Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: An update with a special focus on adolescent and adult women

Enrico Carmina, Didier Dewailly, Héctor F. Escobar-Morreale, Fahrettin Kelestimur, Carlos Moran, Sharon Oberfield, Selma F. Witchel, Ricardo Azziz

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

BACKGROUND: Non-classic congenital hyperplasia (NCAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by androgen excess. OBJECTIVE AND RATIONALE: We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of NCAH. A meta-analysis of epidemiological data was also performed. SEARCH METHODS: Peer-reviewed studies evaluating NCAH published up to October 2016 were reviewed. Multiple databases were searched including MEDLINE, EMBASE, Cochrane, ERIC, EBSCO, dissertation abstracts, and current contents. OUTCOMES: The worldwide prevalence of NCAH amongst women presenting with signs and symptoms of androgen excess is 4.2% (95% confidence interval: 3.2-5.4%). The clinical consequences of NCAH expand from infancy, i.e. accelerated growth, to adolescence and adulthood, i.e. premature pubarche, cutaneous symptoms and oligo-ovulation in a polycystic ovary syndrome (PCOS)-like clinical picture. The diagnosis of NCAH relies on serum 17-hydroxyprogesterone (17-OHP) concentrations. A basal 17-OHP concentration ≥2 ng/ml (6 nmol/l) should be used for screening if more appropriate in-house cut-offvalues are not available. Definitive diagnosis requires a 17-OHP concentration ≥10 ng/ml (30 nmol/l), either basally or after cosyntropin-stimulation. Molecular genetic analysis of the CYP21A2 gene, which is responsible for 21-hydroxylase activity, may be used for confirmation purposes and should be offered to all patients with NCAH along with genetic counseling because these patients frequently carry alleles that may result in classic CAH, the more severe form of the disease, in their progeny. Treatment must be individualized. Glucocorticoid replacement therapy may benefit pediatric patients with accelerated growth or advanced bone age or adult women seeking fertility, whereas adequate control of menstrual irregularity, hirsutism and other cutaneous symptoms is best served by the use of oral contraceptive pills and/or anti-androgens. Some women may need ovulation induction or assisted reproductive technology to achieve pregnancy. Patients with NCAH have a higher risk of miscarriage and may benefit from glucocorticoid treatment during pregnancy. WIDER IMPLICATIONS: Evidence-based diagnostic and treatment strategies are essential for the proper management of women with NCAH, especially considering that these patients may need different therapeutic strategies at different stages during their follow-up and that appropriate genetic counseling may prevent the occurrence of CAH in their children.

Original languageEnglish (US)
Article numberdmx014
Pages (from-to)580-599
Number of pages20
JournalHuman Reproduction Update
Volume23
Issue number5
DOIs
StatePublished - Sep 1 2017

Fingerprint

Hyperplasia
Androgens
Genetic Counseling
Glucocorticoids
Cosyntropin
17-alpha-Hydroxyprogesterone
Steroid 21-Hydroxylase
Therapeutics
Congenital adrenal hyperplasia due to 21 hydroxylase deficiency
Pregnancy
Hirsutism
Skin
Assisted Reproductive Techniques
Ovulation Induction
Polycystic Ovary Syndrome
Spontaneous Abortion
Growth
Oral Contraceptives
Ovulation
MEDLINE

Keywords

  • 17-hydroxyprogesterone
  • 21-hydroxylase deficiency
  • Androgen excess
  • Hirsutism
  • Hyperandrogenism
  • Miscarriage
  • Non-classic congenital adrenal hyperplasia
  • Polycystic ovary syndrome
  • Pregnancy
  • Prematurepubarche

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

Carmina, E., Dewailly, D., Escobar-Morreale, H. F., Kelestimur, F., Moran, C., Oberfield, S., ... Azziz, R. (2017). Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: An update with a special focus on adolescent and adult women. Human Reproduction Update, 23(5), 580-599. [dmx014]. https://doi.org/10.1093/humupd/dmx014

Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited : An update with a special focus on adolescent and adult women. / Carmina, Enrico; Dewailly, Didier; Escobar-Morreale, Héctor F.; Kelestimur, Fahrettin; Moran, Carlos; Oberfield, Sharon; Witchel, Selma F.; Azziz, Ricardo.

In: Human Reproduction Update, Vol. 23, No. 5, dmx014, 01.09.2017, p. 580-599.

Research output: Contribution to journalArticle

Carmina, E, Dewailly, D, Escobar-Morreale, HF, Kelestimur, F, Moran, C, Oberfield, S, Witchel, SF & Azziz, R 2017, 'Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: An update with a special focus on adolescent and adult women', Human Reproduction Update, vol. 23, no. 5, dmx014, pp. 580-599. https://doi.org/10.1093/humupd/dmx014
Carmina, Enrico ; Dewailly, Didier ; Escobar-Morreale, Héctor F. ; Kelestimur, Fahrettin ; Moran, Carlos ; Oberfield, Sharon ; Witchel, Selma F. ; Azziz, Ricardo. / Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited : An update with a special focus on adolescent and adult women. In: Human Reproduction Update. 2017 ; Vol. 23, No. 5. pp. 580-599.
@article{b9f2b844ebee4e10a0915417aa8cc836,
title = "Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: An update with a special focus on adolescent and adult women",
abstract = "BACKGROUND: Non-classic congenital hyperplasia (NCAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by androgen excess. OBJECTIVE AND RATIONALE: We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of NCAH. A meta-analysis of epidemiological data was also performed. SEARCH METHODS: Peer-reviewed studies evaluating NCAH published up to October 2016 were reviewed. Multiple databases were searched including MEDLINE, EMBASE, Cochrane, ERIC, EBSCO, dissertation abstracts, and current contents. OUTCOMES: The worldwide prevalence of NCAH amongst women presenting with signs and symptoms of androgen excess is 4.2{\%} (95{\%} confidence interval: 3.2-5.4{\%}). The clinical consequences of NCAH expand from infancy, i.e. accelerated growth, to adolescence and adulthood, i.e. premature pubarche, cutaneous symptoms and oligo-ovulation in a polycystic ovary syndrome (PCOS)-like clinical picture. The diagnosis of NCAH relies on serum 17-hydroxyprogesterone (17-OHP) concentrations. A basal 17-OHP concentration ≥2 ng/ml (6 nmol/l) should be used for screening if more appropriate in-house cut-offvalues are not available. Definitive diagnosis requires a 17-OHP concentration ≥10 ng/ml (30 nmol/l), either basally or after cosyntropin-stimulation. Molecular genetic analysis of the CYP21A2 gene, which is responsible for 21-hydroxylase activity, may be used for confirmation purposes and should be offered to all patients with NCAH along with genetic counseling because these patients frequently carry alleles that may result in classic CAH, the more severe form of the disease, in their progeny. Treatment must be individualized. Glucocorticoid replacement therapy may benefit pediatric patients with accelerated growth or advanced bone age or adult women seeking fertility, whereas adequate control of menstrual irregularity, hirsutism and other cutaneous symptoms is best served by the use of oral contraceptive pills and/or anti-androgens. Some women may need ovulation induction or assisted reproductive technology to achieve pregnancy. Patients with NCAH have a higher risk of miscarriage and may benefit from glucocorticoid treatment during pregnancy. WIDER IMPLICATIONS: Evidence-based diagnostic and treatment strategies are essential for the proper management of women with NCAH, especially considering that these patients may need different therapeutic strategies at different stages during their follow-up and that appropriate genetic counseling may prevent the occurrence of CAH in their children.",
keywords = "17-hydroxyprogesterone, 21-hydroxylase deficiency, Androgen excess, Hirsutism, Hyperandrogenism, Miscarriage, Non-classic congenital adrenal hyperplasia, Polycystic ovary syndrome, Pregnancy, Prematurepubarche",
author = "Enrico Carmina and Didier Dewailly and Escobar-Morreale, {H{\'e}ctor F.} and Fahrettin Kelestimur and Carlos Moran and Sharon Oberfield and Witchel, {Selma F.} and Ricardo Azziz",
year = "2017",
month = "9",
day = "1",
doi = "10.1093/humupd/dmx014",
language = "English (US)",
volume = "23",
pages = "580--599",
journal = "Human Reproduction Update",
issn = "1355-4786",
publisher = "Oxford University Press",
number = "5",

}

TY - JOUR

T1 - Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited

T2 - An update with a special focus on adolescent and adult women

AU - Carmina, Enrico

AU - Dewailly, Didier

AU - Escobar-Morreale, Héctor F.

AU - Kelestimur, Fahrettin

AU - Moran, Carlos

AU - Oberfield, Sharon

AU - Witchel, Selma F.

AU - Azziz, Ricardo

PY - 2017/9/1

Y1 - 2017/9/1

N2 - BACKGROUND: Non-classic congenital hyperplasia (NCAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by androgen excess. OBJECTIVE AND RATIONALE: We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of NCAH. A meta-analysis of epidemiological data was also performed. SEARCH METHODS: Peer-reviewed studies evaluating NCAH published up to October 2016 were reviewed. Multiple databases were searched including MEDLINE, EMBASE, Cochrane, ERIC, EBSCO, dissertation abstracts, and current contents. OUTCOMES: The worldwide prevalence of NCAH amongst women presenting with signs and symptoms of androgen excess is 4.2% (95% confidence interval: 3.2-5.4%). The clinical consequences of NCAH expand from infancy, i.e. accelerated growth, to adolescence and adulthood, i.e. premature pubarche, cutaneous symptoms and oligo-ovulation in a polycystic ovary syndrome (PCOS)-like clinical picture. The diagnosis of NCAH relies on serum 17-hydroxyprogesterone (17-OHP) concentrations. A basal 17-OHP concentration ≥2 ng/ml (6 nmol/l) should be used for screening if more appropriate in-house cut-offvalues are not available. Definitive diagnosis requires a 17-OHP concentration ≥10 ng/ml (30 nmol/l), either basally or after cosyntropin-stimulation. Molecular genetic analysis of the CYP21A2 gene, which is responsible for 21-hydroxylase activity, may be used for confirmation purposes and should be offered to all patients with NCAH along with genetic counseling because these patients frequently carry alleles that may result in classic CAH, the more severe form of the disease, in their progeny. Treatment must be individualized. Glucocorticoid replacement therapy may benefit pediatric patients with accelerated growth or advanced bone age or adult women seeking fertility, whereas adequate control of menstrual irregularity, hirsutism and other cutaneous symptoms is best served by the use of oral contraceptive pills and/or anti-androgens. Some women may need ovulation induction or assisted reproductive technology to achieve pregnancy. Patients with NCAH have a higher risk of miscarriage and may benefit from glucocorticoid treatment during pregnancy. WIDER IMPLICATIONS: Evidence-based diagnostic and treatment strategies are essential for the proper management of women with NCAH, especially considering that these patients may need different therapeutic strategies at different stages during their follow-up and that appropriate genetic counseling may prevent the occurrence of CAH in their children.

AB - BACKGROUND: Non-classic congenital hyperplasia (NCAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by androgen excess. OBJECTIVE AND RATIONALE: We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of NCAH. A meta-analysis of epidemiological data was also performed. SEARCH METHODS: Peer-reviewed studies evaluating NCAH published up to October 2016 were reviewed. Multiple databases were searched including MEDLINE, EMBASE, Cochrane, ERIC, EBSCO, dissertation abstracts, and current contents. OUTCOMES: The worldwide prevalence of NCAH amongst women presenting with signs and symptoms of androgen excess is 4.2% (95% confidence interval: 3.2-5.4%). The clinical consequences of NCAH expand from infancy, i.e. accelerated growth, to adolescence and adulthood, i.e. premature pubarche, cutaneous symptoms and oligo-ovulation in a polycystic ovary syndrome (PCOS)-like clinical picture. The diagnosis of NCAH relies on serum 17-hydroxyprogesterone (17-OHP) concentrations. A basal 17-OHP concentration ≥2 ng/ml (6 nmol/l) should be used for screening if more appropriate in-house cut-offvalues are not available. Definitive diagnosis requires a 17-OHP concentration ≥10 ng/ml (30 nmol/l), either basally or after cosyntropin-stimulation. Molecular genetic analysis of the CYP21A2 gene, which is responsible for 21-hydroxylase activity, may be used for confirmation purposes and should be offered to all patients with NCAH along with genetic counseling because these patients frequently carry alleles that may result in classic CAH, the more severe form of the disease, in their progeny. Treatment must be individualized. Glucocorticoid replacement therapy may benefit pediatric patients with accelerated growth or advanced bone age or adult women seeking fertility, whereas adequate control of menstrual irregularity, hirsutism and other cutaneous symptoms is best served by the use of oral contraceptive pills and/or anti-androgens. Some women may need ovulation induction or assisted reproductive technology to achieve pregnancy. Patients with NCAH have a higher risk of miscarriage and may benefit from glucocorticoid treatment during pregnancy. WIDER IMPLICATIONS: Evidence-based diagnostic and treatment strategies are essential for the proper management of women with NCAH, especially considering that these patients may need different therapeutic strategies at different stages during their follow-up and that appropriate genetic counseling may prevent the occurrence of CAH in their children.

KW - 17-hydroxyprogesterone

KW - 21-hydroxylase deficiency

KW - Androgen excess

KW - Hirsutism

KW - Hyperandrogenism

KW - Miscarriage

KW - Non-classic congenital adrenal hyperplasia

KW - Polycystic ovary syndrome

KW - Pregnancy

KW - Prematurepubarche

UR - http://www.scopus.com/inward/record.url?scp=85029418814&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029418814&partnerID=8YFLogxK

U2 - 10.1093/humupd/dmx014

DO - 10.1093/humupd/dmx014

M3 - Article

C2 - 28582566

AN - SCOPUS:85029418814

VL - 23

SP - 580

EP - 599

JO - Human Reproduction Update

JF - Human Reproduction Update

SN - 1355-4786

IS - 5

M1 - dmx014

ER -