Treatment and Outcome of Congenital Adrenal

International Journal of Pediatric Endocrinology
Treatment and Outcome of Congenital Adrena

l
Hyperplasia: 21-Hydroxylase Deficiency
Guest Editors: Peter A. Lee, John S. Fuqua, and Todd D. Nebesio
Treatment and Outcome of Congenital Adre

nal
Hyperplasia: 21-Hydroxylase Deciency
Treatment and Outcome of Congenital Adre

nal
Hyperplasia: 21-Hydroxylase Deciency
Guest Editors: Peter A. Lee, John S. Fuqua,
and Todd D. Nebesio
Copyright 2010 Hindawi Publishing Corporation. All rights reserved.

This is a special issue published in volume 2010 of International Journal of Pediatric Endocrinology. All articles are open access articles
distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Editor-in-Chief
Scott A. Rivkees, Yale University, USA
Senior Associate Editors

Fergus Cameron, Australia
Durval Damiani, Brazil
D. M. Styne, USA
Associate Editors
Lucia Ghizzoni, Italy
John Achermann, UK
Jerey Gruen, USA
Jesus Argente, Spain
Melvin Grumbach, USA
Rubina A. Heptulla, USA
Alicia Belgorosky, Chile
Andrew A. Bremer, USA
Peter C. Hindmarsh, UK
Z. Hochberg, Israel
Atilla Buyukgebiz, Turkey
Ali S. Calikoglu, USA
Paul L. Hofman, New Zealand
Ieuan A. Hughes, UK
Thomas O. Carpenter, USA
F. G. Cassorla, Chile
Ritika Kapoor, UK
Christopher J. H. Kelnar, UK
Liciano Cavallo, Italy
G. P. Chrousos, Greece
G. E. Krassas, Greece
Filiz Mine Cizmecioglu, Turkey S. H. LaFranchi, USA
P. Cohen, USA
Roberto Lanes, Venezuela
Wayne S. Cutfield, New Zealand P. A. Lee, USA
D. Daneman, Canada
Juliane Leger, France
Louis C. K. Low, Hong Kong
Mehul Dattani, UK
Cheri Deal, Canada
Xiaoping Luo, China
Markus Luster, Germany
Catherine Dinauer, USA
Horacio Domene, Argentina
Mohamad Maghnie, Italy
Veronica V. Mericq, Chile
Kim C. Donaghue, Australia
Erica A. Eugster, USA
Deborah Merke, USA
Walter Miller, USA
Hugo Fidele, Argentina
Louis J. Muglia, USA
Christa Flueck, Switzerland
Primus E. Mullis, Switzerland
Gary L. Francis, USA
M. Freemark, USA
Craig Munns, Australia
Myron Genel, USA
Maria New, USA

Stephen ORiordan, UK
Moshe Phillip, Israel
Michel Polak, France
Aman B. Pulungan, Indonesia
Michael Bernd Ranke, Germany
Robert G. Rapaport, USA
Allen W. Root, USA
A. L. Rosenbloom, USA
R. G. Rosenfeld, USA
Sonia Sachs, USA
Jerey Sachs, USA
Shadab Salehpour, Iran
David Sandberg, USA
Lars Savendahl, Sweden
D. A. Schatz, USA
Nalini S. Shah, India
Constantine A. Stratakis, USA
Byung-Kyu Suh, Korea
Louis Underwood, USA
Anju Virmani, India
Stuart A. Weinzimer, USA
Sei-Won Yang, Republic of Korea
David Zangen, Israel
Contents
Treatment and Outcome of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deciency, Peter A. Le
e,
John S. Fuqua, and Todd D. Nebesio
Volume 2010, Article ID 276843, 1 page
A Summary of the Endocrine Society Clinical Practice Guidelines on Congenital Adrenal Hyperpla
sia
due to Steroid 21-Hydroxylase Deciency, Phyllis W. Speiser, Ricardo Azziz, Laurence S. Baskin,
Lucia Ghizzoni, Terry W. Hensle, Deborah P. Merke, Heino F. L. Meyer-Bahlburg, Walter L. Miller,
Victor M. Montori, Sharon E. Oberfield, Martin Ritzen, and Perrin C. White
Volume 2010, Article ID 494173, 5 pages
Nonclassic Congenital Adrenal Hyperplasia, Selma Feldman Witchel and Ricardo Azziz
Management of the Adult with Congenital Adrenal Hyperplasia, Richard J. Auchus
Duration of Suppression of Adrenal Steroids after Glucocorticoid Administration, John S. Fuqua,
Deborah Rotenstein, and Peter A. Lee
Dexamethasone Therapy of Congenital Adrenal Hyperplasia and the Myth of the Growth Toxic
Glucocorticoid, Scott A. Rivkees
Nocturnal Dexamethasone versus Hydrocortisone for the Treatment of Children with Congenital
Adrenal Hyperplasia, Andrew Dauber, Henry A. Feldman, and Joseph A. Majzoub
Mineralocorticoid Deciency and Treatment in Congenital Adrenal Hyperplasia, Raja Padidela and
Peter C. Hindmarsh
Alternative Strategies for the Treatment of Classical Congenital Adrenal Hyperplasia: Pitfalls and
Promises, Karen J. Loechner, James T. McLaughlin, and Ali S. Calikoglu
Primary Caregivers of Children Aected by Disorders of Sex Development: Mental Health and Ca
regiver
Characteristics in the Context of Genital Ambiguity and Genitoplasty, David A. Fedele, Katherine Ki
rk,
Cortney Wolfe-Christensen, Timothy M. Phillips, Tom Mazur, Larry L. Mullins, Steven D. Chernausek, an
d
Amy B. Wisniewski
The Medical Home Concept and Congenital Adrenal Hyperplasia: A Comfortable Habitat!,
Selma Feldman Witchel
An Evidence-Based Model of Multidisciplinary Care for Patients and Families Aected by Classic
al
Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deciency, Traci L. Schaeer,
Jeanie B. Tryggestad, Ashwini Mallappa, Adam E. Hanna, Sowmya Krishnan, Steven D. Chernausek,
Laura J. Chalmers, William G. Reiner, Brad P. Kropp, and Amy B. Wisniewski
Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia:
Guidance from the CARES Foundation Initiative, Richard J. Auchus, Selma Feldman Witchel,
Kelly R. Leight, Javier Aisenberg, Ricardo Azziz, Tania A. Bachega, Linda A. Baker, Arlene B. Baratz,
Laurence S. Baskin, Sheri A. Berenbaum, David T. Breault, Barbara I. Cerame, Gerard S. Conway,
Erica A. Eugster, Stephanie Fracassa, John P. Gearhart, Mitchell E. Gener, Katharine B. Harris,
Richard S. Hurwitz, Aviva L. Katz, Brinda N. Kalro, Peter A. Lee, Gretchen Alger Lin, Karen J. Loechner,
Ian Marshall, Deborah P. Merke, Claude J. Migeon, Walter L. Miller, Tamara L. Nenadovich,
Sharon E. Oberfield, Kenneth A. Pass, Dix P. Poppas, Michele A. Lloyd-Puryear, Charmian A. Quigley,
Felix G. Riepe, Richard C. Rink, Scott A. Rivkees, David E. Sandberg, Traci L. Schaeer,
Richard N. Schlussel, Francis X. Schneck, Ellen W. Seely, Diane Snyder, Phyllis W. Speiser,
Bradford L. Therrell, Carol VanRyzin, Maria G. Vogiatzi, Michael P. Wajnrajch, Perrin C. White,
and Alan E. Zuckerman
The Role of Support Groups, Advocacy Groups, and Other Interested Parties in Improving the Care of
Patients with Congenital Adrenal Hyperplasia: Pleas and Warnings, Peter A. Lee and Christopher P. Houk
Growth and Reproductive Outcomes in Congenital Adrenal Hyperplasia, Todd D. Nebesio and
Erica A. Eugster
Long-Term Gynecological Outcomes in Women with Congenital Adrenal Hyperplasia due to
21-Hydroxylase Deciency, T. H. Johannsen, C. P. L. Ripa, E. Carlsen, J. Starup, O. H. Nielsen, M. Schwartz,
K. T. Drzewiecki, E. L. Mortensen, and K. M. Main
Bone Health Should Be an Important Concern in the Care of Patients Aected by 21 Hydroxylase
Deciency, Anne Bachelot, Zeina Chakhtoura, Dinane Samara-Boustani, Jerome Dulon, Philippe Touraine,
and Michel Polak
Congenital Adrenal Hyperplasia: Classication of Studies Employing Psychological Endpoints,
Stephanie A. Stout, Margarita Litvak, Natashia M. Robbins, and David E. Sandberg
Health-Related Quality of Life, Mental Health and Psychotherapeutic Considerations for Women
Diagnosed with a Disorder of Sexual Development: Congenital Adrenal Hyperplasia, Matthew A. Malouf,
Arpana G. Inman, Amanda G. Carr, Jill Franco, and Lindsey M. Brooks
Normal Intelligence in Female and Male Patients with Congenital Adrenal Hyperplasia,
Sheri A. Berenbaum, Kristina Korman Bryk, and Stephen C. Duck
Review of Outcome Information in 46,XX Patients with Congenital Adrenal Hyperplasia
Assigned/Reared Male: What Does It Say about Gender Assignment?, Peter A. Lee and
Christopher P. Houk
Hindawi Publishing Corporation

Volume 2010, Article ID 276843, 1 page
doi:10.1155/2010/276843
Editorial
Treatment and Outcome of Congenital Adrenal Hyperplasia:
21-Hydroxylase Deciency
Peter A. Lee,1, 2 John S. Fuqua,1 and Todd D. Nebesio1

1
2
James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46032, USA
Hershey Medical Center, Penn State University College of Medicine, Hershey, PA 17033, USA
Correspondence should be addressed to Peter A. Lee, leepa@iupui.edu

Received 31 December 2010; Accepted 31 December 2010
Copyright 2010 Peter A. Lee et al. This is an open access article distributed under the Creative Commons Attribution Licen
se,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The use of glucocorticoids to treat individuals with

congenital adrenal hyperplasia (CAH) was first reporte
d by
both Wilkins and Bartter in 1950. Since that time, the c
are
of these patients has improved dramatically, and th
rough
the eorts of dedicated medical researchers, it continues
to
improve today. With early detection by newborn screeni
ng,
initiation of treatment in infants with salt-wasting CAH
has
led to reduced morbidity and mortality. This special
issue
of the International Journal of Pediatric Endocrinolo
gy is
intended to review the state of the art in medical treat
ment
and psychological management as well as evaluations of t
he
outcomes of patients with CAH.
We begin with a summary of the recent Endocrine S
ociety Clinical Practice Guideline, which provides an overv
iew
of the diagnosis and treatment of CAH across the lifesp
an.
We then move on to discussions concerning the diag
nosis
and treatment of nonclassic CAH and the managem
ent of
the various forms of CAH in the adult patient. Alth
ough
hydrocortisone has been the treatment of choice for
many
years in children with CAH, more potent glucocortic
oids
such as dexamethasone are considered by some to be supe
rior. A series of articles addresses the choice of glucocor
ticoid
and the timing of administration. The section on treatm
ent
finishes with discussions of mineralocorticoid replace
ment
and newer therapeutic modalities.
The next section deals with psychological managemen
t,
specifically with regards to psychosocial stress in fam
ilies
of aected patients. We then move on to models

of care
provision, including establishment of a medic
al home,
multidisciplinary care, and a discussion of t
he roles of
support and advocacy groups in the care of individua
ls with
CAH.
Assessments of treatment outcomes are critical for eorts

to improve care. This issue finishes with a series of papers
reviewing CAH outcomes, including growth in children,
gynecologic and reproductive issues in women, bone health,
and psychological, cognitive, and gender identity outcomes.
The guest editors hope that this issue will, in a small
way, advance their understanding of CAH and stimulate

additional research and multidisciplinary teamwork, with
the goal of improving the lives of those aected with this
potentially devastating condition.
Peter A. Lee
John S. Fuqua
Todd D. Nebesio

doi:10.1155/2010/494173
Commentary
A Summary of the Endocrine Society Clinical Practice
Guidelines on Congenital Adrenal Hyperplasia due to Steroid
21-Hydroxylase Deciency
Phyllis W. Speiser,1 Ricardo Azziz,2 Laurence S. Baskin,3 Lucia Ghizzoni,4 Terry W. Hens
le,5
Deborah P. Merke,6 Heino F. L. Meyer-Bahlburg,7 Walter L. Miller,3 Victor M. Montori,8
Sharon E. Obereld,9 Martin Ritzen,10 and Perrin C. White11
1Division
of Pediatric Endocrinology, Cohen Childrens Medical Center of New York, Hofstra University School of Medicine,
400 Lakeville Rd., Suite 180, New Hyde Park, NY 11040, USA
2Cedars-Sinai Medical Center, Los Angeles, CA, USA
3University of California San Francisco, San Francisco, CA, USA
4University of Turin, Turin, Italy
5Columbia University, New York, NY, USA
6National Institutes of Health Clinical Center and The Eunice Kennedy Shriver National Institute of Child Health and
Human Development, Bethesda, MD, USA
7New York State Psychiatric Institute, Columbia University, New York, NY, USA
8Mayo Clinic, Rochester, MN, USA
9Childrens Hospital of New York-Presbyterian, Columbia University College of Physicians and Surgeons, New York, NY, USA
10Karolinska Institute, Stockholm, Sweden
11University of Texas Southwestern Medical Center, Dallas, TX, USA
Correspondence should be addressed to Phyllis W. Speiser, pspeiser@lij.edu
Received 11 March 2010; Accepted 24 March 2010
Copyright 2010 Phyllis W. Speiser et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properl
y
cited.
Steroid 21-hydroxylase deficiency accounts for about 95% of cases of congenital adrenal hyperplasia (CAH).
Newborns are
currently being screened for the classical forms of this disease throughout the United States and in 12 other countries. As su
ch,
it seems important to develop the best practice guidelines for treating not only infants and children, but aected adults as w
ell.
This report gives a brief overview of the most recent expert opinion and clinical practice guidelines for CAH as formulated by
The
Endocrine Society Task Force.
1. Introduction
The Endocrine Society, along with 6 sister medical soci

eties
in North America and Europe, as well as a patient educ
eort to include more information regarding adult patients.
ation
and support organization, recently sponsored the dev In addition, the 2010 Endocrine Society Guideline had the
benefit of panel members who are experts in evidence based
elopment of an updated set of guidelines for clinicians treati medicine, specifically, systematic literature review and metaanalysis. As readers may be aware, there are very few hig
ng
child and adult patients with congenital adrenal hyperpl h
quality randomized, controlled clinical trials dealing with
asia
CAH treatment. Notwithstanding this obstacle, the Task
(CAH) due to 21-hydroxylase deficiency [1]. The
Force combined the results of meta-analyses in two topical
reader is
referred to brief [2] and comprehensive [3] reviews of t and controversial areas of CAH treatment, with experts
opinions, tempered with valuable judgments to arrive at
his
disease for background. A Consensus Statement had be the recommendations. The guidelines were reviewed and
approved sequentially by The Endocrine Societys Clinical
en
published jointly by representatives of pediatric en
docrine
societies in 2002 [4, 5], and the present Task Force mad
e an
2
Guidelines Subcommittee and Clinical Aairs Core Com
mittee, members responding to a web posting, The Endocri
ne
Society Council, and finally by representatives of ea
ch of
the cosponsoring sister medical societies. At each stage t
he
Task Force incorporated changes in response to writ
ten
comments. Thus, the document represents the collec
tive
wisdom of a large and diverse group of practitioners.
The following is a summary of recommendations
presented in each of ten areas of interest. A descripti
on of
the GRADE system for ranking the quality of
medical
evidence is reviewed in [6]. In brief, recommendat
ions
are relatively firmly held and graded 1, whereas less
wellsupported suggestions are graded 2. The numbe
r of
symbols following recommendations and suggestions ree
ct
the strength of the evidence.
2. Newborn Screening
The Task Force believes that newborn screening for
CAH
due to 21-hydroxylase deficiency should be incorporat
ed
into all newborn screening programs (1
OO). Ideally, t
he
first-tier screening test, a 17-hydroxyprogesterone (17OHP)

immunoassay, should be standardized to one type of a
ssay.
At present most programs use DELFIA. We reco
mmend
that norms be stratified by gestational age
(1
OO),
rather than by birthweight [7]. Second-tier confi
rmatory
tests by liquid chromatography/tandem mass spectro
metry
are recommended to improve CAH screenings
positive
predictive value [8], presently hovering around 1% f
or most
US programs. As of this paper, the throughput o
f tandem
mass spectrometry is not fast enough for this metho
d to be
used as a primary screen. Each screening program, r
egion, or
country should adopt specific protocols to deal with p
ositive
newborn screens (1
OO).
3. Prenatal Treatment of CAH

Prenatal therapy to minimize virilization of aected
female
fetuses in empiric protocols with arbitrary fixed
doses of
dexamethasone administered from the mid-first t
rimester
have been in use for close to three decades [9, 10].
The lack
of adequately detailed and controlled long-term
follow-up
studies on the ospring of treated pregnancies is dis
appointing. In the centers with the most experience, fewer
than 50%
of mothers and ospring have responded to question
naires
(Meyer-Bahlburg, H, personal communication). The T

should be pooled. Noninvasive determination of fetal sex
ask
Force expressed concern about this, and about the f from fetal cell-free DNA in the mothers blood could help
avoid treatment of male fetuses. The latter technique is
act
that, as presently practiced, 7 unaected male fetuses widespread in Europe, but has not yet been approved for
commercial use in the United States. Additionally, it would
must
be of interest to determine whether the dexamethasone dose
be treated for each aected female. Numerous stud
could be reduced later in gestation to improve safety without
ies in
experimental animal models and retrospective studi sacrificing ecacy.
es of
human glucocorticoid (GC)-treated non-CAH pregnancie 4. Diagnosis of NCCAH/CAH after Infancy
s,
have revealed potential adverse eects (summarized in An early morning (before 0800) baseline serum 17-OHP by
[11]).
liquid chromatography/tandem mass spectrometry appears
For these reasons, prenatal therapy should be
to be the screening test of choice in symptomatic individpursued
uals after infancy (1
OO). A screening serum 17-OHP
through protocols approved by Institutional Review Boar greater than 6 nmol/l or 200 ng/dl [12] warrants obtaining
ds
a complete adrenocortical profile following cosyntropin
at centers capable of collecting outcomes data on a stimulation to dierentiate 21-hydroxylase deficiency from
suother enzyme defects and to make the diagnosis in borderline
ciently large number of patients so that risks and benefit cases (1
OO). Genotyping is now widely available and is
s of
helpful when results of the adrenocortical profile following
this treatment can be defined more precisely (2
OO). Tcosyntropin stimulation test are equivocal, or for purposes
o
of genetic counseling (2OOO).
this end, data from multicenter studies with similar pro
tocols
5. Medical Treatment of CAH in

Growing Patients
The GC of first choice for maintenance therapy of children

with CAH is hydrocortisone [13] in tablet form. For infants,
tablets may be crushed, weighed, and mixed with a small
amount of liquid and delivered immediately by medication
syringe, rather than from bulk suspension preparations that
deliver uneven doses (1O).
It is recognized that prednisolone and dexamethasone are sometimes useful in treating patients refractory to hydrocortisone [14], however, the
Task Force recommends against the routine chronic use of
long-acting potent GCs in growing patients (1
OO). All
patients with classic CAH should receive mineralocorticoid
(MC) supplementation in the form of oral udrocortisone
and sodium chloride supplements in the newborn period
and early infancy, and as needed throughout life (1
OO).
GC dosage should be increased in stressful situations
such as febrile illness (>38.5C), gastroenteritis with dehydration, surgery accompanied by general anesthesia, and
major trauma (1
OO). We recommend against the use
of increased GC doses in mental and emotional stress,
minor illness, and before physical exercise, as this would
greatly increase the frequency of supraphysiologic dosing
(1OOO). We also recommend against the use of stress
doses of GC in patients with nonclassic CAH unless their
adrenal function is suboptimal or iatrogenically suppressed
(1OOO). We suggest that patients who require treatment
always wear or carry medical identification indicating that
they have adrenal insuciency (2OOO).
Patients should be regularly monitored for signs of
GC excess, inadequate androgen suppression in cases of
inadequate GC treatment, or hypertension with excess MC
and/or sodium (1
OO). We recommend monitoring

treatment by consistently timed hormone measurem
ents
3
(1OOO). Endogenous adrenal steroid secretion
should
not be completely suppressed in order to avoid a
dverse
eects of overtreatment (1
OO). In
e
measurements, we suggest regular
ght,
weight, and physical examination;
X-ray
assessment is also suggested after 2
OOO).
addition to hormon
monitoring of hei
annual bone age
years of age (2
6. Treatment of NCCAH in Childhood

Nonclassic CAH (NCCAH) is not generally considere
d an
absolute indication for glucocorticoid or mineralocortico
id
replacement therapy. Children diagnosed with NC
CAH
should be oered treatment when they have inappropria
tely
early onset and rapid progression of pubarche or bone ag
e.
Adolescent females with overt virilization or erratic me
nses
may also benefit from treatment (2
OO). Asymptomati
c
individuals with NCCAH need not be treated (1
OO).
Moreover, previously treated NCCAH patients should
be
given the option of discontinuing therapy when
their
symptoms resolve (2
OO).
7. Complications of CAH
All GC-treated patients should be monitored for iatroge
nic
Cushing syndrome (1
OO). Elements of the visit helpfu
l
in this regard are the growth chart for height and
weight
in children, distribution of body fat, presence of pigment
ed
striae, blood pressure measurements, and blood gluc
ose
determinations. Since osteopenia and osteoporosis are r
are in
pediatric CAH patients, routine evaluation of bone mine
ral
density is discouraged in children, but should be consider
ed
in any patient who has been subjected to chronic hi
gh
doses of glucocorticoids or who has sustained fractu
res
(2OOO). Adrenal nodules have been identified
more
frequently in CAH patients and carriers than in the gen
eral
population [15], however, adrenal imaging (generall
y CT
scans) ought to be reserved for those patients who
have
an atypical clinical or biochemical course due to th
e high
radiation burden of frequent screening (2OOO). Ma
les
with classic CAH should be periodically scre

ened with
ultrasound for testicular adrenal rests [16]. The
latter can
often be managed medically by more eectively suppr
essing
the pituitary-adrenal axis.
8. Feminizing Surgery
The vast majority of genetic females aected w
ith classic
CAH have female gender identity and behavior, tom
boyish
play and male occupational preferences notwithsta
nding
[17, 18]. In addition, most aected women can bear
healthy
ospring, if desired [19]. This rationale is the basis
for the
suggestion that severely virilized (Prader stage 3) f
emales
be considered for clitoral and perineal reconstru
ction in
infancy. This type of surgery should only be perform
ed by
experienced surgeons in centers with similarly exper
ienced
pediatric endocrinologists, mental health profession
als, and
social work services (2
OO). At present, the proced
ures
favored by pediatric urologists are neurovascular-sparing

clitoroplasty and vaginoplasty using total or partial urogenital mobilization [20] (2OOO). Continued long-term
outcome studies of early surgery are to be encouraged.
9. Alternative Therapies
Preservation of statural growth potential is an important goal
for clinicians caring for CAH children. Suboptimal height
outcomes are potentially related to late diagnosis and treatment, overtreatment with glucocorticoids, or nonadherence
to the medical regimen. It is eminently possible to achieve
adult height within the normal range with standard steroid
therapy alone (mean height 1.0 SD corrected for parental
height among >1000 published cases [Muthusamy K et al.
JCEM, in press, 2010]). Thus, the Task Force recommends
against the use of alternative treatment approaches, for
example, growth hormone and/or treatment to delay puberty
or epiphyseal fusion for most children with CAH (1
OO).
Children with predicted height SD 2.25 may be considered
for such growth-promoting treatments in appropriately
controlled trials (2OOO). Further prospective, randomized, and carefully controlled studies would be helpful in
determining whether the use of growth-promoting drugs
increases adult height in patients with CAH (2OOO).
Unlike endogenous continuously variable cortisol secretion, current glucocorticoid replacement therapy is given
between once and three times daily. It would therefore be
desirable to develop new treatment approaches that could
4
Whereas adult males with classic CAH should contin
ue
their glucocorticoids indefinitely, men with NCCAH seldo
m
require treatment. Any CAH patient with impaired fertili
ty
should consult a reproductive endocrinologist and/or fert
ility specialist (2
OO).
In the adult population, long-acting glucocorticoids su
ch
as prednisolone and dexamethasone may be used judiciou
sly
without concern about growth inhibition, but pat
ients
should be monitored at least yearly for iatrogenic Cus
hing
syndrome. Clues to overtreatment include centripetal
obesity, striae, hypertension, glucose intolerance, and low b
one
density.
Genetic counseling should be given to parents of know
n
CAH patients preconceptually, or at birth of a first
CAH
child, and to aected adolescents at the transition to ad
ult
care (1OOO). A multidisciplinary team
consisting of
pediatric and adult endocrinologists, reproductive endo
cri-
both minimize daily GC exposure and more closely mimic

the physiologic state. Recent research eorts along these lines
have included a long-acting oral form of hydrocortisone [21]
and use of continuous subcutaneous hydrocortisone infusion
by insulin pump [22].
Bilateral adrenalectomy has been considered in selected
individuals who have failed medical therapy, especially in
adult females with SW CAH and infertility [23]. In all
such cases, the risk for noncompliance with postoperative
replacement therapy must be evaluated prior to surgery. The
Task Force advises against routine adrenalectomy to treat
CAH (2OOO).
10. CAH in Adulthood

As in younger subjects, when the diagnosis of NCCAH is suspected, screening may be done with an early morning serum
measurement of 17OHP by liquid chromatography and
tandem mass spectrometry. Menstruating women should
be screened in the early follicular phase of the menstrual
cycle [24]. If equivocal, the result should be confirmed by
performing a cosyntropin stimulation test before ordering
genotyping (1
OO). As discussed above, only individuals
with a significant degree of hyperandrogenism or those who
desire fertility need to be treated (2OOO). CAH women
should be screened for their gynecological history, and pelvic
examination should be performed beginning in adolescence.
Pelvic ultrasound should be reserved for CAH patients with
irregular menstrual cycles (2OOO).

nologists, gynecologists, and urologists is the ideal s
etting for
transitioning CAH patients to adult care (2OOO).
11. Pregnancy
Pregnant women with CAH are best followed joi
ntly by
endocrinologists and obstetricians, while continui
ng their
prepregnancy doses of hydrocortisone/prednisolon
e and
udrocortisone therapy. GC doses often need to be inc
reased
during pregnancy, and should be adjusted before sym
ptoms
and signs of GC insuciency occur. The usual
hormone
measurements to assess control are not informative
during
pregnancy. Stress doses of hydrocortisone should
be used
during labor and delivery. Dexamethasone should
not be
given to pregnant women with CAH, if the mot
her is the
treatment target. This drug is not inactivated by pla
cental 11hydroxysteroid dehydrogenase type 2, and as such ma
y cause
fetal adrenal suppression (1
OO).
12. Mental Health
It is suggested that patients with CAH and psychos [4] P. E. Clayton, W. L. Miller, S. E. Oberfield, et al., Consensus
statement on 21-hydroxylase deficiency from the European
ocial
Society for Paediatric Endocrinology and the Lawson Wilkins
Pediatric Endocrine Society, Hormone Research, vol. 58, no. 4,
problems associated with disorders of sexual develo
pp. 188195, 2002.
pment
be referred to mental health sta with specialized expe [5] P. E. Clayton, S. E. Oberfield, E. Martin Ritzen, et al., Consensus: consensus statement on 21-hydroxylase deficiency
rtise
from the Lawson Wilkins Pediatric Endocrine Society and
in managing such problems. Toward this goal, the T
the European Society for Pediatric Endocrinology, Journal
ask
of Clinical Endocrinology and Metabolism, vol. 87, no. 9, pp.
Force suggests the development, evaluation, and impleme
40484053, 2002.
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doi:10.1155/2010/625105
Review Article
Nonclassic Congenital Adrenal Hyperplasia
Selma Feldman Witchel1 and Ricardo Azziz2, 3
Division of Pediatric Endocrinology, Childrens Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine,
Pittsburgh, PA 15224, USA
2 Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
3 Department of Obstetrics and Gynecology, and Medicine, The David Geen School of Medicine at UCLA,
Los Angeles, CA 90095, USA
1
Correspondence should be addressed to Selma Feldman Witchel, selma.witchel@chp.edu

Received 3 March 2010; Accepted 5 April 2010
Academic Editor: Peter Allen Lee
Copyright 2010 S. F. Witchel and R. Azziz. This is an open access article distributed under the Creative Commons Attributi
on
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properl
y
cited.
Nonclassic congenital adrenal hyperplasia (NCAH) due to P450c21 (21-hydroxylase deficiency) is a common autosomal recess
ive
disorder. This disorder is due to mutations in the CYP21A2 gene which is located at chromosome 6p21. The clinical features
predominantly reect androgen excess rather than adrenal insuciency leading to an ascertainment bias favoring diagnosis i
n
females. Treatment goals include normal linear growth velocity and on-time puberty in aected children. For adolescent an
d
er
adult women, treatment goals include regularization of menses, prevention of progression of hirsutism, and fertility. This pap
will review key aspects regarding pathophysiology, diagnosis, and treatment of NCAH.
1. Introduction
Nonclassic congenital adrenal hyperplasia (NCAH) d
to nonclassic lipoid adrenal hyperplasia [7]. This review will

focus on NCAH due to CYP21A2 mutations.
2. Molecular Genetics
ue to
To date, 127 mutations have been reported in CYP21A2
P450c21 (21-hydroxylase) deficiency is a common
autosomal
(http://www.hgmd.cf.ac.uk/); these mutations range from
recessive disorder due to mutations in the CYP21A complete loss of enzyme function to partial enzyme activity.
2 gene.
Most of the mutations result from recombination between
This disorder was first described in 1957 by Decourt et the active gene, CYP21A2, and its highly homologous nonal.
functional pseudogene, CYP21A1P (i.e., gene conversion),
[1]. Reported prevalences in women with androgen which is located in close proximity within the HLA region
excess
on chromosome 6p21.3. Nevertheless, approximately 10
range from 0.6% to 9% (Table 1). Higher prevalences ha 12 mutations account for the majority of the aected
ve
alleles. The majority of the CYP21A2 mutations reported
been reported in Ashkenazi Jewish, Mediterranean, Mid to date are associated with simple virilizing or salt-wasting
dleclassic congenital adrenal hyperplasia (CAH). Functional
Eastern and Indian populations. Reported gene frequenc studies indicate that these mutations result in 05% residual
ies
enzymatic function [34].
vary among ethnic groups and geographic region [2, 3].
Functional analysis of mutations associated with NCAH
NCAH due to mutations in other steroidogenic generally indicates a 5080% loss of enzymatic (21enzyme genes, such as 11-hydroxylase
hydroxylase) function. Individuals with NCAH are generally
(CYP11B1) and
3-hydroxysteroid dehydrogenase (HSD3B2), is extre
mely
rare [4, 5]. The phenotypic spectrum for mutations in th
e
cytochrome P450 oxidoreductase (POR) gene has
been
expanded to include amenorrhea, infertility, and lo
w sex
steroid hormone levels [6]. Partial loss of function misse
nse
mutations in the steroidogenic acute regulatory
protein
(StAR) gene has been associated with nonclassic
lipoid
adrenal hyperplasia; mutations in the ACTH rec
eptor
(MC2R) gene or the melanocortin 2 receptor access
ory
protein (MRAP) gene are associated with phenotypes si
milar
Table 1: Prevalence of NCAH due to 21-hydroxylase deficiency among hyperandrogenic women.

Country
USA (NE)
USA (NE)
USA (NE)
USA (SE)
USA (SW)
USA (SE)
Canada
Puerto Rico
Ireland
England
France
France
Portugal
Italy (South)
Italy (North)
Italy (Palermo)
Spain
Czech Republic
Greece
Turkey (Ankara)
Turkey (Istanbul)
Turkey (Kayseri)
Turkey (Central Anatolia)
Israel
India
India
Total # of Women
22
139
164
86
83
873
72
100
96
50
400
69
129
372
85
950
270
298
107
32
61
285
63
170
60
63
# NCAH (%)
2 (9%)
2 (1.4%)
4 (2.4%)
2 (2.3%)
1 (1.2%)
18 (1.6%)
4 (5.5%)
1 (1.0%)
6 (6.2%)
1 (2.0%)
24 (6.0%)
16 (23%)
23 (17.8%)
14 (4.0%)
1 (1.1%)
41 (4.5%)
6 (2.2%)
8 (2.7%)
10 (9.3%)
1(3%)
20 (33%)
6 (2.1%)
6 (9.5%)
14 (8.2%)
3 (8.3%)
3 (5.7%)
Citation
Emans et al., 1983 [8]
Cobin et al., 1985 [9]
Azziz and Zacur, 1989 [10]
Azziz et al., 1993 [11]
Chetkowski et al., 1984 [12]
Azziz et al., 2004 [13]
Innanen and Vale, 1990 [14]
Romaguera et al., 2000 [15]
McLaughlin et al., 1990 [16]
Turner et al., 1992 [17]
Kuttenn et al., 1985 [18]
Blanche et al., 1997 [19]
Pall et al., (in press) [20]
Carmina et al., 1987 [21]
Motta et al., 1988 [22]
Carmina et al., 2006 [23]
Escobar-Morreale et al., 2008 [24]
Fanta et al., 2008 [25]
Trakakis et al., 2008 [26]
Akinci et al., 1992 [27]
Yarman et al., 2004 [28]
Unluhizarci et al., 2010 [29]
Kamel et al., 2003 [30]
Eldar-Geva et al., 1990 [31]
Mithal et al., 1988 [32]
Khandekar et al., 1990 [33]
adolescent girls.
compound heterozygotes bearing dierent CYP21A2 mut

ations on each allele. The missense mutation, V281L, acc
ounts
for at least one of the CYP21A2 alleles for most p
atients
with NCAH. This genetic variant is commonly identi
fied
among Eastern Europeans especially those of Ashke
nazi
Jewish descent. Other missense mutations associated
with
NCAH include P30L, P453S, and R339H. Novel mutation
s
associated with NCAH include R369W and I230T [35]. O
nehalf to two-thirds of individuals with NCAH carry one all
ele
encoding for a severe defect in enzyme function (wh
ich
would result in classic CAH if present on both alleles) a
nd
an allele encoding a mild defect in enzyme function on th
e
other allele. Roughly, phenotype correlates with mol
ecular
genotype and reects the residual activity of the mi
lder
mutation [3638]. Nevertheless, utilizing rigid criteria
to distinguish among salt wasting, simple virilizing and NCAH
can
be problematic because impaired 21-hydroxylase

function
represents a continuum of decreased enzyme activit
y.
3. Pathophysiology
In broad terms, the virilizing forms (simple
virilizing,
salt-wasting, and nonclassic) of CAH are charact
erized by
mutations that significantly impair cortisol biosynthe
sis and
lead to the accumulation of steroid intermediates proximal to

the deficient enzyme. The resulting loss of cortisol negative
feedback inhibition leads to increased hypothalamic corticotrophin releasing hormone (CRH) and pituitary adrenocorticotrophic hormone (ACTH) secretion. With decreased
P450c21 activity, conversions of 17-hydroxyprogesterone
(17-OHP) to 11-deoxycortisol, and progesterone (P4) to
deoxycorticosterone, are impaired. Elevated 17-OHP, P4,
and androstenedione concentrations are typically found.
The excessive ACTH stimulation also results in fasciculatareticularis zone hypertrophy, resulting in the adrenal hyper-

than the wild type. The net result is an increased precu
rsor
to product ratio, independent of ACTH levels. Hence, P4
and
17-OHP levels in these patients may remain above nor
mal
even in the presence of excessive glucocorticoid administ
ration [41]. In addition, genetic variations at other lo
ci may
inuence steroid metabolism and steroid responsivenes
s.
Alterations in ovarian and gonadotropic function, wit
h
the appearance of a polycystic ovary-like phenotype,
also
contribute to the androgen excess of these patients
[42,
43]. Functional ovarian abnormalities in patients with C
AH
and/or NCAH may relate to a number of etiologies, inclu
ding
disruption of the hypothalamic-pituitary-ovarian
(HPO)
axis by persistently elevated progesterones (e.g. P4
and/or
17-OHP) or androgens, and/or a direct glucocorti
coid
eect. Androgen excess impairs hypothalamic sensitivit
y to
progesterone resulting in a persistently rapid GnRH
pulse
frequency which favors LH hypersecretion [44]. This
LH
hypersecretion initiates and maintains a vicious cyc
le in
which excessive ovarian androgen secretion intensifies
the
consequences of the excessive adrenal androgen productio
n.
In fact, women with NCAH demonstrate higher LH conc
entrations than normal women [42]. Prenatal programmin
g of
the hypothalamus due to excessive in utero androgen exp
osure may contribute to LH hypersecretion and reproduct
ive
plasia typical of the syndrome, and possibly increased

adrenocortical nodularity. Individuals with NCAH generally
have adequate mineralocorticoid secretion.
Unfortunately, the pathophysiology of NCAH (and
CAH) is more complicated than this description would
suggest. For example, patients with NCAH usually have no
evidence of ACTH or CRH excess. In fact, some have an overresponsive glucocorticoid response to ACTH stimulation,
possibly reective of subtle adrenal hyperplasia [39]. Another
mechanism resulting in excessive adrenal androgen secretion
especially in NCAH results from the alteration in enzyme
kinetics due to the CYP21A2 missense mutations [40]. The
mutated enzyme protein is synthesized, but is less ecient
3
dysfunction among women with classical forms
of CAH
[45, 46]. However, in utero exposure to excessive an
drogens
is unlikely to play a major role in the pathophysiolog
y among
women with NCAH.
Finally, while the 17,20-lyase activity of P450c1
7 towards
4 substrates (conversion of 17-OHP to
androstenedione)
is not significant in humans, it is possible that
patients
with CAH and NCAH may experience increased andr
ogen
excess due to a backdoor or alternative pathway conv
erting
either P4 or 17-OHP to more potent androg
ens such
as dihydrotestosterone (DHT) [47]. Enzymes invo
lved in
this alternative pathway include 5-reductases
and 3hydroxysteroid dehydrogenases. The ovarian expre
ssion of
5-reductase may contribute to excessive ovarian and
rogen
secretion in NCAH as well as PCOS [48].
Overall, a more thorough understanding of th
e pathophysiologic mechanisms underlying the symptomatolo
gy of
NCAH will improve our ability to select eective the
rapeutic
regimens and choose reliable markers indicative of t
herapeutic success. For example, available data would sugge
st that the
measurement of P4 or 17-OHP may not be the most a
ccurate
marker of therapeutic ecacy, and suppression of ex
cessive
androgen secretion from both ovaries and adrenals
may be
necessary for optimum steroidogenic control.
4. Clinical Features
Individuals with NCAH generally present with signs were found to have NCAH; 17-OHP, androstenedione,
and testosterone concentrations were significantly elevated
and
among the children with NCAH compared to the remainder
symptoms of androgen excess rather than symptoms ree [49]. In a multicenter study including 220 individuals with
ctNCAH, 92%, 8%, and 4% of patients diagnosed under the
ing glucocorticoid deficiency. Children may present wi age of 10 years, 1019 years, and 2029 years, respectively,
th
had a history of premature adrenarche [50].
premature pubarche (i.e. the development of pubic
Additional features in children include tall stature,
hair,
accelerated linear growth velocity, and advanced skeletal
axillary hair, and/or increased apocrine odor prior t maturation. Examination of the external genitalia may reveal
o age
clitoral enlargement in some girls without genital ambiguity.
8 years in girls and age 9 years in boys). In one Phallic enlargement with prepubertal testes may be noted
study,
in boys. Although tall as children, the accelerated skeletal
4.2% of 238 French children with premature p maturation promotes premature epiphyseal fusion leading
ubarche
to short stature in adulthood. Typically, these symptoms are
more prominent among children with classic CAH.
During adolescence and adulthood, an ascertainment
bias favors the diagnosis in females due to the nature of the
hyperandrogenic symptoms. Symptoms include hirsutism,
acne, alopecia, anovulation, and menstrual dysfunction. In a
multicenter study, the most common symptoms among adolescent and adult women were hirsutism (59%), oligomenorrhea (54%), and acne (33%) [50]. Presenting symptoms
in 161 women with NCAH were hirsutism (78%), menstrual
dysfunction (54.7%), and decreased fertility (12%) [51].
Not all individuals with NCAH will be symptomatic. A
study of the phenotype/genotype relationship in 330 family
members revealed 9 symptomatic aected individuals, 42
clinically asymptomatic aected individuals, 242 heterozygotic carriers, and 37 unaected individuals [51]. As found
in this study, aected males are generally asymptomatic and
usually identified following the diagnosis of a female family member. Peripubertal gynecomastia and adrenocortical
incidentaloma are extremely uncommon presenting features
[52, 53].
4.1. Acne. Acne can occur among patients with hyperandrogenism and may be the primary clinical manifestation of
CAH. Severe cystic acne refractory to oral antibiotics and
retinoic acid has been attributed to NCAH.
4.2. Alopecia. Additionally, male pattern baldness in young
women with this disorder has been noted as the sole presenting symptom. Severe androgenic alopecia in association with
marked virilization has also been reported in older women.
4.3. Hirsutism. Hirsutism is defined as the excessive growth
of coarse terminal hairs in androgen-dependent areas.
Hirsutism must be distinguished from hypertrichosis which
is defined as generalized excessive growth of androgenindependent hair, and may be related to the use of certain
medications (e.g., phenytoin, minoxidil, diazoxide, glucocorticoids, and cyclosporine), familial factors, or metabolic
disorders (e.g., thyroid disturbances and anorexia nervosa).
The modified Ferriman-Gallwey score provides a semisubjective method to assess the magnitude of hair growth
in nine androgen-dependent areas such as the mustache
area, chin, upper chest, abdomen, and back [54]. Although
4
a modified Ferriman-Gallwey score of 6 to 8 is usu
ally

considered to indicate hirsutism, variation amon
g ethnic
groups occurs. Cosmetic treatments may reduce the
ability to
clinically detect hirsutism. Whereas hirsutism is uncom

mon
in children or young adolescents, the prevalence of hirsu
tism
and alopecia tends to increase over time [55]. Virilizatio
n and
masculinization are terms used to describe the presence
of
more severe symptoms of androgen excess. Specifically, these
terms refer to the presence of clitoromegaly, masculine
body
habitus, male pattern hair loss, and voice changes.
These
features, with the exception of occasional mild clitorome
galy,
are not typically present in NCAH patients.
4.4. Ovulation, Menstruation and Reproductive Fun
ction.
Women with NCAH often present with amenorrhea
(primary or secondary), chronic anovulation, and infert
ility.
Ultrasonography may demonstrate ovarian morpho
logy
reminiscent of polycystic ovary syndrome (PCOS). Polyc
ystic
ovary morphology may be present in about half of wome
n
with NCAH [56].
Many women with NCAH are relatively fertile [57, 58
].
However, NCAH carries a greater risk of subfertilit
y, in
part due to the prevailing ovulatory dysfunction. Report
s in
women with classic CAH suggest that elevated progestero
ne
concentrations play an important role in preventing
menstrual cyclicity and fecundity [59, 60]. Likewise, persist
ently
elevated levels of progesterones during the follicular
phase
in women with NCAH may interfere with the qualit
y of
cervical mucus, impeding penetration by sperm. In addi
tion,
elevated levels of 17-OHP and/or P4 during the preovula
ry
(follicular) phase of the menstrual cycle may re
sult in
inadequate endometrial maturation and impaired em
bryo
implantation.
Among 203 pregnancies in 101 women with NC
AH,
138 pregnancies preceded the mothers diagnosis of NC
AH.
Spontaneous miscarriages were more common in the pre
gnancies prior to NCAH diagnosis [57]. Another serie
s of
women with NCAH desiring pregnancy reported simi
lar
findings with a decrease in spontaneous miscarriages dur
ing
glucocorticoid treatment [61]. Potential limitations

of these
studies are that both are retrospective and larg
ely include
women ascertained by reproductive endocrinologist
s.
Since 21-hydroxylase deficient NCAH is an au
tosomal
recessive disorder, the recurrence risk is 25% for pr
egnancies
of the biological parents of the proband. Thus, siblin
gs of the
proband may benefit from diagnostic evaluation for
NCAH.
For women with NCAH, the risk of having a child wit
h saltlosing or simple virilizing classical forms of CA
H depends
in part on the probability that the father is a
carrier and
mothers genotype. Moran et al. found that the preva
lence
of 21-OH-deficiency among liveborn children was
2.5%
which was higher than the 0.2% calculated pre
valence. In
addition, at the time of the study 15% of children of
mothers
with NCAH had been also diagnosed with NCAH
[57].
Bidet et al. also found the prevalence of CAH to be g
reater
than anticipated [61]. The suggested explanatio
n for the
higher than expected prevalence of CAH and NCAH i
n these
populations may be the tendency for aected in
dividuals
to marry within their own ethnic background; some ethnic

groups are enriched for CYP21A2 variants.
5. Other Considerations
5.1. Precocious Puberty. Although more commonly observed
in children with classic CAH, skeletal maturation may be
significantly advanced among children with NCAH and
may be associated with gonadotropin-dependent precocious
puberty [62]. Typically, the signs and symptoms of puberty
become conspicuous after the initiation of glucocorticoid
treatment. In this situation, the hypothalamic GnRH pulse
generator prematurely resumes pulsatile GnRH secretion
leading to increased LH and FSH secretion resulting
in increased gonadal steroid production. The precocious
puberty is considered to be secondary to the excessive adrenal
steroid secretion and advanced skeletal maturation associated with NCAH. Some children with secondary GnRHdependent precocious puberty benefit from treatment with
GnRH-super agonists such as leuprolide acetate or histrelin.
5.2. Bone Mineral Density. Glucocorticoids inuence bone
metabolism by suppressing osteoblast activity, promoting
increased bone resorption by osteoclasts, and interfering
with calcium absorption from the gastrointestinal tract
[63]. Thus, the need for chronic glucocorticoid therapy
leads to concerns regarding bone density for individuals
with CAH. Since DXA is based on a two-dimensional
technique, interpretation of areal bone mineral density

diagnosed with NCAH; her genetic analysis showed V28
1L
and I172N [70]. A 57 year old man ascertained by findi
ng
an adrenal incidentaloma was diagnosed with NCAH
; he
had elevated serum 17-OHP concentrations and urinary
17ketosteroid excretion [71]. Adrenal myelolipomas have
been
reported among untreated adults with NCAH [72].
5.5. Contiguous Gene Deletion Syndrome. The CYP21A2
and
CYP21A1P genes map to the HLA complex at chromosom
e
6p21. Another gene located in this region of the g
enome
encodes for tenascin-X (TNXB). Tenascin-X is a
large
extracellular matrix protein which is expressed in the d
ermis
of the skin, and cardiac and skeletal connective tissue. L
oss of
function TNXB mutations are associated with hypermob
ility
Ehlers-Danlos syndrome [73]. Individuals with CYP2
1A2
deletions may have haploinsuciency for TNXB and
may
manifest joint hypermobility, joint subluxations, and ch
ronic
assessed by DXA scan can be confounded by bone width

and height. Thus, DXA can underestimate bone mineral
density in shorter individuals [64]. Available data, derived
from outcome reports for individuals with classic CAH, are
inconsistent due to varying glucocorticoid doses, potential
compliance issues, and subject heterogeneity [65, 66]. In
theory, inadequate treatment would lead to androgen excess
that would be anticipated, in turn, to increase BMD. On the
other hand, excessive glucocorticoid replacement treatment
would be expected decrease BMD. At this time, outcome
data regarding BMD in NCAH are limited. Nevertheless, it
has been suggested that maintaining vitamin D suciency
should be a goal for individuals with CAH [67].
5.3. Gonadal Rest Tumors. During early gestation, cells
destined to become the steroid producing cells of the adrenal
cortex and gonads dierentiate from neighboring regions
of the coelomic epithelium. Subsequently, some adrenal
precursor cells migrate, descend into the scrotum with the
testes, retain ACTH responsiveness, and can develop into
testicular adrenal rest tumors (TARTs) [68]. Such tumors
have generally been described in boys or men with classic
CAH and poor compliance [69]. Incomplete detection and
underdiagnosis of NCAH in men hinders accurate ascertainment of the frequency of TARTs in men with NCAH.
5.4. Adrenal Tumors. Adrenal tumors have rarely been identified among individuals with NCAH. Following discovery
of an adrenal incidentaloma, an 88 year old women was
5
musculoskeletal pain [74]. A girl with classic CAH w
as found
to have a quadricuspid aortic valve, single kidney, b
icornuate
uterus, and vesicoureteral reux [75]. Thus, it is po
ssible that
the Ehlers-Danlos phenotype could occur among
patients
with NCAH who carry a continuous gene deletion inv
olving
this region on one allele and V281L on the oth
er allele.
Nevertheless, to date, no such case has been report
ed.
5.6. Metabolic Consequences. Factors associated
with increased risk for metabolic consequences cluster i
n women
with NCAH. These factors include obesity, hyperten
sion, and
insulin resistance. The androgen excess may indepen
dently
contribute to this risk due to atherogenic lipid profile
s. Using
the minimal model to assess insulin sensitivity, insu
lin sensitivity was found to be decreased in six untreated non
obese
women with NCAH compared to control subjects
[76].
Comparison of metabolic parameters in women wit
h PCOS,
women with NCAH, and healthy control women showed adrenal hyperplasia, both CAH and NCAH, demonstrate
that
heterosexual preferences [82]. Despite the impression that
metabolic parameters were comparable among women w
women with NCAH primarily have postnatal androgen
ith
excess, the frequency of homosexuality and bisexuality was
NCAH, lean women with PCOS, and healthy control wo
slightly increased in one study compared to non-CAH
men
controls [82]. Limitations of this study include small sample
whereas metabolic dysfunction was evident in the o
size and cross-sectional design. It is also unclear how
bese
representative the subjects are relative to other women with
women with PCOS [20]. Available studies regarding ins
NCAH.
ulin
Infertility is inextricably related to self-esteem and
sensitivity have provided inconsistent results and g
psychosocial
adjustment. The anatomic concerns related to
enerally
women
with
classic CAH such as pain with vaginal peneinvolve women with classical forms of CAH [77, 78].
tration
are
generally
not germane for women with NCAH
Platelet dysfunction is another feature that c
[83].
As
surgical,
medical,
and psychological treatments
an be
associated with insulin resistance. To distinguish bet have improved, more women with classic and NCAH have
successfully completed pregnancies and given birth [84].
ween
the consequence of hyperandrogenism and hyperinsulinis
m,
7. Diagnosis
agonist-induced platelet function was studied. Wh
ereas
Individuals with the salt-wasting and simple virilizing forms
platelet aggregation in samples from women with P of CAH are generally recognized in the newborn period, and
COS
most aected females are detected by the genital ambiguity.
was high, platelet aggregation in samples from women wWithout a family history, males with classic CAH are
ith
identified through newborn screening programs. In general,
NCAH was comparable to the healthy controls [79].
newborn screening programs fail to detect individuals with
NCAH [85].
Newborn screening programs measure of 17-OHP in
6. Psychosocial Considerations and
whole
blood spots collected on filter paper. The 17-OHP
Quality of Life
results for infants with NCAH are often not as elevated
Gender role develops as a result of societys expec as those for infants with classic CAH. Another confounder
is that preterm infants, heterozygotic carriers, and sick
tations
infants have 17-OHP concentrations which overlap the
concerning behavior. Prenatal factors such as hormon concentrations measured in infants with NCAH. Thus,
es
imperfect recall occurs almost by design because of the need
and environmental exposures are hypothesized to inuenc to avoid excessive numbers of false positive results while
e
trying to maintain adequate sensitivity and specificity to
gender role. Yet, the specific details regarding how prena detect infants with classic CAH. Given the comparatively
tal
mild course of NCAH during childhood and the anxiety and
androgen exposure aects gender identity of girls with cl costs involved in false positive results, treatment based solely
assic
on elevated hormone levels in the absence of symptoms may
CAH remain to be clarified [80, 81]. Most women only increase the risk for iatrogenic adrenal insuciency
with
without any clear therapeutic benefit. Thus, risk/benefit
analysis of confirming the diagnosis of NCAH in a neonate
prior to the development of symptoms is unresolved due to
the lack of outcome data [86].
The clinical features of NCAH in postpubertal adults
may be dicult to dierentiate from those of the polycystic
ovary syndrome (PCOS) or, in children, from premature
adrenarche. Although random 17-OHP concentrations are
usually diagnostic in classical forms of CAH, random 17OHP concentrations may be within the normal range for
individuals with NCAH. Thus, the acute ACTH stimulation
test remains the gold standard to confirm decreased 21hydroxylase activity. Following collection of a blood sample
to measure baseline hormone concentrations, synthetic
ACTH (Cortrosyn, 0.25 mg) is administered. A second blood
sample is collected 3060 minutes later. Correlation of
hormone concentrations with genetic analyses has suggested
6
that mutations are likely to be identified on both alleles
when

the ACTH-stimulated 17-OHP value exceeds 150
0 ng/dL,
although a few NCAH patients, particularly if ol
der, will
demonstrate ACTH-stimulated 17-OHP levels between

1000
and 1500 ng/dL. In one study, among 123 women
with
NCAH confirmed by molecular CYP21A2 analysis, m
ean
basal 17-OHP and mean ACTH-stimulated 17-OHP
concentrations were 1300 1420 ng/dL and 4080 2040
ng/dL,
respectively [51].
In general, it is impractical to perform an acute ACT
H
stimulation test in all women suspected of NCAH (
e.g.
those with hyperandrogenic features or ovulatory/menstr
ual
dysfunction). Various investigators have suggested th
e use
of unstimulated levels of 17-OHP as a predictor of NCA
H
[24, 57, 87, 88]. Levels of 170300 ng/dL have
been found
to be useful as a screening tool, best if obtained in
the
morning and, most importantly (to reduce false positive
s),
in the follicular (preovulatory) phase of the menstrual c
ycle
Among 129 Portuguese women with hyperandrogenism a
nd
menstrual dysfunction, 87% of women with NCAH, 25%
of
lean women with PCOS, 20% of obese women with PCO
S,
and 7% of control women had basal 17-OHP concentrati
ons
>200 ng/dL [20]. In childhood, NCAH may present
with
premature adrenarche. In a sample of 238 French chil
dren
with premature pubic hair, of which 4.2% had NCAH, th
e
use of a 17-OHP cut-o value of greater than 200
ng/dL
provided a 100% sensitivity and 99% sensitivity fo
r the
detection of NCAH in this cohort [49].
Genetic testing should not be considered a firstline
diagnostic study in individuals suspected of NCAH.
However, genetic studies may be useful in those patien
ts (men
or women) who are considering future fertility. Gen
etic
testing can identify those individuals who are comp
ound
heterozygotes and may carry an allele encoding a se
vere
defect in CYP21A2. Overall, screening using morning
17OHP concentrations, obtained in the follicular phase
in
reproductive-aged females, and followed, if positive,
by an
acute ACTH stimulation remain the essential clinical to
ols to
diagnose NCAH.
8. Laboratory Analysis
Laboratory techniques used to measure 17-OHP i
nclude
radioimmunoassays (RIA), enzyme-linked immunoso
rbent
assays (EIA) and time-resolved uoroimmunoassays (
FIA).
While there may be variability between the lab
oratories,
our studies indicate a high degree of correlation
between
laboratories [50]. As noted above, the presence
of crossreacting steroids of fetal adrenal origin may hin
der the
interpretation of 17-OHP concentrations in prete
rm and
term infants. Recent technical improvement involve
tandem
mass spectrometry (MS) linked to liquid chroma
tography
(LC) [89]. Detection of 17-OHP from dried whol
e blood
spots using LC followed by tandem mass sp
ectrometry
(LC/MS/MS) has been reported [90]. The use of LC/
MS/MS
may improve the sensitivity and specificity of
newborn
screening. The use of LC/MS/MS is not only limi
ted to
newborns, the sensitivity and specificity of this t
echnique
make it applicable for 17-OHP determinations for children,

adolescents, and adults.
When considering genetic testing, an important limitation is that molecular genetic analysis can be confounded
by the complexity of the CYP21A2-CYP21A1P loci. Multiple
mutations can occur on one allele so that the identification
of two mutations does not always signify CAH because
both mutations may occur on the same allele (cis). Copy
number variation involving the CYP21A2-CYP21A1P region
may result in multiple copies of CYP21A2 on a single allele. In
addition, most commercially available screening panels assay
for the 1012 most common mutations, and may not be able
to detect all mutations [91]. Inclusion of a DNA sample from
at least one parent and/or a child may discriminate between
variants on the same (cis) or dierent (trans) alleles.
9. Treatment
Treatment needs to be directed towards the symptoms. In
other words, treatment should not be initiated merely to
decrease abnormally elevated hormone concentrations. Clinical goals of treatment include normal linear growth velocity,
normal rate of skeletal maturation, on-time puberty, and
appropriate weight status for children and adolescents.
For adolescent and adult women, goals of therapy include
regularization of menstrual cycles, prevention of progressive
hirsutism and acne, and fertility. For each child, adolescent,
and adult with NCAH, the benefits of treatment should
be weighed against the potential risks of acute adrenal

against the potential benefits of treatment. Most untreat
ed
individuals with NCAH manifest an adequate respon
se to
stress. One eective regimen involves hydrocortison
e, 6
15 mg/m2/day divided into three daily doses. Many clinic
ians
suggest that reverse circadian dosing with the highest hy
drocortisone dose at night provides improved control,
but no
consensus exists regarding how to divide the doses [56,
94].
All individuals on glucocorticoid therapy require instruc
tion
regarding stress doses, including parenteral therapy,
and
should wear medical alert identifying badges/jewelry.
For daily treatment, prednisone, prednisolone, or
dexamethasone may also be used in adults. Because of the p
otential detrimental eect of glucocorticoids on the fetu
s [95],
various practitioners suggest that a glucocorticoid t
hat is
inactivated by placental 11-hydroxysteroid
dehydrogenase
type II (e.g. hydrocortisone, prednisone, and prednisolo
ne)
insuciency secondary to iatrogenic adrenal suppression

due to glucocorticoid treatment. Treatment of hirsutism may
also necessitate adjunctive cosmetic methods such as laser,
electrolysis, and depilatories.
Glucocorticoid treatment can be utilized for children and
adolescents with significantly advanced skeletal maturation.
Although treatment with oral contraceptives alone may
be sucient in oligomenorrheic, acneic, or mildly hirsute
adolescents and adult women not seeking fertility, early
glucocorticoid treatment may be beneficial to decrease the
risk of persistent anovulation. In a crossover design involving
eight women with NCAH, oral contraceptive therapy was
associated with increased SHBG and decreased free testosterone concentrations. As would be anticipated, menstrual
cyclicity was restored with oral contraceptive therapy [92].
The use of anti-androgens (e.g. utamide, cyproterone
acetate, or finasteride) should also be considered in women
complaining of excess unwanted hair growth or scalp hair
loss (androgenic alopecia). Despite minimal changes in
testosterone and androstenedione concentrations, greater
improvement in hirsutism was noted with the use of cyproterone acetate compared to hydrocortisone among women
with NCAH [93]. Thus, for adolescent and adult women
with NCAH who are taking glucocorticoids, the addition of
oral contraceptives or anti-androgens may allow for lower
glucocorticoid dosage.
Among adults, treatment is generally reserved for symptomatic individuals, as the risks of iatrogenic adrenal suppression with glucocorticoid treatment need to be balanced
7
should be used in sexually active females who are no
t on a
highly eective contraceptive [95] or who become p
regnant,
unless specifically intending to suppress the fetal adre
nal (see
below). As the androgen secretory potential of t
he adrenal
cortex declines with age [96], the demand for glucoc
orticoids
to suppress adrenal androgen secretion in N
CAH may
ameliorate with age. Stress doses of hydrocortisone
are essential for aected individuals maintained on gluco
corticoid
treatment. For emergency situations, including l
abor and
delivery and surgery, the empiric stress dose is
parenteral
hydrocortisone (Solu-Cortef), 100 mg, IV or IM.
Laboratory goals include normalization of and
rostenedione and testosterone levels; alternatively, supp
ression of
DHEAS levels occurs with minimal doses of glucocor
ticoids.
Normalization of 17-OHP or P4 concentrations i
ndicates
excessive hormone replacement therapy, unless so int
ended
in patients seeking fertility (see below).
Women seeking fertility may benefit from the
use of
ovulatory agents (clomiphene or menotropins). Prelimin

and chromosomal sex are known, 7/8 fetuses are needlessly
arexposed to prenatal dexamethasone [100]. Overall, the risk of
ily, the preconception use of concomitant glucocortico
a patient with NCAH of having a child with CAH is relatively
ids
low (2.5%) [57]. Therefore, couples who conceive and whose
appears to reduce the risk of miscarriages in NCAH pati
genetic diagnosis is not known should not be considered for
ents
prenatal dexamethasone suppression, unless they have had a
conceiving [57]. In addition, in this setting max
prior child with salt-losing or simple virilizing CAH. Those
imum
choosing to use prenatal dexamethasone should do so only
suppression of 17-OHP and P4 could potentially allow m
as participants of IRB-approved research studies [101].
aximum endometrial proliferation and improve implantati
on.
10. Conclusions
In addition, all women with NCAH desiring to conc
Nonclassic congenital adrenal hyperplasia is a common autoeive
should undergo genetic screening to determine the presen somal recessive disorder that can present in childhood, adoce
lescence, and adulthood. The typical symptoms of hirsutism,
of severe CYP21A2 mutations (and, hence, the risk of h oligomenorrhea, infertility, acne, and premature pubarche
aving
lead to an ascertainment bias in favor of identifying aected
a child with CAH), and if a severe allele is presentwomen. The nature of the symptoms leads to consideration
then
of polycystic ovary syndrome in the dierential diagnosis.
genetic screening of the father should also be under Although NCAH is a genetic disorder, the use of morning
taken.
follicular phase 17-OHP concentrations and acute ACTH
Many of these patients benefit from preconception ge stimulation tests are essential diagnostic studies due t
netic
o
counseling.
the complexity of the CYP21A2 locus. Once the diagnosis
In patients who conceive and whose child is considere is confirmed, genetic analysis may be useful. The specific
d
treatment should be individualized and directed towards the
at high risk for intrauterine virilization (i.e. a individuals symptoms and current medical needs.
female
infant) consideration may be given to using hig
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11
Metabolism. In press.

doi:10.1155/2010/614107
Review Article
Management of the Adult with Congenital Adrenal Hyperplasi
a
Richard J. Auchus
Division of Endocrinology and Metabolism, Department of Internal Medicine, UT Southwestern Medical Center,
5323 Harry Hines Boulevard, Dallas, TX 75390-8857, USA
Correspondence should be addressed to Richard J. Auchus, richard.auchus@utsouthwestern.edu
Received 13 February 2010; Accepted 9 March 2010
Academic Editor: Peter Allen Lee
Copyright 2010 Richard J. Auchus. This is an open access article distributed under the Creative Commons Attribution Lice
nse,
Congenital adrenal hyperplasia (CAH), most commonly due to 21-hydroxylase deficiency (21OHD), has been studied by
pediatric
endocrinologists for decades. Advances in the care of these patients have enabled many of these children to reach adulthood
. In
contrast to the course and management of the disease in childhood, little is known about CAH in adults. In many patients, th
e
proclivity to salt-wasting crises decreases. Linear growth ceases, and reproductive function becomes an issue. Most importan
tly,
management must minimize the potential for long-term consequences of conventional therapies. Here we review the existing
literature regarding comorbidities of adults with 21OHD, goals of treatment, and approaches to therapy, with an emphasis on
need for improved management strategies.
1. Introduction
As discussed elsewhere, the congenital adrenal hyperpla
sias
(CAHs) are genetic defects in cortisol biosynthesis.
Low
cortisol removes feedback inhibition of adrenocorticotro
pin
(ACTH) secretion, which causes adrenal hyperplasia.
The
clinical consequences of CAH derive from both the shunti
ng
of cortisol precursors along other pathways and the biol
ogical activities of these precursors and their unusual meta
bolites, which accumulate above the block. Treatments
will
ideally replace the glucocorticoid deficiency and no

rmalize
both mineralocorticoid and androgen biosynthesis wi
thout
inducing untoward eects from the drugs thems
elves. The
most common cause of CAH is 21-hydroxylase d
eficiency
(21-OHD) [1], which aicts about 1 : 15,000 live bir
ths [2].
Since the introduction of cortisone therapy by
Wilkins et
al. in the early 1950s [3], these children have
been able
to survive into adulthood. Now that over a half
century
has passed, one would think that abundant infor
mation
would have accumulated on the care of adults
with CAH,
as is now the case for children [4]. Regrettably
, very little
is known about the physiology and management of a

dults
with CAH, and what is known is essentially limited to 21
1.1. Why Is So Little Known? Genetic disorders, which
OHD.
manifest with congenital disease, are largely the providence
of pediatrics. With the completion of the Human Genome
Project, internists have become more aware of genetic disorders, but largely the focus has been on susceptibility genes
for cancer, diabetes, and cardiovascular diseases. Training
in the care of patients with congenital biosynthetic defects,
such as glycogen storage diseases and CAH, is generally not
considered an important component of internal medicine
residencies and endocrinology fellowships.
Consequently, few doctors who care for adults, even
those at academic medical centers, are adequately trained or
interested in rare genetic diseases. This scenario is evidently
the case for CAH. Most internal medicine endocrinology
trainees will see only a few patients with CAH, mainly if
they rotate in the pediatric endocrinology clinic, and many
will never see a single adult with CAH during their training.
A search of the NIH CRISP database revealed only a few
grants awarded to the study of CAH in the last 5 years,
none of which were awarded to investigators in departments
of internal medicine. Without interest and research in
academic centers, there is little chance that internal medicine
endocrinology fellows will receive adequate training in
CAH.
2
1.2. Children Are Not Little Adults. The endocrine physi
ology
of childhood is dominated by growth and pubertal d
evelopment. Adults do neither, but they do age, and many ha
ve
children or at least wish to become parents. With age, t
hey are
prone to all the maladies of adult life, including heart di
sease,
osteoporosis, and cancer. Consequently, the focus and go
als
of treatment are quite dierent in adults and c
hildren.
Treatment of CAH in infancy and early childhood st
rives
first to prevent salt-wasting and hypotensive crises
due to
adrenal insuciency. Treatment of adults with CAH sho
uld
be tailored to meet the needs of the patient at the
present
time, but with a long-term view of mitigating consequen
ces
of therapy. As a rule, the medications used and intensit
y of
monitoring will vary as the objectives change with time
[5].
1.3. Young Adults with Chronic Diseases Are Weary of See
ing
Doctors. This feeling is particularly true if the doctor kn
ows
very little about their condition and shows little int
erest

or concern for their specific needs. Many patient
s with
CAH have stopped seeing physicians altogether a
nd have
discontinued corticosteroid replacement for long peri
ods of
time [6]. Women may become comfortable living in
a state
of androgen excess and may even experience fati
gue from
testosterone withdrawal if therapy is resumed.
Men with
CAH of experience few symptoms from reducing or s
topping
therapy, until they become seriously ill or their
testicular
rests become uncomfortably large. These considerati
ons are
important in understanding the approach to the adu
lt with
CAH, both medically and psychologically.
2. Physiology of CAH in Adults

Many of the general principles are the same as for c
hildren
with CAH, but the importance of the various fa
ctors is
considerably dierent. All subsequent discussion
will be
limited to 21-OHD.
2.1. Basic Adrenal Physiology. Cytochrome
P450c21
(CYP21A2) deficiency precludes aldosterone and
cortisol
synthesis, limiting steroidogenesis to the reactions catal

protein cytochrome b5 (b5) is low [8, 9]. In contrast, the
yzed
zona reticularisin which ACTH also stimulates steroid
by 3-hydroxysteroid dehydrogenase type 2 (3productionhas abundant CYP17A1, b5, and thus high
HSD2),
17,20-lyase activity, but these cells are deficient in 3-HSD2
cytochrome P450c17 (CYP17A1), and a bit to cytoc
and have robust DHEA-sulfotransferase activity (SULT2A1).
hrome
Furthermore, the adrenal gland lacks 17-HSD3, the enzyme
P450c11 (CYP11B1) (Figure 1(a)). Low cortisol incr
responsible for reduction of AD to T in the testis, but
eases
contains AKR1C3 (17-HSD5) [7], which has weak activity
ACTH production, ooding the adrenal steroidoge
in catalyzing this reaction [10]. Consequently, the adrenal
nic
gland of a patient with 21-OHD has high capacity to
machinery with upstream precursors (Figure 1(b)).
synthesize DHEAS, but little of this 19-carbon precursor
Over
escapes the adrenal as T.
time, the adrenals enlarge due to the chronic trophic sti
Alternative routes to 5-reduced, 19-carbon steroids have
mulus
been described in other species [11, 12]. These routes involve
of ACTH. Consequently, the adult adrenal of a patient w
the 5-reduction of 21-carbon pregnanes P4 and 17-OHP,
ith
followed by 3-reduction, to yield 5-pregnan-3-ol-2021-OHD makes large amounts of a few steroids, m
one (allopregnanolone) and its 17-hydroxy derivative, 5ainly
pregnane-3, 17-diol-20-one (Pdiol). Pdiol is then cleaved
progesterone (P4), 17-hydroxyprogesterone (17-OHP),
to androsterone by the 17,20-lyase activity of CYP17A1.
dehydroepiandrosterone and its sulfate (DHEA[S]), pl
Androsterone reduction by 17-HSD enzymes yields 5us
androstane-3, 17-diol (Adiol), which is metabolized by
lesser amounts of androstenedione (AD), testosteron
oxidative 3-HSD enzymes such as 17-HSD6 (RODH) [13]
e (T)
to DHT (Figure 2(b)). Via this pathway, DHT is formed
[7], and 21-deoxycortisolwhich has little glucocorti
without the intermediacy of T or AD [14]. Considerable
coid
genetic and biochemical evidence suggests that this route
or mineralocorticoid activity.
contributes to DHT formation and genital virilization in
Due to zonation, two critical enzyme activities requir
female fetuses with cytochrome P450-oxidoreductase defied
ciency, presumably due to the accumulation of 17-OHP [15
for T synthesis are physically separated in the adrenal g
18]. In 21-OHD, intra-adrenal 17-OHP accumulates as well;
land.
consequently, this pathway is likely to be important in the
The zona fasciculata cells, which contain 3-HSD2 activ
fetus with 21-OHD [19]. In adults with 21-OHD, however,
ity,
the pathway may not be very active, due to lower expression
also contain CYP17A1; however, these cells have low 17
of 5-reductase activity in the adult adrenal.
,20lyase activity because expression of the important c
ofactor
2.2. Extra-Adrenal Steroid Metabolism. Based on the above
discussion, the adrenal glands of adults with 21-OHD
produce little T and huge amounts of other steroids, yet none
are active hormones except for P4. Nevertheless, without
proper treatment, AD, T, and DHT concentrations are high
in women and men with 21-OHD, and a high proportion
of T in men with 21-OHD derives from the adrenal. This T is
produced by peripheral metabolism of the adrenal secretions,
primarily in the liver but also in skin and even target tissues.
The peripheral metabolism of steroids is more dicult to
define than the intra-adrenal steroidogenic pathways, due to
redundancy of enzymes, competing routes of metabolism,
and variability amongst individuals. Nevertheless, steroid
sulfatase (STS) is present in liver, skin, and many other tissues
[20], and these tissues also contain 3-HSD type 1 [21].
Conversion of AD to T is eciently catalyzed by 17-HSD3,
but its cognate gene is only expressed in the Leydig cell of
the testis. As mentioned above, 17-HSD5 also has weak
activity for conversion of AD to T [10], but other routes from
DHEA to T also exist. DHEA can be reduced by 17-HSD1,
which is an ecient enzyme [22], to androst-5-ene-3, 17diol, a substrate for 3-HSDs, yielding T (Figure 2(a)). Even
17-HSD2, which is thought of as an inactivating enzyme

Cholesterol
CYP11A1 StAR
3
Renin/AngII
Pregnenolone
3-HSD2
Progesterone
CYP21A 2 11-deoxy- CYP11B2 Cortico- CYP11B 2 18-hydroxy- CYP11B2

corticosterone
sterone
corticosterone
CYP17A1
Zona glomerulosa
CYP17A1
Zona fasciculata
17-hydroxy- 3-HSD2 17-hydroxy- CYP21A2 11-deoxy- CYP11B 1

Cortisol
pregnenolone
progesterone
cortisol
CYP17A1
Cyt b5
Aldosterone
CYP17A1
Cyt b5
AKR1C3
Dehydroepi- 3-HSD2
stenedione
androsterone
Zona reticularis
Testosterone
SULT2A1
Dehydroepiandrosterone
sulfate
Andro(a)
Renin/AngII
Cholesterol
CYP11A1 StAR
Pregnenolone
Progesterone
3-
CYP11B2
HSD2
Corticosterone
CYP11B2
CYP17A1
CYP17A1
Zona glomerulosa
2
17-hydroxy- 3-HSD217-hydroxypregnenolone
progesterone
CYP17A1
Cyt b5
CYP17A1
Cyt b5
androsterone
Aldosterone
CYP21A2 11-deoxycorticosterone CYP11B1

CYP21A 11-deoxyCortisol
cortisol
21-Deoxycortisol
Dehydroepi- 3-HSD2
18-hydroxy- CYP11B2
corticosterone
Zona fasciculata
Zona reticularis
Andro- AKR1C3
Testosterone
stenedione
SULT2A1
sulfate
(b)
Figure 1: Steroid biosynthesis in 21-OHD. (a): Normal steroid biosynthetic pathways within each zone of the human adrenal gland. The
dashed arrows indicate minor reactions. (b): Altered steroid biosynthesis in 21-OHD. The block (heavy vertical line) shunts precursors to
19-carbon steroids (heavy curved black arrow at left).
by eciently converting T to AD [23], achieves a p

seudoequilibrium in intact cells with 1-2% T generated from
AD
and increases the apparent potency of AD as an an
drogen
in model systems [24]. In liver and skin, 5-reductase ty
pe
1 [25] further activates T to DHT, but T and DHT
are
also substrates for UDP-glucuronyl transferases
(UGTs),
which conjugate active androgens and their metabolit

es for
excretion in the urine [26]. Consequently, the route(
s) from
DHEA to T even in normal women are not obvious, a
nd the
biochemistry is even more complex in 21-OHD, as a
ndrogen
precursor production is very high.
eral metabolism vary considerably amongst individuals and

might explain to some degree the dierences in disease
control for adults with 21-OHD. Conversely, greater accumulation of P4 can contribute to anovulation and infertility
in women with 21-OHD. For these reasons, not only
the control of steroids exiting the adrenal, but also the
In addition to peripheral conversion of DHEA[S] to

active androgens, P4, which accumulates 2 steps prior to
the block, can be 21-hydroxylated by hepatic cytochromes
P450 [27, 28] to yield 11-deoxycorticosterone (DOC), a
potent mineralocorticoid. The extent and routes of periph-

Cholesterol
pregnenolone
CYP11A1
StAR
Pregnenolone
Progesterone
3-HSD2
CYP17A1
CYP17A1
SRD5A1
17-hydroxy- 3-HSD2 17-hydroxyprogesterone
5-pregnan-17- AKR1C
5-pregnane-
ol-3, 20-dione
3, 17-diol-20-one
CYP17A1
Androsterone
AKR1C
5-dihydrotestosterone
17-HSD6
5-androstane3, 17-diol
Periphery Adrenal
(a)
sulfate
STS
SULT2A1
Dehydroepi- 3-HSD1
androsterone
CYP19A1
Androstenedione
AKR1C3
Estrone
17-HSD1
17-HSD1
Androstenediol
3-HSD1
Testosterone
CYP19A1
Estradiol
SRD5A
5-dihydrotestosterone
(b)
Figure 2: Alternate and peripheral androgen synthesis pathways. (a): the alternate or backdoor pathway to DHT, with intra- and extraadrenal compartments demarcated. (b): simplified diagram of peripheral androgen and estrogen metabolism.
As with physiology, the principles governing the treat

extra-adrenal metabolism of these steroids is an import
ant
consideration in understanding the physiology of CAH in
the
adult.
3. Management of CAH in Adults
ment
of adults with CAH share many similarities with
those for
children with CAH; however, the dierences relate t
o growth,
pubertal development, and fertility. In addition, the
care of
adults is often more individualized based on patient
choices
than in children.
3.1. General Approach to the Patient. As previously

mentioned, the treatment goals of patients with 21-OHD ev much less frequently, typically only during a severe concurrent illness. During childhood, tight control prevents
olve
with the transition to adulthood. Salt-wasting crises premature somatic growth and development of secondary
sexual characteristics, but both concerns are no longer
occur
germane in adulthood. The three major concerns for the
adult with 21-OHD are: (1) the prevention of adrenal and
gonadal hyperplasia and neoplasia; (2) the prevention of
long-term consequences of adrenal replacement therapies,
and (3) the restoration of fertility in those who desire to
have children. Consequently, the intensity and complexity
of treatment regimen is individualized and changed over
time to meet the needs of the patient and to optimize the
risk/benefit ratio.
Mineralocorticoid replacement with 9-udrocortisone
acetate, 0.050.2 mg/d, is usually continued, with the goal
of a suppressed or low-normal plasma renin activity, which
blunts the hypovolemic drive to ACTH production. In
most developed nations, the sodium content of the adult

diet is high, and salt craving in adults with 21OHD is
uncommon. In fact, children [29] and adults [30] w
ith
21-OHD are prone to develop hypertension, prompti
ng
reduction or rarely discontinuation of mineralocortic
oid
dosing, or the paradoxical need for antihypertensive
drugs
plus udrocortisone acetate. To titrate mineralocortic
oid
replacement, the serum potassium concentrations, pl
asma
renin activity, and blood pressure in the sitting and stan
ding
positions are monitored, with the goals of renin as
low as
possible, normokalemia, and lack of orthostasis.
Glucocorticoid replacement therapy remains of c
entral
importance in the adult with 21-OHD, despite the distur
bing
fact that many patients will discontinue or neglect
their
treatment for months at a time. Hydrocortisone re
mains
the safest drug for long-term replacement, as is the case
for
other forms of adrenal insuciency. Regimens that requ
ire 3
doses a day, as is often used in children to suppress adre
nal
19-carbon steroid production, pose compliance
diculties
for some adults with busy schedules. Most patients mana
ge
to take 2 doses a day consistently, patterned after
doses
used for adrenal insuciency, such as 1520 mg on arisi
ng
and 510 mg after the midday meal. The disadvanta
ge of
5
such a two-dose regimen is the tendency for ACTH t
o rise
robustly in the early morning hours prior to the first
dose,
which worsens control, at least for a few hours until
the first
dose. In children, several groups have found empiric
ally that
administration of the largest dose at bedtime is
associated
with tightest control of adrenal steroidogenesis. Oth
er groups
have argued that the half-life of hydrocortisone is so
short
that an evening dose is only eective in suppre
ssing the
morning ACTH rise if a highly supraphysiologic
dose is
administered, such that hydrocortisone should be giv
en during the day only [31]. Addition of an evening dose ca
n cause
poor sleep and worsen weight gain and other glucoco
rticoidrelated side eects, but not in all patients. Unf
ortunately,
well-designed and controlled studies comparing
various
regimens are lacking, so the clinician is advised to
generally
try the safest and most physiologic replacement
regimen,
and then to intensify therapy gradually if sympt
oms and
signs of undertreatment become evident. Sustain
ed-release
hydrocortisone preparations administered once d
aily with
promising pharmacokinetics have been developed [3
2], but
these products currently are not widely available.
To simplify dosing and to increase suppression of
ACTH,
synthetic glucocorticoids such as prednisone, prednis
olone,
methylprednisolone, and dexamethasone may be employe

the advantage of mitigating many of the side eects of
d.
taking these drugs chronically while utilizing their capacity
The problem with these drugs is that long-term
to suppress DHEAS production longer and more completely
usage
than hydrocortisone.
almost invariably results in iatrogenic Cushing synd
Chronic ACTH excess juxtaposed with chronic glucorome,
corticoid therapy, often at supraphysiologic doses, might
due to their potency and long half-life. Dexamethaso
place patients with 21-OHD at high risk for long-term
ne
complications [5]. The adrenal glands become progressively
needs only to be given once daily, with bedtime ad
hyperplastic in most patients with 21-OHD, and adrenal
ministumors, including massive myelolipomas [34], have been
tration being the most eective means to suppress
described. In addition to these tumors, a paradoxically
ACTH
increased prevalence of hypertension has been found in
and adrenal 19-carbon steroid production [31]. In f adolescents [29] and adults [30] with 21-OHD. Reduced
act,
bone mineral density has been found in 21-OHD in most
the suppressive eect of single dose of dexamet
studies [35, 36], but the degree is moderate, and frank
hasone
osteoporosis is uncommon. Other reports note a higher
on DHEAS production often lasts longer than 24 ho prevalence of glucose intolerance, obesity, and dyslipidemia
urs.
in adults with 21-OHD compared to controls [30], raising
Prednisolone or prednisone may also be used once
their risk for cardiovascular disease [37]. These health
daily
problems are similar to those maladies associated with poor
as in adrenal insuciency [33], but divided doses
quality of life in patients with adrenal insuciency [38]
may
or cured Cushings disease [39] after long-term followup.
be better in certain situations discussed below. Co Curiously, concomitant androgen excess might mitigate
mbined
some of the catabolic consequences of chronic glucocorticoid
regimens, using more potent steroids only a few da
exposure, and some benefit is suggested by the observation
ys per
that the increased risks appear not large, and major health
week, are more complicated, but this approach feat
problems are not consistently seen.
ures
Above all, the management of the patient with 21OHD should recognize that these patients are vulnerable
to all the other diseases that people without this condition
suer, and they require the same general healthcare as any
adult. Women should receive cervical smears, breast exams,
and/or mammograms at the standard ages, and men require
screening for prostate disease. Men and women should
have blood pressure and cholesterol screening, colon cancer
screening, education to avoid smoking and to follow a
healthy lifestyle, and care for acute illnesses. Glucocorticoid
doses should be increased for surgery and for acute illness
when volume depletion from high fever, vomiting, diarrhea,
or poor oral intake occursbut not for any minor illness or
injury.
3.2. Special Considerations for Women. In women with 21OHD, two additional key issues are: (1) whether androgen
excess symptoms are currently a problem, and (2) if the
patient trying to conceive a child now. At a minimum, all
women with 21-OHD must receive replacement doses of
hydrocortisone and udrocortisone acetate, as would any
other patient with adrenal insuciency. Higher doses and
more potent steroids are used to the extent demanded
by the two issues above. A normal serum testosterone
and absence of androgen excess symptoms indicate adequate glucocorticoid treatment. If not, measurement of
17-hydroxyprogesterone and androstenedione, preferably
in the follicular phase, will help to assess the degree of
control. Chronic normalization of 17-hydroxyprogesterone
indicates overtreatment and should be avoided, as values well
above normal are acceptable if androgen concentrations are
6
controlled and the patient is clinically well. The ex
ception
would be during specific times when fertility is sought.

Androgen excess is always a problem for these wo
men,
but the degree and its clinical consequences vary
tremen-
dously, and there is no reason to expose the woma

n to
higher doses of corticosteroids if no benefit will be deriv
ed.
If control has been poor in childhood, the patient s
eems
to be more vulnerable to androgen excess, possibly
due to
greater adrenal hyperplasia. In addition, women wit
h 21OHD often develop a secondary polycystic ovary syndrom
e
(PCOS), such that androgens and 17-OHP also derive fro
m
the ovaries and persists even after adrenal suppression
[40].
Consequently, menses may remain irregular even with g
ood
control of the adrenal axis. If pregnancy is not desired,
oral
contraceptive pills provide several benefits, including
lowering ovarian androgen production, maintaining mon
thly
menses, and raising sex hormone binding globulin (SHB
G),
which lowers free testosterone and mitigates some
of the
hyperandrogenism with lower doses of glucocorticoid the
rapy. Antiandrogen therapy is a logical approach for treat
ment
of 21-OHD, but with the exception of multidrug regimen
s
[41], has received little attention. Spironolactone, an e
ective
and inexpensive agent used to treat other forms of hirsu
tism
and PCOS, is dicult to use in 21-OHD because it
is
both androgen and mineralocorticoid receptor antago
nist,
which causes salt loss. With the exception of utam
ide
[41], androgen antagonists and 5-reductase inhi
bitors
(finasteride and dutasteride) have not been formally stud
ied
in women with 21-OHD, although some patients
have
experimented with regimens containing these drugs. To
pical
agents, such as eornithine cream, and mechanical method
s
(laser, electrolysis, shaving, and plucking) should n
ot be
neglected.
For women who are trying to become pregnant, 21OHD
introduces multiple barriers to conception. In the first pl
ace,
a minority of women with 21-OHD even attempt to bec
ome
pregnant [42], especially those with the most severe or
saltwasting disease [43]. The reasons for their not attempt
ing
pregnancy include vaginal abnormalities, such as inadeq
uate
caliber for coitus or strictures following repair [

43] and
dyspareunia [42]. Chronic hyperandrogenism adds p
hysical
and psychological challenges for these women. Finally
, even
in those who wish to become mothers, chronic oligoa
novulation is common due to high androgens and secondary
PCOS
[40], whereas high circulating progesterone [4
4], which
accumulates 2 steps behind the block, prevents f
avorable
endometrial maturation and cervical mucus formati
on [45].
Unlike the multiple options available for wo
men not
attempting pregnancy, the only approach that will im
prove
the hormonal milieu for ovulation and impla
ntation is
to intensify the glucocorticoid therapy, and the
clinician
should not be reluctant to use supraphysiologic dosin
g for
several months to accomplish this purpose. In a
ddition to
controlling androgen excess, follicular phase proge
sterone
should be suppressed below 2 nmol/L (0.6 ng/mL) to
favor
fertilization and implantation [46]. This goal can be
achieved
with prednisolone or hydrocortisone divided into 2 o
r more
commonly 3 daily doses, as an evening dose is often n
ecessary
to lower morning serum progesterone adequately. A r
ecent
report demonstrated that 21/23 women with 21-OHD who

desired pregnancy became pregnant and had live births using
these regimens [46]. In these women, prenatal therapy is
another issue if their spouse is a carrier; this topic is reviewed
elsewhere.
Despite years of work and innovative surgical approaches, vaginal reconstruction remains a major problem
in girls with 21-OHD. Often staged procedures are employed
with the goal of urinary hygiene and appropriate clitoral
reduction in the neonate. The trend now is to minimize
surgery in the newborn and child and to leave complete
establishment of an adequate vaginal orifice for when the
woman becomes sexually active. Consequently, many adult
women with 21-OHD face the need for definitive reconstruction surgery. The choice of procedure is important,
but the woman must be motivated to use lubricants and
dilatators regularly to obtain the best results and satisfaction.
Traditional skin or bowel grafts often give suboptimal results,
particularly in severely virilized girls [47]. Buccal mucosa
grafts have shown good results in series with limited followup
and may become a procedure of choice in the future [48, 49].
3.3. Special Considerations for Men. Men with 21-OHD are
spared the disturbing and disfiguring eect of contrasexual
hormone excess, which probably renders men with 21OHD more prone to neglect their treatment than women.
Unfortunately, men are not spared some of the long-term
health consequences of both 21-OHD and glucocorticoid
therapy, and male physiology and anatomy predispose these

men to other problems. Adrenal androgen excess, when
severe, can suppress gonadotropins and lead to testicular
atrophy and infertility [50]. Reduced fertility has been
observed in small cohorts of men with 21-OHD [5153], but
aberrant androgen metabolism is only one reason.
The second major cause of infertility and testicular
dysfunction in men with 21-OHD is the presence and
hyperplasia of adrenal rest tumors in the testes (TARTs).
The prevalence of TART in men with 21-OHD is as high as
50%, if ascertained by sensitive ultrasonography or magnetic
resonance imaging [51, 54]. These TARTs can become large
and cause pain in addition to impaired testicular function.
Treatment of the TARTs with intensified glucocorticoid
replacement may cause regression and restoration of normal
sperm counts [55].
At a minimum, men with 21-OHD should have an
annual testicular exam, and screening ultrasonography is
recommend by some authorities. If a mass is found, glucocorticoid treatment is intensified, such as dexamethasone
0.752 mg/d [55]. If the mass regresses, the treatment is
continued for several weeks to months until a satisfactory result is obtained. If the mass does not shrink with
dexamethasone, testicular cancer should be excluded by
referral to an urologist. Surgical resection of the TARTs
eectively controls testicular size and Leydig cell function
but fails to restore fertility [56]. It is likely that, when a
large TART is present, the testis is already damaged from
increased pressure in the testicular capsule, which reduces
testicular blood ow and obstructs the seminiferous tubules

[52, 53]. Consequently, if preservation of fertility is a pr
iority,
the TARTs should be managed early and aggressively
with
medical therapy.
Replacement doses of hydrocortisone suce for
most
men with 21-OHD, but which laboratory parameters sh
ould
be monitored to guide glucocorticoid dosing is not known
.
If the 17-OHP is normal, the patient is overtreated
, but
values up to about 100 nmol/L (3,000 ng/dL) are proba
bly
a good target. The goal is to have a normal testos
terone
and normal gonadal function in the absence of TARTs, an
d
men with a 17-OHP <3,000 are unlikely to have large T
ARTs
[57]. Measurement of adrostenedione and gonadotropi
ns
is appropriate if gonadal dysfunction becomes eviden
t to
determine if the adrenals or testes are the dominant sou
rce
of androgens. The presence of TARTs prompts intensificatio
n
of therapy to induce regression regardless of a
pparent
hormonal control.
7
3.4. Indications for and Consequences of Bilateral Adre
nalectomy Adults with 21-OHD. The curative potential of
bilateral adrenalectomy for children with 21-OHD ha
s been
recognized, and its utility has been debated aggr
essively
[58]. In adults with 21-OHD, unique indicati
ons have
arisen. First, massive adrenal myelolipomas may
develop
[34] and can be bilateral [59] and require surgical r
emoval.
Second, although infertility in both men and women i
s often
managed with intensified glucocorticoid therapy, ad
equate
control cannot be achieved medically in some ca
ses, and
surgical management is required. Restoration of fer
tility in
women [46, 60] and men [61] with 21-OHD after bil
ateral
or unilateral adrenalectomy, respectively, has been o
bserved
and should be considered as an alternative approach
.
4. Summary
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l

doi:10.1155/2010/712549
Review Article
Duration of Suppression of Adrenal Steroids after
Glucocorticoid Administration
John S. Fuqua,1 Deborah Rotenstein,2 and Peter A. Lee1, 3
Section of Pediatric Endocrinology and Diabetology, James Whitcomb Riley Hospital for Children,
School of Medicine, Indiana University, Indianapolis, IN 46202, USA
2 Pediatric Alliance, Pittsburgh, PA 15218, USA
3 The Milton S. Hershey Medical Center, College of Medicine, Pennsylvania State University,
Hershey, PA 17033, USA
1
Correspondence should be addressed to John S. Fuqua, jsfuqua@iupui.edu
Received 22 December 2009; Accepted 27 January 2010

Academic Editor: Todd Nebesio
Copyright 2010 John S. Fuqua et al. This is an open access article distributed under the Creative Commons Attribution Lic
Cortisol(nmol/L)
ense,
Hydrocortisone has long been the treatment of choice for congenital adrenal hyperplasia (CAH). However, treatment with this
medication remains problematic. Patients with 21-hydroxylase deficiency CAH have significant diurnal variation in the secreti
on
of 17-hydroxyprogesterone (17OHP). When considering treatment strategies, this variation must be considered along with th
e
pharmacokinetic and pharmacodynamic properties of exogenous glucocorticoids. Orally administered hydrocortisone is high
ly
bioavailable, but it has a short time to maximum concentration (Tmax) and half life (T1/2). While prednisone has a somewhat
longer Tmax and T1/2, they remain relatively short. There have been several studies of the pharmacodynamics of hydrocortiso
ne.
We present data indicating that the maximum eect of hydrocortisone in CAH patients is seen 3 hours after a morning dose.
After
ver,
an evening dose, suppression of adrenal hormones continues until approximately 0500 the next day. In both situations, howe
there is a large degree of intersubject variability. These data are consistent with earlier published studies. Use of alternate sp
ecimen
types, possibly in conjunction with delayed release hydrocortisone preparations under development, may allow the practitio
ner
to design a medication regimen that provides improved control of androgen secretion. Whatever dosing strategy is used, clini
cal
judgment is required to ensure the best outcome.
1. Introduction
2. Variability of Cortisol and

17-Hydroxyprogesterone (17OHP) Secretion
Glucocorticoids and mineralocorticoids are mainstays of When assessing the ecacy of CAH treatment with dierent
doses of glucocorticoids, one must take into account normal
the
diurnal secretory patterns. It has long been known that
treatment of individuals with congenital adrenal hyperp cortisol production rates range between 59 mg/m2/day. This
lasia
holds true for neonates, children, adolescents, and adults
(CAH). Several dierent glucocorticoids are in com [1, 2]. The serum concentration of cortisol in normal
individuals with typical sleep-wake patterns begins to rise
mon
use, including hydrocortisone, prednisone/prednisol at about 0400 and reaches its peak between 0700 an
one,
d
and dexamethasone. Each of these agents has dierent p 0900 [3]. Over time, this diurnal variation is constant
within individuals, although person-to-person variability
harmacokinetic and pharmacodynamic properties, and tailo is large [4]. Similarly, the variation of 17OHP secretion
ring
over a 24-hour period has long been recognized [5, 6].
their dosing to provide individualized and appropriate coUntreated subjects with CAH experience increasing serum
ntrol of adrenal androgen secretion remains a major clini
cal
challenge. In this article, we will review the secretory p
atterns
of adrenal steroids and discuss the pharmacokinetic
s of
hydrocortisone and prednisolone. We will then present d
ata
from ourselves and others regarding the pharmacodynam
ics
of hydrocortisone and review principles of treatment rel
ating
to steroid dosing.

concentrations of 17OHP between 2400 and
0400. After
1200, 17OHP levels spontaneously fall, although even a 2000

t
their nadir they remain much higher than normal [7,
1500
8].
In treated patients with CAH, a similar pattern is observed.
Charmandari et al. studied steroid secretory patterns in 36 1000
treated children and adolescents with CAH [9]. They divide
d
500
the 24-hour day into two periods: daytime, defined as 0400
1600, and nighttime, defined as 1600-0400. Mean 17O

HP
levels for 19 individuals who were relatively unsuppres
sed
were 5296 ng/dL during the daytime and 2350 ng/dL during
the nighttime. In the 17 subjects who were more completely
suppressed, this diurnal variation was present but not as
apparent. In this group, daytime 17OHP concentrations
averaged 59 ng/dL, and nighttime concentrations averaged
36 ng/dL.
Time (hours)
Oral
Intravenous
Figure 1: Pharmacokinetic profile following the morning admin-
3. Pharmacokinetics of Commonly Used

Glucocorticoids
An understanding of the pharmacokinetics of hydroc
ortisone and prednisone/prednisolone is helpful when planni
ng
a treatment regimen for CAH, particularly in regar
ds to
the timing of multiple doses and when adjusting do
ses to
improve control.
3.1. Hydrocortisone. Hydrocortisone is rapidly abs
orbed
after an oral dose, and concomitant food intake does
not
appear to prevent absorption [10]. Hydrocortisone
has a
high degree of intestinal permeability, crossing the inte
stinal
mucosa in a passive fashion. The bioavailability aft
er oral
administration is high, >90% [11], and the time to
peak
concentration (Tmax) is roughly 1-2 hours. However,
this
depends on the exact formulation administered, because
it
is thought that the rate dependent step in absorption is t
he
dissolution of hydrocortisone tablets [10]. The eliminati
on
half-life (T1/2) of hydrocortisone is also short, 1.82 hou
rs
following either oral or intravenous administration.
The
pharmacokinetics of hydrocortisone are nonlinear, in
part
due to extensive protein binding. As a result, highe
r doses
result in more rapid clearance rates [11]. Hence, d
oubling
the dose does not lead to doubling of the area
under
the curve of plasma hydrocortisone versus time.

A typical
pharmacokinetic profile of hydrocortisone is s
hown in
Figure 1.
3.2. Prednisone/Prednisolone. Similar to

hydrocortisone,
prednisone is also rapidly and nearly completely
absorbed
after an oral dose. However, prednisone itself is biol
ogically
inactive, and before having any eect, its 11keto group
must be reduced by hepatic 11--hydroxysteroid
dehydrogenase to form the active drug, prednisolone. Al
though
this transformation occurs rapidly, it does ac
count for
the delayed Tmax of prednisone versus prednisol
one (2.6
hours versus 1.3 hours, resp.) [11]. There is bi
directional
interconversion of prednisone and prednisolone, wit
h 76%
recycling, although the enzyme kinetics favor the for
mation
of prednisolone [13]. The T1/2 of both predniso
ne and
prednisolone have been reported to be 3-4 hours
. Studies
in children suggest that the T1/2 may be shorter, 2.2

hours [11, 14], possibly due to a more rapid clearance
rate [15]. The kinetics do not appear to be altered by
gastrointestinal disease or renal transplant status [16, 17],
but untreated hypothyroidism leads to a dramatic decrease
in clearance [18]. Prednisone/prednisolone has complex,
nonlinear pharmacokinetics due to protein binding which
becomes saturated at higher doses. This leads to increasing
clearance rates and a decrease

in the peak concentration
achieved per milligram dose. However, this phenomenon

has been recognized at doses well
those used for
above
nonstressed CAH patients [11].
Meanserum
testosteroneconcentration
afterAMhydrocortisone(ng/dL)
4. Pharmacodynamics of Commonly Used

Glucocorticoids

103
25
102
8
20
15
10
5
7
When used to treat CAH, both the pharmacokinetics and

pharmacodynamics of steroid preparations must be considered. Superimposed on the pharmacokinetics are the diurnal
variations in ACTH, cortisol, 17OHP, androstenedione, and
testosterone secretion. Thus, timing of administration of the
steroid relative to adrenal hormone secretion becomes a critical factor when interpreting subsequent levels. There have
been limited studies of the eectiveness of hydrocortisone
administration at suppressing endogenous hormone concentrations in subjects with CAH [8, 9, 19, 20]. The studies have
been performed almost exclusively in individuals receiving
hydrocortisone treatment, with only a few subjects receiving
prednisone.
We studied 16 subjects (9 males) with 21-hydroxylase
deficiency CAH at a mean age of 12.2 5 years who were
receiving hydrocortisone three times daily [19]. Institutional
review board approval and informed consent/assent were
obtained. After an overnight admission with their usual
evening hydrocortisone dose, subjects were administered
their usual morning dose of steroid after obtaining baseline
serum concentrations of 17OHP, androstenedione, and
Meanserum
androstenedioneconcentration
Meanserum
17-hydroxyprogesteroneconcentration
istration of intravenous and oral doses of hydrocortisone in 16

subjects with CAH, at a median age of 10.6 years. Figure taken from
[12]. Society for Endocrinology, 2001. Used with permission.

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International Journal of Pediatric Endocrinology