Placental Aromatase Deficiency: Difference between revisions
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==[[Placental aromatase deficiency historical perspective|Historical Perspective]]== | ==[[Placental aromatase deficiency historical perspective|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. | |||
* Most of the cases were that of women during the third trimester of pregnancy presenting with maternal virilization resulting in hirsutism and acne. | *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. | ||
*Most of the cases were that of women during the third trimester of pregnancy presenting with maternal virilization resulting in hirsutism and acne. | |||
==Classification== | ==Classification== | ||
| Line 14: | Line 15: | ||
==[[Placental aromatase deficiency pathophysiology|Pathophysiology]]== | ==[[Placental aromatase deficiency pathophysiology|Pathophysiology]]== | ||
* [[CYP19A1]] gene is responsible for the production of enzyme [[Aromatase|aromatase]], which converts androgens to different forms of estrogen | |||
*[[CYP19A1]] gene is responsible for the production of enzyme [[Aromatase|aromatase]], which converts androgens to different forms of estrogen | |||
*[[Mutation]] is inherited in an [[autosomal recessive]] mode. | *[[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 CYP19A1 gene leads to deficiency or absence of activity of aromatase . | *Estrogen is involved in sexual development in females prior to birth and the levels peak during pregnancy. Mutation in CYP19A1 gene leads to deficiency or absence of activity of aromatase . | ||
* As a result, there is decrease in production of estrogen due to lack of conversion of androgens to estrogen and increase in [[testosterone]] and androstenedione levels. | *As a result, there is decrease in 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]]. | *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]]. | ||
==[[Placental aromatase deficiency causes|Causes]]== | ==[[Placental aromatase deficiency causes|Causes]]== | ||
* [[CYP19A1 gene]] mutation primarily causes Placental Aromatase 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 suggest that it is more prevalent in consanguineous marriages and both are heterozygous carriers of the mutation. | *[[CYP19A1 gene]] mutation primarily causes Placental Aromatase 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 suggest that it is more prevalent in consanguineous marriages and both are heterozygous carriers of the mutation. | |||
==[[Placental aromatase deficiency differential diagnosis|Differentiating Any Disease from other Diseases]]== | ==[[Placental aromatase deficiency differential diagnosis|Differentiating Any Disease from other Diseases]]== | ||
*[[Congenital adrenal hyperplasia]] can be considered as a [[differential]] in female patients. | *[[Congenital adrenal hyperplasia]] can be considered as a [[differential]] in female patients. | ||
While, in male patients; | While, in male patients; | ||
| Line 34: | Line 39: | ||
*[[Congenital hypogonadotropic hypogonadism]]. | *[[Congenital hypogonadotropic hypogonadism]]. | ||
* can be considered as the [[differential diagnosis]] of Placental Aromatase Deficiency. | *can be considered as the [[differential diagnosis]] of Placental Aromatase Deficiency. | ||
==[[Placental aromatase deficiency epidemiology and demographics|Epidemiology and Demographics]]== | ==[[Placental aromatase deficiency epidemiology and demographics|Epidemiology and Demographics]]== | ||
* Placental Aromatase Deficiency is a rare [[autosomal recessive]] disorder. | |||
* The [[prevalence]] is unknown . | *Placental Aromatase Deficiency is a rare [[autosomal recessive]] disorder. | ||
* There are only few cases that have been described in the literature. | *The [[prevalence]] is unknown . | ||
*There are only few cases that have been described in the literature. | |||
==Risk Factors== | ==Risk Factors== | ||
*The [[risk factors]] evident with placental aromatase deficiency includes [[placental ischemia]] and [[preeclampsia]] . | *The [[risk factors]] evident with placental aromatase deficiency includes [[placental ischemia]] and [[preeclampsia]] . | ||
==Screening== | ==Screening== | ||
*There is insufficient evidence to recommend routine [[screening]] for Placental aromatase deficiency. | |||
==Natural History , Complications and Prognosis== | ==Natural History , Complications and Prognosis== | ||
* Placental aromatase deficiency is a rare entity. | *Placental aromatase deficiency is a rare entity. | ||
* Defective synthesis of estrogen in aromatase deficiency may result in : | *Defective synthesis of estrogen in aromatase deficiency may result in : | ||
*[[Delayed Puberty]] | *[[Delayed Puberty]] | ||
| Line 60: | Line 66: | ||
*Bone disorders like [[osteoporosis]] | *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. | *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== | ==Diagnosis== | ||
===Diagnostic Study of Choice=== | ===Diagnostic Study of Choice=== | ||
* There are no established criteria for the diagnosis of Placental Aromatase Deficiency. The diagnosis may be made [[clinically]]. | |||
*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. | *[[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=== | ===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. | |||
*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=== | ||
*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. | *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. | *Males are usually normal. They may be tall and have reduced bone age. | ||
===Laboratory Findings=== | ===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.<ref name="pmid24485503">{{cite journal| author=Bulun SE| title=Aromatase and estrogen receptor α deficiency. | journal=Fertil Steril | year= 2014 | volume= 101 | issue= 2 | pages= 323-9 | pmid=24485503 | doi=10.1016/j.fertnstert.2013.12.022 | pmc=3939057 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24485503 }} </ref> | *An elevated concentration of serum [[testosterone]] and reduced levels of [[estrogen]] is diagnostic of Placental Aromatase Deficiency. | ||
* Urinary levels of androgens are usually normal or elevated. | *In aromatase deficient girls, basal and GnRH-stimulated FSH levels are elevated.<ref name="pmid24485503">{{cite journal| author=Bulun SE| title=Aromatase and estrogen receptor α deficiency. | journal=Fertil Steril | year= 2014 | volume= 101 | issue= 2 | pages= 323-9 | pmid=24485503 | doi=10.1016/j.fertnstert.2013.12.022 | pmc=3939057 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24485503 }} </ref> | ||
*Urinary levels of androgens are usually normal or elevated. | |||
===Electrocardiogram=== | ===Electrocardiogram=== | ||
* There are no [[ECG]] findings associated with Placental Aromatase Deficiency. | |||
*There are no [[ECG]] findings associated with Placental Aromatase Deficiency. | |||
===X-ray=== | ===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. | |||
*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=== | ===Echocardiography or Ultrasound=== | ||
* Ultrasound may be helpful in the diagnosis of [[polycystic ovary syndrome]] which occurs as a sequalae in female patients. | |||
*Ultrasound may be helpful in the diagnosis of [[polycystic ovary syndrome]] which occurs as a sequalae in female patients. | |||
===CT scan=== | ===CT scan=== | ||
* There are no [[CT]] scan findings [[associated]] with Placental Aromatase Deficiency. | |||
*There are no [[CT]] scan findings [[associated]] with Placental Aromatase Deficiency. | |||
===MRI=== | ===MRI=== | ||
* There are no [[MRI]] findings [[associated]] with Placental Aromatase Deficiency. | |||
*There are no [[MRI]] findings [[associated]] with Placental Aromatase Deficiency. | |||
===Other Imaging Findings=== | ===Other Imaging Findings=== | ||
* There are no other imaging findings [[associated]] with Placental Aromatase Deficiency. | |||
*There are no other imaging findings [[associated]] with Placental Aromatase Deficiency. | |||
===Other Diagnostic Studies=== | ===Other Diagnostic Studies=== | ||
* There are no other diagnostic studies associated with Placental Aromatase Deficiency. | |||
*There are no other diagnostic studies associated with Placental Aromatase Deficiency. | |||
==Treatment== | ==Treatment== | ||
===Medical Therapy=== | ===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.<ref name="pmid24485503">{{cite journal| author=Bulun SE| title=Aromatase and estrogen receptor α deficiency. | journal=Fertil Steril | year= 2014 | volume= 101 | issue= 2 | pages= 323-9 | pmid=24485503 | doi=10.1016/j.fertnstert.2013.12.022 | pmc=3939057 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24485503 }} </ref> | *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.<ref name="pmid24485503">{{cite journal| author=Bulun SE| title=Aromatase and estrogen receptor α deficiency. | journal=Fertil Steril | year= 2014 | volume= 101 | issue= 2 | pages= 323-9 | pmid=24485503 | doi=10.1016/j.fertnstert.2013.12.022 | pmc=3939057 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24485503 }} </ref> | |||
*Treatment options for males include transdermal estradiol that helps in increasing bone mineral density. | *Treatment options for males include transdermal estradiol that helps in increasing bone mineral density. | ||
===Surgery=== | ===Surgery=== | ||
*[[Surgical]] [[intervention]] may be an option for ambiguous genitalia. | *[[Surgical]] [[intervention]] may be an option for ambiguous genitalia. | ||
===Primary Prevention=== | ===Primary Prevention=== | ||
Revision as of 09:11, 16 June 2021
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 [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.
- Most of the cases were that of women during the third trimester of pregnancy presenting with maternal virilization resulting in hirsutism and acne.
Classification
- There is no established system for the classification of Placental Aromatase Deficency.
Pathophysiology
- CYP19A1 gene is responsible for the production of 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 CYP19A1 gene leads to deficiency or absence of activity of aromatase .
- As a result, there is decrease in 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 Aromatase 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 suggest 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;
- 5 alpha reductase deficiency :The levels of testosterone and estrogen are normal.
- 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.
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.[1]
- 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.[1]
- 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.
Reference
- ↑ 1.0 1.1 Bulun SE (2014). "Aromatase and estrogen receptor α deficiency". Fertil Steril. 101 (2): 323–9. doi:10.1016/j.fertnstert.2013.12.022. PMC 3939057. PMID 24485503.