Female pseudohermaphroditism refers to children with a chromosomal karyotype of 46XX, ovaries as gonads, but male external genitalia manifestations such as clitoral enlargement, hypospadias, and fused labia majora. The cause is due to excessive androgen exposure in the fetus. Male pseudohermaphroditism involves children with a male chromosomal karyotype of 46,XY, and gonads that are testes or absent, with more complex underlying causes.

bubble_chart Etiology

1. Female Pseudohermaphroditism:

1. Congenital adrenal hyperplasia, when there is a deficiency of 21-hydroxylase or 11-hydroxylase in corticosteroid synthesis, female virilization occurs.
2. During pregnancy, if the mother develops virilizing tumors, such as ovarian cysts, luteinoma, or arrhenoblastoma that secrete excessive androgens, or benign adrenal tumors, the mother may exhibit virilization, and the fetus may also develop virilized external genitalia.
3. The use of androgen-like drugs by the mother during pregnancy can also cause virilization in female fetuses.

2. Male Pseudohermaphroditism:

(1) Gonadal Dysgenesis

In cases of complete or partial gonadal dysgenesis with XY sex chromosomes, there may be H-Y antigen-positive complete or partial gonadal dysgenesis and poor testicular differentiation. This may be due to the inability to release H-Y antigen or a lack of functional H-Y antigen.

When there is a deficiency of Müllerian inhibiting factor and embryonic testosterone secretion, 46,XY males may exhibit female internal genitalia and bilateral streak gonads. Hereditary gonadal dysgenesis can be X-linked recessive or dominant (see Turner syndrome section for details).

(2) Congenital Anorchia (Agenesis)

Leydig cell hypoplasia, where the testes lack Leydig cells, may result in the presence of seminal vesicles and hyalinized vas deferens. Such patients show little or no response to exogenous hCG.

In males with isolated Müllerian inhibiting factor deficiency, varying degrees of fallopian tubes and uterus may develop, but male puberty appears normal.

(3) Gonadotropin Deficiency

Gonadotropin deficiency can lead to abnormal sexual differentiation, as seen in Kallmann syndrome, where patients lack gonadotropins and have anosmia and micropenis. During fetal development, the lack of LH stimulation reduces testosterone secretion, preventing proper penile development in utero. Additionally, LH or/and FSH may lack bioactivity, resulting in incomplete virilization of external genitalia. Such cases may respond to hCG stimulation.

(4) Testicular Enzyme Deficiency

Deficiency in testosterone-synthesizing enzymes reduces embryonic testosterone production, leading to various developmental defects in male internal genitalia and incomplete virilization of external genitalia. At birth, ambiguous genitalia may be present. Complete deficiency of enzymes such as 3β-hydroxysteroid dehydrogenase or 17-hydroxylase may result in female external genitalia, while partial deficiency may manifest as micropenis, bifid scrotum, or hypospadias.

(5) End-Organ Androgen Insensitivity

This may occur due to androgen receptor binding defects, presenting as classic testicular feminization syndrome. Blood testosterone and dehydroepiandrosterone levels are normal or elevated, estradiol is increased, and LH secretion is elevated, leading to gynecomastia and primary amenorrhea in males.

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Testosterone cannot be reduced to dihydrotestosterone, preventing the complete differentiation and development of external genitalia into male characteristics. This manifests as a newborn with a small penis and urogenital sinus, featuring two openings at the base of the penis: one for the urethra and the other a blind vaginal pouch. Most patients are raised as females, but during puberty, some male secondary sexual characteristics emerge. Laboratory tests reveal an abnormally high testosterone/dihydrotestosterone ratio. This condition is inherited as an autosomal recessive trait.

bubble_chart Diagnosis

In male pseudohermaphroditism, the gonads may be completely undeveloped, forming a cord-like structure; or there may be testicular tissue while the internal genitalia are entirely female, with fallopian tubes, uterus, and a blind-ending vagina; or the development may be partially male. The external genitalia can appear entirely female, predominantly male, or exhibit varying degrees of intersex characteristics. The testicular tissue may remain undescended in the abdominal cavity, or be located in the inguinal region or within the labia majora of female external genitalia.

For infants with ambiguous genitalia, an early diagnosis of the disease cause is essential to determine the child's sex as soon as possible. Generally, gender reassignment treatment should be completed before the age of 2. The examination methods include the following:

1. Chromosomal karyotype: First, perform a fluorescent Y-body test on a buccal mucosal smear, followed by chromosomal karyotype analysis, which is a crucial step in determining sex.
2. Phenotypic sex: Internal genitalia should be examined under anesthesia to understand the intra-abdominal structure, which provides guidance for sex assignment decisions.
3. Disease cause analysis: Congenital enzyme deficiencies can be considered in conjunction with adrenal cortical function and clinical manifestations, aiding in the diagnosis of virilization in females. Daily injections of hCG 3000u/m2 for 3–5 days, followed by measurements of testosterone and its precursors, can help diagnose enzyme defects. Elevated urinary 17-ketosteroids may be observed, along with measurements of plasma testosterone, estradiol, pituitary gonadotropin concentrations, or dihydrotestosterone levels. Alternatively, an intravenous bolus of LHRH (50–100μg) can be administered to measure LH, FSH, and sex hormones to assess the hypothalamic-pituitary-gonadal axis function, providing further evidence for disease cause diagnosis.
4. Fibroblast testing for androgen receptors.
5. Intravenous pyelography and laparoscopy.
6. If necessary, exploratory laparotomy may be performed, and dysplastic gonads can be promptly removed to prevent malignancy.

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bubble_chart Treatment Measures

Surgical intervention is often necessary to establish an appropriate gender. The choice between establishing a male or female gender should be based on the diagnosis of the disease cause and the anatomical feasibility, aiming for the child to naturally achieve sexual maturation or with the aid of hormone replacement therapy, without necessarily considering the karyotype of cellular chromosomes. Additionally, psychological gender inclination should also be taken into account. Children over the age of 2 already exhibit a distinct psychological gender, influenced by fetal testosterone and gradually formed under the influence of the higher central nervous system postnatally. This should be referenced when selecting the gender. For example, in cases of testicular feminization syndrome, where peripheral tissues do not respond to testosterone despite normal testosterone secretion by the testes, the female gender should be chosen when establishing the gender.

Once the gender to be established is selected, appropriate surgical procedures should be performed. In cases of female virilization, the clitoris should be removed, and the surgery should be performed as early as possible. Repairing hypospadias is most suitable before the child starts school. For undescended testes, surgery is advisable around the age of 5. In cases of testicular feminization, the testes should be removed.