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Placental Aromatase Deficiency

Placental aromatase converts C19 androgens of fetal adrenal origin into estrogens. A deficiency in this enzyme exposes the mother and the female fetus to these androgens, and both become virilized. Development of the uterus and ovaries is unaffected. Missense mutations in the gene encoding aromatase (P450 arom) have been identified placental aromatase deficiency. Endocrine abnormalities persist beyond birth and are characterized by high FSH and low estriol during infancy in affected females and by high FSH and LH with multicystic ovaries at adolescence.

Partial androgen insensitivity syndrome has the same phenotype as 17beta-hydroxysteroid dehydrogenase deficiency, but the hCG-stimulated ratio of androstenedione to testosterone is normal, and the levels of testosterone reached are normal or high. Serum LH may be normal or elevated. Usually, at least one gonad is palpable. The degree of virilization varies considerably within families (Reifenstein syndrome). There is no uterus. Left in situ, the testes visibly enlarge at puberty, and the patient undergoes considerable virilization but inevitably experiences gynecomastia. AR-binding studies in cultured genital skin fibroblasts give low or normal results. AR gene mutations (mostly in exons encoding the steroid-binding domain) have been found, but the proportion of cases with no mutation detected remains disconcertingly high. Therefore, PAIS frequently is a presumptive diagnosis.

Leydig cell hypoplasia or agenesis occurs in a familial form. In several cases, an inactivating mutation in the gene encoding LH receptor has been demonstrated. The phenotype in XY subjects is similar to that in XY gonadal dysgenesis; the external genital genitalia are either female or ambiguous, gonads are usually not palpable, the serum gonadotropin levels are elevated, and testosterone levels are low. Unlike in gonadal dysgenesis, patients with this disorder have no mullerian structures. The inheritance pattern is probably autosomal recessive. Most cases described have been 46,XY, but, in one family, the 46,XX sister had primary ovarian failure, and an LH receptor gene mutation.

Patients with the persistent mullerian duct syndrome have normal male genitalia, and the testes are usually undescended. The presence of mullerian structures (uterus and fallopian tubes) is often discovered by the surgeon at operation. The testes secrete normal amounts of testosterone and should therefore never be removed. The cause of the condition in 50% of cases is a mutation in the gene for MIS and, in the other 50%, a mutation.