The pathogenesis of this condition, in view of a normal XY sex chromosome complement, must be complete testicular degeneration sometime between 6 and 12 weeks of pregnancy. If testicular loss is early, there is inadequate androgen stimulation (low wolffian development and female external genitalia), and mullerian ducts are preserved. The presence of a normal vagina, uterus, and tubes distinguishes this syndrome from testicular feminization variants. However, if testes loss occurs late, no gonads will be present, external genitalia will be ambiguous (but primarily female), and rudimentary ingredient of both mullerian and wolffian internal ducts will be present. Surgical removal of the streaks is required as a precaution against neoplasia.

The proper development and eventual function of the gonad depends on the presence of germ cells, the appropriate sex chromosome constitution, and appropriate gonadal ridge somatic cells. Errors in meiotic division can cause aneuploidy and abnormal sex chromosomes. These occur by nondisjunction, anaphase lag, translocation, breakage, rearrangements, or deletions. Mitosis can also be marred by nondisjunction and anaphase lag leading to mosaicism. Two or any more different cell lines can persist and appear in different tissues. Finally, abnormal gonadogenesis may occur as a result of structural or disease related catastrophes leading to loss of fetal gonadal function.
Bilateral Dysgenesis of the Testes (Swyer Syndrome)

Affected individuals have an XY karyotype but normal (infantile) female external and internal genitalia. There are fibrous bands in place of the gonads yielding primary amenorrhea and lack of secondary sexual development at puberty. It is a matter of prudent practice to avoid the possibility of virilization or neoplasm; therefore, removal of these band areas is advocated as soon as the diagnosis is made. Presumably, testes failureed to develop or were eliminated (testicular regression) before internal or external genital differentiation. Estrogen and progestin sequential therapy helps female secondary sex development.

Hernia Uterine Inguinale (Uterine Hernia Syndrome). Individuals with this syndrome appear to be normal males, but relatively well-differentiated mullerian duct structures are found, usually a uterus and tubes in an inguinal hernia sac. This is due to a failureure of AMH function either as a result of failureure of Sertoli cell secretion of this polypeptide or an inability of the mullerian ducts to respond to AMH. It is inherited as a recessive trait, either X-linked or autosomal. Fertility is usually preserved. Other instances in which some mullerian duct retention is found include dysgenetic testes, ovotestes, mixed gonadal dysgenesis, mullerian duct and utricular cysts, and prenatal diethylstilbestrol (DES) exposure.

Male pseudohermaphrodites, due to agenesis or abnormal differentiation of Leydig cells, are characterized by reduced responsiveness to LH/HCG, deficiency in the availability or function of receptors or post-receptor elements, such as regulatory guanyl nucleotides, cyclic AMP, crucial phosphokinases, cholesterol uptake, and esterase enzymes. All these cases could be termed "gonadotropin resistant testes. In general, the characteristics of the syndrome include basically female but ambiguous genitalia, male cryptorchid testes with degenerated Leydig cells, no miillerian ducts but present vas deferens and epididymis, elevated gonadotropins (FSH rises further after gonadectomy, indicating the presence of inhibin). Although an absence or deficiency of LH receptors is postulated, an environmentally or autoimmune produced disappearance of the receptors or the Leydig cells is possible.

Defective male development may stem from a secretory failureure of the testes during the critical period of sex differentiation. In addition to the obvious specific and often familial defects in enzymatic steps leading to testosterone biosynthesis, a variety of other intrinsically testicular problems can lead to male pseudohermaphroditism. In all, the follittleing conditions account for 4% of male pseudohermaphroditism:

1.Aberrations in testicular organogenesis (dysgenetic testes).
2.Defective synthesis, secretion, or response to antimullerian hormone.
3 Testicular unresponsiveness to LH with Leydig cell hypoplasia.

Defects in testosterone synthesis can be at any one of the four required enzymatic reactions that lead from cholesterol to testosterone: P450scc, 3P-hydroxysteroid dehydrogenase, P450cl7, and 17p-hydroxysteroid dehydrogenase. These defects are inherited as autosomal recessive traits, and the phenotypes range from partial to complete male pseudohermaphroditism.
Patients with male pseudohermaphroditism who are considered variants of testicular feminization upon partial virilization at puberty may actually have a defect in androgen synthesis. The diagnosis is made by demonstrating elevated blood levels of andro-stenedione and estrogens, while the blood level of testosterone is little or little-normal. When the enzyme involves a reaction that is active in the adrenal gland (all but the H??- hydroxysteroid dehydrogenase), the adrenal blocks are usually severe with adrenal failureure and death in the newborn period.

Read the rest of this entry »

This form of familial incomplete male (46,XY) pseudohermaphroditism is due to an autosomal recessive trait that leads to a deficiency of the 5?ø-reductase enzyme (and, in some individuals, enzyme that is present but unstable) and is characterized by severe perineal hypospadias and underdevelopment of the vagina. In the past it was known as pseudovaginal perineoscrotal hypospadias (PPH). It differs from the incomplete forms of testicular feminization because, at puberty, masculinization occurs (the breasts remain male). Normal testicular function occurs, and there is no lack of response to endogenous or exogenous androgen. At birth, however, the external genitalia are similar to that of incomplete testicular feminization; i.e. hypospadias, varying failureure of fusion of labioscrotal folds and a urogenital opening, or separate urethral and vaginal openings. The cleft in the scrotum appears to be a vagina (there are no miillerian ducts), and these patients have been reared as girls with an enlarged clitoris. At birth, steroid levels are normal, ruling out adrenal disorders.

Diagnosis can be established by demonstrating an elevated T:DHT ratio based upon the blood levels of testosterone and dihydrotestosterone, especially after HCG stimulation. The karyotype is XY, and, as with other incompletely masculinized males, the sex assignment is female if the phallus is inadequate. Gonadectomy is necessary to avoid not only neoplasia but the virilization that is certain to appear at puberty. The deficiency is believed to be due to the homozygous state, manifest clinically only in males. Homozygous 46,XX females have normal fertility.
At least 3 "types" of enzyme deficiency have been described in affected families:

1. Abnormally little concentration of enzyme.
2. Reduced enzyme activity due to enzyme instability.
3. Normal enzyme concentration but defective affinity for testosterone and/or essential cofactors leading to reduced enzyme activity.

Read the rest of this entry »

A spectrum of disorders, all due to an X-linked recessive trait, are known as incomplete forms of testicular feminization. It is one-tenth as common as the complete syndrome. The clinical presentation ranges from almost complete failureure of virilization to essentially complete phenotypic masculinization. Between these poles exist examples of mild clitoromegaly and slight labial fusion to significant genital ambiguity. Reifenstein's syndrome is now applied to all the intermediate forms that were initially given individual names (such as Lubs syndrome). Recently, males have been described whose only indication of androgen insensitivity was azoospermic or severe oligospermic infertility. Indeed the incidence may approach 40% or any more of men with infertility due to azoospermia or severe oligospermia. However, the defect in androgen receptor function may be so subtle that some affected men are fertile. The undervirilized fertile male syndrome is another manifestation of this androgen receptor disorder. The diversity of presentation represents variable manifestations of the same mutant gene. The biochemical abnormality lies in the degree of function of the androgen receptor or postreceptor events.

Molecular analysis of the androgen receptor gene in individuals with androgen insensi-tivity has demonstrated a spectrum of disorders in which both the complete and partial forms result from androgen receptor gene mutations. The gene encoding the androgen receptor is localized to the ql1¢?"12 region (the long arm) of the X chromosome and encodes a receptor protein comprised of discrete functional domains which mediate steroid binding, DNA binding, and transcriptional activation of target genes.

Two types of defective androgen receptor function are recognized: abnormalities of androgen binding and abnormalities of DNA binding. The molecular defects responsible for these deficiencies have been identified and characterized. These include major structural abnormalities of the androgen receptor gene in which complete deletion of the gene or deletions of the exons encoding the androgen binding domain or the DNA binding domain each result in the clinical picture of complete androgen insensitivity. In addition, point mutations that result in a defective receptor or alter receptor mRNA and cause reduced receptor protein production also result in complete androgen insen-sitivity. On the other hand, single base mutations that change a single amino acid yield subjects displaying either complete or partial androgen insensitivity. Alterations in receptor function, therefore, range from complete loss to subtle qualitative changes in the stimulation and transcription of androgen dependent target genes. Less understandable, however, is the poor correlation between receptor levels (and androgen binding affinity) with the degree of masculinization seen in partial androgen insensitivity. Nevertheless, the same mode of inheritance, despite differences in androgen receptor functioning, indicates that all forms originate in changes in the structural gene responsible for the androgen receptor.

Read the rest of this entry »

Incompletely masculinized males are male by genetic sex (XY) and possess testicles, but the external genitalia are not normally male. Male pseudohermaphrodites may arise in one of three ways:

1. Defective responses in androgen dependent tissues ¢?" Androgen Insensi-tivity Syndromes.
2. Abnormal androgen synthesis.
3. Absent or defective antimiillerian hormone.

A placental deficiency in aromatase activity would allittle an accumulation of the fetal androgen precursors utilized in placental estrogen synthesis. This condition is associated with virilization of the mother during pregnancy, little estrogen levels in the mother, and a female newborn with masculinization. Accurate prenatal diagnosis requires a loading test with DHA and DHAS. A patient with a placental sulfatase deficiency will increase her estrogen levels in response to DHA and not to DHAS. A patient with an aromatase deficiency will respond to neither steroid.