Disease Description The etiology, clinical presentation, and treatment of intersexual malformations are complex. In brief, the clinical manifestations of male fetuses are called “hermaphroditism” because of short penis, hypospadias and blind vagina formation due to insufficient testosterone synthesis or impaired action of testosterone during development, or female fetuses are exposed to excessive androgens during development, causing penis-like enlargement of the clitoris and fusion of labia majora, resulting in indistinguishable gender at birth. This is called “hermaphroditism”. The academic definition is the inconsistent expression of chromosomes, gonads, and external genitalia, which is now called abnormal sexual development disease. The identification and determination of chromosomal sex, gonadal sex, external genital sex and social sex in patients with sexually developmental disorders is the basis for the management of such disorders. Disease classification: Endocrine disorders, masculine disorders, gynecological endocrinology, plastic surgery, urology; Pathogenesis The sexual differentiation of normal males depends on the adequate amount of androgens and their ability to perform their physiological effects properly. Male pseudohermaphroditism (46, XY, DSD) can occur in varying degrees of severity depending on the degree of androgen deficiency or impairment of its action; female sexual differentiation does not require the participation of estrogen secreted by the ovaries. When there is no androgenic action, the sexual differentiation primordium naturally differentiates into the female internal and external genitalia. On the contrary, when disturbed by inappropriate androgen action for various reasons, the female embryo will show different degrees of masculinization, which is known as female pseudohypergynosis (46, XX, DSD). If the karyotype is 46, XY, the Y chromosome contains an important gene that determines male sex, called the “SRY gene”, and the primordial gonads of the embryo differentiate into testes, if the testes can synthesize and secrete testosterone normally, and if the 5α reductase activity in the body is normal and can convert some of the testosterone into dihydrotestosterone, and if the androgen receptor function is normal, the embryo will show different degrees of masculinization. receptors function normally, then the embryo differentiates into a normal male. Otherwise, the embryo will have insufficient masculinization, which is manifested by different degrees of malformation of its internal and external genitalia. For example, a female fetus with a karyotype of 46,XX, sexual differentiation will result in masculinization manifestations such as enlarged clitoris and fused labia majora due to exposure to excessive levels of androgens, which may originate from the adrenal glands or from exogenous drugs and food. In addition, congenital adrenocortical hyperplasia (e.g., 17α hydroxylase deficiency), P450 oxidoreductase deficiency, and many other diseases can have clinical manifestations of hermaphroditism. Therefore, the differential diagnosis of the diseases is very complicated. Pathogenesis and pathophysiology Under normal conditions, sexual differentiation in males and females begins with identical progenitors. The karyotype determines the direction of gonadal differentiation, which in turn determines the secretion of sex hormones. Androgens, which originate from the testes, are the key hormones that govern the male life, creating bulging muscles and normal erectile function. Just as a key can only unlock the corresponding door, testosterone in the body must pass through its specific receptors in order to function. If the receptors are not functioning properly, the normal biological effects of testosterone will not be achieved despite the presence of large amounts of androgens. This condition is called “androgen resistance”. In these patients, it is difficult to promote penile growth even with large amounts of androgen supplementation, because these androgens cannot find the appropriate receptors in the body to work. Another common disorder is “5 alpha reductase deficiency”. In the human body, a portion of testosterone is converted to dihydrotestosterone by the enzyme 5α reductase in order to better perform its specific biological role: promoting the differentiation and development of the male external genitalia. If 5α reductase is deficient, testosterone in the body cannot be successfully converted to dihydrotestosterone in the skin area of the external genitalia, and despite normal testosterone levels, complete masculinization cannot be achieved, manifesting as short penis, different degrees of hypospadias and cryptorchidism. Females are at relatively less risk of developing hermaphroditism. Some female fetuses, if exposed to higher amounts of androgens during maternal in utero development, may show signs of masculinization such as penis-like clitoral hypertrophy and labia majora fusion. In such patients, early detection and removal of the cause of elevated androgen levels can help in the treatment of the disease. Clinical manifestations The clinical manifestations of abnormal sexual differentiation diseases are diverse. The abnormalities of the external genitalia can be completely male or completely female, and more often they manifest as a phenotype between female and male: enlarged clitoris, penis-like clitoris, hypospadias, fused labia majora, scrotal-like labia, closed vagina, micropenis, cryptorchidism, etc. Hypospadias is the opening of the urethra on the ventral side of the penis. It is a congenital vulvar malformation and is one of the most common signs of abnormal sexual differentiation disorders and is generally considered to be the result of too low androgen levels or the inability of androgens to function adequately. Clitoral enlargement is a condition in which the length and diameter of the clitoris significantly exceeds normal size and is commonly seen in female patients with high androgen status. Micropenis and cryptorchidism are often a sign of low androgen levels or inadequate action of androgens. Some disorders of sex hormone synthesis disorders (e.g. 17α hydroxylase deficiency) show significant clinical differences depending on the degree of enzyme deficiency. Diagnosis and differential diagnosis The differential diagnosis of disorders of abnormal sexual development begins with clarification of the karyotype. At the same time, the examination revolves around the malformations of the internal and external genitalia, including physical examination, imaging and ultrasound. During the physical examination, the symmetry and degree of masculinization of the vulva needs to be evaluated. Primitive labial-scrotal folds can develop into labia majora or into varying degrees of labial-scrotal fusion. The neonate’s penis may appear as a typical young female clitoris, and the urethral opening is located at the tip of the penis. One or two openings communicating with the ventral cavity may be present. There can also be varying degrees of fusion of the labial urethral folds. Depending on the degree of fusion, the urethral opening can be located either below the penis or at the tip of the penis. The differential diagnosis also requires the measurement of sex hormone levels. Functional tests are necessary to clarify the diagnosis of the presence of gonads in the affected child. One of the HCG excitation tests helps to clarify the presence of functional testicular tissue in the body. Exploratory laparoscopy and gonadal biopsy help to finally establish the diagnosis. Androgen resistance and 5 alpha reductase deficiency are the most common causes of male hermaphroditism. The differential diagnosis of these disorders also requires the measurement of dihydrotestosterone. Currently, only about half of the patients with hermaphroditism can be diagnosed definitively by various tests. Advances in molecular genetics have allowed rapid and definitive diagnosis of the cause of many single gene mutation disorders. It is also useful for genetic counseling for fertility. First aid measures Usually no emergency treatment is required. Treatment Once the diagnosis is clear, the gender orientation can be determined based on the cause and development of the external genitalia and the wishes of the patient and parents. Surgical plastic surgery can partially reshape the external genitalia, but it is difficult to achieve satisfactory results in terms of function. Gender is influenced by multiple factors, including family and society, and requires a careful decision after a joint discussion between the physician, the patient and his or her family. Patients with female pseudohermaphroditism with a karyotype of 46,XX need to consider whether an enlarged clitoris should undergo reconstructive surgery. The timing of the surgery may be chosen to occur in infancy or in adulthood. Once the physician and the patient’s family agree on the gender choice, surgery of the external genitalia should be performed as early as possible, preferably before the child himself is aware of the problem of hermaphroditism, in order to minimize the adverse psychological effects of the disease and the surgery on the child. Vaginoplasty is usually performed after puberty, since devices to help dilate the vagina need to be placed for a long time after surgery to prevent artificial vaginal stenosis from occurring. Recent studies have shown that if only mild enlargement of the clitoris is manifested, it can shrink on its own after correction of high androgen levels and should be followed and observed with minimal surgery. Patients with male pseudohermaphroditism with karyotype 46,XY can undergo urethral repair and penile remodeling plastic surgery in steps depending on the severity of hypospadias. One of the goals of the surgery is to be able to allow the patient to urinate in a standing position. For patients with scrotal dysplasia, scrotoplasty or transplantation may be considered. Because the possibility of cryptorchidism becoming malignant is significantly higher than in the general population, orchiectomy is required for patients who choose to be female by gender. For patients whose gender is male, if the testicles cannot be lowered to the scrotum through medication or surgery, they can be followed up by long-term regular ultrasound examination to closely observe the possible malignant changes of the testicles, or they can be surgically removed and treated with long-term androgen replacement therapy. For children with congenital abnormal development of external genitalia, multidisciplinary collaboration is needed to deal with them: doctors from endocrinology, plastic surgery, psychology, genitourinary medicine and family members discuss together and make a comprehensive analysis and evaluation before choosing a treatment plan. A long-term follow-up and education plan needs to be developed for the patient himself and his family. External genital anomalies and the subsequent treatment process can be very traumatic for the patient himself and his family. Sex hormonal disorders in the early embryonic period can also interfere with the sexual differentiation of his brain, and it is necessary to provide long-term psychological support and care for such patients. The prognosis of the disease usually does not affect the life expectancy, but it can seriously affect the quality of life. Disease prevention There are different preventive measures for different causes of the disease. For example, sex hormone abuse should be avoided during pregnancy; women should avoid androgen-rich drugs and foods; and those with a family history of hermaphroditism should talk to their obstetrician promptly during pregnancy for prenatal counseling. For certain diagnosed diseases, amniotic fluid or chorionic villus aspiration is feasible to test the fetus for relevant genes, which can help determine whether the fetus carries this disease-causing gene.