Depending on the severity of testicular feminization syndrome, various symptoms of the disease are possible:
- discrepancy between the structure of the genital organs and gender;
- underdevelopment of the genital organs;
- inconsistency of secondary sexual characteristics (body type, hair type, voice timbre, etc.) with gender;
- infertility (lack of pregnancy for one year with regular unprotected sexual activity).
Forms
Depending on the sensitivity to male sex hormones, there are full And incomplete form testicular feminization syndrome.
- Full form characterized by the birth of a child with a genetic male sex (set of chromosomes 46, XY) and male gonads - testicles - but external genitalia developed according to the female type. The child has no penis and scrotum, the testicles remain in abdominal cavity, there are labia majora and vagina. In this case, at birth, a conclusion is made about the birth of a girl. The child grows and develops in accordance with his age. Upon reaching the age of 14-15 years, the child does not have menstruation (monthly uterine bleeding associated with the physiological rejection of the endometrium - the inner layer of the uterine mucosa), which forces parents to seek medical care. During the process of medical diagnosis, it turns out that the child is a boy, which does not correspond to the passport gender. In rare cases, the full form of testicular feminization syndrome is diagnosed accidentally in adult women who suffer from infertility.
- Incomplete form:
- with predominant development according to the female type: a child is born with external genitalia developed primarily according to the female type. However, during puberty, in addition to the absence of menstruation, the formation of secondary male sexual characteristics is observed (broad shoulders, narrow hips, characteristic hair growth, deepening of the voice, etc.), as well as a restructuring of the male type of genital organs (enlargement of the clitoris in the form of a penis);
- with predominantly male development, characterized by various manifestations. These may be underdeveloped or completely male-type genitals. In the latter case, the boy grows and develops in accordance with age norms, but upon the onset of puberty he experiences infertility due to the lack of sperm production (male reproductive cells). In some cases, gynecomastia is possible - enlargement of the mammary glands.
Reasons
- A mutation (breakage) in a gene - a piece of hereditary information that carries information about the formation of a receptor (a sensitive area on the cell membrane) for male sex hormones.
- The disease is inherited (passed from generation to generation, the carrier of the mutation is the mother), but sometimes the mutation occurs spontaneously (in a fetus conceived by healthy parents).
- During embryonic development, the male fetus develops full-fledged testicles - male gonads, which begin to produce male sex hormones. However, as a result of the loss of tissue sensitivity to them, the development of the external genitalia occurs according to the female type.
Diagnostics
- Analysis of the medical history and complaints (health status of the newborn, were there any anomalies in the structure of the genital organs (position of the testicles in the scrotum, location of the urethra, etc.), how did puberty proceed, did it correspond to age norms, is sexual life normal, are there any complaints for infertility, etc.).
- Analysis of family history (whether relatives had similar diseases).
- A general (physical) examination is necessary to identify deviations in the development of secondary sexual characteristics (body type and hair growth, development of mammary glands, muscles), possible signs of disease internal organs(examination of the skin, measurement of blood pressure, height, weight, waist circumference), etc.
- Karyotyping is the study of the number and composition of chromosomes (carriers of hereditary information) to determine genetic sex.
- Molecular genetic research to identify a mutation (breakage) of a section of a chromosome (carrier of hereditary information), which leads to a decrease in the sensitivity of tissues to male sex hormones.
- Examination by a urologist (the doctor examines the external genitalia for developmental anomalies, palpates the scrotum area, conducts a digital rectal examination, during which the condition of the prostate gland is determined, etc.).
- Laboratory determination of hormones in blood and urine. The list of hormones depends on the specific situation and is determined by the doctor. Most often these are: sex hormones, adrenal hormones, pituitary hormones (an organ that produces hormones that affect growth, metabolism and reproductive function), thyroid gland, etc.
- Ultrasound examination (ultrasound) of the abdominal and pelvic organs. Ultrasound allows you to suspect abnormalities in the structure of the genital organs, determine the presence of ovaries or testicles that have not descended into the scrotum, identify possible concomitant malformations (for example, underdevelopment of one of the kidneys), etc.
- Magnetic resonance imaging (MRI) allows us to make the most accurate conclusion about the structure of the genital organs.
Treatment of testicular feminization syndrome
Treatment varies significantly depending on the form of the disease, manifestations and age of the patients.
Basic provisions.
- Surgical removal of testicles:
- to eliminate an aesthetic defect;
- in the case of the formation of an inguinal hernia (when the testicles do not descend into the scrotum, but remain in the abdominal cavity);
- for the prevention of testicular cancer (with this disease, the testicles are prone to malignant degeneration);
- to prevent virilization (the appearance of male characteristics) when not full form syndrome with predominant development of the female type.
- Plastic surgery to shape or enlarge the vagina in complete and incomplete forms of the syndrome with female development.
- Plastic surgery to enlarge and correct the shape of the penis in boys with an incomplete form of the male type syndrome.
- Plastic surgery on the mammary glands for gynecomastia (enlargement of the mammary glands in men) with incomplete male pattern.
- Hormone replacement therapy at different periods of life with female or male sex hormones, depending on the form and manifestations of testicular feminization syndrome.
- Psychotherapy for the formation of the correct concept of gender and treatment of sexual behavior disorders.
Complications and consequences
- Impossibility of sexual activity as a result of improper development of the external genitalia.
- Infertility.
- Social maladjustment.
- Disorders of urination due to incorrect location of the urethra.
- Tumors of the testicles that have not descended into the scrotum in a timely manner.
Prevention of testicular feminization syndrome
- Regular visit once a year by men.
- Genetic counseling at the stage of family planning and during pregnancy in risk groups for the development of testicular feminization syndrome (in familial cases of the disease and consanguineous marriages).
Morris syndrome (androgen insensitivity syndrome) is a genetic disease accompanied by a disorder in the structure of receptors sensitive to male sex hormones.
It is transmitted from mother to child, the type of inheritance is X-linked. The probability of having a child with Morris syndrome in a family where the woman is a carrier of the pathological gene is 25%.
The incidence of this disease in the human population is about 1 case per 30,000 - 50,000 people. Diagnosing it is difficult, because Outwardly, phenotypically, a person is no different from those around him.
Note. This syndrome was first discovered back in the 19th century, when Dr. Georgius Steglehner described the results of the autopsy of a young girl. In her pelvic cavity, instead of female genital organs (uterus, ovaries), male genital organs (testicles) were found. Subsequently, 80 years later, a similar case was described by Sergei Ivanovich Blagovolin in Russia.
Mechanism of disease development
In the embryonic period, up to 6-7 weeks, the genital organs of both boys and girls are formed in the same way. Further, under the influence of androgens, the formation of male genital organs occurs, and in their absence, female genital organs.
People with Morris syndrome have the XY (male) genotype, so the internal genital organs begin to form in a male pattern. However, since the receptors that perceive signals from androgens do not work, this process stops and, under the influence of estrogens, ends with the formation of the external female genital organs.
After birth, people with androgen insensitivity syndrome continue to experience feminization. During puberty, breasts enlarge, feminine facial features, wide hips, narrow shoulders and waist appear. The only difference is the almost complete absence of hair growth on the genitals and armpits, as well as amenorrhea.
Clinical picture
Depending on the degree of androgen insensitivity, 2 forms of the disease are distinguished:
- full;
- incomplete.
The first is characterized by a lack of response to the effects of male sex hormones. Externally, the girls are slender, beautiful, pretty, with an active lifestyle, purposeful, easily attract the attention of the opposite sex, and physically resilient.
A gynecological examination reveals:
- lack of female-type hair (thick hair on the head);
- blind-ending vagina (normal size or reduced);
- hypoplasia of the labia minora;
- During bimanual examination, the uterus and ovaries are absent.
Note. The most famous examples of women with this syndrome are (allegedly) Joan of Arc and Queen Elizabeth Tudor of England.
The incomplete form is characterized by partial preservation of receptor sensitivity.
Women with this form of the disease have the following features:
- poorly developed mammary glands;
- penis-shaped clitoris;
- shortened vagina;
- the presence of underdeveloped hair in the genital area.
Psychologically, in most cases, people with androgen insensitivity syndrome perceive themselves as women.
Diagnostics
The absence of menstruation before the age of 18 allows one to suspect the disease for the first time. For this reason, the girl consults a gynecologist. The second reason to visit a doctor is infertility.
During the examination, the gynecologist prescribes:
- blood test to determine the level of sex hormones ( high level both estrogen and testosterone);
- Ultrasound of the pelvis (absence of internal female genital organs, and testicles are also detected).
Once abnormalities are identified, the patient is referred for a consultation with a geneticist, who makes a diagnosis.
Treatment
The only complaint of a woman with Morris syndrome is infertility. There is no cure for this problem, but only alternative options: adoption, surrogacy.
Important! The presence of testicles in the abdominal cavity is an indication for their removal after the end of puberty, because they tend to become malignant over time.
While maintaining male identity, often with an incomplete form of the disease, sex reassignment surgery and androgen therapy are possible, but the effectiveness of these measures is low.
The main help for women with Morris syndrome is psychological.
It must be remembered that androgen insensitivity syndrome is not a death sentence. Most women live happily without any restrictions. The only prohibition is participation in professional sports competitions. It is important for every woman to appreciate her uniqueness and perceive herself as she is.
Testicular feminization syndrome (STF) - a disease caused by complete or partial absence tissue sensitivity to androgens caused by impaired affinity of androgen receptors or postreceptor defects.
SYNONYMS
Androgen insensitivity syndrome, androgen resistance syndrome, false male hermaphroditism, male pseudohermaphroditism.
EPIDEMIOLOGY
The incidence of STF is 1 in 50,000–70,000 births. Prevalence of STF among all patients with false male hermaphroditism is 15–20%. Among the causes of primary amenorrhea in persons with female STF phenotype ranks third in frequency of occurrence after gonadal dysgenesis and congenital uterine aplasia and vagina (Rokitansky-Küster syndrome).
CLASSIFICATION
Depending on the degree of insensitivity of peripheral receptors to androgens, the full form is distinguished (with complete insensitivity to androgens) and incomplete form (when sensitivity is initially partially preserved or partially restored during puberty).
ETIOLOGY
The cause of the disease is mutations in the androgen receptor (AR) gene. Mutations cause resistance peripheral receptors for testosterone and dehydrotestosterone. The syndrome is inherited by X-linked recessive type (about 60% of patients have a family history).
DEVELOPMENT MECHANISM
During embryogenesis, the gonads in STF differentiate as full-fledged functioning testes. However, due to AR gene defect, patient tissues are insensitive to testosterone and dehydrotestosterone - hormones that form male phenotype (urethra, prostate, penis and scrotum), and at the same time its sensitivity to estrogen is preserved. This leads to natural (the phenomenon of autonomous feminization) formation of the female phenotype without derivatives of the Müllerian ducts (fallopian tubes, uterus and upper third of the vagina), since the products of MIS substances Sertoli cells are not damaged.
CLINICAL CHARACTERISTICS
The clinical picture of the full form of STF is characterized by:
- the presence of female external genitalia;
- blindly closed vagina;
- well-developed mammary glands (gynecomastia);
- absence of the uterus, fallopian tubes and prostate;
- absence of somatic developmental anomalies;
- lack of pubic and axillary hair growth.
The incomplete form of the disease is similar to the complete one, but is characterized by sexual hair growth and the absence of masculinization (virilization) of the external genitalia. The variability of clinical forms of STF is extensive (from phenotypic woman to phenotypic man with primary infertility) and depends on the severity androgen receptor defect.
DIFFERENTIAL DIAGNOSTIC MEASURES
ANAMNESIS
Patients with STF typically have a history of inguinal hernias (left-sided or bilateral). During puberty period in such patients, despite the timely development of the mammary glands, menarche does not occur, puberty There is no hair growth. In incomplete forms of the disease, congenital virilization of the external genitalia is possible. organs. In those variants of the incomplete form, when during puberty under the influence of gonadotropic stimulation partial sensitivity of peripheral tissues to androgens occurs, “pubertal” virilization is possible clitoris, decreased voice timbre.
PHYSICAL EXAMINATION
With normal growth and the absence of somatic developmental anomalies, patients with STF are characterized by large hands and large feet. Anthropometric indicators are characterized by a lag in the size of the pelvis, and the pelvis the coefficient corresponds to an intermediate value between male and female age standards. The body type of patients with STF is more masculine than eunuchoid. Disturbed at puberty sequence of appearance of secondary sexual characteristics. The mammary glands are developed accordingly 3– Grade 4 according to Tanner, but the areolas of the nipples of the mammary glands are pale in color. The full form of STF is characterized by lack of sexual hair. In the incomplete form, axillary hair growth is weakly expressed and is determined pronounced pubic hair to varying degrees. The full form is characterized by a typical female structure external genitalia, deep, blindly ending vagina. The incomplete form is characterized virilization of the external genitalia of varying degrees. G.H.G. Sinnecker et al in 1996 proposed V degrees of androgenization of the external genitalia in incomplete form of STF.
- Male type (I degree):
- spermatogenesis is impaired;
- virilization is impaired during puberty;
-spermatogenesis and virilization are impaired during puberty. - Predominantly male type (II degree):
- isolated hypospadias;
- micropenis;
-high degree hypospadias with a divided scrotum;
- isolated hypospadias and micropenis. - Ambivalent type (III degree):
-micropenis resembles a clitoris;
-the scrotum is divided, resembling the labia;
-perineal-scrotal hypospadias; - Predominantly female type (IV degree):
- the clitoris is hypertrophied;
-labia fused;
-the clitoris is hypertrophied and the labia are fused;
-urogenital sinus with a short, blind vagina. - Female type (V degree):
- signs of virilization are absent until puberty;
-enlarged (to the size of a micropenis) and virilized clitoris during puberty.
LABORATORY RESEARCH
In the blood serum of pubertal patients, the level of LH is increased, FSH levels are within the limits of women standard values, estradiol levels do not reach the lower limits of normal for women, and testosterone levels corresponds to the male norm. A genetic study revealed negative sex chromatin and a male karyotype. At molecular genetic research reveals mutations in the androgen receptor gene.
INSTRUMENTAL EXAMINATIONS
The biological (bone) age of patients mainly corresponds to the calendar age. In 50% of patients with STF (mainly in the full form of the disease) BMD is reduced, and osteoporosis is detected in 24.5%. According to complex ultrasound and X-ray mammographic examination, in 82% of patients with STF, despite satisfactory external development; during the initial examination, cysts and hyperplasia are detected in the mammary glands glandular tissue in combination with diffuse stromal fibrosis. On ultrasound of the pelvic organs, the uterus is absent, the gonads are visualized with dimensions of 2.5x3.0x4 cm. They are located high at the internal openings of the inguinal canals, along the inguinal canals, rarely in the lower thirds of the canals or in the labia (mostly on the left).
Differential diagnosis of STF must be carried out with gonadal dysgenesis, incomplete masculinization (defect of the testosterone 5α reductase gene) and with other forms of XY sex reversion. In case of insufficiency enzyme testosterone 5αreductase, the level of dehydrotestosterone in the blood serum of patients, compared with age standards for boys, is significantly reduced, but testosterone values do not go beyond the limits normal indicators and upon examination, in contrast to patients with STF, pronounced sexual hair growth is determined. From patients with XY gonadal dysgenesis, patients with STF are distinguished by the presence of mammary glands with scant hair growth, blindly closed vagina, absence of the uterus, the presence of testicles in the abdominal cavity or along the inguinal canals, as well as low FSH levels with a relatively low LH concentration. With differential When diagnosing other forms of sex reversal, consultation with an endocrinologist or geneticist is indicated. Whenever psychological problems- consultation with a psychologist or psychotherapist.
TREATMENT
TREATMENT GOALS
The goal of treating patients with the full form of STF is to prevent tumor degeneration of the testicles located in abdominal cavity. In case of incomplete form of STF, it is necessary to prevent pubertal virilization of the external genitalia. organs and deepening of the voice. In the presence of congenital virilization of the external genitalia, feminizing plastic. In the postoperative period, patients with these forms of STF undergo HRT to replenish estrogen deficiency. This helps prevent the development of postgonadectomy syndrome, secondary gonadotropinomas and some symptoms characteristic of menopause.
INDICATIONS FOR HOSPITALIZATION
Determination of the Y chromosome in the karyotype for a female phenotype is an absolute indication for bilateral removal testicles in order to prevent tumor degeneration of the gonads. Indications for hospitalization are considered the need for feminizing plastic surgery of the external genitalia and the need for colpoelongation Sherstnev's method.
DRUG TREATMENT
When removing the testicles, patients with STF before reaching puberty must undergo HRT during puberty (12–14 years old). Treatment is carried out for the normal formation of secondary sexual characteristics and to prevent the development eunuchoid body proportions. It is advisable to prescribe “natural” HRT (estriol, estradiol) or “synthetic” estrogens with subsequent transition to monophasic bihormonal therapy. Best effect obtained when using HRT with drugs containing estrogen and gestagen, since they prevent the development estrogen-dependent hyperplasia of breast tissue and in conditions of androgen resistance are performed in such patients the role of the only endogenous estrogen antagonists. Bihormonal therapy with drugs containing estrogen and gestagen, promotes the development of the terminal ducts of the mammary glands and sensitizes the brain to influence of estrogens, forming sex-appropriate sexual behavior in adolescents. In recent years prefer combination drugs containing estradiol (Cliogest©, Femoston ©, Climodien ©). Antigonadotropic and estrogenizing effect of the combination of estradiol with dienogest (Climodien ©) higher than the combination of the drug with medroxyprogesterone (Indivina ©).
Treatment is carried out until the average age of physiological menopause. In addition to HRT, if a decrease in BMD is detected, Osteogenon is prescribed © 1 each
tablet 3 times a day for 4–6 months annually. Treatment is carried out under the control of densitometry and bone age until the growth zones close. It is advisable to conduct six-month courses of therapy with calcium preparations.
SURGICAL TREATMENT
Surgical treatment - removal of the gonads. In case of congenital virilization, it is necessary to carry out feminizing plastic surgery of the external genitalia, and, if necessary, bloodless colpoelongation.
Due to the increased risk of neoplastic transformation of the testicles located in the abdominal cavity, all Patients immediately after diagnosis undergo bilateral removal of the gonads, preferably laparoscopic access, and also perform feminizing plastic surgery of the external genitalia. Question about surgical or conservative (colpoelongation) correction of vaginal length should be decided no earlier than 6 months after the start of hormonal therapy, since the depth of the vagina increases under the influence of estrogens.
INDICATIONS FOR CONSULTATION WITH OTHER SPECIALISTS
Patients with STF are prescribed a consultation with a mammologist if a pathology of the mammary glands is detected based on the results annual control ultrasound. Consultation with a psychologist or psychotherapist is mandatory for patients with STF.
FOLLOW-UP
Patients with STF receive lifelong HRT (until the average age of physiological menopause is reached) under the supervision of levels of gonadotropic hormones and estradiol in blood serum, blood lipid profile, BMD, condition uterus and mammary glands according to ultrasound data.
INFORMATION FOR THE PATIENT
The patient should be informed about the need for long-term (up to 45–55 years) HRT in order to compensate for the deficiency the influence of estrogenic hormones, affecting not only the mammary glands, but also the brain, blood vessels, heart, skin, bone tissue, etc. Against the background of HRT, annual monitoring of the condition of hormonal-dependent organs is necessary.
FORECAST
Despite the fact that patients with STF are absolutely infertile, timely surgical intervention followed by HRT provides a normal quality of life.
REFERENCES
Wolf A.S., Mittag Yu.E. Atlas of pediatric and adolescent gynecology. - M.: GEOTARMEDIA, 2004.
Dedov I.I., Semicheva T.V., Peterkova V.A. Sexual development of children: norm and pathology. - Moscow, 2002.
Kiseleva I.A. Optimization of management tactics for patients with XY sex reversal. - Moscow, 2006.
Kurilo L.F. Genetically determined male disorders reproductive system// Sat. Sexology and andrology. -1996. - P. 28–46.
Kiseleva I.A., Dzenis I.G. Diagnosis of some forms of male pseudohermaphroditism in childhood and adolescence age // Obstetrics and gynecology - 2003. - No. 5. - P. 44–48.
Dzeranova L.K., Marchenko E.V., Pishchulin A.A. and others. Full form of testicular feminization syndrome // Obstetrics and gynecology. - 2001, No. 2. - P. 56–58.
Litvinov V.V., Baskakov P.N., Khomulenko I.A. and others. On the diagnosis and treatment of intersex conditions // Problems reproductions. - 2000. - Volume 6, No. 3. - P. 50–52.
Sarafoglou K., Ostrer H. Familial Sex Reversal: A Review // The Journal of Clinical Endocrinology & Metabolism. - 2000. - Vol. 85, N 2. - P. 483–493.
Migeon C.J., Wisniewski A.B., Brown T.R. 46, XY Intersex individuals: phenotypic and etiologic classification, knowledge of condition, and satisfaction with knowledge in adulthood // Pediatrics - 2002. - Vol. 110, N 3. - P. 15–23.
Androgen resistance can be thought of as a condition in which androgens, even if present in sufficient quantities, do not produce the expected physiological effects in their target tissues.
Apart from the action of exogenous factors (for example, some medicines with antiandrogenic properties), androgen resistance is always the result of dysfunction of androgen receptors (AR), which are the most important link between the steroid hormone and the cellular response.
All defects in these receptors are genetic in nature and are ultimately determined by abnormalities in the androgen receptor gene. Studies of many hundreds of patients reveal various mutations of this gene. Deletions of the entire gene, losses of several exons, deletions or insertions of individual base pairs, mutations of splice sites, as well as various point missense mutations have been described.
Despite the fact that the mutations underlying androgen resistance cannot be detected in every patient, DNA analysis has taken a strong place as a routine procedure for the clinical diagnosis of such conditions. The practical significance of the relevant studies is also diminished by the fact that the same changes in the AR gene can manifest themselves in different phenotypes. Nevertheless, limited correlations between the nature of the mutations and the clinical manifestations of the pathology still exist: complete or partial deletions of the AR gene, nonsense mutations and splice site mutations usually cause severe forms of androgen resistance.
Point missense mutations, leading to the replacement of individual amino acids in the receptor protein, can manifest as complete or partial androgen resistance.
Modern molecular genetic techniques have replaced androgen binding tests, which previously were a necessary element of diagnosis, from the range of diagnostic techniques. These tests were based on recording the binding of androgens to fibroblast receptors obtained from genital skin biopsies. Pathological results were divided into three groups:
1) complete absence of androgen receptor binding (“receptor-negative androgen resistance”);
2) quantitatively impaired, but qualitatively normal binding;
3) qualitatively impaired binding of androgens, for example, a decrease in their binding affinity or an increase in thermolability.
In some patients with clinically apparent androgen resistance, androgen binding testing does not clarify the situation at all ("androgen receptor-positive resistance").
Receptor-negative patients have a clinical picture of testicular feminization. With this exception, there is no reliable correlation between androgen binding parameters and clinical phenotype.
With normal androgen receptor function, taking the steroid stanozolol reduces the level of SHBG in the blood serum. With defects in androgen receptors, this reaction is disrupted, and the more severely, the higher the degree of androgen resistance. This phenomenon is used in the so-called SHBG test. For three days, stanozolol is administered daily (in the evenings) at a dose of 0.2 mg/kg body weight. Before and after the start of the test and on days 5, 6, 7 and 8, the SHBG level is determined. If the lowest value is below 63% of the initial level, a violation of androgen receptors is beyond doubt.
Testicular feminization
Testicular feminization is the most severe form of androgen resistance. Distinguish full And incomplete forms of this pathology.
The first occurs among newborn genetic boys with a frequency of approximately 1:50,000; the latter is much less common. The karyotype of patients with testicular feminization is 46 XY, i.e. genetically they are indeed male. In contrast to the less severe forms of androgen resistance, which are discussed below, such patients are typically female in appearance. Therefore, it is appropriate to call them “women” with testicular feminization. The latter also corresponds to their psychosexual orientation, which is undoubtedly female. Often these patients turn to a gynecologist first if the diagnosis has not previously been established by a pediatrician.
Full form of testicular feminization
With the complete form of testicular feminization, all manifestations of androgen action are absent. The external genitalia have a normal female appearance. The vagina ends blindly and is sometimes shortened. Because the production and effects of anti-Müllerian hormone (AMH) are normal, the Müllerian ducts regress in these patients. This explains their lack of a uterus and fallopian tubes. Gonads can be located in the abdominal cavity, inguinal canals, or less commonly in the labia.
Testicular feminization is often discovered almost by accident, during surgery for an inguinal hernia in childhood. In fact, in girls with a bilateral inguinal hernia, testicular feminization is one of those diagnoses that should be assumed first. The gonads have histological characteristics of the testes, but there is no spermatogenesis in them. The older the patient, the more often adenomatous changes are found in the gonads. Whether they are hyperplasia or true adenomas is unclear. The nodular structures, which can reach significant sizes and can be confused with malignant ovarian tumors, are composed of testicular germinal and interstitial cells. In most cases, Sertoli cells predominate.
Since the level of estrogen in the blood is sufficient, the distribution of adipose tissue, muscle mass and breast development are typical for healthy women. If the testes are still in situ, the source of estrogen is direct secretion of the gonads plus peripheral production of androgens. Gonadectomized patients require replacement therapy with exogenous estrogens. Patients are usually taller and have larger teeth than the average healthy woman, which is attributed to the action of genes on the Y chromosome. In individuals of both sexes, sexual hair growth is determined by the effect of androgens, therefore patients with testicular feminization are distinguished by very scanty growth of pubic and axillary hair or their complete absence. This striking clinical sign has the greatest diagnostic value.
Testicular feminization is characterized by primary amenorrhea and incurable infertility. Often, patients first consult a doctor specifically about amenorrhea, which ultimately allows them to establish the correct diagnosis. In postpubertal patients, serum LH levels are significantly elevated, whereas FSH levels increase only moderately or remain normal. The concentration of testosterone is within the male norm or even exceeds it, and the level of estradiol is higher than in healthy men. In the prepubertal period, serum LH and testosterone levels are usually normal.
Diagnosis of testicular feminization is a multi-stage process. The first suspicion usually arises on clinical examination for unexplained amenorrhea or when testicular tissue is found in an inguinal hernia. The discrepancy between genetic and phenotypic sex, revealed by karyotyping, largely determines the nature of the further diagnostic search. In addition to extensive endocrinological testing (including a hCG test in prepubertal children), the current diagnostic standard requires DNA analysis. The SHBG test can also provide significant information. Androgen binding studies are no longer necessary. Some patients with testicular feminization have reduced activity of the 5a-reductase enzyme. The physiological basis of this phenomenon is unclear, but it should be taken into account to distinguish testicular feminization from primary 5a-reductase 2 deficiency in so-called perineal-scrotal hypospadias with pseudovagina.
Testicular feminization is inherited as an X-linked recessive trait. Only genetically male individuals are affected; women can only be asymptomatic carriers of the defective gene. In the family history, positive indications are found in 2/3 of cases. Sick relatives should be looked for exclusively on the maternal side. On the maternal side, the probands have two female relatives who have never had menstruation or children.
A thorough examination of family history is important not only from a diagnostic point of view. Parents of a sick child should be warned that the risk of having a second sick child is 25%. Often, other members of the family also have a risk of having a child with this pathology. Therefore, we recommend that any family, at the first occurrence of a child with testicular feminization, undergo genetic counseling. Whether a patient with testicular feminization should be informed of his diagnosis is a complex issue.
Deciphering the diagnosis, including data on the presence of testicular cells in the gonads and the male karyotype, can have tragic consequences for patients who perceive themselves as women.
Therefore, many doctors, including us, until recently did not consider it necessary to fully disclose the diagnosis to the patient. But now we are leaning towards a more individual approach, taking into account the patient’s age, her mental characteristics and the degree to which she is already aware of her condition. In certain circumstances, full disclosure of the diagnosis may be warranted. In such cases, it is important to let the patient understand that her male sex hormones do not have a biological effect, and therefore sexual differentiation at the main stage went towards the formation of a female rather than a male phenotype.
Treatment
With testicular feminization, there is a high risk of malignant degeneration of the gonads. The total incidence of malignant gonadal tumors in patients under 50 years of age exceeds 30%. Therefore, the indications for surgical removal of testicular tissue are absolute.
Opinions vary regarding the optimal age for gonadectomy. We believe that it is better to operate on patients at the earliest possible age than at the age of 16-20 years. The risk of malignant transformation before age 12 appears to be small, although it can never be excluded with certainty. In addition, in childhood, surgery is less traumatic for the psyche than in adolescence. Even with incomplete disclosure of the diagnosis, girls in the latter age group are much more conscious of the loss of their “ovaries” and the ability to have children. Proponents of removing the gonads at a later age emphasize the fact that under the influence of estrogens directly secreted by the gonads and formed from androgens during their peripheral conversion, puberty in girls can occur spontaneously. This, of course, matters, but nevertheless we see more advantages in early gonadectomy than in late one.
Upon reaching the age of expected puberty (as well as in cases of later removal of the gonads), estrogen replacement therapy should be started. Its technique does not differ from that of estrogen replacement therapy carried out for other indications. No other treatment is usually required. Women with testicular feminization are fully adapted to their feminine role and can have a normal sex life. Patients worried about their diagnosis or those who have not come to terms with incurable infertility may need psychotherapeutic help
Incomplete form of testicular feminization
In the spectrum of conditions characterized by androgen resistance, the incomplete form of testicular feminization occupies an intermediate place between the complete form of this pathology, on the one hand, and Reifenstein syndrome, on the other. The phenotype of patients is predominantly female, but already at birth there are some signs of mild virilization, which may become more pronounced by the time of puberty.
Examination of the genitals in sick children reveals a mild degree of clitoral hypertrophy and partially fused labia. During puberty, the degree of masculinization of the external genitalia sometimes increases. With an incomplete form of testicular feminization - in contrast to complete - sexual hair development develops normally. Another important difference is the preservation of the Wolffian duct derivatives. The epididymis, vas deferens, and seminal vesicles, although hypoplastic, are constantly exposed during surgery. Contrary to previous beliefs, there are no other striking differences in clinical presentation, endocrine shifts, or molecular genetics between complete and incomplete forms of testicular feminization. Endocrine replacement therapy is carried out in the same way as for the full form of this pathology. The possibility of increased virilization by the time of puberty speaks in favor of early gonadectomy.
Reifenstein syndrome
Patients with Reifenstein syndrome are virilized to a greater extent than patients with testicular feminization, but to a lesser extent than men with normally functioning androgen receptors. There is no single clinical or laboratory sign pathognomonic for this syndrome. The diagnosis of Reifenstein syndrome is based rather on the general impression of somewhat insufficient virilization.
In the anatomy of the external genitalia, either male or female characteristics can predominate, but some duality is always observed.
The most characteristic feature is perineal-scrotal hypospadias, although even less severe hypospadias in combination with a bifid scrotum does not exclude the diagnosis of Reifenstein syndrome. The penis is small, and hypoplastic testicles are usually located in the inguinal canals, less often in the scrotum or abdominal cavity. Although pubic and axillary hair growth is normal, androgen-dependent hair growth is weak on other parts of the body. A very typical symptom is the development of gynecomastia at puberty.
Semen analysis in Reifenstein syndrome reveals azoospermia, and effective ways There is no treatment for infertility in patients in this group. This syndrome is characterized by the absence of Müllerian structures (uterus, fallopian tubes), but the epididymis, vas deferens and seminal vesicles may be more or less developed.
Endocrine parameters are similar to those of testicular feminization: serum testosterone and FSH levels are normal or slightly elevated, and LH levels clearly exceed the normal range. Quantitative disturbances in androgen binding are usually found. In some cases, binding may be completely absent, in others it remains normal.
Due to the high variability of clinical manifestations of Reifenstein syndrome, its treatment must be selected for each patient strictly individually. The psychosexual orientation of patients is usually male, and the goal of treatment is to enhance male phenotypic characteristics. Hypospadias, cryptorchidism, gynecomastia and other anatomical anomalies are subject to surgical correction. There are no sufficiently reliable data on the risk of malignant degeneration of the gonads in this syndrome. In cryptorchidism, the testicles should either be relegated to the scrotum or, if orchidopexy is not possible, completely removed. For the earliest possible detection of malignant changes in the testicles located in the scrotum, they must be regularly checked by palpation or ultrasound. Patients should be taught methods of self-control. The doctor should check the condition of the gonads at least once a year, and preferably every 6 months.
If the gonads are not removed, patients with Reifenstein syndrome do not experience androgen deficiency and therefore it is unclear whether they need additional exogenous hormones. Unconditional evidence of the positive effect of androgen therapy has not yet been obtained. If the patient himself asks to prescribe hormones, this can be done, but such therapy must be carried out under the strict supervision of a specialist. The possibility of some additional virilization in these cases cannot be excluded. If orchidectomy cannot be avoided, additional administration of exogenous androgens becomes mandatory. The principles of such treatment are outlined in Chapter 15.
Shawl-shaped scrotum with hypospadias
In this type of androgen resistance, the bifurcated scrotum covers the front of the penis and, in addition, there is severe hypospadias. Sometimes cryptorchidism is also observed. Spermatogenesis is severely impaired. The physique does not differ in any features, but less sexual hair growth, lack of voice changes and impotence may be noted. There is no gynecomastia. When examining three sick members of the same family (brothers), a clear decrease in the binding capacity of androgen receptors was discovered. Supplemental testosterone did not improve signs of insufficient virilization and androgen resistance.
X-linked spinal and bulbar muscle atrophy (Kennedy disease)
X-linked spinal and bulbar muscular atrophy (SBMA) is another pathological condition, which is based on dysfunction of androgen receptors. SBMA is inherited as an X-linked recessive trait. Therefore, symptoms may only appear in men; women remain asymptomatic carriers of the defective gene. As with testicular feminization and Reifenstein syndrome, the primary cause of the disease is a mutation in the androgen receptor gene. However, the nature of the mutation is specific to SBMA and is not observed in the conditions described above. This special type of mutation is called a triplet repeat expansion.
The first exon of the androgen receptor gene contains repeating tandemly arranged CAG triplets. The number of these triplets is a polymorphic molecular feature, i.e. It varies from person to person. In healthy individuals, this number ranges from 9 to 36, and in patients with SBMA - from 38 to 62. Since these two series of values do not overlap, determining the length of CAG repeats is a highly specific diagnostic test.
The CAG repeat is translated into the amino acid sequence of the receptor protein, where each triplet encodes a glutamine residue. The polyglutamine sequence is located at the terminal region of the receptor protein, which functions as an activator of androgen-controlled genes. An abnormally long sequence of polyglutamines qualitatively and quantitatively disrupts this activating function of the receptor. Receptor proteins with extended polyglutamine sequences somehow influence spinal and bulbar motor neurons. This explains why such neurons in SBMA slowly degenerate, leading to clinically apparent neurological deficits.
The disease usually appears between 20 and 40 years of age, but can occur later, up to 60 years of age. When first seeing a doctor, patients usually complain of slowly progressing neurological symptoms. SBMA is characterized by painful muscle spasms during physical activity and involuntary muscle cramps, which may be the initial signs of the disease. Then there is weakness of the proximal muscle groups, especially lower limbs. Later, muscle weakness and atrophy spread to the shoulders, face, and more distal extremities. The disease usually progresses slowly and lasts for several decades. In advanced stages of SBMA, severe bulbar symptoms such as dysarthria and dysphagia may develop.
Endocrine changes usually occur later than neurological symptoms. More than half of patients with SBMA develop gynecomastia. The testicles atrophy, as a result of which sperm production is disrupted, leading to secondary infertility. By the time clinical manifestation testicular dysfunction, more than 70% of patients already have children. LH and FSH levels are often elevated, but this is not necessarily a sign. Serum testosterone concentrations are slightly reduced in only 1/3 of patients. There is often diabetes mellitus or subclinical impaired glucose tolerance.
The most striking neurological symptoms are weakness or absence of tendon reflexes, as well as atrophy, weakness and involuntary muscle twitching. Electromyography and histological studies indicate a neurological cause of muscle atrophy. The speed of excitation along the motor nerves is normal or only slightly reduced. The conduction speed of the sensory nerves is slightly lower than normal, but this is not clinically manifested. Serum levels of the muscle enzyme creatine kinase are usually no more than 5 times the normal range. SBMA is not always easy to distinguish from other slowly progressive neuromyopathies. Sometimes helpful clues can be gleaned from family history. In any case, the diagnosis must be confirmed by the presence of a typical androgen receptor gene mutation.
There are no etiotropic treatments for this disease. Any therapeutic measures remain symptomatic and must take into account the specific complaints of the individual patient. We are not convinced that exogenous androgen treatment is appropriate for men with SBMA. With the exception of a few cases of unfavorable clinical course, life expectancy for SBMA remains normal or only slightly below normal.
Minimal forms of androgen resistance
In the 80s XX century Based on studies of androgen binding, the existence and widespread existence of minimal forms of resistance to these hormones have been postulated. In the literature, such forms were called “syndrome male infertility" (SMS) and "insufficient virilization syndrome of fertile males" (SFIMS). These names were believed to reflect very mild degrees of androgen resistance, leading either only to oligo or azoospermia (SFS), or to some effeminate appearance while maintaining normal fertility (SFIMS Our experience suggests that SMS and SNVFM have never had clear clinical criteria. Highly effective DNA diagnostic methods also do not detect the predominance of any mutations in the androgen receptor gene in patients who differ only in their pathological spermatogram.
In the first exon of the AR gene in healthy men, there are from 9 to 36 repeats of the CAG sequence. According to a number of authors, in men with impaired fertility, the average number of CAG triplets in this part of the gene is slightly higher than in fertile men in the control group, but this is not confirmed by everyone. Given the existing controversy, as well as the fact that the number of CAG triplets in the gene of infertile men in no case exceeded normal (from 9 to 36), the pathophysiological and clinical significance of the postulated expansion of such repeats should be treated with skepticism. Current data do not provide grounds for including analyzes of the CAG sequence of the AP gene in the routine practice of examining men with unexplained disorders of spermatogenesis.
Testicular feminization syndrome, or Morris syndrome, is a genetically determined pathology in which male people externally have female characteristics, but their internal reproductive organs resemble male ones. The disease is one of the forms of hypergonadotropic hypogonadism, that is, underdevelopment of the gonads, despite the normal or even increased production of pituitary hormones that stimulate the activity of the genital organs.
Pathology also refers to false hermaphroditism, when a person’s appearance does not correspond to his genetic gender.
Description of the disease
The pathology, which is also called “androgen insensitivity syndrome,” is caused by a genetic mutation of cells in which they become resistant to the action of male sex hormones (androgens). Babies with male XY chromosomes are born looking like girls. However, such patients do not have a uterus, fallopian tubes or ovaries, and the vagina is a short, blind cavity. At the same time, patients have male gonads (testes), located not in the absent scrotum, but in the abdominal cavity or inguinal canal.
Full androgen resistance syndrome is usually discovered during puberty, when a girl should begin to experience but does not. Many of these patients lack axillary and pubic hair. They are completely infertile and also have a high risk of bone fractures due to early-onset osteoporosis.
There are also options for partial androgen insensitivity. Men with this disease have a very small penis and enlarged mammary glands. One of the forms of Morris syndrome, Reifenstein syndrome, is accompanied only by impaired spermatogenesis (sperm formation) in apparently healthy men.
Causes of the disease and type of inheritance
The gene responsible for the development of testicular feminization syndrome is located on the X chromosomes. It is responsible for the formation of receptors on the surface of cells that respond to male sex hormones released into the blood. Due to a gene mutation, tissues stop responding to androgens, and develop only under the influence of female sex hormones.
The mode of inheritance of Morris syndrome is X-linked recessive. This means that the mutated gene is located on one of the mother's X chromosomes. Since it is recessive, the gene on the second X chromosome suppresses its activity, and the woman does not have any symptoms of the disease. Half of the eggs have a pathological gene, and the other half is normal.
A man's karyotype is 46 XY, and he always receives the X chromosome from his mother, and the Y chromosome from his father. The probability of having a boy with the pathology in women who are carriers of the pathological gene is 50%. If a girl is born, then in half of the cases she will become a carrier of the disease, and in other cases she will be healthy, having received “normal” X chromosomes from her mother and father.
Thus, without taking into account the sex of the unborn child, the risk of having a sick baby in a carrier of a pathological gene is 25%. The same type of inheritance is characteristic of hemophilia, one of the most famous recessive X-linked diseases.
In case of incomplete form of testicular feminization syndrome external structure may be male, and with timely treatment of cryptorchidism and hypospadias, such a patient can have children. Moreover, all of his daughters will be carriers of the pathological gene, and all of his sons will be completely healthy people who will not pass on the pathology to their offspring.
The reasons why such a mutation occurs and Morris syndrome develops are unknown. Due to the lack of normal tissue sensitivity to testosterone in the body developing fetus Normal male sexual characteristics are not yet formed in utero, although the sex glands are present and they secrete the appropriate hormones. “Unclaimed” male sex hormones can undergo biochemical metabolism and turn into female hormones ().
Frequency of occurrence and types of disease
Complete androgen insensitivity syndrome occurs in 2-5 per 100 thousand boys born. Partial insensitivity to male sex hormones is somewhat more common.
Depending on the degree of action of androgens on the body, testicular feminization syndrome can manifest itself in different ways:
Clinical manifestations
A patient with this pathology is genetically a man, but has the external sexual characteristics of a woman. However, he does not have a uterus, and there is practically no axillary or pubic hair (this is a very specific diagnostic sign). Due to the absence of the uterus, there is no menstruation and the patient cannot become pregnant. In some patients, the labia are partially fused, the clitoris is enlarged and the vagina is shortened.
The absence of a uterus is due to the fact that signs of pathology begin to form in the prenatal period. With this disease, the Müllerian ducts, from which the uterus is formed, are normally reduced, as it should be with a “male” genotype, but under the influence not of sex, but of other, specific “anti-Müllerian” hormones, to which tissue sensitivity is preserved.
Doctors note the external attractiveness of their patients, which is associated with the active effect of estrogen on their body. They have good skin, nails, beautiful hair that is not prone to loss (alopecia).
Possible symptoms of Morris syndrome:
- there is a vagina, but no cervix and uterus;
- breasts developed according to the female type;
- The testicles are located in the abdomen or inguinal canal.
The most common symptom is a bilateral inguinal hernia in a girl.
During the life of the patient, abnormally located testicles degenerate into malignant neoplasms, so they must be surgically removed in a timely manner.
People with this disease have the 46 XY male genotype in their cells. However, the hormones that are produced in the existing testicles do not affect the body, and it develops according to the female type. The patient feels like a woman, has a heterosexual orientation, that is, prefers contacts with men.
It is often believed that such a historical figure as the Maid of Orleans (Joan of Arc) had testicular feminization syndrome. This, according to historians, is evidenced by her determination, activity and other masculine character traits, as well as the absence of menstruation. However, “masculine” character traits are not at all a mandatory sign of Morris syndrome. Interestingly, even in scientific studies, the influence of the Y chromosome on behavior in this disease has not been proven.
Complications and consequences
Androgen insensitivity syndrome leads to infertility.
The main complications that may develop are:
- inguinal hernia due to improper placement of the testicles in the inguinal canal;
- hypospadias, accompanied by urethritis, cystitis, pyelonephritis;
- cryptorchidism with subsequent development of testicular cancer.
Diagnostics
Recognizing pathology in childhood is difficult. The exception is cases of detection of testicles in the abdominal cavity or inguinal canal during a random examination. In most patients, Morris syndrome is diagnosed during puberty with a long absence of menstruation.
The incomplete form is usually recognized earlier, since in this case the external genitalia are changed in such a way that they have features of both female and male.
Required examination:
- . Examination by a geneticist to determine the chromosome set. If only one X chromosome is detected in a woman, the diagnosis is confirmed.
- Ultrasound or MRI of the pelvic organs.
- Blood tests to determine the level of hormones: testosterone (increased), luteinizing hormone (increased), follicle-stimulating hormone (increased, but to a lesser extent than luteinizing hormone).
- To separate such types of sex development disorders in boys as testicular feminization syndrome and another disease from the same group (type 2 5α-reductase deficiency), it is necessary to determine the AR and SRD5A2 genes. Sometimes this is of fundamental importance, because in case of a rare disease - type II 5α-reductase deficiency - hormonal therapy is effective, and therefore it is immediately better to raise the child as a boy.
Therapeutic measures
Treatment for Morris syndrome depends on its severity, psychological characteristics of the patient and is determined individually. The main goal of therapy is to avoid the development of such a severe psychological disorder as gender dysphoria.
With complete form, patients are usually raised as girls, with incomplete form - as boys.
Hormone replacement therapy
If a child feels like a boy, then to restore male gender identity, adolescents can be prescribed appropriate sex hormones, for example, testosterone. It is often used in the form of an ointment used to increase the size of the penis. If treatment with male hormones is not started during puberty, then in adults it will no longer be effective, and then high doses of testosterone are prescribed intramuscularly. During adolescence, the mammary glands begin to enlarge in most patients, in which case they are removed.
The drug AndroGel is used in the treatment of Morris syndrome, as hormone replacement therapy for testosterone deficiency
However, since the development of the disease is not associated with a lack of male hormones, but with the insensitivity of tissues to them, testosterone hormone therapy often does not lead to the desired result and does not cause male-type hair growth. muscle mass and other similar signs. On the contrary, the appearance of the patients is more reminiscent of women. Therefore, even with an incomplete form of the disease, the patient is offered removal of the testicles and injection female hormones, and, if necessary, breast surgery. This is especially necessary when the patient perceives himself psychologically as a woman.
If a decision is made not to carry out treatment with androgens, then it is necessary to prescribe female sex hormones. They begin to be accepted if the child feels like a girl, at 10-11 years old. Tablets or patches containing ethinyl estradiol are used.
Hormones for replacement purposes are introduced before the average age of menopause - about 50 years.
Psychological support
This help is very important for patients with testicular feminization syndrome. It is useful to communicate with people suffering from this disease, their emotional support and life advice. IN foreign countries There is a developed network of psychological assistance groups for such people.
Due to the peculiarities appearance and the low effectiveness of prescribing male hormones, it is better to raise a child with this disease as a girl.
Surgical assistance
The standard operation for Morris syndrome is removal of the testicles. Risk them cancerous tumor at the age of 20 it is 3%, and by 50 it is already 30%. Therefore, an orchiectomy must be performed before the child reaches 18 years of age.
Because patients perceive themselves as women, they may require vaginal plastic surgery. It is performed after reaching 18 years of age. An alternative to surgery is bloodless colpopoiesis, which allows you to lengthen the vagina without the intervention of a surgeon using a special device - an elongator. It begins to be used from the age of 16 years.
If there is significant deformation of the external genitalia in young children, cosmetic reconstructive surgery is performed to give the genitals a normal shape.
In mild forms of incomplete Morris syndrome, surgical treatment of cryptorchidism with relocation of the testicles to the scrotum and correction of hypospadias is possible.
Forecast
Patients with Morris syndrome cannot become pregnant or donate cellular material for fertilization. The use of surrogacy is impossible for the same reason - the patient most often simply does not have gonads. That's why the only way to become a mother for patients with complete Morris syndrome - adoption.
Otherwise, the prognosis of the disease is good. It does not affect life expectancy. Patients can seek good results in sports, but they cannot take part in women's teams because they have a male genetic makeup.
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