REVIEW ARTICLE
Adrenal Diseases During Pregnancy: Pathophysiology,
Diagnosis and Management Strategies
Mahdi Kamoun, MD, Mouna F. Mnif, PhD, Nadia Charfi, PhD, Faten H. Kacem, MD,
Basma B. Naceur, MD, Fatma Mnif, PhD, Mohamed Dammak, MD, Nabila Rekik, PhD
and Mohamed Abid, PhD
Abstract: Adrenal diseases—including disorders such as Cushing’s
syndrome, Addison’s disease, pheochromocytoma, primary hyperaldos-
teronism and congenital adrenal hyperplasia—are relatively rare in
pregnancy, but a timely diagnosis and proper treatment are critical
because these disorders can cause maternal and fetal morbidity and
mortality. Making the diagnosis of adrenal disorders in pregnancy is
challenging as symptoms associated with pregnancy are also seen in
adrenal diseases. In addition, pregnancy is marked by several endocrine
changes, including activation of the renin-angiotensin-aldosterone sys-
tem and the hypothalamic-pituitary-adrenal axis. The aim of this article
was to review the pathophysiology, clinical manifestation, diagnosis
and management of various adrenal disorders during pregnancy.
Key Indexing Terms: Pregnancy adrenal disease; Cushing’s syndrome;
Adrenal insufficiency; Pheochromocytoma; Primary hyperaldosteronism;
Congenital adrenal hyperplasia. [Am J Med Sci 2014;347(1):64–73.]
A drenal diseases—including disorders such as Cushing’s syn-
drome (CS), adrenal insufficiency (AI), pheochromocytoma,
primary hyperaldosteronism (PHA) and congenital adrenal hyper-
plasia (CAH)—are relatively rare in pregnancy, but a timely diag-
nosis and proper treatment are critical because these disorders can
cause maternal and fetal morbidity and mortality.1,2 They may
manifest for the first time during pregnancy or before pregnancy
undiagnosed or diagnosed and treated. They may present with
either hormonal hypofunction or hyperfunction.2 Making the
diagnosis of adrenal disorders in pregnancy is challenging as
symptoms associated with pregnancy are also seen in adrenal
diseases. In addition, the fetal-placental unit alters the maternal
endocrine function and hormonal feedback mechanisms and
the renin-angiotensin-aldosterone (RAAS) undergoes various
changes during pregnancy.1,2
The aim of this article was to review the pathophysiol-
ogy, clinical manifestation, diagnosis and management of
various adrenal disorders during pregnancy.
HYPOTHALAMUS-PITUITARY-ADRENAL AXIS
PHYSIOLOGY IN NORMAL PREGNANCY
Adrenal Steroidogenesis
Pregnancy is associated with marked changes in the
hypothalamus-pituitary-adrenal (HPA) axis, resulting in a state of
increasing HPA function. The fetoplacental unit has a marked
steroidogenic capacity, causing 2-fold to 3-fold increase in
From the Endocrinology Department, Hedi Chaker Hospital, Sfax,
Tunisia.
Submitted December 16, 2012; accepted in revised form January 21,
2013.
The authors have no financial or other conflicts of interest to disclose.
Correspondence: Mahdi Kamoun, MD, Endocrinology Department,
Hedi Chaker Hospital, Magida Boulila Avenue, 3029 Sfax, Tunisia (E-mail:
mahdi_kamoun@yahoo.fr).
64 The American Journal of the Medical Sciences
maternal plasma cortisol concentrations during pregnancy, and
these concentrations may overlap those seen in CS.3 The increases
in plasma cortisol are noted as early as 11 weeks of gestation
(Figure 1).4 Furthermore, placental estrogen production enhances
release of cortisol binding globulin (CBG) from the liver, leading
to an increase in total cortisol concentrations and a decrease in
cortisol clearance. With displacement of cortisol from CBG by
progesterone, plasma-free cortisol concentrations also rise.4,5 Sali-
vary cortisol, another measure of plasma-free cortisol, is more than
2-fold increase compared with nonpregnant controls in the third
trimester. Pregnancy is indeed considered to be a natural variant of
hypercortisolism. Plasma 17 hydroxysteroids rise during preg-
nancy as well.2
Plasma adrenocorticotropic hormone (ACTH) concentra-
tions rise dramatically through pregnancy, with a surge during
labor and delivery, followed by a rapid decrease within 2 days
postpartum (Figure 1).4 Placentally derived ACTH may be
a potential contributor to hypercortisolism in pregnancy. Simi-
larly, placental corticotropin-releasing hormone (CRH) rises sev-
eral 100-fold during pregnancy, reaching very high concentrations
at term1,2,6 (Figure 2). In contrast to CS and despite this state of
HPA axis activation, the normal maternal diurnal variation of
plasma cortisol is maintained throughout pregnancy.1,2,7
Renin-Angiotensin-Aldosterone System
Human pregnancy induces many changes in the RAAS
(Figure 3). Many studies have shown that in normal pregnancy,
there is an increase in almost all of the components of the
RAAS.9 There is an early increase in renin concentrations
because of extrarenal renin secretion by the ovaries and maternal
decidua and the stimulatory effect of estrogen on the renal renin
release (Figure 4).10 Angiotensinogen synthesis by the liver is
increased by the increased estrogen concentrations. This leads
to increase in serum angiotensin II and aldosterone concentra-
tions (Figure 5).2,8,11,12 Deoxycorticosterone, a potent mineralocor-
ticoid, increases from 2-fold normal in early pregnancy to more
than 100 ng/dL in the third trimester (Figure 5), which may
contribute to sodium retention of pregnancy.2,12,13
Progesterone, concentrations of which are markedly
increased in pregnancy, is a competitive inhibitor of aldosterone
in the distal tubule. It reduces sodium reabsorption and also
contributes to reduced systemic vascular resistance. Therefore,
the physiological effects of increased aldosterone are attenuated
in pregnancy.2 Progesterone also demonstrates an antikaliuretic
effect, and therefore, hypokalemia may be ameliorated during
pregnancy in women with PHA.14
Control of the Adrenal Cortex
In contrast to the usual negative feedback action of
cortisol in the hypothalamus, there is increased production in
placental CRH in response to cortisol (Figure 6).15 The effect of
placental CRH on maternal pituitary is unclear.16 Placental
ACTH is shown to be stimulated by CRH and seems to be

Volume 347, Number 1, January 2014
 Adrenal Diseases and Pregnancy

FIGURE 3. Sequential increases in plasma renin activity (mean 6

SE) during normal pregnancy and at 4 to 6 weeks postpartum in
a sample of 19 women. The data were normalized to postpartum
concentrations (control values represented by dashed lines).
Values are mean 6 SE.8 Asterisks denote differences in concen-
trations over time. *P , 0.05; ***P , 0.001. PP, postpartum; PRA,
plasma renin activity.

of “cortisol resistance” induced by elevation of progesterone

(Figure 6).16
It should also be noted that the fetus is protected in early
gestation from the effects of maternal hypercortisolism by
placental 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD
FIGURE 1. Serial increases in serum cortisol (B) and ACTH ( )  2). The latter converts active glucocorticoids—cortisol and cor-
during pregnancy in normal controls throughout pregnancy. Blood
ticosterone—to their inactive 11-keto-metabolites.16 However,
samples were obtained weekly from 5 normal pregnant women
and from 3 women during labor and on the second postpartum in late gestation, there is a reversal of 11b-HSD 2 activity in
day. In addition, umbilical cord plasma was obtained from the favor of the active hormone in the uterus that may contribute to
newborn infants of 3 of these subjects. The vertical bars correspond fetal lung maturation.17
to the magnitude of the standard error of the mean.4 Normal
concentrations in nonpregnant women: total plasma cortisol: 10 to
25 ng/mL; ACTH: 10 to 60 pg/mL. ACTH, adrenocorticotropic CUSHING’S SYNDROME
hormone; PP, postpartum.
CS is uncommon in pregnancy, likely because hyper-
cortisolism results in ovulatory disturbances and relative
not suppressible by glucocorticoids. There is also lack of sup-
infertility. To date, approximately 140 cases of CS in pregnancy
pression of cortisol after 1-mg dexamethasone because of the
have been reported.1
high concentrations of bound cortisol and the presence of a state

FIGURE 2. Mean plasma CRH concentrations in 203 women FIGURE 4. Distribution of active renin concentrations during
followed to term. CRH concentrations increase significantly dur- pregnancy and at 6 weeks PP in a sample of 7 normal pregnant
ing pregnancy and show a rapid acceleration after 25 weeks of women.10 The short horizontal lines represent the mean value.
gestation.6 CRH, corticotropin-releasing hormone. PP, postpartum.

Ó 2013 Lippincott Williams & Wilkins 65

Kamoun et al
FIGURE 5. Mean concentrations of cortisol, aldosterone and
deoxycorticosterone throughout normal pregnancy.4,12 NP,
nonpregnant value.
Etiologies
A benign adrenal tumor is more likely to be the cause of
CS in women who are pregnant.1,2 Of the total number of CS
cases, adrenal adenomas comprise about half of cases in preg-
nancy. This contrasts with the distribution of causes in the non-
pregnant women, in whom pituitary-dependent disease
predominates. Only about one third of the cases of CS in preg-
nancy are caused by pituitary tumors.1,2 This unusual pattern
may be attributed to the fact that patients with an adrenal ade-
noma are most likely to be purely cortisol producing, thus their
FIGURE 6. HPA axis during pregnancy. CRH is released from the
placenta into both the maternal and fetal compartments. There is
increased production in pCRH in response to cortisol. pACTH
stimulates the maternal adrenal gland. Estrogen increases CBG,
leading to an increase in total cortisol levels. Progesterone has
antiglucocorticoid effects in the mother. 11b-HSD 2 protects the
fetus from the effects of maternal cortisol. A, adrenal; ACTH,
adrenocorticotropin hormone; CRH, corticotropin-releasing hor-
mone; CBG, corticosteroid-binding globulin; H, hypothalamus;
P, pituitary; pACTH, placental adrenocorticotropin hormone;
pCRH, placental corticotropin-releasing hormone; 11b-HSD 2,
11b-hydroxysteroid dehydrogenase type 2.
66
ovulatory function remains unaffected.18 Less frequent causes
include adrenal carcinoma, ACTH-independent hyperplasia,
ectopic ACTH secretion and unspecified causes.19,20 In addi-
tion, several cases of pregnancy-dependent CS have been
described and are likely because of ectopic LH/hCG receptors
in the adrenal gland.21,22 Recurrent CS with postpartum remis-
sion has been reported as well.23
Clinical Features
The clinical presentation of CS in pregnancy may be
difficult to recognize, because pregnant women without true CS
may show symptoms and clinical features suggestive of hyper-
cortisolism, such as central weight gain, edema, moon facies,
abdominal striae, hypertension and glucose intolerance.1,2 Clues
to diagnosis of CS in pregnancy are that the striae are typically
large and purple compared with the white striae seen in normal
pregnancy. In addition to the abdominal wall, the striae in CS
may also involve the axilla, thighs and breasts.1,2
The presence of proximal myopathy, hypertension,
neuropsychiatric complications, hirsutism, acne and pathologic
fractures may also help to distinguish CS from normal
pregnancy symptoms.24
Diagnosis
The biochemical diagnosis of the CS in pregnancy is
more challenging than in the nonpregnant state and is
confounded by the normal pregnancy rise in total serum
cortisol, serum and urine free cortisol (UFC) and ACTH.
As in the nonpregnant state, investigation should occur
in 3 stages (Figure 7):
1. Screening test for hypercortisolemia
2. Definitive biochemical diagnosis
3. Determination of the etiology.
Screening and Definitive Diagnosis
Urinary or plasma cortisol concentrations in CS may
overlap with levels seen in normal pregnancy. Thus, random
measurement of these parameters is not helpful. The best
screening test in pregnancy is a 24-hour urine collection for free
cortisol.25 Lindsay et al20 have proposed that, during the second
and third trimesters of gestation, UFC concentrations greater
than 3 times the upper normal limit can be considered to be
consistent with pathological hypercortisolism. In addition, dem-
onstration of loss of circadian rhythm of free and total cortisol
could be helpful in establishing the diagnosis of CS in preg-
nancy.1 Midnight plasma or salivary cortisol concentrations
would therefore be helpful, but unfortunately, no pregnancy-
specific cutoff points have been developed.20
The 1.0-mg overnight dexamethasone suppression test is
inaccurate in patients during pregnancy because of false-
positive results during pregnancy due to blunted response to
dexamethasone.1,2,18
To conclude, current data suggest that a combination of
UFC concentrations greater than 3 times the upper normal limit
and elevated midnight plasma or salivary cortisol concentrations
could be the best strategies for screening and diagnosis of CS in
pregnancy.26
Determination of the Etiology
Once hypercortisolemia is confirmed, the next step is to
determine the cause and differentiate between pituitary adeno-
mas, adrenal tumors and other rarer causes.
In the nonpregnant population, measuring plasma ACTH
concentrations discriminates between ACTH-dependent and
Volume 347, Number 1, January 2014

FIGURE 7. Suggested diagnostic algorithm for CS in pregnancy.
ACTH, adrenocorticotropin hormone; CS, Cushing’s syndrome;
HDST, high-dose dexamethasone suppression test; MRI, magnetic
resonance imaging; UFC, urinary free cortisol; US, ultrasound.
ACTH-independent hypercortisolism. In pregnancy, ACTH
concentrations may be elevated irrespective of the etiology.
This is likely because of both the placental ACTH production
and the placental CRH-stimulated pituitary ACTH production.
Therefore, corticotropin concentrations are not useful in
distinguishing between pituitary and adrenal etiologies. How-
ever, if ACTH concentrations are suppressed, further bio-
chemistry tests may not be required and imaging of the
adrenals can be conducted.17
The role of the 8-mg overnight dexamethasone suppres-
sion test in pregnancy is unknown. Perhaps, it has utility in
distinguishing adrenal from pituitary causes of CS in preg-
nancy, whereas in nonpregnant population, this test aims to
distinguish Cushing’s disease from ectopic ACTH secretion.17
The role of CRH stimulation test and bilateral inferior
petrosal sinus corticotrophin sampling has not been clearly
defined and should only be considered for use when there is
persistent diagnostic uncertainty after ACTH measurement and
high-dose dexamethasone suppression test.17,26
Pituitary magnetic resonance imaging (MRI) with gadoli-
nium enhancement should be obtained in all nonpregnant patients
with suspected Cushing’s disease. During pregnancy, however,
the administration of gadolinium has not been proven to be safe
and should be avoided, at least during the first trimester. It should
be also noted that MRI during pregnancy may show more false-
positive diagnoses as the pituitary volume is usually increased.17
In cases with suppressed plasma ACTH concentrations
and failure to suppress serum cortisol after high-dose dexameth-
asone testing, adrenal imaging is recommended. Adrenal ultra-
sound imaging is safe but has limited sensitivity for smaller tumor
sizes. MRI is preferred to computed tomography during preg-
nancy because of the risks associated with ionizing radiation.17
Ó 2013 Lippincott Williams & Wilkins
Adrenal Diseases and Pregnancy
Maternal and Fetal Complications
The complications of CS to both the mother and the
fetus are severe. Maternal complications include hypertension,
pre-eclampsia, gestational diabetes mellitus, myopathy and
opportunistic infections. Premature labor occurs in more than
50% of cases. Hypercortisolism in pregnancy may also cause
poor wound healing, osteoporotic fracture, severe psychiatric
complications, congestive heart failure and death.1,2,24,27
The fetus may suffer from intrauterine growth restriction,
prematurity, mortality from spontaneous abortion and still-
birth.1,2,18,27 Fetal adrenal suppression occurs rarely, and signs
of glucocorticoid excess have not been reported, suggesting that
placental degradation of cortisol protects the fetus.27
Treatment
The fetal and maternal outcome seems to be improved
when the hypercortisolemic state is treated. Surgical treatment
is reported to be the most effective treatment option in
gestational CS.18 Transsphenoidal surgery has been conducted
successfully to treat Cushing’s disease, and in cases of adrenal
adenomas and carcinomas, adrenal surgery has successfully
been performed using a laparoscopic approach.28,29 Cortisol
replacement is required after both adrenal and pituitary surgery
and should be continued until the hypothalamic-pituitary-adre-
nal axis returns to normal.
If surgical therapy is contraindicated, medical therapy
may be considered. Metyrapone (inhibitor of 11b-hydroxylase)
has been used most frequently and has generally been well
tolerated. Other drugs such as ketoconazole or cyproheptadine
have been attempted in patients intolerant of metyrapone
despite their antiandrogenic effects and possible risk of intra-
uterine fetal growth restriction. Aminoglutethamide may cause
fetal masculinization, and mitotane is teratogenic, and both
should be avoided.18,29
ADRENAL INSUFFICIENCY
AI is very rare in pregnancy, and the exact prevalence is
unknown. In the largest series published to date, which comes
from Norway, the incidence of primary AI was 1:3000 pregnan-
cies. In this series, 5 women with AI gave birth to 6 children.30
Etiologies
Autoimmune adrenalitis is the most common cause of
primary AI in developed countries, and tuberculosis is more
common in the developing world. Both isolated autoimmune
adrenalitis and in the context of autoimmune polyglandular
syndrome type II (Addison’s disease, type 1 diabetes and thyroid
autoimmune disease) have been associated with pregnancy.1,31
Other causes include primary lymphocytic hypophysitis, fungal
infections, hemorrhage, bilateral metastases and infarction.1
Secondary AI may also occur as a result of hypothalamic
or pituitary diseases.1 The prevalence of AI because of long-
term exogenous corticosteroid administration is unknown, and
there are only a few case reports of this complication in
pregnancy.32,33
Clinical Presentation
Diagnosis of AI may be missed in the first trimester as
many clinical symptoms can occur in normal pregnancies such
as fatigue, dizziness, syncope, nausea and vomiting, weight loss
and increased pigmentation.1,2 Addisonian hyperpigmentation
may be distinguished from physiological skin changes in preg-
nancy by its presence on the mucous membranes, on extensor
surfaces and on nonexposed regions of the body.1,2 Excessive
67
Kamoun et al
dizziness, orthostatic hypotension, syncope, nausea, vomiting
and weight loss should evoke the diagnosis of AI, mainly if
there is personal or familial history of autoimmune diseases.34,35
Diagnosis
AI is associated with laboratory findings of hypona-
tremia (or a reduction in serum sodium . 5 mmol/L), hyper-
kalemia, hypoglycemia, eosinophilia and lymphocytosis.
Hyperkalemia is not always present, because of the pregnancy
increase in the RAAS. An early morning plasma cortisol con-
centration of ,3.0 mg/dL (83 nmol/L) confirms AI, whereas
a cortisol .19 mg/dL (525 nmol/L) in the first or early second
trimester excludes the diagnosis in a clinically stable patient.36,37
Plasma cortisol concentrations may be in the normal “nonpreg-
nant” range because of the increase in CBG concentrations in the
second and third trimesters but will not be appropriately elevated
for the stage of pregnancy.1
When the plasma cortisol concentration is low for
pregnancy and the plasma ACTH is elevated, primary AI is
diagnosed and the 250-mg corticotropin stimulation test should
be performed. Recently, normal basal and ACTH-stimulated
values have been established for pregnant women.38 The same
study found baseline and stimulated salivary cortisol concen-
trations to be a better measure of cortisol secretion.38 With
primary AI, ACTH concentrations will be elevated and a value
above 100 pg/mL (22 pmol/L) is consistent with the diagnosis.
However, ACTH will not be low with secondary forms because
of the placental production of this hormone. Adrenal antibodies
may assist in confirming idiopathic AI, as approximately 90%
of patients will have 21-hydroxylase antibodies.1,39
Maternal and Fetal Complications
According to the analyses from Norwegian and Swedish
registries, women with primary AI had a reduced parity. Concom-
itant autoimmune diseases such as premature ovarian insufficiency
and lack of androgens in women with primary AI are possible
causes of this subfertility.40–42 Appropriately treated patients can
expect to have uneventful pregnancies of normal duration and
without fetal complications. However, AI during pregnancy is asso-
ciated with a high incidence of serious fetal and maternal compli-
cations, such as suboptimal birth weight, intrauterine growth
retardation, preterm delivery and postpartum adrenal crises, if the
disorder is not recognized and adequately treated.40–42 Maternal
antiadrenal autoantibodies may cross the placenta, but usually not
in sufficient quantities to cause fetal or neonatal AI.
Treatment
Pregnant patients with AI should be managed in
a multidisciplinary center that includes an endocrinologist, an
obstetrician and a pituitary surgeon, if needed. Hydrocortisone
is the preferred glucocorticoid replacement treatment as it is
more physiologic than other available glucocorticoids and it is
degraded by the placental enzyme 11b-HSD 2; therefore, it
does not cross the placenta and only affects the mother. The
recommended dose is 12 to 15 mg/m2 of body surface area and
needs to be adjusted according to clinical judgment.35,40 Higher
doses are needed at times of stress and during onset of labor.1
Hydrocortisone 50 mg intravenous is generally given in the
second stage of labor, and further dosing can be adjusted based
on the course of labor. Because of the antimineralocorticoid
effect of progesterone, the fludrocortisone dose needs to be
increased depending on serum potassium and blood pressure.40
In an event of a cesarean delivery, intravenous or intramuscular
hydrocortisone at a dose of 100 mg should be given initially
and then every 6 to 8 hours, with tapering of the dose over the
68
next 48 hours. Patients who have received glucocorticoids as
anti-inflammatory therapy are presumed to have adrenal axis
suppression for at least 1 year. These patients should be treated
with stress doses of glucocorticoids during labor and delivery.40
PHEOCHROMOCYTOMA
Pheochromocytoma in pregnancy is rare with an inci-
dence of 0.007%.2,43 Yet, despite being an uncommon condi-
tion in pregnancy, its timely recognition is extremely important,
because if it remains undiagnosed and untreated, maternal and
fetal mortality amounts to 40% to 50%.2,43,44
Etiologies
Similar to the general population, most cases of pheo-
chromocytoma in pregnancy are sporadic and unilateral, with
10% being malignant, bilateral or familial (multiple endocrine
neoplasia II, von Hippel-Lindau’s syndrome and type 1 neuro-
fibromatosis).2 Rarely, the adrenal tumor may be a neuroblas-
toma and not a pheochromocytoma, and there have been case
reports of presentation during pregnancy.45
Clinical Presentation
The diagnosis of pheochromocytoma should be considered
in pregnant women with severe or paroxysmal hypertension,
particularly in the first half of pregnancy or in association with
orthostatic hypotension or episodic symptoms of pallor, anxiety,
headaches, palpitations, chest pain or diaphoresis. Symptoms may
occur or worsen during pregnancy because of the increased
vascularity of the tumor and mechanical factors such as pressure
from the expanding uterus.2 In addition, it has been suggested that
the maximum estrogen levels in pregnancy may serve as a growth
factor, leading to adrenal tumor amplification.44
It should be noted that there are several signs and
symptoms that may be of some help in differentiating pheochro-
mocytoma from pregnancy-related hypertension (gestational
hypertension and preeclampsia). The latter develops after
20 weeks and is typically continuous. In contrast, hypertension
in the context of pheochromocytoma can develop during any
gestational phase and is often paroxysmal. Other signs of
pregnancy-related hypertension, such as ankle edema, proteinuria
and an elevated plasma uric acid, are not compatible with
pheochromocytoma. The occurrence of hypertensive complica-
tions during pregnancy, such as heart failure, pulmonary edema
and unexplained shock, should evocate the diagnosis of pheo-
chromocytoma. Similarly, the presence of unexplained orthostatic
hypotension should arouse suspicion of pheochromocytoma
because this feature is uncommon in pregnancy-related hyper-
tension. Finally, a thorough physical examination should uncover
physical signs of type 1 neurofibromatosis, such as café au lait
spots, skin freckling or cutaneous fibromas.44
Diagnosis
No alteration in catecholamine metabolism develops
specifically because of the pregnant state. Therefore, laboratory
screening of pheochromocytoma is not different from that in
nonpregnant women and is usually based on the measurement
of plasma or 24-hour urinary metanephrine concentrations.2
Plasma fractionated free metanephrines provide the best test
for excluding or confirming pheochromocytoma with a high
sensitivity and should therefore be the test of first choice for
diagnosis of the tumor.46
Drug treatment is more likely to be a source of false-
positive than false-negative test results. In addition to cardiovas-
cular drugs (methyldopa and labetalol), tricyclic antidepressants
Volume 347, Number 1, January 2014

have to be considered as interfering sources of false-positive test
results.47 Provocative tests should be avoided because they have
an insufficient diagnostic accuracy and carry serious risks.48
Tumor localization should be initiated once biochemical
test results confirm the diagnosis of a catecholamine-secreting
tumor. MRI and ultrasonography are the preferred methods for
localization of tumors in pregnant patients because they avoid
exposing the fetus to ionizing radiation. Metaiodobenzylguani-
dine scintigraphy is not considered safe for pregnant women
and therefore is contraindicated in pregnancy.2,49 Figure 8
shows a suggested diagnostic algorithm for pheochromocytoma
in pregnancy, based on a stepwise analysis of gestational
hypertension.
Maternal and Fetal Complications
Pregnancy complicated by pheochromocytoma is a life-
threatening situation for both mother and fetus.44 As the uterus
enlarges and an actively moving fetus compresses the neo-
plasm, maternal complications such as severe hypertension,
hemorrhage into the neoplasm, hemodynamic collapse, myocar-
dial infarction, cardiac arrhythmias, congestive heart failure and
cerebral hemorrhage may occur.2,44
The highest risk of cardiovascular complications is in the
peripartum period. At that stage, the patient is particularly prone
to cardiovascular risks because of labor, abdominal palpation,
anesthesia, delivery or the use of certain medications like
analgesics. Frequently used antiemetic medications during preg-
nancy, such as metoclopramide, should also be avoided. All these
factors may precipitate a pheochromocytoma crisis by invoking
a sudden and strong tumoral release of catecholamines.44
FIGURE 8. Diagnostic and therapeutic strategy of pheochro-
mocytoma during pregnancy based on a stepwise evaluation of
hypertension. *Medical preparation with hypotensive drugs and
with first use of a-adrenoreceptor blockers. **After 24 weeks of
gestation, surgery may be performed after elective cesarean
delivery.
Ó 2013 Lippincott Williams & Wilkins
Adrenal Diseases and Pregnancy
There is minimal placental transfer of catecholamines,
likely because of high placental concentrations of catechol-O-
methyltransferase and monoamine oxidase. Adverse fetal effects
such as hypoxia are a result of catecholamine-induced uteropla-
cental vasoconstriction and placental insufficiency and a result of
maternal hypertension, hypotension or vascular collapse.44
Treatment
Preoperative management with alpha-adrenergic block-
ers (eg, phenoxybenzamine) is safe in pregnancy. Beta-blockers
(propranolol) should not be used without prior alpha-blockage
because unopposed alpha-adrenergic activity may lead to
vasoconstriction and a hypertensive crisis. Combined alpha-
and beta-blockers (eg, labetalol) have also been used in
pregnancy without adverse fetal effects.44 In addition, pregnant
patients should be advised to increase their salt and fluid intake
in this 2-week preparation period because this reduces the risk
of postoperative hypotension.50
The definitive treatment of pheochromocytoma is surgi-
cal removal. Laparoscopy is the new gold standard in treating
adrenal pheochromocytomas, with fewer intraoperative and
postoperative complications than conventional laparotomy.
Before 24 weeks of gestation, surgical excision may proceed
once adequate a-blockade is established, despite a high risk of
miscarriage. After 24 weeks of gestation, increasing uterine size
makes abdominal exploration and access to the tumor difficult.
Therefore, optimum results are obtained if surgery is delayed
and performed after elective cesarean delivery.44
Vaginal delivery has been associated with higher rates of
maternal mortality than cesarean delivery. Labor may result in
uncontrolled release of catecholamines secondary to pain and
uterine contractions.44,51 However, in the well-blocked patient,
vaginal delivery may be possible using intensive pain manage-
ment with epidural anesthesia.44,52
PRIMARY HYPERALDOSTERONISM
PHA is very uncommon in pregnancy (approximately
equal to 30 cases have been described since 1962).2,53
Etiologies
PHA in pregnancy is most often caused by an adrenal
adenoma.53,54 Only a few cases of idiopathic hyperaldosteron-
ism have been reported.55 There are also rare reports of gluco-
corticoid-remediable hyperaldosteronism, a hereditary form of
PHA, in pregnancy.2
Clinical Presentation
Suggestive features of PHA in pregnancy include
moderate to severe hypertension (85%), proteinuria (52%)
and hypokalemia (55%). Other symptoms may include head-
ache, malaise and muscle cramps.56,57
Hypertension usually worsens as the pregnancy pro-
gresses.58 Pregnant women with PHA can remain normoten-
sive, and in small cases, blood pressure can decline
spontaneously.55 This is likely because of the antagonizing
effect of progesterone on mineralocorticoid receptors and
peripheral vasorelaxation. The mechanisms for worsening of
hypertension or conversely for appearance of normotension
are unknown. A possible explanation is that hypertension might
persist or worsen when aldosterone concentrations exceed the
normal pregnancy range so that progesterone is no longer able
to antagonize its action.55
69
Kamoun et al
Diagnosis
The diagnosis of PHA is difficult in pregnancy. Urinary
potassium wasting can be less than that in nonpregnant women
with PHA because of the antimineralocorticoid effect of pro-
gesterone. The normal increase in aldosterone into the hyper-
aldosteronism range during pregnancy makes baseline plasma
aldosterone concentrations difficult to interpret. Plasma renin
concentrations should be decreased in PHA and are increased
during pregnancy. In pregnant patients with PHA, renin levels are
suppressed and are therefore helpful in diagnosis.2,17 The plasma
aldosterone concentration-to-plasma renin activity ratio may
improve diagnostic accuracy, but more normal data on this ratio
in pregnancy are probably required.56,59
Because of the potential risks associated with volume
expansion and captopril administration, a confirmatory test is not
required for the diagnosis of PHA in pregnancy.17 Imaging stud-
ies are necessary to localize adrenal adenomas. Ultrasonography
and MRI are the preferred imaging methods in pregnant women.2
Figure 9 summarizes approach of pregnant women with PHA.
Maternal and Fetal Complications
Pregnancies in patients with PHA are often characterized
by maternal and fetal complications, including end-organ
damage, placental abruption, preterm delivery, intrauterine
death and fetal distress.55
Treatment
If an adrenal adenoma is detected, unilateral adrenalec-
tomy is the treatment of choice. Laparoscopic adrenalectomy has
also been performed safely for pregnant patients, after a strict
FIGURE 9. Diagnosis and treatment algorithm for PHA during
pregnancy. *In cases of adrenal unilateral mass, medical treat-
ment is recommended if the HT is controlled and surgery is de-
layed until the postpartum period. HT, hypertension; PAC,
plasma aldosterone concentration; PHA, primary hyper-
aldosteronism; PRA, plasma renin activity.
70
preoperative blood pressure control.58,60 Surgical therapy may be
delayed until postpartum if hypertension can be controlled with
agents safe in pregnancy, such as amiloride, methyldopa, labeta-
lol and calcium channel blockers.59,61,62 There is little information
on the use of spironolactone in pregnancy. This drug crosses the
placenta and has antiandrogen action that can cause ambiguous
genitalia in a male fetus. Therefore, spironolactone is theoretically
contraindicated in pregnancy.2 Recently, Cabassi et al53 reported
a case of PHA during pregnancy, treated with eplerenone, a selec-
tive aldosterone receptor antagonist, but until now, there are no
enough data in the literature supporting or discouraging its use in
pregnancy.
ADRENAL INCIDENTALOMAS
Although the identification of an adrenal mass as an
incidental finding is common in the general adult population,
such findings have been only rarely described during preg-
nancy. This probably relates to the limited amount of imaging
conducted during pregnancy apart from obstetric ultrasound.2
In general, the approach to management of incidentally
discovered mass is to exclude hormonal hypersecretion and
differentiate malignant and benign lesions according to their
imaging characteristics.2,63 The balance of risks and benefits for
the surgical removal of adrenal incidentaloma during pregnancy
needs to be reassessed.2 Fallo et al64 reported a case of a preg-
nant woman with an adrenal mass discovered serendipitously,
who was followed up during gestation and underwent adrenal-
ectomy shortly after delivery. No evidence of adrenal change in
morphology and function was found throughout pregnancy.
Molecular and immunohistochemical analysis showed expres-
sion of estrogen receptors in the adrenal adenoma. The authors
concluded that estrogen oversecretion during pregnancy was
not a risk factor for tumor progression. Therefore, close obser-
vation with endocrine investigations and ultrasonography could
be an appropriate approach to patient with adrenal incidentalo-
ma during pregnancy, delaying the decision of surgical inter-
vention after delivery.64
FERTILITY AND PREGNANCY IN CAH
CAH refers to a group of inherited autosomal recessive
disorders that cause a deficiency in an adrenal enzyme, resulting
in altered cortisol and aldosterone secretion. The loss of
negative feedback inhibition by cortisol leads to increased
hypothalamic-pituitary-adrenal axis activity and subsequent
hyperplasia of the adrenal gland. The most frequent CAH
variant, accounting for 95% of all affected patients, is 21-
hydroxylase deficiency (21-OHD) and because of mutations in
the CYP21A2 gene.65
Different forms are recognized in CAH because of 21-
OHD: classic CAH, the most severe form comprises both salt-
wasting and simple virilizing forms and the nonclassic (NC)
form that may be asymptomatic or associated with signs of
postnatal or even adult onset androgen excess. The classic form
has a frequency of about 1 in 10,000 to 1 in 15,000 in the
general population, whereas the NC form is more common with
an estimated incidence of about 1 in 1,000.65
Reported Fertility and Pregnancy Rates in
CAH Women
Traditionally, reduced fertility and pregnancy rates have
been reported in women with classic CAH. Fertility rates of 60%–
80% and 7%–60% have been reported in women with classic
simple virilizing and classic salt-wasting CAH, respectively.66 Fer-
tility is only mildly reduced in NC form and seems to be mainly
Volume 347, Number 1, January 2014

because of hormonal imbalance. However, without glucocorticoid
treatment, an increased miscarriage rate has been reported.67,68
Pregnancies are commonly normal and uneventful in
women with classic CAH. Thus, fertility rather than pregnancy
rates seem to be reduced compared with the general population.69,70
More recent reports show significant increase in fertility
rates, even among patients with classic CAH, possibly as
a result of earlier treatment of CAH, improved compliance with
therapy and surgical advances in genital reconstruction.70
Causes of Subfertility in Women With CAH
Several factors have been suggested to contribute to this
subfertility such as androgen excess, adrenal progesterone
hypersecretion, consequences of genital reconstructive surgery,
secondary polycystic ovarian syndrome and psychosexual
factors.71–73
Gestational Management
The following guidelines are for the treatment of women
during pregnancy and delivery who have classic CAH resulting
from a 21-OHD.74
Maternal clinical status should be assessed regularly
during gestation to determine the need for increased glucocor-
ticoid or mineralocorticoid therapy. Excessive nausea, vomit-
ing, salt craving and poor weight gain may indicate AI.74 Blood
glucose should be monitored because gestational diabetes may
be more frequent among pregnant women with CAH.74 Mater-
nal hormone concentrations should be evaluated in the context
of laboratory-specific reference ranges for pregnancy.75 Free
testosterone concentrations should be targeted to the high nor-
mal range for pregnancy. Glucocorticoid replacement should
consist of either prednisolone or hydrocortisone because dexa-
methasone is not inactivated by placental 11b-HSD 2 and there-
fore can cause fetal adrenal suppression and low birth weight.74
During labor and delivery, the mother should receive increased
doses of hydrocortisone, as in distressing situations.74
Elective cesarean delivery should be considered espe-
cially for those who have had reconstructive surgery of external
genitalia. Women with CAH often have android pelvis
characteristics increasing risk for cephalopelvic disproportion
and dystocia.74
Although there have been few reports of masculinization
of external genitalia, this problem seems to be very rare and
girls born to women with CAH are generally unaffected. In fact,
the placenta serves as a metabolic barrier and reduces fetal
exposure to maternal androgens through placental aromatiza-
tion of maternal testosterone and androstenedione. Other
maternal factors that can contribute to fetal protection include
a reduction in bioavailable testosterone because of increased
sex hormone binding globulin concentrations and the potential
antiandrogenic effects of progesterone.72
CONCLUSIONS
Adrenal disorders in pregnancy are not common and
may be difficult to diagnose because many signs and
symptoms associated with pregnancy are also seen in adrenal
diseases. In addition, pregnancy is marked by several
endocrine changes, including activation of the RAAS and
the HPA axis. Despite being rare, adrenal disorders in
pregnancy can be associated with considerable fetal and
maternal mortality and morbidity if not recognized and
treated. Earlier recognition and treatment of these conditions
would improve outcomes for the fetus and mother.
Ó 2013 Lippincott Williams & Wilkins
Adrenal Diseases and Pregnancy
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