First, etiology
The main reasons for male pseudohermaphroditism are: first, incomplete androgen action, where testosterone synthesis is normal, but the action of androgens appears abnormal. Second, defects in the synthesis of testicular hormones, when stromal cell differentiation is impaired or enzymes have hereditary defects, it can lead to incomplete differentiation of the male reproductive tract and external genitalia of the 46,XY fetus, thus resulting in male pseudohermaphroditism. Third, structural abnormalities or gene mutations of the Y chromosome, or other chromosomal abnormalities leading to incomplete gonadal development.
Second, pathogenesis
The pathogenesis of male pseudohermaphroditism is related to defects in the following androgen action links: decreased androgen production, such as 3β-HSD, 17β-HSD, and 5α-reductase defects; AR gene mutation, causing a decrease in AR number and dysfunction; 5α-reductase defect, unable to convert testosterone to dihydrotestosterone (DHT); abnormal androgen metabolism in target cells, etc., among which AR mutation is the main cause of complete and incomplete testicular feminization.
The human androgen receptor (AR) gene is located at Xq11-12, and more than 200 AR gene mutations have been found, of which gene single-base mutations account for more than 90%. AR gene mutations cause a decrease in AR binding affinity and DNA structure abnormalities, including complete gene deletion, deletion of exons encoding the androgen binding site or DNA binding site, and point mutations, etc.
1. Complete Testicular Feminization:The chromosomal sex of patients with testicular feminization is 46,XY, and it often presents as a familial disease, with family analysis indicating X-linked recessive disease. A mutation occurs in the androgen receptor gene near the centromere on the long arm of the X chromosome, resulting in a lack of specific proteins that bind to androgens in target cells. Although there is biologically active androgen, it does not bind to it and loses its reactivity. The hypothalamus is also insensitive to androgen and loses the negative feedback mechanism, leading to the pituitary gland secreting a large amount of gonadotropin to stimulate the proliferation of stromal cells. It has now been confirmed that the androgen receptor gene is located at Xq11-12, with a length greater than 90kb, having 8 exons, where exon 1 occupies the entire amino terminal and has the function of initiating transcription. Most patients with testicular feminization are gene point mutations or base pair deletions, leading to defects in the androgen receptor. This causes the male external genitalia to be blocked in transformation and to differentiate into the female phenotype, resulting in the onset of the disease.
Such patients are insensitive to testosterone due to the lack of androgen receptors in the target tissue, and it is the most common type among male pseudohermaphroditism, with an incidence of about 1:120,000 in newborns. There is a family history of the disease. The testes look like predevelopment cryptorchidism under the microscope, the seminiferous tubules become thin, filled with Sertoli cells and immature spermatogenic cells, spermatogenesis is impaired, but stromal cells still proliferate, and this kind of testis is prone to malignancy.
2. Incomplete testicular feminization:Also known as 5α-reductase deficiency, genetic research has confirmed that the karyotype of patients is 46,XY. The parents have normal phenotypes, and the incidence increases with consanguineous marriage. Family analysis can usually be traced back to a common ancestor with the disease. Both sexes exhibit abnormal enzyme defects, and both sexes have carriers of normal genes, supporting autosomal recessive inheritance.
It is known that in the target tissues sensitive to androgens, testosterone is converted into dihydrotestosterone by the action of 5α-reductase and exerts its effect; testosterone and dihydrotestosterone are indispensable in the process of male differentiation of the internal reproductive organs. If the male fetus lacks 5α-reductase in the early stage of development, there will be a lack of dihydrotestosterone in the target tissue, leading to abnormal development of the external genitalia, often presenting as female or indistinguishable between male and female.
Based on the results of 5α-reductase activity measurement, the disease can be divided into two types: enzyme deficiency and enzyme instability. Gene analysis results show that the cause of enzyme activity deficiency is due to mutations and deletions in the gene, or the inability of the enzyme to bind to testosterone, or the impact on the function of the enzyme; or mutations outside the gene encoding the enzyme affect the expression of the gene.