Testicular feminization

　　1. Etiology

　　Research on fibroblasts from patients' genital skin collected in the 1970s found that the fibroblasts had androgen resistance and could not bind to androgens. Subsequent studies have shown that the serum and nuclear binding ability of androgen-receptor complexes in some patients' genital skin fibroblasts is normal, but the androgen-receptor complex is unstable: increased dissociation rate, defective up-regulation of the receptor, decreased affinity for ligand binding, short retention time of ligands in the nucleus, and instability to changes in temperature and other conditions.

　　2. Pathogenesis

　　The AR gene is located on Xq11～12, encoding 910～919 amino acids, with 8 exons. Exon 1 is at the N-terminus and is related to the gene's transcriptional function. Exons 2 and 3 each encode a zinc finger, forming a highly conserved DNA-binding domain. After the receptor binds to the ligand, the masked heat shock protein is released, binding to hormone response elements (transcriptional enhancer nucleotide sequences), activating the transcriptional process. Exon 4 is the hinge region, containing a nuclear localization signal, which is essential for the receptor-ligand complex to be fixed in the nucleus. Exons 5 to 8 are the androgen-binding domain, which are highly affinity binding sites for androgens. After binding to androgens, they cause receptor conformational changes, phosphorylation, dimerization, nuclear localization, and activation of transcription.

　　The general rule is that the clinical manifestations of patients are related to the severity of androgen receptor (AR) defects. Those with completely non-binding receptors to androgens almost have no androgenic manifestations, while those with partial binding ability may have partial androgenization. AR gene mutations most frequently occur in exons 5 to 7, with arginine accounting for only 4% of the total amino acid residues of the receptor, but arginine mutations account for 40% of all mutations. The four arginine residues at positions 774, 831, 840, and 855 and the valine residue at position 866 are the sites with the highest mutation probability. AR gene mutations result in the loss or reduction of the receptor's ability to bind to androgens, or instability of the receptor-ligand complex, which is easily dissociated under the influence of temperature or other environmental factors, resulting in the inability of androgens to exert normal physiological effects in target tissues.

　　Complications mainly include ambiguous genitalia, small penis, perineal urethral fistula, blind pouch vagina, absence or underdevelopment of the prostate, testes located in the inguinal canal or labia pudenda fold, underdeveloped testes without normal sperm, and inability to reproduce. Secondly, breast enlargement may occur, presenting a feminized appearance. And other secondary sexual characteristics changes due to decreased androgens and relative increase in estrogens, such as: no beard, no pubic hair, no Adam's apple, etc.

　　The patient's karyotype is normal male type (46, XY), the gonads are functional testes, the external genitalia are of normal female type, the labia majora are underdeveloped, blind pouch vagina, 2/3 of patients have no uterus and fallopian tubes, and the remaining 1/3 only have remnants. The epididymis and vas deferens are generally absent. In rare cases, there may be underdeveloped Wolffian duct derivatives, the testes are located in the labia majora, inguinal canal, or abdominal cavity. The histological examination of the testes is normal before puberty, but the seminiferous tubules shrink and spermatogonia become sparse after puberty, with no spermatogenesis. Leydig cells show adenomatous hyperplasia, and the testes have a tendency to develop malignant tumors, with an incidence rate of 4% to 9% in adulthood.

　　During puberty, female secondary sexual characteristics develop, with breast development similar to normal females, female body shape, sparse pubic and armpit hair, about 1/3 of patients have no pubic and armpit hair growth at all, the clitoris is small or normal, the labia minora are underdeveloped, primary amenorrhea, and normal intelligence.

　　The characteristic changes in the plasma hormone profile are an increase in LH and testosterone levels, but this is not necessarily manifested in infancy. During puberty, the feedback regulatory effect of androgens on the hypothalamus-pituitary axis is lost, leading to an increase in the frequency and amplitude of LH pulses, an increase in LH secretion, and stimulation of Leydig cells to synthesize and secrete more testosterone. The testes secrete more E2, and in addition, testosterone and △4A are converted to more E2 in peripheral tissues by aromatase, resulting in an increase in plasma E2 concentration, causing feminization under hyperandrogenism. FSH levels are normal or slightly elevated, and due to the stimulation of E2, SHBG levels increase. DHT levels are generally lower than normal, as testosterone is reduced to DHT by 5α-reductase in target tissues. If the patient undergoes bilateral orchiectomy, plasma LH and FSH levels will further increase, indicating that under conditions of androgen resistance, E2 has a feedback regulatory effect on gonadotropins.

　　This disease is an X-linked recessive genetic disease with no specific preventive information. Early detection and early treatment are the key to prevention and treatment. Regular prenatal examinations should be performed during pregnancy, and if any abnormalities are found, further chromosome tests can be performed to determine whether the disease is present. Once diagnosed with the disease, pregnancy must be terminated immediately. Early detection of the disease is of great significance for preventing the birth of disease-affected children.

　　Characteristic changes in plasma hormone profiles: increased levels of LH and testosterone, normal or slightly increased levels of FSH, and generally lower levels of DHT than normal. Prepubertal patients can optionally undergo HCG stimulation tests. Regularly perform ultrasounds, monitor testicles and breast development, and conduct chromosome and genetic testing.

       Consume adequate high-quality protein. The main sources of high-quality protein are animal proteins such as poultry, eggs, fish, meat, and soybean protein. Eat fresh vegetables and fruits, avoid eating cold, spicy, and irritating foods, and avoid eating too much food containing estrogens or androgens.

　　1. Treatment

　　Children diagnosed before puberty should have regular ultrasound monitoring of testicular development. After the breasts are fully developed during puberty, the testicles should be removed, and then estrogen replacement therapy should be given. For those with abnormally short vaginas, mold expansion may sometimes be sufficient to enlarge and lengthen the vagina. If mold expansion surgery fails, vaginal shaping surgery is required.

　　2. Prognosis

　　Testicles have a tendency to develop malignant tumors, and the incidence rate after adulthood is 4% to 9%.