Placental Aromatase Deficiency

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Overview

Aromatase deficiency is an autosomal recessive disorder in which there is a decrease or absence in the level of aromatase in the body which leads to impairment in the conversion of androgens to estrogen. This is due to a genetic mutation in the CYP19A1, a subtype of Cytochrome P450. Patient affected by this disease typically presents with maternal virilization, amenorrhea in puberty in females. Males are rarely affected.

Historical Perspective

• The evidence of the disease goes back to year 1991, when the first case of aromatase deficiency occurred in 24year old primigravida and the female fetus showed pseudohermaphroditism.
• The majority of affected individuals were women during the third trimester of pregnancy manifesting with maternal virilization resulting in hirsutism and acne.

Classification

• There is no established system for the classification of placental aromatase deficiency.

Pathophysiology

• CYP19A1 gene is responsible for the production of the enzyme aromatase, which converts androgens to different forms of estrogen.
• Mutation is inherited in an autosomal recessive mode.
• Estrogen is involved in sexual development in females prior to birth and the levels peak during pregnancy. Mutation in the CYP19A1 gene leads to deficiency or absence of activity of aromatase.
• As a result, there is a decrease in the production of estrogen due to lack of conversion of androgens to estrogen and increase in testosterone and androstenedione levels.
• In pregnant women , excess androgens cross the placenta and enter into the maternal circulation leading to virilization. Female fetuses who are affected have ambiguous genitalia while males develop osteoporosis.

Causes

• CYP19A1 gene mutation primarily causes placental dromatase deficiency and the placenta is not capable of converting androgenic precursors of estrogen to estradiol. Mutations on exons 3,5 and 9 have been reported.
• Studies suggested that it is more prevalent in consanguineous marriages and both are heterozygous carriers of the mutation.

Differentiating Any Disease from other Diseases

• Congenital adrenal hyperplasia can be considered as a differential in female patients.

• While, in male patients, it should be differentiated from:

• • 5 alpha-reductase deficiency, which the levels of testosterone and estrogen are normal. (testosterone is normal or elevated? please add a reference for this statement)
  • Estrogen resistance syndrome
  • 46,XY disorder of sex development due to isolated 17, 20 lyase deficiency.
  • Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency.
  • Congenital hypogonadotropic hypogonadism.
  • can be considered as the differential diagnosis of Placental Aromatase Deficiency.???????

Epidemiology and Demographics

• Placental Aromatase Deficiency is a rare autosomal recessive disorder.
• The prevalence is unknown .
• There are only few cases that have been described in the literature.
• First case in male was reported in 1995.

Risk Factors

• The risk factors evident with placental aromatase deficiency includes placental ischemia and preeclampsia .

Screening

• There is insufficient evidence to recommend routine screening for Placental aromatase deficiency.

Natural History , Complications and Prognosis

• Placental aromatase deficiency is a rare entity.

• Defective synthesis of estrogen in aromatase deficiency may result in :

• Delayed Puberty
• Insulin resistance
• Polycystic ovary syndrome
• Bone disorders like osteoporosis

• In patients with Aromatase deficiency lifetime hormone replacement therapy is mandatory. We can see osteoporosis as an outcome in male patients with late diagnosis, and these skeletal defects tend to remain even after hormonal treatment and sometimes require surgical correction. Moreover, the effects on glucose and lipid metabolism like adiposity and reproductive defects such as infertility are also not corrected by estradiol treatment.

Diagnosis

Diagnostic Study of Choice

• There are no established criteria for the diagnosis of Placental Aromatase Deficiency. The diagnosis may be made clinically.
• Genetic analysis and location of a mutation in the CYP19A1 gene may be done for the confirmation of the Placental aromatase deficiency.

History and Symptoms

• The hallmark of Placental Aaromatase Deficiency is maternal virilization. A positive history of hirsutism, deepening of voice and cystic acne is suggestive of Placental Aromatase Deficiency.

Physical Examination

• Physical examination of patients with Placental Aromatase Deficiency is usually remarkable for virilization and masculinization in mother during pregnancy, clitoromegaly, and primary amenorrhea in girls during childhood and puberty.
• Males are usually normal. They may be tall and have reduced bone age.

Laboratory Findings

• An elevated concentration of serum testosterone and reduced levels of estrogen is diagnostic of Placental Aromatase Deficiency.
• In aromatase deficient girls, basal and GnRH-stimulated FSH levels are elevated.
• Urinary levels of androgens are usually normal or elevated.

Electrocardiogram

• There are no ECG findings associated with Placental Aromatase Deficiency.

X-ray

• An x-ray may be helpful in the diagnosis of osteoporosis which manifests mainly in males. Findings on an x-ray suggestive of osteoporosis include loss of bone mass, cortical thinning, and minor fractures.

Echocardiography or Ultrasound

• Ultrasound may be helpful in the diagnosis of polycystic ovary syndrome which occurs as a sequalae in female patients.

CT scan

• There are no CT scan findings associated with Placental Aromatase Deficiency.

MRI

• There are no MRI findings associated with Placental Aromatase Deficiency.

Other Imaging Findings

• There are no other imaging findings associated with Placental Aromatase Deficiency.

Other Diagnostic Studies

• There are no other diagnostic studies associated with Placental Aromatase Deficiency.

Treatment

Medical Therapy

• Hormone replacement therapy like oral conjugated estrogen may be useful to stimulate pubertal growth spurt, breast development and induce menstruation in females. This may also lead to resolution of cystic ovaries and promote bone growth .
• After 14 years of age, combination oral contraceptive may be used.
• Treatment options for males include transdermal estradiol that helps in increasing bone mineral density.

Surgery

• Surgical intervention may be an option for ambiguous genitalia.

Primary Prevention

• There are no established measures for the primary prevention of Placental aromatase deficiency.

Secondary Prevention

• There are no established measures for the secondary prevention of Placental aromatase deficiency.