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Latest revision as of 20:15, 27 April 2022

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Rupashi; José Eduardo Riceto Loyola Junior, M.D.[2]

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. Patients affected by this disease typically present with maternal virilization, amenorrhea during puberty in females. Males are rarely affected.

Historical Perspective

The evidence of the disease goes back to the year of 1991, when the first case of aromatase deficiency occurred in a 24-year old primigravida and the female fetus showed pseudohermaphroditism.^[1]
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

Placental aromatase deficiency is a rare autosomal recessive disorder.
The 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 an 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.^[2]

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.^[3]
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.^[4]
While, in male patients, it should be differentiated from:
- 5 alpha-reductase deficiency, which the levels of both testosterone is low to normal and dihydrotestosterone level is decreased.^[5]
- 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.

Epidemiology and Demographics

The prevalence of placental aromatase deficiency is unknown.^[6]
There are only a few cases that have been described in literature.
The first case in males was reported in 1995.^[7]

Risk Factors

The risk factors evident with placental aromatase deficiency include placental ischemia and preeclampsia.^[8]

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^[2]
Bone disorders such as osteoporosis

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.^[9]

History and Symptoms

The hallmark of placental aromatase deficiency is maternal virilization. A positive history of hirsutism, deepening of the voice, and cystic acne is suggestive of placental aromatase deficiency.^[6]^[10]

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.^[11]
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.^[12]
In aromatase deficient girls, basal and GnRH-stimulated FSH levels are elevated.^[6]
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.^[13] 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 sequela in female patients.^[2]

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

In patients with aromatase deficiency, lifetime hormone replacement therapy is mandatory.
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 the resolution of cystic ovaries and promote bone growth.
After 14 years of age, the combination oral contraceptive may be used.^[6]
Treatment options for males include transdermal estradiol that helps in increasing bone mineral density.^[10]

Surgery

Surgical intervention may be an option for ambiguous genitalia.^[14]

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

↑ Shozu M, Akasofu K, Harada T, Kubota Y (1991). "A new cause of female pseudohermaphroditism: placental aromatase deficiency". J Clin Endocrinol Metab. 72 (3): 560–6. doi:10.1210/jcem-72-3-560. PMID 1825497.
↑ ^2.0 ^2.1 ^2.2 Akçurin S, Türkkahraman D, Kim WY, Durmaz E, Shin JG, Lee SJ (2016). "A Novel Null Mutation in P450 Aromatase Gene (CYP19A1) Associated with Development of Hypoplastic Ovaries in Humans". J Clin Res Pediatr Endocrinol. 8 (2): 205–10. doi:10.4274/jcrpe.2761. PMC 5096477. PMID 27086564.
↑ Ludwikowski B, Heger S, Datz N, Richter-Unruh A, González R (2013). "Aromatase deficiency: rare cause of virilization". Eur J Pediatr Surg. 23 (5): 418–22. doi:10.1055/s-0032-1324798. PMID 23093430.
↑ Agrawal SS, Chakraborty PP, Sinha A, Maiti A (2019). "Child with '46, XX' disorder of sex development: clues to diagnose aromatase deficiency". BMJ Case Rep. 12 (12). doi:10.1136/bcr-2019-232575. PMC 7001710 Check |pmc= value (help). PMID 31801784.
↑ Sinnecker GH, Hiort O, Dibbelt L, Albers N, Dörr HG, Hauss H; et al. (1996). "Phenotypic classification of male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency". Am J Med Genet. 63 (1): 223–30. doi:10.1002/(SICI)1096-8628(19960503)63:1<223::AID-AJMG39>3.0.CO;2-O. PMID 8723114.
↑ ^6.0 ^6.1 ^6.2 ^6.3 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.
↑ Baykan EK, Erdoğan M, Özen S, Darcan Ş, Saygılı LF (2013). "Aromatase deficiency, a rare syndrome: case report". J Clin Res Pediatr Endocrinol. 5 (2): 129–32. doi:10.4274/Jcrpe.970. PMC 3701920. PMID 23748068.
↑ Perez-Sepulveda A, Monteiro LJ, Dobierzewska A, España-Perrot PP, Venegas-Araneda P, Guzmán-Rojas AM; et al. (2015). "Placental Aromatase Is Deficient in Placental Ischemia and Preeclampsia". PLoS One. 10 (10): e0139682. doi:10.1371/journal.pone.0139682. PMC 4596497. PMID 26444006.
↑ Harada N, Ogawa H, Shozu M, Yamada K, Suhara K, Nishida E; et al. (1992). "Biochemical and molecular genetic analyses on placental aromatase (P-450AROM) deficiency". J Biol Chem. 267 (7): 4781–5. PMID 1371509.
↑ ^10.0 ^10.1 Zirilli L, Rochira V, Diazzi C, Caffagni G, Carani C (2008). "Human models of aromatase deficiency". J Steroid Biochem Mol Biol. 109 (3–5): 212–8. doi:10.1016/j.jsbmb.2008.03.026. PMID 18448329.
↑ Conte FA, Grumbach MM, Ito Y, Fisher CR, Simpson ER (1994). "A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom)". J Clin Endocrinol Metab. 78 (6): 1287–92. doi:10.1210/jcem.78.6.8200927. PMID 8200927.
↑ Mazen I, McElreavey K, Elaidy A, Kamel AK, Abdel-Hamid MS (2017). "Aromatase Deficiency due to a Homozygous CYP19A1 Mutation in a 46,XX Egyptian Patient with Ambiguous Genitalia". Sex Dev. 11 (5–6): 275–279. doi:10.1159/000485278. PMID 29324451.
↑ Rochira V, Carani C (2009). "Aromatase deficiency in men: a clinical perspective". Nat Rev Endocrinol. 5 (10): 559–68. doi:10.1038/nrendo.2009.176. PMID 19707181.
↑ Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K (1995). "Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens". J Clin Endocrinol Metab. 80 (12): 3689–98. doi:10.1210/jcem.80.12.8530621. PMID 8530621.

[pmid1825497-1] Shozu M, Akasofu K, Harada T, Kubota Y (1991). "A new cause of female pseudohermaphroditism: placental aromatase deficiency". J Clin Endocrinol Metab. 72 (3): 560–6. doi:10.1210/jcem-72-3-560. PMID 1825497.

[pmid27086564-2] 2.0 ^2.1 ^2.2 Akçurin S, Türkkahraman D, Kim WY, Durmaz E, Shin JG, Lee SJ (2016). "A Novel Null Mutation in P450 Aromatase Gene (CYP19A1) Associated with Development of Hypoplastic Ovaries in Humans". J Clin Res Pediatr Endocrinol. 8 (2): 205–10. doi:10.4274/jcrpe.2761. PMC 5096477. PMID 27086564.

[pmid23093430-3] Ludwikowski B, Heger S, Datz N, Richter-Unruh A, González R (2013). "Aromatase deficiency: rare cause of virilization". Eur J Pediatr Surg. 23 (5): 418–22. doi:10.1055/s-0032-1324798. PMID 23093430.

[pmid31801784-4] Agrawal SS, Chakraborty PP, Sinha A, Maiti A (2019). "Child with '46, XX' disorder of sex development: clues to diagnose aromatase deficiency". BMJ Case Rep. 12 (12). doi:10.1136/bcr-2019-232575. PMC 7001710 Check |pmc= value (help). PMID 31801784.

[pmid8723114-5] Sinnecker GH, Hiort O, Dibbelt L, Albers N, Dörr HG, Hauss H; et al. (1996). "Phenotypic classification of male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency". Am J Med Genet. 63 (1): 223–30. doi:10.1002/(SICI)1096-8628(19960503)63:1<223::AID-AJMG39>3.0.CO;2-O. PMID 8723114.

[pmid24485503-6] 6.0 ^6.1 ^6.2 ^6.3 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.

[pmid23748068-7] Baykan EK, Erdoğan M, Özen S, Darcan Ş, Saygılı LF (2013). "Aromatase deficiency, a rare syndrome: case report". J Clin Res Pediatr Endocrinol. 5 (2): 129–32. doi:10.4274/Jcrpe.970. PMC 3701920. PMID 23748068.

[pmid26444006-8] Perez-Sepulveda A, Monteiro LJ, Dobierzewska A, España-Perrot PP, Venegas-Araneda P, Guzmán-Rojas AM; et al. (2015). "Placental Aromatase Is Deficient in Placental Ischemia and Preeclampsia". PLoS One. 10 (10): e0139682. doi:10.1371/journal.pone.0139682. PMC 4596497. PMID 26444006.

[pmid1371509-9] Harada N, Ogawa H, Shozu M, Yamada K, Suhara K, Nishida E; et al. (1992). "Biochemical and molecular genetic analyses on placental aromatase (P-450AROM) deficiency". J Biol Chem. 267 (7): 4781–5. PMID 1371509.

[pmid18448329-10] 10.0 ^10.1 Zirilli L, Rochira V, Diazzi C, Caffagni G, Carani C (2008). "Human models of aromatase deficiency". J Steroid Biochem Mol Biol. 109 (3–5): 212–8. doi:10.1016/j.jsbmb.2008.03.026. PMID 18448329.

[pmid8200927-11] Conte FA, Grumbach MM, Ito Y, Fisher CR, Simpson ER (1994). "A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom)". J Clin Endocrinol Metab. 78 (6): 1287–92. doi:10.1210/jcem.78.6.8200927. PMID 8200927.

[pmid29324451-12] Mazen I, McElreavey K, Elaidy A, Kamel AK, Abdel-Hamid MS (2017). "Aromatase Deficiency due to a Homozygous CYP19A1 Mutation in a 46,XX Egyptian Patient with Ambiguous Genitalia". Sex Dev. 11 (5–6): 275–279. doi:10.1159/000485278. PMID 29324451.

[pmid19707181-13] Rochira V, Carani C (2009). "Aromatase deficiency in men: a clinical perspective". Nat Rev Endocrinol. 5 (10): 559–68. doi:10.1038/nrendo.2009.176. PMID 19707181.

[pmid8530621-14] Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K (1995). "Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens". J Clin Endocrinol Metab. 80 (12): 3689–98. doi:10.1210/jcem.80.12.8530621. PMID 8530621.

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@@ Line 1: / Line 1: @@
 __NOTOC__
 {{SI}}
-{{CMG}} {{AE}}
+{{CMG}} {{AE}} Rupashi; {{Jose}}
 ==Overview==
-Aromatase deficiency is an [[autosomal recessive]] disorder in which there is a decrease or absence in the level of [[Aromatase|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.
+Aromatase deficiency is an [[autosomal recessive]] disorder in which there is a decrease or absence in the level of [[Aromatase|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]]. Patients affected by this disease typically present with maternal [[virilization]], [[amenorrhea]] during puberty in females. Males are rarely affected.
 ==[[Placental aromatase deficiency historical perspective|Historical Perspective]]==
+*The evidence of the disease goes back to the year of 1991, when the first case of aromatase deficiency occurred in a 24-year old primigravida and the female fetus showed pseudohermaphroditism.<ref name="pmid1825497">{{cite journal| author=Shozu M, Akasofu K, Harada T, Kubota Y| title=A new cause of female pseudohermaphroditism: placental aromatase deficiency. | journal=J Clin Endocrinol Metab | year= 1991 | volume= 72 | issue= 3 | pages= 560-6 | pmid=1825497 | doi=10.1210/jcem-72-3-560 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1825497  }} </ref>
-*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.<ref name="pmid1825497">{{cite journal| author=Shozu M, Akasofu K, Harada T, Kubota Y| title=A new cause of female pseudohermaphroditism: placental aromatase deficiency. | journal=J Clin Endocrinol Metab | year= 1991 | volume= 72 | issue= 3 | pages= 560-6 | pmid=1825497 | doi=10.1210/jcem-72-3-560 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1825497  }} </ref>
 *The majority of affected individuals were women during the third trimester of [[pregnancy]] manifesting with maternal [[virilization]] resulting in [[hirsutism]] and [[acne]].
@@ Line 16: / Line 15: @@
 ==[[Placental aromatase deficiency pathophysiology|Pathophysiology]]==
 *Placental aromatase deficiency is a rare [[autosomal recessive]] disorder.
-*[[CYP19A1]] [[gene]] is responsible for the production of the enzyme [[Aromatase|aromatase]], which converts androgens to different forms of [[estrogen]].
+*The [[CYP19A1]] [[gene]] is responsible for the production of the enzyme [[Aromatase|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.
+*As a result, there is a decrease in the production of [[estrogen]] due to lack of conversion of androgens to [[estrogen]] and an 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]].<ref name="pmid27086564">{{cite journal| author=Akçurin S, Türkkahraman D, Kim WY, Durmaz E, Shin JG, Lee SJ| title=A Novel Null Mutation in P450 Aromatase Gene (CYP19A1) Associated with Development of Hypoplastic Ovaries in Humans. | journal=J Clin Res Pediatr Endocrinol | year= 2016 | volume= 8 | issue= 2 | pages= 205-10 | pmid=27086564 | doi=10.4274/jcrpe.2761 | pmc=5096477 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27086564  }} </ref>
 ==[[Placental aromatase deficiency causes|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.<ref name="pmid23093430">{{cite journal| author=Ludwikowski B, Heger S, Datz N, Richter-Unruh A, González R| title=Aromatase deficiency: rare cause of virilization. | journal=Eur J Pediatr Surg | year= 2013 | volume= 23 | issue= 5 | pages= 418-22 | pmid=23093430 | doi=10.1055/s-0032-1324798 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23093430  }} </ref>
+*[[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.<ref name="pmid23093430">{{cite journal| author=Ludwikowski B, Heger S, Datz N, Richter-Unruh A, González R| title=Aromatase deficiency: rare cause of virilization. | journal=Eur J Pediatr Surg | year= 2013 | volume= 23 | issue= 5 | pages= 418-22 | pmid=23093430 | doi=10.1055/s-0032-1324798 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23093430  }} </ref>
-*Studies suggested that it is more prevalent in consanguineous marriages and both are heterozygous carriers of the [[mutation]].
+*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]]==
-*[[Congenital adrenal hyperplasia]] can be considered as a [[differential]] in female [[patients]].
+*[[Congenital adrenal hyperplasia]] can be considered as a [[differential]] in female [[patients]].<ref name="pmid31801784">{{cite journal| author=Agrawal SS, Chakraborty PP, Sinha A, Maiti A| title=Child with '46, XX' disorder of sex development: clues to diagnose aromatase deficiency. | journal=BMJ Case Rep | year= 2019 | volume= 12 | issue= 12 | pages=  | pmid=31801784 | doi=10.1136/bcr-2019-232575 | pmc=7001710 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31801784  }} </ref>
 *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)
+**[[5 alpha-reductase deficiency]], which the levels of both [[testosterone]] is low to normal and [[dihydrotestosterone]] level is decreased.<ref name="pmid8723114">{{cite journal| author=Sinnecker GH, Hiort O, Dibbelt L, Albers N, Dörr HG, Hauss H | display-authors=etal| title=Phenotypic classification of male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency. | journal=Am J Med Genet | year= 1996 | volume= 63 | issue= 1 | pages= 223-30 | pmid=8723114 | doi=10.1002/(SICI)1096-8628(19960503)63:1<223::AID-AJMG39>3.0.CO;2-O | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8723114  }} </ref>
 **[[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.???????
 ==[[Placental aromatase deficiency epidemiology and demographics|Epidemiology and Demographics]]==
-*The [[prevalence]] of placental aromatase deficiency is unknown. <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>
+*The [[prevalence]] of placental aromatase deficiency is unknown.<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>
-*There are only few cases that have been described in the literature.
+*There are only a few cases that have been described in literature.
-* First case in male was reported in 1995.<ref name="pmid23748068">{{cite journal| author=Baykan EK, Erdoğan M, Özen S, Darcan Ş, Saygılı LF| title=Aromatase deficiency, a rare syndrome: case report. | journal=J Clin Res Pediatr Endocrinol | year= 2013 | volume= 5 | issue= 2 | pages= 129-32 | pmid=23748068 | doi=10.4274/Jcrpe.970 | pmc=3701920 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23748068  }} </ref>
+* The first case in males was reported in 1995.<ref name="pmid23748068">{{cite journal| author=Baykan EK, Erdoğan M, Özen S, Darcan Ş, Saygılı LF| title=Aromatase deficiency, a rare syndrome: case report. | journal=J Clin Res Pediatr Endocrinol | year= 2013 | volume= 5 | issue= 2 | pages= 129-32 | pmid=23748068 | doi=10.4274/Jcrpe.970 | pmc=3701920 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23748068  }} </ref>
 ==Risk Factors==
-*The [[risk factors]] evident with placental aromatase deficiency includes [[placental ischemia]] and [[preeclampsia]] .<ref name="pmid26444006">{{cite journal| author=Perez-Sepulveda A, Monteiro LJ, Dobierzewska A, España-Perrot PP, Venegas-Araneda P, Guzmán-Rojas AM | display-authors=etal| title=Placental Aromatase Is Deficient in Placental Ischemia and Preeclampsia. | journal=PLoS One | year= 2015 | volume= 10 | issue= 10 | pages= e0139682 | pmid=26444006 | doi=10.1371/journal.pone.0139682 | pmc=4596497 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26444006  }} </ref>
+*The [[risk factors]] evident with placental aromatase deficiency include [[placental ischemia]] and [[preeclampsia]].<ref name="pmid26444006">{{cite journal| author=Perez-Sepulveda A, Monteiro LJ, Dobierzewska A, España-Perrot PP, Venegas-Araneda P, Guzmán-Rojas AM | display-authors=etal| title=Placental Aromatase Is Deficient in Placental Ischemia and Preeclampsia. | journal=PLoS One | year= 2015 | volume= 10 | issue= 10 | pages= e0139682 | pmid=26444006 | doi=10.1371/journal.pone.0139682 | pmc=4596497 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26444006  }} </ref>
 ==Screening==
@@ Line 55: / Line 53: @@
 *[[Delayed Puberty]]
 *[[Insulin resistance]]
-*[[Polycystic ovary syndrome]]
+*[[Polycystic ovary syndrome]]<ref name="pmid27086564">{{cite journal| author=Akçurin S, Türkkahraman D, Kim WY, Durmaz E, Shin JG, Lee SJ| title=A Novel Null Mutation in P450 Aromatase Gene (CYP19A1) Associated with Development of Hypoplastic Ovaries in Humans. | journal=J Clin Res Pediatr Endocrinol | year= 2016 | volume= 8 | issue= 2 | pages= 205-10 | pmid=27086564 | doi=10.4274/jcrpe.2761 | pmc=5096477 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27086564  }} </ref>
 *Bone disorders such as [[osteoporosis]]
@@ Line 61: / Line 59: @@
 ===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.
+*[[Genetic analysis]] and location of a [[mutation]] in the [[CYP19A1]] [[gene]] may be done for the confirmation of the placental aromatase deficiency.<ref name="pmid1371509">{{cite journal| author=Harada N, Ogawa H, Shozu M, Yamada K, Suhara K, Nishida E | display-authors=etal| title=Biochemical and molecular genetic analyses on placental aromatase (P-450AROM) deficiency. | journal=J Biol Chem | year= 1992 | volume= 267 | issue= 7 | pages= 4781-5 | pmid=1371509 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1371509  }} </ref>
 ===History and Symptoms===
-*The hallmark of placental aromatase deficiency is maternal [[virilization]]. A positive history of [[hirsutism]], deepening of the voice, and [[cystic acne]] is suggestive of placental aromatase deficiency.
+*The hallmark of placental aromatase deficiency is maternal [[virilization]]. A positive history of [[hirsutism]], deepening of the voice, and [[cystic acne]] is suggestive of placental aromatase deficiency.<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><ref name="pmid18448329">{{cite journal| author=Zirilli L, Rochira V, Diazzi C, Caffagni G, Carani C| title=Human models of aromatase deficiency. | journal=J Steroid Biochem Mol Biol | year= 2008 | volume= 109 | issue= 3-5 | pages= 212-8 | pmid=18448329 | doi=10.1016/j.jsbmb.2008.03.026 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18448329  }} </ref>
 ===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]].<ref name="pmid8200927">{{cite journal| author=Conte FA, Grumbach MM, Ito Y, Fisher CR, Simpson ER| title=A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). | journal=J Clin Endocrinol Metab | year= 1994 | volume= 78 | issue= 6 | pages= 1287-92 | pmid=8200927 | doi=10.1210/jcem.78.6.8200927 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8200927  }} </ref>
 *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.
+*An elevated concentration of serum [[testosterone]] and reduced levels of [[estrogen]] is diagnostic of placental aromatase deficiency.<ref name="pmid29324451">{{cite journal| author=Mazen I, McElreavey K, Elaidy A, Kamel AK, Abdel-Hamid MS| title=Aromatase Deficiency due to a Homozygous CYP19A1 Mutation in a 46,XX Egyptian Patient with Ambiguous Genitalia. | journal=Sex Dev | year= 2017 | volume= 11 | issue= 5-6 | pages= 275-279 | pmid=29324451 | doi=10.1159/000485278 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29324451  }} </ref>
 *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.
+*Urinary levels of [[androgens]] are usually normal or elevated.
 ===Electrocardiogram===
@@ Line 84: / Line 82: @@
 ===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.<ref name="pmid19707181">{{cite journal| author=Rochira V, Carani C| title=Aromatase deficiency in men: a clinical perspective. | journal=Nat Rev Endocrinol | year= 2009 | volume= 5 | issue= 10 | pages= 559-68 | pmid=19707181 | doi=10.1038/nrendo.2009.176 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19707181  }} </ref> 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 sequela in female [[patients]].
+*Ultrasound may be helpful in the [[diagnosis]] of [[polycystic ovary syndrome]] which occurs as a sequela in female [[patients]].<ref name="pmid27086564">{{cite journal| author=Akçurin S, Türkkahraman D, Kim WY, Durmaz E, Shin JG, Lee SJ| title=A Novel Null Mutation in P450 Aromatase Gene (CYP19A1) Associated with Development of Hypoplastic Ovaries in Humans. | journal=J Clin Res Pediatr Endocrinol | year= 2016 | volume= 8 | issue= 2 | pages= 205-10 | pmid=27086564 | doi=10.4274/jcrpe.2761 | pmc=5096477 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27086564  }} </ref>
 ===CT scan===
@@ Line 108: / Line 106: @@
 ==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 the resolution of cystic ovaries and promote bone growth.
+*In [[patients]] with aromatase deficiency, lifetime hormone replacement therapy is mandatory.
-*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 the resolution of cystic ovaries and promote bone growth.
-*Treatment options for males include transdermal estradiol that helps in increasing bone mineral density.<ref name="pmid18448329">{{cite journal| author=Zirilli L, Rochira V, Diazzi C, Caffagni G, Carani C| title=Human models of aromatase deficiency. | journal=J Steroid Biochem Mol Biol | year= 2008 | volume= 109 | issue= 3-5 | pages= 212-8 | pmid=18448329 | doi=10.1016/j.jsbmb.2008.03.026 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18448329  }} </ref>
+*After 14 years of age, the 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>
-*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.
+*Treatment options for males include transdermal [[estradio]]l that helps in increasing bone mineral density.<ref name="pmid18448329">{{cite journal| author=Zirilli L, Rochira V, Diazzi C, Caffagni G, Carani C| title=Human models of aromatase deficiency. | journal=J Steroid Biochem Mol Biol | year= 2008 | volume= 109 | issue= 3-5 | pages= 212-8 | pmid=18448329 | doi=10.1016/j.jsbmb.2008.03.026 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18448329  }} </ref>
 ===Surgery===
@@ Line 117: / Line 116: @@
 ===Primary Prevention===
-*There are no established measures for the [[primary prevention]] of Placental aromatase deficiency.
+*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.
+*There are no established measures for the [[secondary prevention]] of placental aromatase deficiency.
 ==Reference==
 {{Reflist|2}}
+[[Category:Up to Date]]