Congenital adrenal cortical hyperplasia

　　The etiology of this disease is not yet clear. Most scholars do not agree with the pathogenesis from ACTH-dependent to non-dependent transition. It has been confirmed that AIMAH can be caused by factors other than ACTH, and it has been found that the abnormal expression of gastrin-releasing peptide (GIP), arginine vasopressin (AVP), and β2-adrenergic receptor in the adrenal glands can cause AIMAH.

　　I. Etiology

　　Almost all CYP21 mutations are the result of recombination between CYP21 and CYP21P (unequal exchange or transversion). About 20% of mutated alleles carry deletion mutations. About 75% of mutated alleles are the result of gene conversion. In 32% of salt-losing patients, one allele has a large segmental deletion or transversion mutation, and in 56% of patients, a point mutation in intron 2 causes abnormal RNA splicing. In vitro experiments have confirmed that these mutations result in the complete or almost complete loss of 21-hydroxylase activity. In simple virilizing type, the most common mutated allele (35%) is a substitution mutation at the 172nd amino acid codon (Ile to Asn), which retains only 2% to 11% of the normal 21-hydroxylase activity. The most common mutation in the non-classical type (39%) is a mutation at the 281st amino acid (Val to Leu).

　　There is a high degree of correlation between genotype and phenotype, so DNA analysis can predict enzyme activity to some extent, and then infer clinical manifestations.

　　II. Pathogenesis

　　The adrenal glands synthesize three types of steroids: ① Glucocorticoids (cortisol is the most important); ② Mineralocorticoids (aldosterone is the most important); ③ Androgens. The secretion of cortisol has a diurnal rhythm and is crucial in stressful situations; its deficiency can cause adrenal crisis including hypotension and hypoglycemia, which can lead to death if not treated in time. Excessive androgen production in the adrenal glands can lead to intrauterine masculinization, with female infants born with ambiguous genitalia, and both males and females can experience early adrenal puberty at a slightly older age. Deficiency in adrenal and gonadal androgen production can lead to insufficient masculinization in males, and the lack of adolescent development. In CAH, the activity of steroid synthesis enzymes is decreased to varying degrees, leading to abnormal secretion of glucocorticoids, mineralocorticoids, and sex hormones, resulting in varying degrees of clinical manifestations. The degree of enzyme activity decrease and clinical phenotype are determined by the severity and type of gene mutation. To better understand the clinical manifestations of CAH, it is necessary to briefly understand the biochemical and genetic status of adrenal cortical steroid hormones.

　　1. The P450SCC gene (CYP11A) is a single gene of 20kb located on the long arm of chromosome 15 (15q23-24).Expressed in all steroid cells.

　　2, 3β-HSD (3β-hydroxysteroid Dehydrogenase II, 3β-hydroxysteroid dehydrogenase II).This microsomal hydroxysteroid dehydrogenase is associated with the membrane and the smooth endoplasmic reticulum. It catalyzes the conversion of the hydroxyl group at carbon 3 into a ketone and a double bond from the B ring (delta5 steroids) to the A ring (delta4 steroids). It acts on four substrates: pregnenolone is converted into progesterone, 17α-hydroxypregnenolone is converted into 17α-hydroxyprogesterone, dehydroepiandrosterone (DHEA) is converted into androstenedione, and androstenedione is converted into testosterone. There are two different isozymes: type II is active in the adrenal and gonads, and type I is active in other tissues (skin, placenta, breast, etc.). The 3β-HSD gene (HSDβ1 and HSDβ2) has 93% homology and is located on chromosome 1 (1p13.1).

　　3, P450C17 (17α-hydroxylase/17,20 lyase).P450C17 is a microsomal enzyme associated with the smooth endoplasmic reticulum. It catalyzes two different and completely independent reactions: 17α-hydroxylase and 17,20 lyase reactions. Through 17α-hydroxylation, pregnenolone is converted into 17α-hydroxypregnenolone, and progesterone is converted into 17α-hydroxyprogesterone. These two substrates are cleaved at the C17,20 carbon chain to generate dehydroepiandrosterone and androstenedione. The gene encoding this enzyme is a single gene (CYP17) located on chromosome 10 (10q24.3).

　　When P450C17 is completely absent (such as in the glomerular band), aldosterone can be synthesized, but cortisol and sex hormones cannot be synthesized. If only 17α-hydroxylase activity exists, cortisol can be synthesized, while sex hormones must depend on two activities, namely 17α-hydroxylase and 17,20 lyase activity. For example, before puberty, the synthesis of adrenal cortical cortisol is normal, but there is no synthesis of sex hormones, indicating the presence of 17α-hydroxylase activity but no 17,20 lyase activity.

　　4, P450C21 (21-hydroxylase).P450C21 is also associated with the smooth endoplasmic reticulum, actually competing with P450C17 for electrons from membrane-bound P450 reductase. It converts progesterone and 17α-hydroxyprogesterone into 11-deoxycorticosterone (DOC) and 11-deoxycorticosterone, respectively. Two CYP21 genes are located on chromosome 6 (6p21.3), in the middle of the human leukocyte antigen (HLA), between HLA-B and HLA-DR. The CYP21 gene encodes biologically active enzymes. The pseudogene is called CYP21P. CYP21P shares more than 93% homology with CYP21, but due to some harmful mutations, this gene does not transcribe mRNA for P450C21. The high homology between CYP21P and CYP21 genes allows for gene conversion, which is one of the reasons for the high incidence of CYP21 gene mutations.

　　5, P450C11β (C11β-hydroxylase).The adrenal fascicle is active and mainly involves the synthesis of cortisol. Located on the inner membrane of the mitochondria, it converts 11-deoxycorticosterone into cortisol and 11-deoxycorticosterone into corticosterone. Its coding gene is located on chromosome 8 (8q21-22).

　　Mutations in the coding genes for the above steroid hormones can lead to hormone synthesis disorders and CAH. Defects in CYP21 and CYP11β can cause feminization in females, while defects in HSD3β2, CYP17, and StAR can cause androgen synthesis disorders, leading to insufficient masculinization in males. Some types of HSD3β2 defects can cause mild masculinization in females.

　　The steroidogenesis pathway in the gonads and adrenal glands is the same, so some clinical manifestations are due to abnormal steroid synthesis in the gonads, rather than abnormal adrenal hormone secretion. During fetal development, the regression of the Müllerian duct structures is due to the presence of non-steroidal substances produced by the testes, namely the Müllerian inhibitory substance. Therefore, fetuses without testes will have normal female internal reproductive anatomy regardless of the level of androgens. In fetuses with normal testes, the Müllerian duct structures will not develop regardless of the level of androgens.

　　Congenital defects in certain adrenal enzymes can lead to abnormal steroid production. In females, it can cause pseudohermaphroditism, and in males, it can cause giant reproductive organs. The enzyme defect is accompanied by excessive androgenic products in the fetus, and the female Müllerian duct structures (i.e., ovaries, uterus, and vagina) develop normally, while the excessive androgens exert their masculinizing effects in the urogenital system and reproductive nodules, leading to the fusion of the vagina and urethra, a low and open clitoris, and often hypertrophied labia. In severe cases, there may be hypospadias and cryptorchidism. The adrenal cortex may cause varying degrees of cortisol deficiency due to the majority of secretion being androgenic steroids with synthetic metabolism.

　　With the premature maturation and closure of epiphyses, adult height is significantly lower than normal; varying degrees of adrenal cortical insufficiency may occur, such as vomiting, diarrhea, dehydration, severe metabolic acidosis, difficultly corrected hyponatremia, hyperkalemia, leading to decreased blood volume, decreased blood pressure, shock, and circulatory failure; poor testicular development, azoospermia or oligospermia; male patients may have true precocious puberty, and female patients may have delayed menarche, secondary oligomenorrhea, or amenorrhea; and lead to a decrease in the fertility of both males and females.

　　1. Increased ACTH secretion causes bilateral adrenal cortical hyperplasia, with the hyperplastic cortex continuously synthesizing large amounts of androgens and salt-corticoid hormones that cause hypertension.

　　2. Deficiency of 20-22 carbon chain enzyme leads to a rare congenital lipoid adrenal hyperplasia, often with complete impairment of steroid hormone production. Without sufficient substitute treatment, infants may die early.

　　3. Deficiency of 3&beta-hydroxysteroid dehydrogenase isomerase leads to difficulties in the synthesis of pregnenolone, aldosterone, and cortisol, resulting in excessive production of dehydroepiandrosterone. This unusual syndrome is characterized by hypotension, hypoglycemia, and male pseudohermaphroditism, with women experiencing rare hirsutism and variable pigmentation.

　　4. Deficiency or absence of 21-hydroxylase prevents the conversion of 17-carboxypregnenolone to cortisol, with the most common deficiencies in two forms:

　　Various forms of sodium loss, low or absent aldosterone; common is the non-sodium-losing type, with hirsutism, masculinization, hypotension, and hyperpigmentation.

　　5. Deficiency of 17&alpha-hydroxylase is most common in female patients. Some present with low cortisol levels in adulthood, compensatory increase in ACTH, primary amenorrhea, sexual infantilism, and rarely with male pseudohermaphroditism. Excessive secretion of salt-corticoid hormones causes hypertension, mainly due to increased 11-deoxycorticosterone.

　　6. Deficiency of 11&beta-hydroxylase prevents the formation of cortisol and corticosterone, causing excessive ACTH release, leading to deep pigmentation. Excessive 11-deoxycorticosterone secretion causes hypertension, with no obvious sexual characteristics abnormalities.

　　7. Deficiency of 18-hydroxylase leads to a rare disease, caused by a specific blockage in the final step of aldosterone biosynthesis, resulting in excessive loss of urinary sodium, leading to dehydration and hypotension.

　　8. After puberty, male-type symptoms such as hirsutism and amenorrhea are rarely found. Occasionally, masculinization phenomena occur in middle age, which is called adrenal cortical benign masculinization due to mild enzymatic abnormalities.

　　9. Newborn female infants may have severe hypospadias and cryptorchidism. Boys are usually normal at birth, but the fetus in the womb has excessive androgens, leading to obvious abnormalities.

　　10. Untreated patients may experience hirsutism, muscular development, amenorrhea, and breast development. In male patients, the reproductive organs are abnormally large due to excessive androgens suppressing the secretion of gonadotropins, leading to testicular atrophy. In extremely rare cases, the presence of hyperplastic adrenal cortical remnants within the testes can cause the testes to enlarge and become harder. The majority of patients do not produce seminal fluid after puberty due to adrenal cortical hyperplasia. Patients experience a sudden increase in height between the ages of 3 to 8 years, much taller than their peers, as a result of excessive androgens around the age of 9 to 10 leading to early epiphyseal fusion, causing growth to stop. Adults are shorter, and both males and females exhibit aggressive behavior and increased libido, leading to social and disciplinary problems, which are particularly prominent in some boys.

　　If early diagnosis is made, even before the correction of severe organ malformations by surgery, ACTH secretion can be suppressed. Then the appearance can be normal, and development can be very good. Delayed treatment will inevitably lead to growth retardation, such as complications of coronary heart disease, early death from myocardial infarction. In some female pseudohermaphroditism, menstruation may occur after treatment. When the malformation is not severe or the patient may become pregnant and give birth after surgical correction.

　　1. The screening of neonatal CAH mainly refers to the screening and diagnosis of neonatal 21-OHD. The purpose is to prevent life-threatening adrenal cortical crisis and the resulting brain damage or death, prevent gender identification errors in female patients due to virilization of external genitalia, prevent stunted growth, psychological and physiological development and other disorders caused by excessive androgens, so that the child can receive early diagnosis and treatment before the appearance of clinical symptoms.

　　The neonatal CAH screening method is to take blood from the heel of each newborn baby within 3-5 days after birth, drop it on a special filter paper, and determine the concentration of 17-OHP in the filter paper blood film by using various detection methods, such as enzyme-linked immunosorbent assay (ELISA), fluorescence immunoassay, etc., for early diagnosis. The level of 17-OHP in normal infants after birth can be more than 90nmol/L, and it decreases to normal after 12-24 hours. The level of 17-OHP is related to birth weight, the level of 17-OHP in normal full-term infants is below 30nmol/L, for low birth weight (1500-2700g) it is 40nmol/L, and for very low birth weight (below 500nmol/L) it is typical CAH, 150-200nmol/L can be seen in various types of CAH or false positives. The positive cutoff point for 17-OHP screening should still be determined according to the methods of each laboratory, and adjusted through long-term observation and experience summary. Positive cases need close follow-up, and confirmed by measuring plasma cortisol, testosterone, DHEA, DHA, and 17-OHP levels, etc.

　　2. For CAH patients and their parents, 21-hydroxylase gene analysis should be performed for prenatal diagnosis and treatment. When the mother becomes pregnant again, at 4-5 weeks of gestation, oral dexamethasone (usually 1-1.5mg/d) is taken, at 9-11 weeks of gestation, chorionic villus sampling (CVS) is performed for chromosomal testing, DNA is analyzed for the CYP21B gene, if the above results suggest that the fetus is male, a heterozygote, or a normal fetus, the dexamethasone treatment can be interrupted. If the amniotic fluid test suggests a high possibility of a female pure-homozygous child, then dexamethasone treatment should continue until the birth of the fetus.

　　The level of urinary 17-ketosteroids is higher than that of normal individuals of the same gender and age, and the level of urinary progesterone increases early (this is more sensitive than the level of urinary 17-KS, as progesterone is a precursor of androgens), the increase of blood 17-hydroxyprogesterone level is the most sensitive indicator, suitable for children, chromosomal examination is normal, X-ray examination will find early bone age, lateral urethral bladder造影 will show vagina, urethra and bladder, CT scan can see highly proliferative adrenal glands, urethroscope can see the vagina opening on the posterior wall of the urethra, and can also enter the vagina and see the uterus.

    The diet of patients with congenital adrenal hyperplasia should be light, easy to digest, with an emphasis on eating more vegetables and fruits, and a reasonable diet should be balanced. In addition, patients should also pay attention to avoiding spicy, greasy, and cold foods.

　　Early diagnosis is absolutely necessary. Rational treatment is to administer glucocorticoids, i.e., taking dexamethasone 0.5-1.5mg orally at 11 PM to correct the deficiency and inhibit ACTH secretion. For patients with severe hyponatremia syndrome, fludrocortisone helps maintain blood pressure and weight, and can be used at a dose of 0.05-0.3mg, depending on the severity of the condition and age.

　　After development, surgery can be performed to separate the vagina from the urethra and position the vaginal orifice at the normal location in the perineum. If the clitoris frequently becomes erect, clitoridectomy may be considered. Careful administration of estrogen or medication adjustment immediately after birth can help pseudohermaphrodites maintain a female appearance and improve their psychological state.

　　First, treatment

　　1. Glucocorticoid replacement therapy

　　(1) General discussion: All classic 21-hydroxylase deficiency patients and symptomatic non-classical patients are treated with glucocorticoids, which inhibits the excessive secretion of CRH and ACTH from the hypothalamus and pituitary gland, and reduces the abnormally elevated levels of adrenal androgens in the blood. In children, hydrocortisone (i.e., cortisol itself) is recommended, with a dose of 10-20mg/(m2·d), taken twice or thrice daily. These doses exceed the physiological level of cortisol secretion, which is approximately 6-7mg/(m2·d) in children and adolescents. Although a slight increase in cortisol secretion in newborns is normal [7-9mg/(m2·d)], CAH infants are usually given the minimum dose of 6mg/(m2·d), thrice daily. For children with 21-hydroxylase deficiency, it is necessary to administer supraphysiological doses of glucocorticoids, which are sufficient to suppress adrenal androgens and reduce the possibility of developing adrenal insufficiency.

　　The half-life of hydrocortisone is short, which can reduce the inhibition of growth and the side effects of other types of hormones, such as prednisone and dexamethasone, which have long action times and strong effects. On the other hand, the daily administration of short-acting glucocorticoids once a day cannot effectively control the secretion of hormones from the adrenal cortex.

　　Cortisone acetate is not the first-line drug for 21-hydroxylase deficiency. The bioavailability of cortisone acetate is 80% of hydrocortisone, and its efficacy is only two-thirds of hydrocortisone. In addition, since cortisone must be converted to cortisol to exert biological activity, a decrease in the activity of 11β-hydroxysteroid dehydrogenase reductase will further reduce the efficacy of the drug.

　　Older adolescents and adults can use the minimum dose of prednisone (e.g., 5-7.5mg/d, taken twice a day) or dexamethasone (a total of 0.25-0.5mg, taken once a day or twice a day). It is necessary to carefully monitor the signs of iatrogenic Cushing's syndrome, such as rapid weight gain, hypertension, skin striae, and bone density reduction. Male CAH patients with adrenal remnants need a larger dose of dexamethasone to suppress ACTH.

　　The therapeutic effect is judged by monitoring the levels of 17-OHP and androstenedione (i.e., the suppression of adrenal hormones). In female and prepubertal male patients, testosterone can also be used as a useful indicator. Because excessive treatment has side effects, the secretion of endogenous adrenal cortical steroids should not be completely suppressed. The control range of 17-0HP is best between 1-10ng/ml, and the testosterone level is comparable to that of the same age and gender. The timing of hormone measurement should be fixed in relation to the time of taking medication, preferably at 8 am when ACTH is at its physiological peak, or before the next dose when hydrocortisone levels are at their lowest.

　　Children must have their X-ray bone age checked annually, and the growth line must be carefully monitored. Although careful monitoring of various indicators can be achieved and patients have good compliance, most retrospective studies show that the final height of adults is lower than the expected height based on their parents' height and also lower than the average height of normal people.

　　In addition, atypical CAH patients with salt-losing syndrome must also receive mineralocorticoid replacement therapy, and some patients can increase salt intake in their diet (1-3g/d). Most patients take 0.1mg/d of fludrocortisone. Infants and toddlers sometimes need 0.1-0.2mg per dose, twice a day. The drug dose and salt intake are mainly regulated by measuring blood renin activity.

　　(2)Indications for treatment in atypical patients: Atypical 21-hydroxylase deficiency patients with symptoms and signs of excessive androgen should receive glucocorticoid therapy. Small doses of glucocorticoids are given to children with precocious puberty. Young female atypical patients who experience hirsutism, oligomenorrhea or amenorrhea, or acne should also be treated with glucocorticoids. Infertility should also receive glucocorticoid replacement therapy, as endocrine disorders are the main obstacles to pregnancy, and it is easy to become pregnant after treatment. After glucocorticoid therapy inhibits the excessive secretion of adrenal androgens, the clinical symptoms of excessive androgens are gradually improved. It is difficult to alleviate hirsutism with glucocorticoids alone because the formed follicles are difficult to eliminate. As an auxiliary measure, it is recommended for these patients to undergo aesthetic treatment for hirsutism. Male atypical 21-hydroxylase deficiency patients who receive glucocorticoid therapy show improvements in spermatogenesis and fertility. Male patients with atypical CAH and testicular enlargement should also receive glucocorticoid therapy.

　　For patients with non-classical 21-hydroxylase deficiency whose symptoms have been relieved, or for female non-classical patients who have passed the childbearing age, it may be considered to discontinue glucocorticoid therapy.

　　(3) Stress dose: During adrenal crisis, adrenal crisis management uses 0.9% saline to maintain blood volume (at least 20ml/kg intravenous bolus). After acute expansion, 0.9% saline and a small amount of dextran are used for intravenous maintenance at twice the rate of the maintenance dose. If there is no clear diagnosis, blood samples should be collected for testing androgens, 17-OHP, ACTH, and cortisol before the administration of glucocorticoids. The preferred treatment is hydrocortisone, administered intravenously, as hydrocortisone has mineralocorticoid activity. The initial dose is 25mg for newborns, 50mg for children, and 75-100mg for adolescents and adults. After the initial loading dose, 50-100mg/(m2·d) must be administered intermittently, divided into 6 doses.

　　During stress, the hydrocortisone dose is 40-100mg/(m2·d). It can be taken orally, once every 8 hours, or administered intravenously, once every 6 hours. The dose, route of administration, and frequency of administration are determined according to the stress condition. The drug dose should be increased for any febrile disease (until 24 hours after the fever subsides). The dose is 3-5 times the normal maintenance dose. In more severe stress or when the efficacy of oral medication may be affected, systemic glucocorticoids should be administered. In these cases, a higher dose of 75mg/(m2·d) is required. Hydrocortisone dose should also be increased before surgery. The dose given on the night before surgery is 3-5 times the normal dose, and an intravenous hydrocortisone loading dose is given during the induction of anesthesia. The dose given during induction is similar to the initial dose used in adrenal crisis: 25mg for newborns, 75mg for children, and 75-100mg for adolescents and adults. Stress protection should last for 24-72 hours, depending on the type of surgery and the recovery status. Gradually reduce the dose to the maintenance dose.

　　Patients with non-classical 21-hydroxylase deficiency do not need to be given a stress dose of hydrocortisone during surgery, unless they have previously developed iatrogenic adrenal cortex insufficiency due to long-term glucocorticoid therapy.

　　2. Existing problems in treatment and treatment progress: Over the past 50 years, with the adoption of glucocorticoid and mineralocorticoid replacement therapy, as well as LHRH agonists to control LHRH-dependent precocious puberty, the quality of life of CAH patients has been significantly improved. Despite the many advances, the current treatment regimens cannot enable many CAH children to have normal growth and development, and the treatment of adult CAH may exist iatrogenic Cushing's syndrome, and cannot fully control hyperandrogenism and infertility. Even if the patient's compliance is very good, these problems have not been resolved.

　　In the treatment of 21-hydroxylase deficiency, the use of physiological doses of hydrocortisone can normalize the plasma ACTH levels in CAH patients. Exogenous hydrocortisone (2/d or 3/d) cannot accurately simulate the close temporal relationship between ACTH pulse secretion and cortisol pulse. In addition, CAH patients often show a decreased sensitivity of the central nervous system to the feedback inhibition of glucocorticoids. The decreased sensitivity of glucocorticoids further reduces the central action of glucocorticoid treatment, while peripheral sensitivity to glucocorticoids can be maintained, leading to side effects such as growth suppression.

　　Even though ACTH secretion can return to normal in CAH patients, androgen synthesis cannot return to normal because the steroidal intermediates that are shunted into the androgen pathway after the 21-hydroxylase blockage in the adrenal hormone synthesis process are all more than normal. To prevent excessive endogenous androgen secretion in CAH, it is necessary to reduce the speed of cholesterol side chain cleavage to below normal levels, thereby avoiding excessive accumulation of 17-hydroxyprogesterone and shunting into the androgen pathway. To suppress the speed of cholesterol side chain cleavage to below normal levels through negative feedback, it is necessary to use glucocorticoids in doses exceeding physiological levels. Traditional treatment is difficult to maintain a balance between hypercortisolism and hyperandrogenemia. In patients receiving treatment, hyperglycorticoidism is often observed, such as obesity, decreased growth rate, or other clinical features of Cushing's syndrome. Symptoms and signs of hyperandrogenemia include: virilization in women, precocious puberty in men, and short final height in both women and men. Another complication in children is central precocious puberty, delayed diagnosis of CAH, and patients with poor treatment of adrenal androgen secretion are more prone to true precocious puberty, which makes the problem of excessive adrenal androgen secretion more complex.

　　Patients with CAH often have an adult height lower than normal, which may be due to hypercortisolism (iatrogenic), or hyperandrogenemia indirectly affects the growth axis through hyperestrogenemia, or both of these reasons act together. Retrospective studies show that the final height of patients receiving treatment is relatively independent of the control of adrenal androgen levels. Theoretically, patients treated with hydrocortisone at the closest physiological dose have the worst control of adrenal androgen levels and bone maturation speed, so the final height may decrease due to premature closure of the skeleton. However, on the other hand, excessive glucocorticoids can also suppress growth. Adjusting the dose continuously and finding the best balance according to different individuals is the art of medication. Randomized controlled prospective crossover trials have shown that patients treated with hydrocortisone at 15mg/(m2·d) have a lower possibility of bone suppression than those treated with 25mg/(m2·d).

　　Once growth and development are completed, female CAH patients continue to face issues such as hirsutism, amenorrhea, and infertility. Classic CAH girls often have delayed menarche, similar to ovarian dysfunction in PCOS. Androgens can directly hinder follicle maturation or affect the hypothalamic-pituitary-gonadal axis; however, irregular menstruation, anovulation, and infertility in CAH girls are not always caused by untreated hyperandrogenism. Increased adrenal pregnenolone secretion and increased estrogen levels from adrenal sources are observed in CAH girls. Ovarian dysfunction in CAH girls may also be due to abnormalities at the hypothalamic, pituitary, or ovarian levels.

　　Due to the complex treatment of CAH patients and the existence of the aforementioned many problems, current efforts are dedicated to exploring some new treatment methods. The goal of the new treatment plan is to achieve normal growth and development for CAH children and to maximize the quality of life for adult CAH patients. For example, since estrogen, rather than androgen, is the cause of bone maturation and early closure of the epiphyses, reducing estrogen production can prevent or improve dwarfism to some extent. Some scholars are studying the use of aromatase inhibitors (blocking the conversion of androgens to estrogens) and androgen antagonists (reducing the degree of masculinization) to assist in the treatment of 21-hydroxylase deficiency. These drugs can reduce the dosage of glucocorticoids without further developing female masculinization or accelerating bone maturation, and have achieved preliminary results. Adrenal resection is another controversial treatment method. Some experts suggest that women with severe masculinization and salt-losing (allelic genotypes with enzyme activity of O) should undergo adrenal resection during genital reconstruction surgery (within 1 year of age). The rationale for this method is that women must undergo treatment to suppress the adrenal glands throughout their lives, and surgical removal of the adrenal glands can be curative. Treatment with replacement doses of hydrocortisone and aldosterone after adrenal resection is simpler than using glucocorticoids to suppress the adrenal glands. Additionally, some precursor substances that increase in some types of CAH can cause sodium retention, making treatment more difficult, especially during adrenal crisis. Opponents argue that recent studies on cancer patients show that some adrenal androgens are beneficial to women. Therefore,剥夺 women of all adrenal androgens due to adrenal resection is not entirely beneficial, and other treatment methods should continue to be studied.

　　The latest treatment method for CAH is gene therapy. Some research centers are currently testing this treatment method in animal models.

　　3. Reconstruction Surgery of External Genitalia Before all treatments for genital malformations were aimed at enabling patients to have normal sexual function and fertility. Therefore, 46,XX children with simple male pseudohermaphroditism are usually raised as females, and 46,XY children are raised as males. The initial surgical method was to improve the appearance of the external genitalia at an early stage in life (clitoral hypertrophy is the standard), and later (usually after puberty) make the genitals more suitable for sexual intercourse. Some patients are not satisfied with the surgical results, and the proportion of male sexual orientation among these patients is increasing. Now, the recommended improved surgical method is to perform a one-time complete reconstruction surgery within one year and avoid damaging the sensitive clitoris tissue (clitoroplasty). Because the patients who undergo this surgery are still very young, the treatment results of these new surgical methods cannot be fully evaluated.

　　The goal of treatment for CAH patients now is to achieve the best psychological treatment results while considering reproductive ability. Doctors should provide detailed information about each treatment method to the families of patients, allowing them to make the final decision. In addition, some scholars suggest determining the gender of care in the neonatal period without surgery but until the child is old enough to decide his or her gender preference. There is currently not enough evidence to determine whether this method will cause psychological trauma or whether it will cause less trauma than the traditional surgical method.

　　II. Prognosis

　　1. Adrenal Crisis The only threat to life is adrenal crisis, which can occur in untreated salt-losing infants.

　　2. The impact on growth Due to increased androgen secretion and rapid growth before treatment, bone maturation is accelerated, leading to early closure of the epiphyses, which can result in short stature. Non-edematous male children are prone to delayed diagnosis and short stature, and excessive use of corticosteroids can also cause short stature.

　　3. The impact on sexual development and fertility The main impact on sexual development and fertility is caused by inappropriate treatment.

　　If this condition is treated appropriately in the early stage, the prognosis is good, and normal growth and development as well as fertility can be achieved.