exploratory operation after diagnosis and remove the gonadal bands due to the high incidence of gonadal tumors in them. The indication for immediate surgery is the manifestation of signs of virilization. The natural history of gonadal tumors in this syndrome remains unclear, but the prognosis after surgical removal is usually good.

Testicular absence syndrome (anorchia, testicular regression, gonadal agenesis, agonadism)

Clinical manifestations. Individuals with a 46,XY karyotype who lack or have only rudimentary testicles, but at some stage in fetal life appear undoubted signs of the endocrine function of these glands (for example, obligatory regression of the Müllerian ducts and testosterone secretion), may have a different phenotype. This rather rare disorder should be distinguished from pure gonadal dysgenesis, in which there are no signs indicating the functioning of the gonads during embryonic development. Clinically, the syndrome manifests itself in different ways - the complete absence of virilization, incomplete virilization of the external genital organs of varying degrees, or a normal male phenotype, with the exception of bilateral anorchia.

The purest form of pathology is those with a female phenotype and a 46,XY karyotype. They have no testicles, sexual infantilism is pronounced, and both derivatives of the Mullerian ducts and accessory organs of the male reproductive system are absent. Such patients differ from individuals with 46,XY-form pure gonadal dysgenesis in that they fail to detect any remnants of the gonads: neither gonadal cords nor derivatives of the Müllerian ducts. Testicular failure should occur at the stage between the onset of the formation of a substance that inhibits the Müllerian ducts and the secretion of testosterone, i.e. after the development of the seminiferous tubules, but before the onset of the functioning of the Leydig cells.

In other patients, the clinical picture indicates a later manifestation of testicular insufficiency in the process of intrauterine development, and they may have difficulty in choosing a sex. In some cases, Müllerian duct regression deficiency may be more pronounced than testosterone secretion deficiency, but full development of the Müllerian structures never occurs. In individuals with more significant virilization, the external genitalia have a male phenotype, but both the rudimentary oviducts and the vas deferens can travel simultaneously.

There is also a syndrome of bilateral anorchia in individuals with a male phenotype. At the same time, patients lack Müllerian structures and gonads, but the system of wolf ducts and external genitalia are developed according to male mud. The presence of a micropenis means that failure of androgen-mediated growth of the penis occurs late in embryogenesis, after the anatomical formation of the male urethra has been completed. After the expected time of puberty, some patients develop permanent gynecomastia, others do not.

Pathophysiology. The pathogenesis of the disease is unclear. Testicular regression could be determined by a mutated gene, a teratogen, or trauma. Multiple cases of agonadism in the same family are described, and in some patients the disorder was unilateral, while in others it was bilateral.

The quantitative dynamics of the secretion of sex steroids has not been studied enough. In two patients with a female phenotype and primary amenorrhea, sexual infantilism and the absence of internal genital organs, the kinetics of androgens and estrogens was similar to that in gonadal dysgenesis; the rate of estrogen production was low, testosterone secretion could not be detected at all, which confirms the functional, and not just the anatomical absence of the testicles. In one patient with a male phenotype and bilateral anorchia, the production of testosterone and estrogens was carried out only due to their peripheral formation from plasma androstenedione. However, in some patients in whom the testicles could not be found during laparotomy, the level of testosterone in the blood exceeded that of the castrated individuals; probably, the hormone was produced by the remnants of the testicles.

Treatment. Persons with sexual infantilism and a female phenotype should be treated in the same way as patients with gonadal dysgenesis, ie. they need to inject estrogen in an amount that can cause the development of mammary glands and somatic changes characteristic of a woman. In case of any manifestations of concomitant vaginal agenesis, surgical or conservative methods. Likewise, individuals with a male phenotype and anorchia should be given androgens in an amount that would ensure the development of normal male secondary sexual characteristics. Patients with incomplete virilization or ambisexual development of the external genitalia require an individual approach to the issue of the need for surgical treatment, in addition to hormonal treatment at the time of expected puberty.

Phenotypic sex disorders

Female pseudohermaphroditism

Congenital adrenal hyperplasia. Clinical manifestations. The pathways for the formation of glucocorticoids in the adrenal glands and androgens in the testicles and adrenal glands are shown in 333-3. Three enzymes are involved in the synthesis of both glucocorticoids and androgens (20,22-desmolase, 3b-hydroxysteroid-dehydrogenazan 17a-hydroxylase); insufficiency of any of them prevents the formation of glucocorticoids and androgens and, therefore, leads to both congenital adrenal hyperplasia (due to increased levels of ACTH) and insufficient virilization of the male embryo (male pseudohermaphroditism). Two enzymes are involved in the synthesis of androgens - 17,20-desmolase and 17b-hydroxysteroid dehydrogenase; the lack of any of them leads to pure male hermaphroditism with normal synthesis of glucocorticoids. Deficiency in either of the last two glucocorticoid synthesis enzymes (21-hydroxylase and 11b-hydroxylase) impairs hydrocortisone production; a compensatory increase in ACTH secretion causes adrenal hyperplasia and a secondary increase in androgen production, leading to virilization in women and premature masculinization in men.

333-3. Synthesis pathways for glucocorticoids and androgens.

Adrenal insufficiency in these disorders causes severe and life-threatening pathology in both sexes. This is discussed in detail in Chapter 325. The main features of different forms of congenital adrenal hyperplasia are listed in Table 333-4. Considering disorders of sexual development, it is advisable to analyze enzymatic disorders in steroidogenesis, leading to either female or male pseudohermaphroditism. (One such disorder, 3b-hydroxysteroid dehydrogenase deficiency, causes both male and female hermaphroditism, but since incomplete virilization in males is a more common genital malformation, this enzymatic pathology is considered here as a violation of the differentiation of the male phenotype.)

The most common cause of genital ambisexuality in newborns is congenital adrenal hyperplasia due to 21-hydroxylase deficiency (in Europe it occurs with a frequency of 1:5,000, and in the USA - 1:15,000). Virilization in girls usually manifests itself already at birth, and in boys - in the first 2-3 years of life. Girls are characterized by hypertrophy of the clitoris in combination with its ventral tightening (pathological erection), partial fusion of the labioscotal folds and virilization of the urethra of varying degrees. The internal female reproductive organs and ovaries remain intact, and the Wolffian ducts regress normally, probably because the adrenal glands begin to function relatively late in embryogenesis. The external genitalia in girls are similar to those in boys with bilateral cryptorchidism and hypospadias. The labioscrotal folds are enlarged and wrinkled and resemble the scrotum. In rare cases, virilization reaches such an extent that the male urethra, penis, and prostate gland develop completely in the girl, which leads to an error in determining the sex of newborns. When x-rays after the introduction of a contrast agent into the external genital opening, the vagina, uterus, and sometimes even the fallopian tubes are found. In a few cases, the virilization of girls at birth is slightly or absent at all and manifests itself only later - in childhood, adolescence or maturity. Apparently, this is due to the allelic variation of the mutant genes (the so-called late-appearing, or adult, form of the disorder). Without treatment, sick girls grow rapidly during the first year of life and their virilization progresses. During the period of expected puberty, normal female-type puberty does not occur and menstruation does not appear. Rapid somatic maturation in both sexes leads to premature closure of the epiphyseal fissures and short stature in adulthood.

Table 333-4. Forms of congenital adrenal hyperplasia

Because the differentiation of the male phenotype remains normal, the disease in boys is usually not recognized at birth unless there is overt adrenal insufficiency. However, already in the first years of life, patients experience intensive growth and maturation of the external genital organs, frequent erections and excessive muscle development. Virilization in boys can manifest itself in two ways. Excess secretion of androgens by the adrenal glands inhibits the production of gonadotropins so that the testicles remain immature despite the acceleration of masculinization. In adulthood, such patients, if left untreated, are capable of erection and ejaculation, but they lack spermatogenesis. In other cases, secretion of androgens by the adrenal glands can activate precocious maturation of the hypothalamic-hypothyroidal axis and initiate true precocious puberty, including spermatogenesis (chap. 330). Untreated men may develop ACTH-dependent "tumors" of the testicles, consisting of remnants of adrenal gland cells.

With 21-hydroxylase deficiency, which causes about 95% of cases of congenital adrenal hyperplasia, hydrocortisone production decreases and, consequently, ACTH secretion increases, the growth of the adrenal glands increases, and thus there is a partial or complete compensation for violations of hydrocortisone secretion. Approximately 50% of patients have a partial deficiency of the enzyme, and cortisol secretion remains normal. This form of the disease is called simple virilizing, or compensated. The rest have a more complete deficiency of the enzyme; even enlarged adrenal glands cannot produce adequate amounts of cortisol and aldosterone, leading to severe salt loss with anorexia, vomiting, fluid loss, and collapse in the first weeks of life. This is a chak called salt-wasting form of 21-hydroxylase deficiency. In all untreated patients, excessive production of cortisol precursors is noted, which are formed before the stage catalyzed by 21-hydroxplase, due to which the content of progesterone and 17-hydroxyprogesterone increases in plasma. They act as weak aldosterone antagonists at the receptor level, which in the compensated form requires more than normal aldosterone production to maintain normal sodium balance.

Female pseudohermaphroditism can also be caused by a lack of 11b-hydroxylase. In this case, the blockade of hydroxylation of the 11th carbon atom leads to the accumulation of 11-deoxycortisol and deoxycorticosterone (DOC), a strong salt-retaining hormone, which is accompanied not by salt loss, but by hypertension. Clinical manifestations due to glucocorticoid deficiency and androgen excess are similar to those in 21-hydroxylase deficiency.

Pathophysiology. Both disorders are the result of an autosomal recessive mutation. The incidence of 21-hydroxylase deficiency is approximately 1:50. At least three forms of deficiency of this enzyme have been identified, and all of them are associated with mutations of genes located on the 6th chromosome near the HLA-B locus: the most common type, manifesting as a common autosomal recessive mutation with a change in enzyme activity: a variant due to cryptic an allele that, even in homozygotes, has no clinical manifestations, but causes a typical disease if it coexists with a common variant, and a late onset variant. Carriers of the disease (as well as homozygotes) among members of a given family can be identified by the HLA haplotype. In 11b-hydroxylase deficiency, the association of the mutation with the HLA system remains unknown.

Endocrine pathology in this condition is discussed in Chapter 325. In short, it boils down to an increase in the excretion of ketosteroids, as well as the main metabolites that accumulate above the site of enzymatic blockade. In untreated patients, plasma ACTH is elevated. With a deficiency of 21-hydroxylase, 17-hydroxyprogesterone accumulates in the blood, excreted in the urine mainly in the form of pregnantriol. In case of insufficiency of 11-hydroxylase, 11-deoxincortisol accumulates in the blood, which is excreted in the urine mainly in the form of tetrahydrocortisolone.

Treatment. Sex selection should be determined by chromosomal and gonadal sex, and appropriate surgical correction of the vulva should be performed as soon as possible. early dates. This is very important, because with the right treatment, men and women can become fertile. However, if the correct diagnosis is made late (over 3 years of age), sex selection should only be made after careful consideration of psychosexual orientation.

Conservative treatment with glucocorticoids prevents manifestations of hydrocortisone deficiency, stops rapid virilization and prevents premature somatic development and fusion of the epiphyses. In case of 11b-hydroxylase deficiency, the suppression of pathological steroid secretion leads to the normalization of blood pressure, and in both cases, it ensures the timely onset of menstrual function and the development of female secondary sexual characteristics. In men, glucocorticoid therapy suppresses adrenal androgen secretion and leads to normalization of gonadotropin secretion, testicular development, and spermatogenesis. Substitution therapy is controlled by determining the plasma content of 17-hydroprogssterone, androstenedione. ACTH and renin. In severe forms of 21-hydroxylase deficiency, accompanied by salt loss or an increase in plasma renin activity, treatment with mineralocorticoids is also indicated. In such patients, the adequacy of mineralocorticoid replacement therapy is judged by plasma renin activity. Female pseudohermaphroditism of extra-adrenal genesis. Female pseudohermaphroditism rarely has extra-adrenal causes. In the past, administration of progestins with androgenic side effects (such as 17a-ethnyl-19-nortestosterone) to pregnant women to prevent abortion resulted in masculinization of female fetuses. Female pseudohermaphroditism may also occur in children born to mothers with virilizing tumors (eg, arrhenoblastomas or luteomas of pregnancy); in rare cases, the cause of the disease cannot be established.

Congenital defects of the Müllerian ducts (congenital absence of the vagina, agenesis of Müllerian structures). Clinical manifestations. Congenital hypoplasia, or absence of the vagina, in combination with an anomaly or absence of the uterus (Mayer-Rokitansky-Küster-Hauser syndrome) is second only to gonadal dysgenesis as a cause of primary amenorrhea. In most patients, the disorder is diagnosed at the expected age! o puberty due to the absence of menstruation. Their growth and mental development are normal, and the mammary glands, axillary and pubic hair, and physique correspond to the female type. The uterus may be almost normal, devoid of only the external entrance canal, but is more often represented by rudimentary bicornuate bands with or without a lumen. Some patients experience intermittent pain in the abdomen, indicating the presence of sufficiently functional endometrium to cause retrograde menstruation and/or hematometra.

Approximately 30% of patients have renal anomalies, most often agenesis or ectopia. There is also an fusion of the kidneys in the form of a horseshoe and solitary ectopic kidneys located in the pelvic cavity. 10% of patients have skeletal disorders, and in 60% of them the spine is involved in the process, and in the rest - limbs and ribs. Specific bone changes are characterized by wedging of the vertebrae, their fusion, rudimentary or asymmetric vertebral bodies, and the presence of additional vertebrae. Often at the same time, Klnppel-Feil syndrome is observed (congenital fusion of the cervical vertebrae, short neck, low posterior hairline, as well as soreness and limited movement cervical spine).

Pathophysiology. All patients have a 46,XX karyotype. Most often, the disease occurs sporadically, although a few familial cases have been observed. The pattern of inheritance in most familial cases corresponds to a sex-limited autosomal dominant mutation. It is unclear whether sporadic cases represent new mutations of the same type that defines the familial disorder or if they have a multifactorial cause. Family cases are characterized by inconsistent expressibility; some affected family members have only skeletal or renal abnormalities, while others have other abnormalities in the Müllerian duct derivatives, such as uterine doubling.

In stillborn fetuses, the absence of the uterus and vagina is often combined with bilateral aplasia of the kidneys. Therefore, in all cases, one should be interested in the presence in the family history of isolated disorders of the skeleton or nights, as well as stillbirths, which could be associated with congenital absence of both kidneys in the fetus.

The preservation of ovarian function is evidenced by ovulatory peaks in plasma LH levels and biphasic temperature curves during the cycle. In patients with a normal uterus after surgical plastic surgery of the vagina, pregnancy is possible.

Treatment. Patients with vaginal agenesis can be treated surgically and conservatively. The goal of the surgery is to create an artificial vagina by implanting a rubber canal covered with several layers of skin. Conservative treatment consists in repeated pressure with a simple dilator on the vaginal fossa to ensure its sufficient depth. Since the overall complication rate for surgical treatment is 5-10%, a conservative approach should be attempted in most patients. Surgery may be recommended for women with a well-formed uterus when the possibility of pregnancy persists. In order to preserve the patient’s newly formed vagina by any method, it is advisable to conduct regular sexual life or to carry out instrumental expansion of the organ.

Male pseudohermaphroditism

Violation of the virilization of the male embryo (male pseudohermaphroditism) may be the result of a violation of the synthesis of androgens or their action, anomalies in the regression of the Müllerian ducts, and some unclear reasons. In 80% of cases of male pseudohermaphroditism, androgen synthesis in patients remains normal.

Androgen synthesis disorders. Clinical manifestations. Five enzyme defects are known that lead to impaired testosterone synthesis (330-3) and cause incomplete virilization of the male fetus during embryogenesis. All of these enzymes catalyze the conversion of cholesterol to testosterone at certain steps. Enzymes 20,22-desmolase, 3b-hydroxysteroid dehydrogenase and 17a-hydroxylase are also involved in the synthesis of other adrenal hormones; therefore, their deficiency leads not only to male hermaphroditism, but also to congenital adrenal hyperplasia (Table 333-4). Enzymes 17,20-desmolase and 17b-hydroxysteroid dehydrogenase are involved only in the synthesis of androgens, and their deficiency leads only to male pseudohermaphroditism. Since androgens serve as obligate precursors of estrogens, it is correct to conclude that with all such disorders (except the last stage, catalyzed by 17b-hydroxysteroid-dehydrogenase), estrogen synthesis will also be reduced in patients of both sexes).

Adrenal dysfunctions with three corresponding defects are described in Chapter 325, and only violations of sexual development are considered here. In the 46,XY karyotype, the uterus and fallopian tubes are absent, which indicates normal production by the testes during embryogenesis of the Müllerian duct-inhibiting factor. Masculinization of the wolf ducts, urogenital sinus and urogenital tubercle is different: in some patients these formations are developed normally, in others they are completely absent, therefore, the clinical signs correspond to those in phenotypic men with mild hypospadias or phenotypic women who, until full maturation, resemble patients with complete testicular feminization. This extreme variability of manifestations is due to different degrees of severity of enzyme disorders in different patients and different effects of steroids that accumulate proximal to the sites of metabolic blockade in different disorders. In patients with partial defects and in those whose plasma testosterone levels are within the normal range, the disease can be diagnosed only by determining the steroids that accumulate above the site of metabolic blockade.

20,22-desmolase deficiency (lipoid adrenal hyperplasia) is a form of congenital adrenal hyperplasia in which steroids (neither 17-ketosteroids nor 17-hydroxycortcoids) can be detected in the urine. The disorder affects the step prior to the formation of pregnenolone and is thought to involve one or more enzymes of the 20,22-desmolase complex that converts cholesterol to pregnenolone. The syndrome is characterized by salt loss and severe adrenal insufficiency, most patients die in early childhood. At autopsy, enlarged adrenal glands and testicles infiltrated with lipids are found. In sick boys, incomplete masculinization is noted, while the genitals of girls develop normally.

3b-hydroxysteroid dehydrogenase deficiency is the second most common cause of congenital adrenal hyperplasia. In boys, it is manifested by varying degrees of latency or a complete absence of masculinization up to the presence of a vagina. In newborn girls, signs of moderate virilization are noted due to the weak androgenic activity of dehydroepiandrosterosteroid, the main secreted steroid. If the enzyme is not produced either in the adrenal glands or in the testicles, none of the urinary steroids has d 4 3-keto-configuration, but in patients with a partial defect or damage only to the testicles, a normal or even increased amount of d 4 3-ketosteroids is found in the urine . Most patients have severe salt loss and severe adrenal insufficiency. Patients with severe enzyme deficiency die. In sick boys, puberty proceeds normally, only pronounced gynecomastia is possible. In such cases, the level of testosterone in the blood is at the lower limit of normal, but the concentration of d 5 precursors is increased. In different tissues, enzyme activity is regulated differently, since enzyme deficiency in the testicles may be less pronounced than in the adrenal glands, and in the liver, the enzyme can fully retain its activity against the background of its deep deficiency in the adrenal glands and testicles. Differentiate. individuals with normal activity of liver enzymes from patients with 21-hydroxylase deficiency can only be found that the content of d 5 -pregnentriol in the urine is higher than the level of pregnantriol.

17a-hydroxylase deficiency is characterized by hypogonadism, lack of secondary sexual characteristics, hypokalemic alkalosis, hypertension, and almost complete loss of hydrocortisone secretion in the female phenotype. The secretion of corticosterone and deoxycorticosterone (DOC) by the adrenal glands is increased, and the content of 17-ketosteroids in the urine is reduced. The secretion of aldosterone is small, which is apparently due to the high level of DOC in plasma and a decrease in the content of angiotensin. However, after the introduction of suppressive doses of hydrocortisone, it normalizes. Patients with a karyotype of 46,XX often have amenorrhea, lack of pubertal hair, and hypertension, but since sex steroids are not required for the formation of a female phenotype in embryogenesis, such patients retain the normal phenotype of prepubertal girls. In men, however, enzyme deficiency leads to impaired virilization ranging from complete male pseudohermaphroditism a to ambisexuality of the vulva with a urethra opening into the perineum or scrotum. Boys with partial deficiency of the enzyme during puberty may develop pathological gynecomastia. There are no streets with this disorder of adrenal insufficiency, as they have increased secretion of corticosterone (weak glucocorticoid) and DOC (mineralocorticoid). Hypertension and hypokalemia, which are prominent manifestations of this disorder (even in the neonatal period), disappear after suppression of DOC secretion by appropriate doses of glucocorticoids.

Deficiency of 17,20-desmolase was observed in some families. In sick boys with a set of chromosomes 46,XY, the normal function of the adrenal cortex was preserved, but certain signs of male pseudohermaphroditism were observed. In most patients, ambisexuality of the external genitalia was noted at birth, but some virilization occurs during the period of expected puberty. However, in two patients with a 46,XY karyotype, a female phenotype was observed, virilization at the age of expected puberty did not occur. This disorder was also noted in one woman with a 4b,XX karyotype, suffering from sexual infantilism.

Deficiency of 17b-hydroxysteroid dehydrogenase affects the last stage of androgen biosynthesis - the restoration of the 17-keto group of androstenedione with the formation of testosterone. This violation is the most frequent defect of fer-

333-4. Schematic representation of the internal and external genital organs, as well as the mammary glands in various androgen resistance syndromes.

cops testosterone synthesis. Patients with a 46,XY male karyotype usually have a female phenotype with a blindly terminating vagina, no Müllerian duct derivatives, but testicles and virilized Wolffian duct structures in the inguinal ligament or abdomen. During the expected heart maturation, both virilization (with an increase in the size of the penis and the appearance of hair on the face and trunk) and the development of the mammary glands according to the female type, expressed to varying degrees, occur. In some patients, if left untreated, sexual behavior changes from female to male at puberty. The dynamics of androgens and estrogens has not been studied in detail, but the 17-keto reduction of estrone to estradiol in the gonads is also reduced. The enzyme 17b-hydroxysterond dehydrogenase is normally found in many tissues, except for the gonads. This disorder is characterized by its insufficiency, apparently, only in the gonads. Plasma testosterone levels may be at the lower limit of normal, and therefore, it is important to document an increase in plasma levels of androstenedione to establish a diagnosis.

Pathophysiology. Defects in 17a-hydroxylase and 3b-hydroxysteroid dehydrogenase are inherited in an autosomal recessive manner. Limited data on the familial prevalence of 17,20-dssmolase and 17b-hydroxysteroid dehydrogenase deficiencies indicate either an autosomal recessive or an X-linked recessive mutation. Concerning the insufficiency of 20,22-desmolase, the available data do not allow making a definite conclusion about the type of inheritance.

The nature of secretion and excretion of steroids depends on where one or another metabolic blockade is localized (333-3). As a rule, the secretion of gonadotropins is increased, and as a result, in many patients with incomplete enzyme deficiency, the latter is compensated, so that the constant concentration of end products, such as testosterone, may be normal or close to normal.

In some cases of male pseudohermaphroditism, testosterone is not produced in sufficient quantities due to a deficiency of any one enzyme of androgen synthesis. Such cases include disorders where the main defect is Leydig cell agenesis (possibly due to the absence of LH receptors), or the secretion of a biologically inactive LH molecule. In addition, as noted above, there are a number of testicular developmental disorders, including familial XY gonadal dysgenesis, sporadic testicular dysgenesis, and absent testicular syndrome, in which testosterone deficiency is secondary to gonadal developmental defects.

Treatment. In disorders accompanied by adrenal hypoplasia, replacement therapy with glucocorticoids and, in some cases, mineralocorticoids is indicated. As for the anomalies of the genital organs, the decision to correct them should be made strictly individually. Patients with male hermaphroditism are infertile, which must be taken into account when choosing a sex. In individuals with a female genotype, sex selection does not encounter difficulties (which are present in the diagnosis): patients are brought up as women, at the age of expected puberty, they should be prescribed estrogen replacement therapy to induce the normal development of female secondary sexual characteristics. If, on the other hand, ambisexual genital organs are found in a newborn boy, then the decision of whether to bring him up as a man or as a woman depends on the anatomical defect; as a rule, with more severe disorders, the child should be brought up as a girl and, if possible, perform surgical plastic surgery of the genital organs and removal of the testicles earlier. Persons brought up in the female sex, at the appropriate age, estrogen therapy is also indicated to ensure the normal development of female secondary sexual characteristics. In male-reared individuals, any hypospadias present should be surgically corrected and, during expected puberty, plasma androgen and estrogen levels should be closely monitored to determine the need for chronic testosterone supplementation.

Violations of the action of androgens. Some violations of the formation of the male phenotype are due to a deficiency in the action of androgens. The various phenotypes involved are shown at 333-4 and are summarized in Table 333-5. With this pathology, the formation of testosterone and the regression of the Müllerian ducts proceed normally, but due to the resistance of target cells to the action of androgens, the development of the male type in tone or another degree is disturbed.

Deficiency 5 a -reductases. This autosomal recessive form of male pseudohermaphrodigism is characterized by: 1) the presence in patients of severe perineoscrotal hypospadias with a hood-like foreskin, a ventral urethral groove and an opening of the urethra at the base of the penis; 2) the presence of a blind vaginal pocket of various sizes, opening either into the urogenital sinus, or on the urethra posterior to its opening; 3) the presence of well-developed testicles with normal appendages, vas deferens and seminal vesicles, and the ejaculatory pathways open into the blindly ending vagina; 4) the female physique of patients, not accompanied by the development of the mammary glands of the female type; the presence of normal axillary and pubic hair growth: 5) the absence of female internal genital organs; 6) the presence of normal plasma testosterone levels for men; and 7) varying degrees of masculinization of patients during puberty.

The fact that virilization disturbance during embryogenesis is limited to the urogenital sinus and the anlage of the external genital organs makes it possible to understand the nature of the main defect. Testosterone secreted by the fetal testes serves as an intracellular mediator of differentiation of the Wolffian duct into the epididymis, vas deferens, and seminal vesicle, but virilization of the urogenital sinus and vulva is mediated by dihydrotestosterone. Therefore, in a male embryo with normal testosterone synthesis and normal androgen receptors, the formation of a phenotype characteristic of an individual with this disorder (normal derivatives of the wolf ducts with insufficient masculinization of structures formed from the urogenital sinus, genital tubercle and genital folds) would be expected with insufficient formation of dihydrotestosterone. Since the secretion of LH is regulated by testosterone itself (chapter 330), the plasma levels of this hormone are only slightly elevated in these patients. Therefore, the rates of testosterone and estrogen production remain characteristic of normal men and gynecomastia does not develop.

Deficiency of 5a-reductase in this disorder was established by direct determination of the content of this enzyme in tissue biopsies and fibroblast cultures of patients. Most of them have either a severe deficiency of 5a-reductase or a loss of its function, while others have an enzymatic protein, although it is synthesized at a normal rate, but it differs structurally from a normal enzyme. It remains unclear why virilization at puberty proceeds more actively than the virilization that takes place in the process of sexual differentiation.

receptor pathology. The pathology of androgen receptors can lead to the formation of several different 4-R enotypes. Despite differences in clinical presentation and molecular basis, these disorders share similar endocrinological, genetic, and pathophysiological aspects. First, the main clinical manifestations of the pathology will be considered, and then similar features of the endocrine function and pathogenesis.

Clinical manifestations. The most common form of pseudohermaphroditism is complete testicular feminization (from 1:20,000 to 1:64,000 newborn boys). It is the third most common cause of primary street amenorrhea with a female enotype, after gonadal dysgenesis and congenital absence of the vagina. Women go to the doctor either for inguinal hernia (at prepubertal age) or for amenorrhea (after puberty). The development of the mammary glands in patients, the physique and distribution of hair on the body and on the scalp are characteristic of females, so that many patients look like real women. Axillary and pubic hair is absent or weakly expressed, but there is usually a slight hair growth of the vulva. There is no vegetation on the face. The external genitalia are female, the clitoris is normal or slightly reduced in size. The vagina is short and terminates blindly, but may be absent altogether or in a rudimentary state. All internal genital organs are absent. In patients, only undescended testicles containing normal Leydig cells and seminiferous tubules are found; no spermatogenesis.

The testicles can be localized in the abdominal cavity, along the inguinal canal, or in the labia majora. Sometimes in the paratesticular fascia or in the fibrous bands coming from the testicles, the remnants of Mullerian or Wolf structures travel. Patients are usually tall, bone age and mental development are within the normal range. Psychosexual orientation in relation to behavior, appearance and maternal instincts female,

The main danger of undescended testicles, as in other forms of cryptorchidism (Ch. 330), lies in their tumor degeneration. Because patients experience a normal pubertal growth spurt at the age of expected puberty, feminization occurs, and because testicular tumors rarely develop until post-pubertal age, castration is usually delayed until expected puberty is over. Surgery in the prepubertal age is indicated if the testicles are located in the groin or labia majora and cause discomfort or lead to the formation of a hernia. (When prepubertal hernia repair is indicated, most physicians prefer to simultaneously remove the testicles to reduce the number of operations.) When removing the testicles in prepubertal age, estrogen therapy should be started promptly to ensure normal growth and development of the mammary glands. If castration is done post-puberty, then estrogen replacement therapy will help prevent the onset of menopausal symptoms and other complications of estrogen withdrawal (ch. 331).

Incomplete testicular feminization is about 10 times less common than the complete form. In these cases, the virilization of the external genital organs is slightly pronounced (partial fusion of the labioscrotal folds and mild clitoromegaly), normal pubic hair growth and some virilization, as well as feminization during the expected puberty. The vagina is short and ends blindly, but unlike the full form of pathology, the derivatives of the wolf ducts are often partially developed. Family history is usually uninformative, but in some cases, pathology is found in many family members, and the nature of inheritance indicates the linkage of the trait with the X chromosome. Treatment of patients with complete and incomplete forms of testicular feminization is different. Since virilization occurs in patients with an incomplete form at the age of expected puberty, gonadectomy in the presence of clitoromegaly or posterior labial fusion should be performed at prepubertal age.

Syndrome of Re and fenstein called various forms of incomplete male pseudohermaphroditism. Previously, these forms were considered separate nosological units and were called differently - Reifenstein syndrome, Gilbert-Dreyfus syndrome, Labs syndrome. However, families are now known whose diseased members have varying manifestations of pathology, covering the entire spectrum of phenotypes described by these terms, and it is now generally accepted that the listed syndromes represent different manifestations of a single mutation. Most often, the disease is characterized by the presence of perineoscrotal hypospadias and gynecomastia, but the manifestations of virilization disorders in affected families are different - from phenotypic men with azoospermia to phenotypic women with pseudovagina. Axillary and pubic hair growth corresponds to the sex, but breast hair growth is minimal. The testicles are small, often observed crnptorchism, azoospermia. In some patients, anomalies of the derivatives of the wolffian ducts are noted: for example, they have no or underdeveloped vas deferens. Since the psychosexual orientation of patients in most cases is unconditionally male, hypospadias and crinptorchism should be corrected surgically. The only successful treatment for gynecomastia is surgical removal of the mammary glands.

Syndrome male infertility in the pathology of androgen receptors, it occurs most often and in reality does not represent any form of male pseudohermaphroditism. In some cases, this syndrome is the only manifestation of familial Reifenstein syndrome, and infertility in members of the affected family is due to azoospermia due to receptor disorders. More often, patients with male infertility do not have a family history; pathology of androgen receptors can occur in 20% or more of all men with idiopathic azoospermia. There is no effective treatment for any of these conditions.

Pathophysiology. The karyotype in patients is 46,XY, and the mutant gene is linked to the X chromosome. Approximately 60% of patients with testicular feminization and Reifenstein syndrome and some patients with male infertility syndrome have a family history. It is believed that in the absence of a family history, cases of the disease are due to new mutations.

The dynamics of hormones in all syndromes of androgen receptor disorders is similar. The content of testosterone in plasma and the rate of its production by the testicles are within the normal range or increased. An increase in the rate of testosterone production is due to a high average plasma LH concentration, which in turn is explained by a violation of the feedback mechanism due to the resistance of the hypothalamic-pituitary system to the action of androgens. An increase in the content of LH probably determines the increased production of estrogens by the testicles (ch. 330). (In healthy men, most estrogens are formed by peripheral conversion of blood androgens, but with an increase in plasma LH levels, a significant amount of estrogen is secreted into the blood directly by the testicles.) plasma, and this, in turn, caused an acceleration of the secretion of both testosterone and estradiol by the testicles. When the testicles are removed, the content of gonadotropins increases even more, indicating that the secretion of these hormones is under partial regulatory control. It is likely that under stable conditions and in the absence of an androgen effect, LH secretion is regulated only by estrogens, which causes an increase in the concentration of estrogens in the blood plasma in men. Hormonal shifts in male infertility syndrome are similar to those in other receptor anomalies, but less pronounced. In some patients with this syndrome, plasma levels of LH or testosterone do not rise.

Feminization in the described disorders is caused by two interrelated circumstances. First, androgens and estrogens have opposite effects at the peripheral level, and in healthy males, virilization occurs at an androgen to estrogen ratio of 100:1 or greater; in the absence of the effect of androgens, the action of estrogens on cells is not resisted. Secondly, the production of estradiol exceeds that of healthy men (although it is less than that of healthy women). Varying degrees of androgen resistance, together with varying degrees of increased estradiol production, explain the difference in signs of impaired virilization and increased feminization in four clinical syndromes.

Any of these four syndromes is associated with androgen receptor pathology. Initially, it was shown that in cultures of skin fibroblasts of some patients with complete testicular feminization, high-affinity binding of dihydrotestosterone is almost completely absent. Then it was possible to establish that in other patients with complete testicular feminization, as well as in individuals with incomplete testicular feminization, Reifenstein's syndrome and male infertility syndrome, either a decrease in the number of outwardly normal receptors or qualitative changes in androgen receptors take place.

resistance in the presence of receptors. A form of androgen resistance that does not appear to be associated with either 5a-reductase deficiency or androgen receptor dysfunction was first discovered in a family with testicular feminization syndrome. Then, patients with various phenotypes were described - from incomplete testicular feminization to Reifenstein's syndrome. Hormonal shifts in these cases are similar to those in receptor pathology. The nature of the molecular disorder in these patients remains unclear. The syndrome could be associated with androgen receptor abnormalities so subtle that they cannot be detected by conventional methods. If the defect is indeed localized distal to the receptor, then it could be the inability of cells to generate specific messenger RNAs or a violation of RNA processing. In fact, this disease may represent a heterogeneous group of molecular disorders. Treatment of patients depends on their phenotype.

Mullerian duct persistence syndrome. Affected males have a normal penis but, in addition, fallopian tubes on both sides, uterus, upper vagina, and differently developed vas deferens. Patients often go to the doctor about an inguinal hernia in which the uterus is located; cryptorchidism is also often found. Family history is uninformative in most cases, but several pairs of siblings have been described in which the syndrome should be inherited either as an autosomal recessive or as an X-linked recessive mutation. Since the external genital organs are well developed and normal masculinization of patients occurs at puberty, it is believed that at the critical stage of sexual differentiation, the testicles produce the required amount of androgens. However, regression of the Müllerian ducts does not occur, which can be explained by the inability of the fetal testicles to produce a substance that inhibits the Müllerian ducts, the untimely production of this substance, or the inability of the tissues to respond to this hormone. To minimize the risk of tumor formation and preserve virilization, one-stage or staged orchiopexy should be performed. Malignancies of the uterus or vagina are not described, and since the vas deferens are closely associated with the broad ligaments, the uterus and vagina do not need to be touched during surgery to avoid trauma to the vas deferens and thereby preserve possible fertility.

Defects in the development of the male genital organs. Hypospadias. Hypospadias is a congenital anomaly in which the urethra opens along the midline of the ventral surface of the penis between the normal urethral opening and the perineum. This malformation is often accompanied by some degree of ventral pulling up and bending of the penis (abnormal erection); in the USA it occurs in 0.5-0.8% of newborn boys.

Hypospadias is usually subdivided depending on the location of the urethral opening - on the glans penis, its body, or in the perineoscrotal region. Since penis development is mediated by androgens, hypospadias is thought to be related to some early disruption of androgen production or action during embryogenesis. Indeed, hypospadias occurs in most disorders of male sexual differentiation. Sometimes this malformation is caused by the mother taking progestin drugs in the early stages of pregnancy. Causes (single gene defects, chromosomal abnormalities, and maternal drug use) are now known in about 25% of cases of hypospadias, and the causes of most remain unknown. Surgical treatment.

Cryptorchidism. normal process testicular descent is. probably the least studied aspect of male sexual differentiation, both in regard to the nature of the forces causing testicular movement and the hormonal factors that regulate this process. From an anatomical point of view, testicular descent can be divided into three stages: 1) their transabdominal movement from the place of formation above the kidneys to the inguinal ring;

2) the formation of an opening in the inguinal canal (vaginal process), through which the testicles leave the abdominal cavity; 3) the passage of the testicles through the inguinal canal into the scrotum. This whole process takes more than 6-7 months of pregnancy, starting around the 6th week and not ending completely in some healthy boys even at the time of birth. If androgens are involved in this process, they do not appear to be the only hormones responsible for normal testicular descent. If any of the above processes fail, it can lead to undescended one or both testicles (which occurs in 3% of full-term male newborns and 30% of preterm male fetuses). Cryptorchidism is divided into intra-abdominal, retractile (periodic retraction of the testicles into the inguinal canal), obstructive (permanent location of the testicles in the groin) and high scrotum. In most patients, retractile cryptorchidism is noted, in which in the first 6 weeks - 3 months of life there is a gradual descent of the testicles, so that in late adolescence the pathology persists only in 0.6-0.7% of patients who require artificial reduction of the testicles.

After puberty, the undescended testis functions poorly, but it is not known to what extent the undescended testis is the result and to what extent it is the cause of impaired testicular function. Two main theories have been proposed for the occurrence of cryptorchidism - insufficient intra-abdominal pressure and insufficient endocrine testicular function in terms of either testosterone synthesis or the formation of a substance that inhibits the Müllerian ducts. Indeed, congenital malformations leading to insufficient intra-abdominal pressure or development of the testicles themselves may be accompanied by cryptorchidism. As with hypospadias, however, known causes of cryptorchidism underlie only a small proportion of cases, and the causes of most of the rest remain to be elucidated. Two complications of cryptorchidism matter; at abdominal temperature, spermatogenesis does not occur, and therefore, in order to ensure possible fertility, the correction of the process must be carried out as early as possible. However, the fact that men treated for both unilateral and bilateral cryptorchidism are often infertile suggests that undescended testicles are usually the result, not the cause, of testicular dysfunction. There is also a high incidence of malignant degeneration of undescended testicles, and therefore in all these cases it would be necessary to resort to surgical intervention (Ch. 297).