The sex of men and women can be distinguished on the basis of sex chromosomes, gonadal structure, morphology of internal and external genitalia and secondary sex characteristics, but some patients have different degrees of hermaphroditism, that is, people who do not conform to the typical characteristics of men and women, accounting for about 5 to 10 of the total population, and extremely serious sexual anomalies, especially external genital organs with both male and female characteristics, affect the determination of sex, called hermaphroditism. The types of human gender anomalies are complex, and their causes, clinical manifestations, treatment measures. The causes, clinical manifestations, treatment and prognosis vary. The diagnosis should be made as early as possible to determine the choice of sex and to correct it early.
”Sex” is the biological difference between the two sexes. This difference can be distinguished from different levels or levels such as chromosomal sex, gonadal sex, kinetochore sex, internal and external genital sex, psychological sex and social sex.
Normal sexual differentiation is initiated by the SRY gene on the Y chromosome, which allows the development of primordial gonads into testes, and the production of paramedian tubular suppressors by the supporting cells within the testes, which degenerate the paramedian tubules. The presence of MIS and testosterone and their conversion to dihydrotestosterone by 5-a reductase in local tissues are necessary for male genital differentiation, and MIS, testosterone and dihydrotestosterone must all act through their receptors. Usually chromosomal sex, gonadal sex and phenotypic sex are consistent, and errors in any one of them may affect various levels of gender inconsistency, resulting in various types of gender anomalies.
Gender anomalies are abnormalities in sexual differentiation, especially disordered development of external genitalia, and can be caused by sex chromosome abnormalities, genetic mutations, disorders of sex hormone secretion, impaired response to sex hormones, and environmental changes. In some patients, the gonads, internal and external genitalia or secondary sexual characteristics have different degrees of hermaphroditism, and it is often difficult or impossible to determine the sex of certain newborns because they have vulvar abnormalities.
I. Chromosomal (genetic) sex
1. SRY gene
The presence or absence of the Y chromosome is crucial in human sex determination. Men with Y chromosomes can determine the development of their original gonads as testes, and in general, a male is a male if he has testes. This is because the Y chromosome carries the sex-determining gene SRY on the short arm of the proximal chromosome, which is a molecular-level difference between the sexes.
When chromosomal sex and gonadal sex do not coincide, the clinical manifestation is sexual inversion syndrome. These syndromes include 46.XX males and 46,XY females, where patients have opposite karyotypes and phenotypes.
It is believed that both syndromes are the result of the acquisition or loss (including loss of function due to mutations) of the SRY gene. 46,XX males are individuals who lack the Y chromosome but have testicular development, and most have normal male external genitalia. However, lO of individuals have hypospadias． All individuals are infertile. 46,XY females are individuals with male karyotype sex and female gonadal sex. The female genitalia of 46,XY are infertile individuals with male karyotype and female gonadal sex.
Regarding the etiology of patients with 46, XX males and 46, XY females with sex reversal syndrome. It is associated with translocations or varying degrees of deletion of the SRY gene, mutations in the SRY gene and the organization of chimeric chromosomes.
The SRY gene can be used in clinical applications to identify sex more accurately, gender-related diseases, sex organ aberrations, and prenatal diagnosis, etc. The SRY sex-determining gene may provide a scientific basis for solving the mystery of human birth.
Although the SRY gene plays an important role in sex determination, it is not the only gene, and sex determination may also involve some genes on the X and autosomes, so sex determination and differentiation is the result of multi-gene interaction and orderly regulation.
2.Aberrations in the number of sex chromosomes
When the sex chromosome aberrations can lead to abnormal sexual differentiation. Aberrations in the number of sex chromosomes are common in humans. From the essence of sex determination, the presence of Y chromosome determines the sex phenotype. In males, if there is an extra Y chromosome, XYY syndrome, the main effect of which is the intensification of masculine features, an unusually tall stature, and in a few patients, mental retardation, abnormal personality and behavior, and hypogonadism.
If there is an extra X chromosome with a karyotype of 47,XXY, it is known as K1inefelter syndrome, also known as congenital testicular hypoplasia or primary microchondroplasia. It is a group of disorders characterized by male infertility, lack of secondary sexual characteristics, feminization, intellectual and behavioral impairment, and tall stature.
In females, there is an extra X chromosome, also known as multiple X syndrome, and the patients are short and fat, with delayed skeletal development, short neck, knee ectropion, and some patients have abnormal menstruation and ovarian function. Some patients have abnormal menstruation and ovarian function. Some have reproductive ability. Some patients have mental retardation and behavioral abnormalities.
In people with only one sex chromosome, this chromosome is always X. Turner syndrome is also known as congenital ovarian hypoplasia. The main characteristics of the patient are female phenotype, short stature, webbed neck, mental retardation, and primary amenorrhea. Primary amenorrhea. Secondary sexual characteristics and genital hypoplasia.
In the case of chimeric phenotype (X/XY), a part of all their cells is missing a Y chromosome and they exhibit sexual characteristics that are intermediate between male and female.
II. Sex of gonads
Male testes and female ovaries. The different tissue cells they have are differences between the two sexes at the cellular level.
The Y chromosome plays a key role in sexual differentiation in mammals, and the Y chromosome encodes the SRY gene, the testicular determinant, which causes the gonads to develop as testes rather than ovaries.
As long as a Y chromosome is present (the exact SRY gene is present), the germinal crest develops into a testis on approximately day 7 of the embryo, regardless of the number of X chromosomes.
In contrast, if there is no Y chromosome present (exactly no SRY gene) and there are two or more X chromosomes, the germinal crest develops into an ovary at about 8 or 9 weeks of embryonic life.
1, testicular hypoplasia
1. 1.45, X/46, XY gonadal hypoplasia
In 45, X/46, XY chimeric type with hermaphroditic phenotype, it was found that there are breaks in different parts of the Y chromosome. This structurally abnormal Y chromosome is prone to misalignment and loss during mitosis, resulting in the 45,X/46,XY karyotype.
The patient’s gonads exhibit striae or testicular dysplasia. The external genitalia are hermaphroditic, micropenis, and perineal or scrotal hypospadias. The testes often have incomplete descent. Those with uterus and fallopian tubes often have concomitant vas deferens. Patients have varying degrees of Turner syndrome manifestations. Somatic anomalies such as short stature, elbow ectropion and renal malformations are present. Plasma LH and FSH levels are elevated and testosterone levels are decreased. Patients with this disease have a 2O to 3O% chance of developing malignant tumors of the gonads. These include gonadal germ cell tumors, seminoma, and carcinoma in situ. Early prophylactic resection of the striated gonads and underdeveloped testes is recommended.
1.2.Y chromosome structural abnormalities
Structural abnormalities of the Y chromosome, such as long-arm or short-arm iso-arm, loop and double-adhesion are often accompanied by the loss of genes on the Y chromosome, and if the short-arm sex-determining region is partially lost. This can cause pseudo-hermaphroditism. If the SRY gene is absent or not fully expressed. The external genitalia may appear hermaphroditic or completely female. Bilateral gonads are striated, hypoplastic testes, or both. There may also be varying degrees of Turner syndrome manifestations.
1.3. Fetal testicular degeneration syndrome
It can be familial or sporadic, and the cause is unknown. The clinical manifestations vary greatly depending on the time of testicular degeneration. If testicular degeneration occurs before 8 weeks of embryonic life, the external genitalia are completely female, with uterus and fallopian tubes. There is no sexual development during puberty; if the degeneration occurs between 8 and 12 weeks of embryonic life, the external genitalia may be female type or hermaphroditic, and the uterus, fallopian tubes or epididymis, or vas deferens may be absent or underdeveloped. Or two sets of derivative organs of the reproductive ducts may coexist. If the degeneration occurs at 12-14 weeks of embryonic life, the testes may disappear completely or a pair of small dysplastic testes may remain, located in the groin or abdominal cavity, and the external genitalia are of male type, with the presence of small penis, epididymis and vas deferens.
2.Two kinds of gonadal tissues co-exist
True hermaphroditism refers to the existence of both testes and ovaries in the body, with clinical manifestations of testes and ovaries co-existing, or the existence of oviducts. The karyotype of true hermaphroditism is 46,XX in 80% of true hermaphroditism, but there are also 46,XY or other chimeric karyotypes. Most of them are female in appearance, without beard and throat nodes, and may have breast development. The vulva is masculinized to varying degrees, the clitoris is enlarged, there is pubic hair, and the urethro-vaginal opening is often fused. The gonads may be located in the labia, groin and pelvis.
III. Hormonal sex
The testes produce the male hormone and the ovaries produce the female hormone and the pregnant hormone. The sex of both sexes is determined by their phenotypes. Because of the different hormone content in the two sexes, the male and female sex organs develop in different directions.
Male mammals have a penis, seminal vesicles, and prostate; female mammals have a vagina, cervix, uterus, fallopian tubes, and mammary glands.
In most mammals, each sex has its own specific volume, cartilage and muscle tissue, and these secondary sexual characteristics are usually determined by the hormones secreted by the gonads.
Without the SRY gene, the primitive gonads would develop into ovaries. The ovaries produce estrogen, which induces the development of the Müllerian ducts into the uterus, fallopian tubes, and upper vaginal segment.
The primordial embryo will naturally develop in the female direction in the absence of gonads and in the male direction when subjected to two hormones (usually secreted by the embryonic testes): first, anti-Müllerian duct hormone (AMH), also known as Müllerian duct inhibitory substance (MIS), which destroys the Müllerian duct; second, testosterone, which masculinizes the embryo and stimulates development of the penis, scrotum, and other androgenic structures, and inhibits the development of the primordial mammary gland.
1. Congenital testosterone biosynthesis abnormalities
The process of testosterone biosynthesis involves five enzymes, namely P450scc lyase, 3B-HSD, P450c17 hydroxylase, P450c17 (17,2O) lyase and 1713-I HSD. the first three enzyme defects can involve both adrenal glands and testes and belong to the category of congenital adrenocortical hyperplasia, while the latter two enzyme defects are expressed only in testis. As a result of these enzyme defects, testosterone is affected at different stages of its biosynthesis, causing patients to exhibit different types of male pseudohermaphroditism: e.g., external genitalia exhibiting a feminine or hypermasculine phenotype, clitoral hypertrophy or micropenis, scrotal or perineal hypospadias, possible partial fusion of the labia or blind vaginal canal, testicular IX located in the labia majora, groin, or cryptorchidism. In patients with glucocorticoid and salt corticoid deficiency, early death from adrenal cortical failure can occur if treatment is not timely.
2, Lydi cells do not respond to LH
Leydig (1eydig) cells are underdeveloped or the LH/hCG receptors on Leydig cells are defective. Both will cause the Leydig cells to be unresponsive to LH/hCG stimulation and unable to synthesize testosterone. The external genitalia appear completely female or essentially male with hypospadias. Uterus and fallopian tubes are absent. Epididymis and vas deferens are absent or present.
3. Androgen insensitivity syndrome (AIS)
AIS is an X-linked recessive genetic disorder that often occurs in the same family. AIS was originally a male pseudohermaphroditism, called testicular feminization syndrome, but in the new classification is a sex hormone function abnormality, and its pathogenesis is a developmental abnormality caused by androgen receptor defects. During the embryonic period, the testosterone secreted by the testicular mesenchymal cells of AIS patients fails to stimulate the development of the mesonephric duct to form the male internal genitalia due to androgen receptor abnormalities, and dihydrotestosterone does not act on the genitourinary sinuses and external genitalia, resulting in differentiation into the female vulva and lower vaginal segment. Testicular support cells can secrete normal paramedian tubule inhibitory substances, which can inhibit paramedian tubule epithelial proliferation, thus degenerating the paramedian tubules, so that there are no fallopian tubes, uterus, cervix and upper vaginal segments, resulting in hermaphroditism.
Since testosterone can be converted to estrogen by aromatase, patients with AIS are lO times more sensitive to estrogen than normal males, and therefore show female features after puberty.AIS is divided into two types: complete and incomplete. Patients with incomplete AIS have karyotype 46, XY, often female gender, primary amenorrhea, varying degrees of breast development, male nipples, no uterus and no fallopian tubes. The external genitalia are variously masculinized and the clitoral hypertrophy urethra is located below the clitoris. The vagina is elongated and blind-ended, or the vagina is fused with the urethra, and the testes are located in the groin, or in the inguinal ring of the abdomen.
In complete AIS, there is breast development, female body and female vulva, infantile female genitalia, clitoris is not enlarged, vagina is blind-ended, there is no uterus, pubic hair and axillary hair is sparse.
4.Müller’s duct resistance syndrome
Müllerian duct resistance syndrome is a male with normal development of sexual organs, however, the presence of uterus and fallopian tubes in the body, that is, the permanent presence of Müllerian duct derivative organs. The cause may be a defective testicular testicular support cells (sertoli cells) that fail to secrete Müllerian duct inhibitory factor (MIF) or synthesized MIF that is not biologically active; or abnormal MIF receptors in Müllerian duct cells that allow Müllerian duct differentiation to be completed. The clinical presentation is an inguinal hernia with the contents of the hernia sac being the uterus and fallopian tubes, which may be accompanied by cryptorchidism; in a few patients, the uterus, fallopian tubes and testes are all in the pelvis.
5.Congenital adrenal cortical hyperplasia
Congenital adrenocortical hyperplasia is the main cause of female pseudohermaphroditism, which is an autosomal recessive genetic disorder. It is classified as androgen excess in the new classification, and the lack of some enzymes (mainly 6 kinds) in the process of synthesizing steroid hormones produces too much androgen, making the external genitalia of female infants masculinized to different degrees.
The karyotype is 46,XX, there is normal ovarian development and mesonephric (Müller’s duct) derivation organs (uterus and fallopian tubes), and the external genitalia are hermaphroditic. Due to the lack of testes, the genetic characteristics of the external genital differentiation show a female phenotype, but the patient has varying degrees of male signs due to the influence of androgens. The degree of masculinization is related to the developmental stage at which the fetus is exposed to androgens, for example, after 12 weeks of embryonic life. Intrauterine androgen levels increase, when the growth of the vesico-vaginal septum has separated the vaginal opening from the urethral opening and manifests only as clitoral hypertrophy; if it occurs before 12 weeks. In addition to clitoral hypertrophy, the urogenital sinus may be present. The vaginal and urethral orifices have a common opening. There is partial fusion of the labia and scrotal folds.
6. Excessive intake or production of androgens by the mother
The application of androgens, “fetus transfer drugs” or treatment with synthetic fetus preservation drugs during pregnancy can cause masculinization of the external genitalia of the female fetus. Luteinizing tumors, luteinizing hormone cysts or rare androgen-secreting tumors of the ovaries and adrenal glands during pregnancy can cause fetal masculinization. It is a good idea to take a look at the results.
Internal and external sex organs
People usually rely on the external genitalia to determine the sex of the baby. Patients with abnormal sexual differentiation often have varying degrees of internal and external genital malformations, and malformations of the external genitalia are easily detected. However, during embryonic development, the genitalia of both sexes originate from a common primordium, making the malformed genitalia often intermediate between male and female, and therefore prone to gender confusion and incorrect gender rearing.
The external genitalia of both sexes have a common origin based on the genital nodules, genital bullae and urogenital folds. Testosterone produced by the interstitial cells of the testes plays an important role in the development of the external genitalia. When testosterone is present, the primitive external genitalia evolve in the male direction, with the genital nodules evolving into the penis, the urogenital folds evolving into the penile corpus cavernosum, and the genital bulge on both sides coming together to become the scrotum and causing the testes to descend into the scrotum. In cases of severe impairment of testosterone secretion, the embryo can develop completely in the female state. On the contrary, if the female embryo is subjected to large amounts of androgens during development, such as congenital adrenal cortical hyperplasia, which leads to excessive production of androgens, or if the mother takes drugs containing androgens during pregnancy, the female clitoris can be enlarged to resemble a penis, and both labia majora can fuse to become a scrotum, and other abnormalities.
In addition to the gonads, the internal genitalia include the uterus, adnexa and vagina in women, while in men, they include the spermatic cord, seminal vesicles and prostate gland. Sexual malformations are often associated with testicular, ovarian, uterine, vaginal, and prostatic dysplasia, impaired testicular descent, retention in the abdominal cavity or groin, and the simultaneous presence of testicular, ovarian, or ovo-testicular malformations in a particular body.
The external sex organs mark the first sexual characteristics of men and women. It is the difference between the sexes at the organ level.
The second sexual characteristic male has beard, prominent throat knot, thick bones, sturdy, tall; female pelvis wide, slim, well-developed mammary glands, full of body fat. This is the morphological gender.
V. Social gender
Social gender includes civil gender and dependency gender. After the birth of a baby, the sex of the baby is determined by the medical personnel who delivered the baby and registered with the police registry department is called the civil sex; the sex of the child raised by the parents or guardians according to their own will during the growth process is called the foster sex.
VI. Psychological gender
The third fourth sex characteristic, the psychosocial behavioral gender of men and women, is the difference between the two sexes at the overall level.
From the time of understanding, the gender that is self-identified to the self is the self-identified gender. However, due to the complexity of the clinical manifestations of gender dysphoria, the sex of the baby determined by the delivery personnel at birth according to the external genitalia may be incorrect; there are also parents who raise their children according to their own preferences, such as raising boys as girls or girls as boys, with hair styles, clothing, and environment different from the original civil gender. This kind of long-term incorrect upbringing may have an important impact on self-identification of gender, and self-identification of gender contradicts with normal biological gender, which is a sex-prone disease.
Diagnostic points of gender dysphoria
Patients are usually seen for reasons such as clitoral hypertrophy, penile shortening, hypospadias, absence of menstruation or menstrual discharge through abnormal channels, absence of vagina or vaginal stenosis, cryptorchidism, and gynecomastia.
Detailed medical history inquiry, such as family history of hereditary diseases, maternal illness during pregnancy, medication, exposure to harmful substances, mental condition psychological stress, etc.
In addition to the vulva and breasts, the patient’s height to arm length ratio, posture, skin color, hairline, hair distribution, throat nodes, prostate gland, etc. should not be easily missed. Excessive skin pigmentation often indicates congenital adrenocortical hyperplasia. If there are gonads in the “labia” and groin, it often indicates male pseudohermaphroditism; it is difficult to distinguish between a small penis with combined hypospadias and an enlarged clitoris. In severe female pseudohermaphroditism, it should be noted that sometimes it can also manifest as male infantile vulva. Infantile female vulva, scant or absent pubic axillary hair is often indicative of testicular feminization syndrome.
Blood and urine hormone levels are measured to check LH, FSH, testosterone, estradiol, cortisol, progesterone, growth hormone and steroid levels in the urine.
Examination of chromosome number and structure, serum immunological assay, positive H-Y antigen is closely related to testicular differentiation and male genesis.
CT, MRI, ultrasound, endoscopy if necessary and even dissection combined with gonadal biopsy can provide information about the urogenital sinuses, internal genital ducts, adrenal glands and intra-abdominal gonads, which are commonly used for comprehensive analysis to discern gender anomalies.
Management of gender anomalies
The goal is to give the patient the most appropriate gender diagnosis, to achieve the ability to marry and have sex, and to assist in the completion of childbirth if possible. For newborns and young children, the appropriate gender is selected after a clear diagnosis. For adult patients, the gender should be chosen in relation to their social gender and their own wishes. The external genitalia should be orthopedically corrected as necessary according to gender.
The sex of men and women can be distinguished on the basis of sex chromosomes, gonadal structure, morphology of internal and external genitalia and secondary sex characteristics, but some patients have different degrees of hermaphroditism, i.e. people who do not conform to typical male and female characteristics, accounting for about 5 to 10 of the total population. Extremely severe sexual anomalies, especially external genitalia with both male and female characteristics, affect the determination of sex and are called hermaphroditism. The types of human gender anomalies are complex, and their causes, clinical manifestations, treatment measures. The causes, clinical manifestations, treatment and prognosis vary. Diagnosis should be made as early as possible to determine the choice of sex and to correct it early.