Management of Adrenal Tumors in Pregnancy
CrossMark
Deirdre Cocks Eschler, MDª,*, Nina Kogekar, BAb, Rachel Pessah-Pollack, MD, FACEC,d
KEYWORDS
. Pregnancy . Cushing syndrome . Adrenal cell carcinoma . Adrenal tumor
· Pheochromocytoma . Hyperaldosteronism
KEY POINTS
· Adrenal diseases including Cushing syndrome (CS), primary aldosteronism (PA), pheo- chromocytoma, and adrenocortical carcinoma are uncommon in pregnancy; a high de- gree of clinical suspicion must exist.
· Physiologic changes to the hypothalamus-pituitary-adrenal axis in a normal pregnancy result in increased cortisol, renin, and aldosterone levels, thus making the diagnosis of CS and PA in pregnancy challenging. However, catecholamines are not altered in preg- nancy and allow a laboratory diagnosis of pheochromocytoma that is similar to that of the nonpregnant state.
. Although adrenal tumors in pregnancy result in significant maternal and fetal morbidity, and sometimes mortality, early diagnosis and appropriate treatment often improve outcomes.
INTRODUCTION
Adrenal diseases, including Cushing syndrome (CS), primary aldosteronism (PA), pheochromocytoma, and adrenocortical carcinoma (ACC), are uncommon in preg- nancy. Normal physiologic changes to the hypothalamus-pituitary-adrenal (HPA) axis during pregnancy result in a physiologic hypercortisol state and changes in the renin-aldosterone-angiotensin system (RAAS) result in increased renin and aldoste- rone production in healthy pregnant women. Normal pregnant women are able to overcome these hormonal changes without adverse consequences, but such changes pose a challenge to the diagnosis of a disease state in pregnancy. Undiagnosed CS,
a Endocrinology Division, Department of Medicine, Stony Brook University School of Medicine, HSC T15-060, Stony Brook, NY 11794, USA; b Department of Medicine, Mount Sinai School of Medicine, 1 Gustave L Levy Place, New York, NY 10029, USA; ” Endocrinology Division, Depart- ment of Medicine, Mount Sinai School of Medicine, 1 Gustave L Levy Place, New York, NY 10029, USA; d Department of Endocrinology, ProHealth Care Associates, Ohio Drive, Lake Suc- cess, NY 11042, USA
* Corresponding author. 26 Research Way, East Setauket, NY 11733.
E-mail address: Deirdre.cocks.eschler@gmail.com
http://dx.doi.org/10.1016/j.ecl.2015.02.006
PA, pheochromocytoma, and ACC contribute to significant maternal and fetal morbidity and mortality. This article reviews the normal changes to the HPA axis in pregnancy and describes the diagnosis and management of adrenal disease during pregnancy.
Changes to the Hypothalamus-Pituitary-Adrenal Axis in Pregnancy
Changes in the HPA axis and the RAAS in pregnancy result in an increase in activity of both systems. Although the size and weight of the adrenal gland remain similar to the nonpregnant state, the zona fasciculata, the mostly cortisol-producing zone of the ad- renal gland, is reported to increase in pregnancy.1,2
Hypothalamic-pituitary-adrenal axis
In healthy women, total and free plasma cortisol, adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH), cortisol binding globulin (CBG), and urinary free cortisol (UFC) all increase in pregnancy. Placental CRH is similar to hypo- thalamic CRH,3 although it does not follow a circadian pattern.4 Placental CRH stim- ulates the placenta to produce ACTH,5 which in turn stimulates the maternal adrenal glands to produce cortisol. In addition, the maternal adrenal glands are more respon- sive to ACTH during pregnancy,6 resulting in an increase in free serum cortisol levels and UFC.3 Although much of placental ACTH production is autonomous7 and fails to respond to the negative feedback of glucocorticoids,8 maternal serum cortisol has a positive feedback on placental CRH, further increasing its levels.9 Placental CRH may also stimulate the maternal pituitary to release ACTH.10 Estrogen from the placenta also plays a role by stimulating the production of CBG from the liver, resulting in increased bound and total serum cortisol levels. Progesterone from the placenta may have an antiglucocorticoid effect that contributes to the increase in free cortisol as well, because it creates a state of relative glucocorticoid resistance.11 In addition, there may be an altered set point for pituitary ACTH response to cortisol feedback, with tissues more refractory to cortisol (Box 1).6,7
Although the initial increase in CBG early in pregnancy produces a transient reduc- tion in free cortisol level, maternal ACTH levels increase in response, resulting in a normal cortisol level early in pregnancy3 and increasing cortisol levels at as early as 11 weeks gestation.12 A progressive increase has been described in total and free plasma cortisol, CBG, and 24-hour UFC levels throughout each trimester with free cortisol levels increasing by 1.2-fold, 1.4-fold, and 1.6-fold, and with 24 hour UFC level increasing 1.7-fold, 2.4-fold, and 3.1-fold compared with a control group in the first, second, and third trimesters respectively.13 Maternal serum CRH, derived mostly from the placenta, becomes detectable then steadily begins to increase starting in the middle of the second trimester, with a sharp upswing at the end of gestation. 14,15 ACTH values also increase throughout pregnancy beginning in the late first trimester and peaking during labor and delivery.16,17 CRH and ACTH levels return to nonpreg- nant values within 24 hours of delivery.18 At 2 to 3 months postpartum, plasma free cortisol and UFC levels return to baseline but CBG and total plasma cortisol levels remain increased.13 Although cortisol levels increase throughout pregnancy, diurnal variations of cortisol remain in pregnancy, but with a higher evening nadir.4,6,12
Renin-angiotensin-aldosterone system
Maternal progesterone levels increase throughout gestation, mostly as a result of placental progesterone production.19 Progesterone acts as an antagonist to the mineralocorticoid receptor, likely at the renal tubule level.2º This process results in an increase in sodium secretion20 and an increase in aldosterone production.21 This
Box 1 HPA axis changes in a normal pregnancy
· Increase in zona fasciculata in adrenal gland1,2
. Increase in total and free cortisol and UFC
o Starting about 11 weeks’ gestation
o Free cortisol levels by 1.2-fold, 1.4-fold, and 1.6-fold and 24-hour UFC by 1.7-fold, 2.4-fold, and 3.1-fold in the first, second, and third trimesters respectively13
· Increase in ACTH
o Beginning in the late first trimester, peaking during labor and delivery16,17
· Increase in CRH
· Mostly from placental production
o Detectable then steadily increases in middle of the second trimester, with a sharp increase at the end of gestation 13,15
· Increase in CBG13
· Increase in aldosterone
o Levels increase steadily up to 3-fold to 8-fold then plateau in the third trimester21-23
· Increase in plasma renin activity
o Approximately 4-fold by eighth week; 7-fold at term23
· Increase in deoxycorticosterone. 24,26,27
CRH and ACTH levels return to nonpregnant values within 24 hours of delivery,18 and, at 2 to 3 months postpartum, plasma free cortisol and UFC levels return to baseline but CBG and total plasma cortisol levels remain increased.13
increase in aldosterone parallels that of progesterone and increases steadily throughout pregnancy, plateauing in the third trimester.21-23 Mean plasma aldoste- rone increases 3-fold to 8-fold during pregnancy22,23 and urinary aldosterone also in- creases throughout pregnancy,23 whereas mean urinary sodium and potassium secretion remains constant.23 Plasma renin activity (PRA) also increases throughout pregnancy up to almost 4-fold by the eighth week of pregnancy and 7-fold at term compared with the nonpregnant state23; largely because of an increase in renin sub- strate (angiotensinogen), which increases steadily until the 20th week of gestation.23
There have been different proposed mechanisms for such an upregulation in RAAS. The increase in prostaglandin synthesis and arterial venous shunt of the placental unit cause a decrease in systemic vascular resistance which are thought to initiate an acti- vation of RAAS.23 Extrarenal production of renin by the ovaries and maternal decidua as well as stimulation of renal renin release directly by estrogen24,25 likely contribute to the early increase in renin. The direct effect of estrogen and the estrogen-stimulated increase in CBG from the liver contribute to the increase in PRA, promoting increased angiotensin II levels and ultimately, increased aldosterone production from the adrenal glands.2,23-25 Deoxycorticosterone (DOC), also a potent mineralocorticoid, has an extra-adrenal origin during pregnancy; it is produced from progesterone, with levels increasing significantly in pregnancy.24,26,27
Despite the normal physiologic increase in renin and aldosterone levels in preg- nancy, healthy pregnant women remain normotensive and normokalemic, likely because of the antimineralocorticoid effect of progesterone and the decrease in sys- temic vascular resistance in pregnancy.24
Adrenal Adenomas in Pregnancy
Cushing syndrome in pregnancy
Incidence and epidemiology CS is 3 times more common in women than in men.28,29 Abnormal menses and difficulty conceiving are often present in women with CS, and therefore it is rare for a woman with CS to become pregnant.30 Egg quality may be affected in CS, in part because of hypogonadotropic hypogonadism and possibly because of direct effects of cortisol itself, because glucocorticoid receptors have been found on granulosa cells.31 In one study, the ovaries of women with CS tended to be smaller, with a decrease in the number of primordial follicles, a reduction in all phases of follicular activity, and the presence of patchy fibrosis that was similar to the ovaries of postmenopausal women.32
The cause of CS varies in the pregnant and nonpregnant populations. During preg- nancy, adrenal adenomas account for 40% to 60% of cases (as opposed to 15% in the nonpregnant state), pituitary adenomas account for 15% to 40% (vs >60% in the nonpregnant state), 33,34 and ACC accounts for less than 10% of cases of CS in pregnancy.33 This discrepancy is speculated to be caused by improved ovulation, and subsequently fertility, in adrenal versus pituitary CS because of the lack of increased adrenal androgen levels in adrenal CS.3,33,34 In addition, some adrenal cells that become cortisol-secreting tumors have been shown to express luteinizing hor- mone (LH)/human chorionic gonadotropin (hCG) receptor, which is stimulated during pregnancy.3 There have been many case reports of pregnancy-induced CS that resolved postpartum,35 postulated to be caused by increased expression of LH/ hCG receptors on adrenal tumors that become activated during pregnancy.35-37
Diagnosis A high degree of clinical suspicion must be present to detect CS in preg- nancy because many symptoms overlap with a normal pregnancy, including weight gain, striae, hirsutism, acne, fatigue, central obesity, emotional liability, hypertension (HTN), and glucose intolerance. Signs and symptoms that makes CS more likely include muscle weakness; thick, dark, purple abdominal striae (Fig. 1); pathologic fractures; and hypokalemia (Table 1).3,38,39
In pregnant women without CS, only 40% had a suppression of plasma cortisol after a 1-mg dexamethasone suppression test (DST), a blunting effect that increased with advancing gestational age.17,40 In one study, up to 82% of healthy pregnant women had an abnormal 1 mg DST in the peripartum period41; this effect persisted up to 5 weeks postpartum.42 This finding may be caused by an altered HPA set point in pregnancy, such that higher cortisol levels are needed to suppress ACTH secretion, also compounded by the increase in total serum cortisol level that occurs in
| Non-pregnancy | Pregnancy | |
|---|---|---|
| 1 mg DST | . Highly sensitivity in CD and adrenal CS . Test of choice to diagnose an adrenal incidentaloma43 · False positives can occur with use of OCPs; altered dexamethasone metabolism (eg, certain antiepileptics) | . >80% normal pregnant women have false plus DST41 · Recommend against its use43 |
| 24 hr UFC | · May be useful to diagnose cyclic CS43 · Less reliable in renal failure, alcoholism, depression, morbid obesity | . Test of choice in pregnancy . At least >3 times upper limit normal in 2nd or 3rd trimester (mean 8-fold increase)34,43 |
| Midnight salivary cortisol | · More sensitive for CD | · Not validated . Loss of diurnal cortisol variation (which is preserved but with higher nadir normal pregnancy)4,6,12 |
| Imaging | . Typically pituitary MRI vs adrenal computed tomography depending on suspected etiology | · Pituitary MRI can be obtained without contrast safely in the 3rd trimester and likely safely in the 2nd trimester · Adrenal ultrasonography34,44 |
| Etiology | . >60% due to pituitary adenoma | · 40-60% caused by adrenal adenoma (50% of primary adrenal CS failed to have suppressed ACTH)33,34 |
pregnancy.34 The largest review of CS in pregnancy, by Lindsay and colleagues, 34 summarizes data from 136 pregnancies in 122 women who were diagnosed at an average gestation age of 18 weeks; there was a mean 8-fold increase in UFC level and a loss of diurnal serum cortisol variation in these women.
Accordingly, the Endocrine Society guidelines recommend a UFC level of more than 3 times the upper limit of normal in the second or third trimesters to be used in the diagnosis of CS in pregnancy, and recommend against the use of DST (given the high number of false-positives) as the initial evaluation for CS in pregnant women. 43 The role of salivary cortisol in establishing the diagnosis of CS in pregnancy has not been validated.
Once CS is suspected in pregnancy, establishing the cause may be more chal- lenging than in the nonpregnant state. Although ACTH can be used in the nonpregnant state to identify ACTH-dependent versus ACTH-independent disease, half of pregnant patients with primary adrenal CS fail to have a suppressed serum ACTH level.34 This finding may be caused by placental CRH stimulation of maternal ACTH release giving rise to detectable placental ACTH levels in maternal serum3 as well as by a paradoxic dexamethasone stimulation of placental CRH and ACTH,44 thus potentially creating increased ACTH levels in all pregnant women, but a false-positive increase of ACTH levels in those with adrenal tumors.
In the small number of patients tested, high-dose DSTs were able to identify all pa- tients with ACTH-independent CS (whose cortisol levels failed to suppress); however, not all patients with pituitary-dependent CS had cortisol levels suppressed to less than 80% as expected in nonpregnant patients.34 When high-dose dexamethasone sup- pression test fails to suppress or if ACTH level is low or borderline, an adrenal ultraso- nography scan should be obtained. Adrenal ultrasonography identified 73% of adrenal
adenomas in pregnancy so, if negative, an abdominal MRI scan without contrast should be obtained.34,44
Management Laparoscopic surgical resection is the treatment of choice for a cortisol- secreting adenoma discovered during pregnancy and can be done safely in the sec- ond trimester. 45,46 There is a trend toward an increase in live birth rate with treatment of CS in pregnancy, with no effect seen on premature birth or intrauterine growth re- striction (IUGR) rates. However, these data may be limited by the small number of cases of CS syndrome in pregnancy, with many diagnosed later in pregnancy.34
There are fewer than 2 dozen reports of primary medical therapy used in the treat- ment of CS in pregnancy,34,44 with metyrapone being the most commonly used drug. Metyrapone works rapidly to reduce cortisol levels by inhibiting the conversion of 11-deoxycortisol to cortisol. It can cause an increase in the accumulation of miner- alocorticoid precursors and therefore can lead to HTN and, although controversial, likely increases the risk of preeclampsia. 44,47 Ketoconazole, also a steroidogenesis in- hibitor, has been used successfully in 4 reported cases of CS in pregnancy, and without feminizing a male fetus in one case.44,48 Although a population-based study of its use showed no negative outcomes, 49 hepatic dysfunction is possible and there have been reports of teratogenic effect in rats.50 Both metyrapone and ketoconazole are preg- nancy risk category C, indicating that a risk to the fetus cannot be ruled out. Mitotane, an adrenolytic, is a US Food and Drug Administration (FDA) category D pregnancy risk. Because of its teratogenic potential, it should not be used in pregnancy.51 In the setting of pituitary-dependent CS, cabergoline, a dopamine agonist targeting the pituitary, has been found to be useful in treating some individuals with CS when used at high doses. 52 Studies of cabergoline used in lower doses in pregnancies complicated by prolactino- mas show that it is safe and thus an FDA category B risk. 53-55 To date, there have been 2 published cases of cabergoline used for pituitary-dependent CS in pregnancy.48,56
Outcomes CS in pregnancy poses significant risks to the mother and the fetus. Maternal rates of HTN in pregnancy in patients with CS were almost 70%, with 14% having severe eclampsia, 34 some complicated by HELLP (hemolysis elevated liver en- zymes low platelets) syndrome, 57 and a quarter with diabetes or impaired glucose toler- ance.34 Women were also at an increased risk of osteoporosis and fractures, cardiac failure, psychiatric illness, infection, and death.34 In almost half of the cases, fetuses were born prematurely and almost one-quarter had IUGR. There was an increased risk of spontaneous abortions and stillbirths. 3,34,58
Although the fetus is partially protected from hypercortisolism by placental 11-beta- HSD2 converting most of the cortisol to inactive cortisone, adverse fetal effects are probably related to placental and maternal changes from CS34 as well as the high levels overwhelming this enzyme. In studies of neonates exposed to higher maternal cortisol (in the second trimester) and placental CRH (in the third trimester), there was a reduction in physical and neuromuscular development. 59,60
Primary aldosteronism in pregnancy
Incidence and epidemiology PA, initially called Conn syndrome after the discovery of aldosterone-secreting adenomas, is a state of continued aldosterone synthesis and release, marked by high aldosterone and low renin values and is the most common endo- crine cause of HTN. In the nonpregnant population, about two-thirds of PA cases are caused by bilateral adrenal hyperplasia and one-third are caused by an aldosterone- producing adenoma61; in more than 50% of these cases, serum potassium values are normal.62 Adrenal cortical carcinoma, ectopic production of aldosterone, unilateral ad- renal hyperplasia, and familial hyperaldosteronism are much rarer causes of PA.
PA is more common in women than in men and is often diagnosed when patients are 30 to 50 years old.63 Recent studies indicate that PA may be responsible for up to 10% of all cases of HTN in nonpregnant patients, with an incidence higher in those with HTN with diabetes or obstructive sleep apnea and resistant HTN (HTN uncontrolled on 3 antihypertensive agents or controlled on >4 agents61,62,64).
PA is uncommon in pregnancy, with fewer than 3 dozen cases reported in the liter- ature.2 As seen in CS in pregnancy, PA in pregnancy is most commonly caused by an adrenal adenoma,8 with very few reported cases caused by familial hyperaldosteron- ism type 1, glucocorticoid-remediable hyperaldosteronism,65,66 or idiopathic hyperaldosteronism.67
Several recent studies have found evidence for a role of LH or hCG receptors in aldosterone-producing adenomas (APAs).68-70 Morris and colleagues71 observed increased expression of LH/hCG receptors in tissue resected from an ACC that caused increased aldosterone levels in a pregnant woman. In a different case of PA in preg- nancy caused by an APA, Albiger and colleagues72 reported an increase of aldoste- rone secretion following in vivo hCG stimulation. Therefore, in some cases of PA in pregnancy, it is possible that the increased hCG levels that occur during pregnancy could stimulate aldosterone secretion and/or tumorigenesis via the LH/hCG receptor.
Diagnosis Although values vary by institution, in nonpregnant women, an aldosterone/ renin ratio of greater than 20 ng/dL per ng/ml/h and plasma aldosterone concentra- tion (PAC) greater than 10 ng/dL with a concomitantly suppressed renin level are typi- cally accepted values for a positive screening test.61
Given the normal physiologic increases in renin and aldosterone in pregnancy and the lack of pregnancy-specific references ranges, the diagnosis of PA in pregnancy can be difficult to establish and a high index of suspicion must exist. Features indi- cating a possibility of PA in pregnancy include moderate to severe HTN, proteinuria, and hypokalemia, although all symptoms need not be present.8,73 Some women with PA in pregnancy remain normotensive or even have an improvement in their HTN, possibly because of the antimineralocorticoid effects of progesterone.67 In one report, in 23 women with PA in pregnancy who did not undergo surgery, blood pressure (BP) improved spontaneously in 14%.73 Furthermore, PRA and PAC were measured during pregnancy in only 11 of 27 cases of PA in pregnancy reported and reviewed in the literature. All patients in this series had increased PAC; PRA was more variable and not suppressed in all patients.73 Because of the antikaliuretic ef- fects of progesterone, potassium values may be normal in pregnant women with PA.74
A proposed diagnostic algorithm includes screening with a PRA and PAC. Although pregnancy-specific reference ranges do not yet exist, the mean plasma aldosterone level increases up to 8-fold during pregnancy and PRA increases up to 4-fold by the eighth week of gestation and 7-fold at term.20,21 Although high aldosterone and a non- suppressed plasma renin level do not rule out PA, in patients who have an increased PAC and suppressed PRA, confirmatory testing is not necessary in pregnancy given the potential risks associated with volume expansion and angiotensin-converting enzyme inhibitor use in pregnancy. Abdominal ultrasonography or MRI scan can be performed if there is high clinical suspicion for an adrenal mass.2,8
Management Conservative management with BP control and potassium supplemen- tation is the main goal of medical management of PA in pregnancy with confirmatory testing and subtype differentiation after delivery. Although mineralocorticoid receptor antagonists are the first line of treatment in patients who are not pregnant, they are not proved to be safe in pregnancy. Spironolactone crosses the placenta and is preg- nancy FDA category C drug with use contraindicated in pregnancy because of the
feminization of male rats.75 However, in a case report, high doses of spironolactone used to treat a woman with Bartter syndrome in pregnancy resulted in 2 male fetuses born without signs of feminization, the oldest of whom had entered normal puberty.76 Eplerenone is a more selective aldosterone receptor antagonist with 0.1% less binding affinity for the androgen receptor than spironolactone.77 Eplerenone, pregnancy risk factor B, has been successfully used in controlling HTN and hypokalemia in a case of PA in pregnancy78 as well as for Gitelman syndrome in pregnancy.79
If a unilateral mass is found on abdominal MRI and BP is not controlled with med- ications, a unilateral adrenalectomy should be considered to treat PA in pregnancy.2,8
Outcomes Maternal morbidity and mortality were increased in a review of 29 cases of PA in pregnancy. Eighty-five percent of these woman had an increased BP greater than 140/90 mm Hg and more than half had proteinuria. Complications included pre- term delivery in more than 50% of the cases (61% in subset managed without surgery) and intrauterine fetal demise and placental abruption (with intrauterine fetal demise and placental abruption, all women had proteinuria).73 In the 6 patients with PA who did not have hyporeninemia (<1.0 ng/mL/h), pregnancies were complicated by placental abruption or preterm delivery and intrauterine fetal growth restriction, lead- ing the investigators to recommend that women with PA without suppressed renin level and/or with proteinuria should be aggressively managed and monitored closely for such complications.73 In another review, rates of preeclampsia, placental abrup- tion, fetal growth restriction, and cesarean delivery seen in PA were reported to be similar to those seen in the obstetric population with essential HTN.2
In the few reports of familial, glucocorticoid-remediable aldosteronism (FH1), the women with chronic HTN who become pregnant, although not at increased risk of pre- eclampsia compared with the general obstetric population, did experience a wors- ening of their HTN, with an increased risk of primary cesarean section delivery and a trend toward lower birth rates.66 Given that ACTH enables gene expression in FH1, this worsening of HTN is speculated to be caused by the physiologic increase in ACTH level in pregnancy.66
Pheochromocytoma in pregnancy
Incidence and epidemiology Pheochromocytomas are rare, with an even rarer occur- rence during pregnancy, estimated at an incidence of approximately 0.007%.8,80 Similar to the nonpregnant state, pheochromocytomas are typically unilateral and sporadic, with 10% occurring as bilateral, malignant, or familial (eg, multiple endocrine neoplasia II, von Hippel-Lindau syndrome, and type 1 neurofibromatosis).8,80 The diagnosis is particularly important because undiagnosed and/or untreated pheochro- mocytoma has high maternal and fetal mortality, ranging from 15% to 25%81 in some studies to up to 40% to 50% in other studies.81 Maternal and fetal morbidity and mor- tality decline significantly once the disorder is properly diagnosed and treated.
Clinical features The presenting symptoms of a pheochromocytoma can overlap with the normal symptoms of pregnancy, resulting in a delay in diagnosis. Uncontrolled HTN, either sustained or paroxysmal, is the most common presenting feature during pregnancy. Evaluation for pheochromocytoma should be strongly considered in the setting of labile or sustained HTN, particularly if accompanied by heat intolerance, pal- pitations, and impaired glucose tolerance.82 Other symptoms may be present, and in one study of a cohort of 15 pregnant women with pheochromocytoma, 12 of 15 women presented with headaches in addition to HTN.83
HTN is often mistakenly attributed to preeclampsia, particularly if proteinuria is pre- sent as well. Pheochromocytoma can manifest at any time during pregnancy, whereas
preeclampsia typically presents later in pregnancy, frequently at greater than 20 weeks’ gestation. In addition, the HTN associated with pheochromocytoma per- sists postpartum, whereas the HTN associated with preeclampsia typically resolves. 84
As pregnancy progresses, symptoms often become more apparent, with symptoms more evident with the pregnant woman lying supine, which causes the gravid uterus to compress the tumor and results in paradoxic supine HTN despite a normal BP mea- surement in the sitting or erect position.80 Rat pheochromocytoma (PC 12) cells ex- press estrogen receptors alpha and beta, and G-protein-coupled receptor 30. Treatment with estradiol greatly increases sex hormone binding globulin production and increases the number of estrogen receptor beta-positive cells in differentiated rat pheochromocytoma cells.85 More studies are needed to assess whether there is an increase in estrogen receptors in pheochromocytoma tissue in human models. Rarer presenting symptoms have been reported, including dyspnea, chest pain, sei- zures, and postpartum pulmonary edema. 86
Neuroblastomas can also present similarly during pregnancy and may be misdiag- nosed as pheochromocytoma. A rare malignant tumor derived from the primitive neu- ral crest cells of the adrenal medulla, neuroblastomas can present with HTN and increased 24-hour urine catecholamine levels and vanillylmandelic acid.87
Establishing the diagnosis of pheochromocytoma in pregnancy Similar to the diag- nosis in the nonpregnant state, pheochromocytoma is diagnosed in the setting of quantification of 24-hour urinary fractionated metanephrines and catecholamines and plasma fractionated metanephrines, at least twice the upper limit of the normal range. Under normal circumstances, pregnancy and preeclampsia should not influ- ence catecholamine levels. 84
In a multicenter cohort study of 214 nonpregnant patients with pheochromocytoma compared with 644 patients without pheochromocytoma, plasma free metanephrines and urinary fractionated metanephrines had a higher sensitivity for diagnosing pheo- chromocytoma (99% and 97%, respectively) compared with plasma catecholamines (84%), urinary total metanephrines (77%), and urinary vanillylmandelic acid (64%); however, these tests need further analysis, specifically in pregnant women.88
Imaging used to localize pheochromocytoma If a pheochromocytoma is suspected during pregnancy, the imaging modality recommended is MRI without gadolinium, and/or ultrasonography; however, the ultrasonography is often limited by the gravid uterus and has limited utility in diagnosing extra-adrenal tumors. Other tests, such as stimulation tests and 123-I-metaiodobenzylguanidine scintigraphy, are not consid- ered safe for use during pregnancy.
Medical management of pheochromocytoma in pregnancy There is no clear consensus on the treatment of pheochromocytomas diagnosed during pregnancy and most data are limited to small case studies. Medical therapy, regardless of whether surgical intervention occurs during pregnancy, is a vital aspect of treatment and typically involves alpha-adrenergic blockade with subsequent beta-adrenergic blockade 10 to 14 days later. Alpha-receptor blockade functions to decrease BP and control for expansion of blood volume in pregnant women with pheochromocy- toma. Phenoxybenzamine is the drug of choice during pregnancy (pregnancy class C), although it does cross the placenta and can potentially cause transient hypoten- sion in the neonate.89 Beta-blockade can be initiated after alpha-blockade to control for tachycardia. Antihypertensive drugs during pregnancy can cause fetal issues, including hypoxia and intrauterine growth retardation, as well as placental ischemia and placental abruption. These risks need to be balanced with the potential
complications from uncontrolled HTN, such as hypertensive crisis, pulmonary edema, and cardiac and cerebral complications. 84
Surgical management of pheochromocytoma in pregnancy Surgery is the definitive treatment of pheochromocytoma; however, the timing must be coordinated with respect to trimester of pregnancy and fetal status. If diagnosed early in pregnancy, appropriate medical treatment should be initiated until surgery can occur, with the optimal time for surgical resection being during the second trimester. If diagnosed later in pregnancy, medical treatment should be initiated and surgery deferred until af- ter delivery. Preoperatively, alpha-receptor blockade with subsequent beta-blockade should be initiated. Laparoscopic adrenalectomy is recommended if the tumor mass is less than 7 cm; however, if diagnosed after 24 weeks of gestation, open surgical removal is preferred, timed with elective cesarean section closer to delivery. Cesarean section can be performed simultaneously with resection of the mass with a reduction in maternal and fetal mortality compared with vaginal delivery (31% vs 19%) because of the release of catecholamines during vaginal delivery.89
Patients require postoperative assessment as well as close monitoring because of the possibility of incomplete resection of tumor and recurrence or development of a malignant adrenal mass. In addition, genetic screening is recommended to assess for hereditary causes of pheochromocytoma, including multiple endocrine neoplasia 2A and von Hippel-Lindau syndromes.89
Adrenocortical Carcinoma in Pregnancy
Incidence and epidemiology
ACC is a rare cancer with an estimated incidence of slightly less than 1 case per million in the general population.90,91 The prognosis for ACC is poor, with a 5-year survival rate of around 30%.92-94 More than half of all ACCs are hormone secreting, with cortisol and androgen secretion being the most common. 95,96 ACC is more common in women than in men. There is a bimodal age distribution with the first peak occurring in childhood and a second during the fourth to fifth decades.92,97 Data regarding ACC during pregnancy are limited to case reports, likely as a result of the rarity of the dis- ease as well as the decreased fertility in those women with hypercortisolism and hyperandrogenism. When diagnosed during pregnancy, reported adverse fetal out- comes include premature birth, intrauterine growth retardation, stillbirth, and intrauter- ine death.98 Frequently, there is a delay in diagnosis occurring after delivery.96
Clinical presentation
The presentation of an ACC during pregnancy often relates to the aberrant excess hor- mone production, frequently cortisol alone or in combination with androgens, from the tumor. In one study of 12 pregnant women with ACC, 75% of patients presented with HTN, diabetes, muscle wasting, morphologic changes, virilization, depression, and/or local or regional manifestations or tumor enlargement. One patient had symptomatic hypoglycemia, possibly caused by insulinlike growth factor 2 (IGF-2) hypersecretion; however, this relationship was not firmly established. Two-thirds of patients showed local or metastatic extension and all except 1 patient had surgical resection during preg- nancy or postpartum.96 In another case of a pregnancy complicated by ACC, LH/HCG receptor overexpression on the tumor resulted in excess maternal cortisol and androgen secretion causing partial virilization and ambiguous genitalia in the 46XX female infant.71
Genetic factors
The 2 most commonly observed genetic mutations in ACC are IGF-2 overexpression and constitutive activation of the Wnt/beta-catenin pathway.99 In addition, the sonic
hedgehog (SHH) pathway proteins seem to be upregulated in adult ACCs and down- regulated in pediatric ACCs. 100
Imaging
The risk for malignancy with adrenal tumors increases with tumor size. At clinical pre- sentation, ACCs are often large tumors, measuring more than 6 cm in diameter, and are sometimes found to be invading the adrenal vein and inferior vena cava.101 Im- aging modalities are limited during pregnancy; however, with high clinical suspicion for an adrenal mass, MRI should be considered. In addition to ACC, the differential diagnoses of an adrenal tumor greater than 4 cm should include a large adenoma, myelolipoma, adrenal metastasis from a different primary cancer, pheochromocy- toma, adrenal cyst, ganglioneuroma, or other rare tumors of the adrenal gland (eg, sarcomas or lymphomas). 102 Computed tomography scan characteristics suggestive of a low risk for malignancy include a homogeneous mass with less than or equal to 10 Hounsfield units and smooth margins. 102 On MRI scans, ACC appears heteroge- neous on both T1-weighted and T2-weighted images because of the presence of internal hemorrhage and necrosis. High signal intensity within the tumor may be noted on T1-weighted images because of hemorrhagic byproducts, whereas high signal intensity on T2-weighted images may be caused by areas of necrosis. A het- erogeneous decrease in signal intensity should further raise suspicion for ACC.101
Treatment
A paucity of data exists on treatment options for ACC diagnosed during pregnancy. Given the poor prognosis of this tumor, some investigators have suggested complete surgical resection of the adrenal tumor at the time of diagnosis, regardless of preg- nancy trimester.96
Mitotane has been used in the treatment of endogenous hypercortisolism and ad- renal carcinoma, with data suggesting that treatment may prolong recurrence-free survival in nonpregnant patients with ACC after radical resection. 103 There is concern regarding the teratogenic effects of mitotane use during pregnancy and risk of fetal transfer. A few case reports revealed successful conception on mitotane and use of mitotane during pregnancy without evidence of adrenal dysfunction in the infant104; however, the potential for fetal risks limits this as a treatment option. 105
SUMMARY
Adrenal diseases, including CS, PA, pheochromocytoma, and ACC, are uncommon in pregnancy; a high degree of clinical suspicion must exist. Physiologic changes to the HPA axis in a normal pregnancy result in increased cortisol, renin, and aldosterone levels, thus making the diagnosis of CS and PA in pregnancy challenging. However, catecholamine levels are not altered in pregnancy and allow a laboratory diagnosis of pheochromocytoma that is similar to that of the nonpregnant state. In the case of PA, if BP is controlled with medical therapy, confirmatory testing, subtype differentia- tion, and surgery should occur after delivery. Surgical resection is the treatment of choice for a cortisol-secreting adenoma discovered during pregnancy and can be done safely in the second trimester. In the case of a pheochromocytoma, medical treat- ment should begin immediately and surgery optimized according to gestational age of the baby, with elective cesarean section and concomitant open removal of the pheo- chromocytoma recommended if diagnosed after 24 weeks’ gestation. Regardless of gestational age, surgery is the treatment of choice for ACC in pregnancy. Although ad- renal tumors in pregnancy result in significant maternal and fetal morbidity and some- times mortality, early diagnosis and appropriate treatment often improve outcomes.
REFERENCES
1. Gibson M, Tulchinsky D. The maternal adrenal. In: Tulchinsky D, Ryan KJ, edi- tors. Maternal-fetal endocrinology. Philadelphia: Saunders; 1980. p. 129-43.
2. Monticone S, Auchus RJ, Rainey WE. Adrenal disorders in pregnancy. Nat Rev Endocrinol 2012;8(11):668-78.
3. Karaca Z, Tanriverdi F, Unluhizarci K, et al. Pregnancy and pituitary disorders. Eur J Endocrinol 2010;162(3):453-75.
4. Magiakou MA, Mastorakos G, Rabin D, et al. The maternal hypothalamic- pituitary-adrenal axis in the third trimester of human pregnancy. Clin Endocrinol (Oxf) 1996;44(4):419-28.
5. Petraglia F, Sawchenko PE, Rivier J, et al. Evidence for local stimulation of ACTH secretion by corticotropin-releasing factor in human placenta. Nature 1987; 328(6132):717-9.
6. Nolten WE, Rueckert PA. Elevated free cortisol index in pregnancy: possible regulatory mechanisms. Am J Obstet Gynecol 1981;139(4):492-8.
7. Cousins L, Rigg L, Hollingsworth D, et al. Qualitative and quantitative assess- ment of the circadian rhythm of cortisol in pregnancy. Am J Obstet Gynecol 1983; 145(4):411-6.
8. Kamoun M, Mnif MF, Charfi N, et al. Adrenal diseases during pregnancy: path- ophysiology, diagnosis and management strategies. Am J Med Sci 2014;347(1): 64-73.
9. Robinson BG, Emanuel RL, Frim DM, et al. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta. Proc Natl Acad Sci U S A 1988;85(14):5244-8.
10. Sasaki A, Shinkawa O, Yoshinaga K. Placental corticotropin-releasing hormone may be a stimulator of maternal pituitary adrenocorticotropic hormone secretion in humans. J Clin Invest 1989;84(6): 1997-2001.
11. Allolio B, Hoffmann J, Linton EA, et al. Diurnal salivary cortisol patterns during pregnancy and after delivery: relationship to plasma corticotrophin-releasing- hormone. Clin Endocrinol (Oxf) 1990;33(2):279-89.
12. Demey-Ponsart E, Foidart JM, Sulon J, et al. Serum CBG, free and total cortisol and circadian patterns of adrenal function in normal pregnancy. J Steroid Bio- chem 1982;16(2): 165-9.
13. Jung C, Ho JT, Torpy DJ, et al. A longitudinal study of plasma and urinary cortisol in pregnancy and postpartum. J Clin Endocrinol Metab 2011;96(5): 1533-40.
14. Goland RS, Wardlaw SL, Blum M, et al. Biologically active corticotropin- releasing hormone in maternal and fetal plasma during pregnancy. Am J Obstet Gynecol 1988;159(4):884-90.
15. McLean M, Bisits A, Davies J, et al. A placental clock controlling the length of human pregnancy. Nat Med 1995; 1(5):460-3.
16. Carr BR, Parker CR Jr, Madden JD, et al. Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol 1981;139(4):416-22.
17. Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocr Rev 2005;26(6):775-99.
18. Okamoto E, Takagi T, Makino T, et al. Immunoreactive corticotropin-releasing hormone, adrenocorticotropin and cortisol in human plasma during pregnancy and delivery and postpartum. Horm Metab Res 1989;21(10):566-72.
19. Ryan KJ. Placental synthesis of steroid hormones. In: Tulchinsky D, Gibson M, editors. Maternal-fetal endocrinology. Philadelphia: Saunders; 1980. p. 129-43.
20. Landau RL, Lugibihl K. Inhibition of the sodium-retaining influence of aldoste- rone by progesterone. J Clin Endocrinol Metab 1958;18(11):1237-45.
21. Ledoux F, Genest J, Nowaczynski W, et al. Plasma progesterone and aldoste- rone in pregnancy. Can Med Assoc J 1975;112(8):943-7.
22. Dorr HG, Heller A, Versmold HT, et al. Longitudinal study of progestins, miner- alocorticoids, and glucocorticoids throughout human pregnancy. J Clin Endocri- nol Metab 1989;68(5):863-8.
23. Wilson M, Morganti AA, Zervoudakis I, et al. Blood pressure, the renin- aldosterone system and sex steroids throughout normal pregnancy. Am J Med 1980;68(1):97-104.
24. Abdelmannan D, Aron DC. Adrenal disorders in pregnancy. Endocrinol Metab Clin North Am 2011;40(4):779-94.
25. Langer B, Grima M, Coquard C, et al. Plasma active renin, angiotensin I, and angiotensin II during pregnancy and in preeclampsia. Obstet Gynecol 1998; 91(2):196-202.
26. Casey ML, MacDonald PC. Extraadrenal formation of a mineralocorticosteroid: deoxycorticosterone and deoxycorticosterone sulfate biosynthesis and meta- bolism. Endocr Rev 1982;3(4):396-403.
27. Parker CR Jr, Cutrer S, Casey ML, et al. Concentrations of deoxycorticoster- one, deoxycorticosterone sulfate, and progesterone in maternal venous serum and umbilical arterial and venous sera. Am J Obstet Gynecol 1983;145(4): 427-32.
28. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of Cush- ing’s syndrome: a population-based study. J Clin Endocrinol Metab 2001;86(1): 117-23.
29. Steffensen C, Bak AM, Rubeck KZ, et al. Epidemiology of Cushing’s syndrome. Neuroendocrinology 2010;92(Suppl 1):1-5.
30. Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JD, et al. Menstrual abnormal- ities in women with Cushing’s disease are correlated with hypercortisolemia rather than raised circulating androgen levels. J Clin Endocrinol Metab 1998; 83(9):3083-8.
31. Myers M, Lamont MC, van den Driesche S, et al. Role of luteal glucocorticoid metabolism during maternal recognition of pregnancy in women. Endocrinology 2007; 148(12):5769-79.
32. Iannaccone A, Gabrilove JL, Sohval AR, et al. The ovaries in Cushing’s syn- drome. N Engl J Med 1959;261:775-80.
33. Buescher MA, McClamrock HD, Adashi EY. Cushing syndrome in pregnancy. Obstet Gynecol 1992;79(1):130-7.
34. Lindsay JR, Jonklaas J, Oldfield EH, et al. Cushing’s syndrome during preg- nancy: personal experience and review of the literature. J Clin Endocrinol Metab 2005;90(5):3077-83.
35. Achong N, D’Emden M, Fagermo N, et al. Pregnancy-induced Cushing’s syn- drome in recurrent pregnancies: case report and literature review. Aust N Z J Obstet Gynaecol 2012;52(1):96-100.
36. Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in luteinizing hor- mone-dependent Cushing’s syndrome. N Engl J Med 1999;341(21): 1577-81.
37. Chui MH, Ozbey NC, Ezzat S, et al. Case report: Adrenal LH/hCG receptor over- expression and gene amplification causing pregnancy-induced Cushing’s syn- drome. Endocr Pathol 2009;20(4):256-61.
38. Prebtani AP, Donat D, Ezzat S. Worrisome striae in pregnancy. Lancet 2000; 355(9216):1692.
39. Tajika T, Shinozaki T, Watanabe H, et al. Case report of a Cushing’s syndrome patient with multiple pathologic fractures during pregnancy. J Orthop Sci 2002;7(4):498-500.
40. Odagiri E, Ishiwatari N, Abe Y, et al. Hypercortisolism and the resistance to dexamethasone suppression during gestation. Endocrinol Jpn 1988;35(5): 685-90.
41. Greenwood J, Parker G. The dexamethasone suppression test in the puerpe- rium. Aust N Z J Psychiatry 1984;18(3):282-4.
42. Owens PC, Smith R, Brinsmead MW, et al. Postnatal disappearance of the pregnancy-associated reduced sensitivity of plasma cortisol to feedback inhibi- tion. Life Sci 1987;41(14):1745-50.
43. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93(5):1526-40.
44. Lim WH, Torpy DJ, Jeffries WS. The medical management of Cushing’s syn- drome during pregnancy. Eur J Obstet Gynecol Reprod Biol 2013;168(1): 1-6.
45. Angelico R, Ciangola IC, Mascagni P, et al. Laparoscopic adrenalectomy for hemorrhagic adrenal pseudocyst discovered during pregnancy: report of a case. Surg Laparosc Endosc Percutan Tech 2013;23(5):e200-4.
46. Toutounchi S, Makowska A, Krajewska E, et al. Laparoscopic treatment of Cush- ing’s syndrome in a woman in late pregnancy - a case presentation. Wideochir Inne Tech Malo Inwazyjne 2011;6(4):261-3.
47. Connell JM, Cordiner J, Davies DL, et al. Pregnancy complicated by Cushing’s syndrome: potential hazard of metyrapone therapy. Case report. Br J Obstet Gy- naecol 1985;92(11):1192-5.
48. Berwaerts J, Verhelst J, Mahler C, et al. Cushing’s syndrome in pregnancy treated by ketoconazole: case report and review of the literature. Gynecol Endo- crinol 1999;13(3):175-82.
49. Kazy Z, Puho E, Czeizel AE. Population-based case-control study of oral keto- conazole treatment for birth outcomes. Congenit Anom (Kyoto) 2005;45(1):5-8.
50. Amaral VC, Nunes GP Jr. Prednisone reduces ketoconazole-induced skeletal defects in rat fetuses. Arch Toxicol 2009;83(9):863-71.
51. Leiba S, Weinstein R, Shindel B, et al. The protracted effect of o,p’-DDD in Cush- ing’s disease and its impact on adrenal morphogenesis of young human em- bryo. Ann Endocrinol (Paris) 1989;50(1):49-53.
52. Pivonello R, De Martino MC, Cappabianca P, et al. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endo- crinol Metab 2009;94(1):223-30.
53. Lebbe M, Hubinont C, Bernard P, et al. Outcome of 100 pregnancies initiated under treatment with cabergoline in hyperprolactinaemic women. Clin Endocri- nol (Oxf) 2010;73(2):236-42.
54. Ono M, Miki N, Amano K, et al. Individualized high-dose cabergoline therapy for hyperprolactinemic infertility in women with micro- and macroprolactinomas. J Clin Endocrinol Metab 2010;95(6):2672-9.
55. Stalldecker G, Mallea-Gil MS, Guitelman M, et al. Effects of cabergoline on preg- nancy and embryo-fetal development: retrospective study on 103 pregnancies and a review of the literature. Pituitary 2010; 13(4):345-50.
56. Woo I, Ehsanipoor RM. Cabergoline therapy for Cushing disease throughout pregnancy. Obstet Gynecol 2013; 122(2 Pt 2):485-7.
57. Castro RF, Maia FF, Ferreira AR, et al. HELLP syndrome associated to Cushing’s syndrome-report of two cases. Arq Bras Endocrinol Metabol 2004;48(3):419-22 [in Portuguese].
58. Chico A, Manzanares JM, Halperin I, et al. Cushing’s disease and pregnancy: report of six cases. Eur J Obstet Gynecol Reprod Biol 1996;64(1):143-6.
59. Ellman LM, Schetter CD, Hobel CJ, et al. Timing of fetal exposure to stress hor- mones: effects on newborn physical and neuromuscular maturation. Dev Psy- chobiol 2008;50(3):232-41.
60. Gillman MW, Rich-Edwards JW, Huh S, et al. Maternal corticotropin-releasing hormone levels during pregnancy and offspring adiposity. Obesity (Silver Spring) 2006; 14(9): 1647-53.
61. Galati SJ, Hopkins SM, Cheesman KC, et al. Primary aldosteronism: emerging trends. Trends Endocrinol Metab 2013;24(9):421-30.
62. Rossi GP, Bernini G, Caliumi C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 2006; 48(11):2293-300.
63. Fujiyama S, Mori Y, Matsubara H, et al. Primary aldosteronism with aldosterone- producing adrenal adenoma in a pregnant woman. Intern Med 1999;38(1): 36-9.
64. Persell SD. Prevalence of resistant hypertension in the United States, 2003- 2008. Hypertension 2011;57(6): 1076-80.
65. Hamilton E, O’Callaghan C, O’Brien RM, et al. Familial hyperaldosteronism type 1 in pregnancy. Intern Med J 2009;39(2): 135-6.
66. Wyckoff JA, Seely EW, Hurwitz S, et al. Glucocorticoid-remediable aldoste- ronism and pregnancy. Hypertension 2000;35(2):668-72.
67. Ronconi V, Turchi F, Zennaro MC, et al. Progesterone increase counteracts aldo- sterone action in a pregnant woman with primary aldosteronism. Clin Endocrinol (Oxf) 2011;74(2):278-9.
68. Nicolini G, Balzan S, Morelli L, et al. LH, progesterone, and TSH can stimulate aldosterone in vitro: a study on normal adrenal cortex and aldosterone produc- ing adenoma. Horm Metab Res 2014;46(5):318-21.
69. Rao CV. Human adrenal LH/hCG receptors and what they could mean for adre- nal physiology and pathology. Mol Cell Endocrinol 2010;329(1-2):33-6.
70. Saner-Amigh K, Mayhew BA, Mantero F, et al. Elevated expression of luteinizing hormone receptor in aldosterone-producing adenomas. J Clin Endocrinol Metab 2006;91(3):1136-42.
71. Morris LF, Park S, Daskivich T, et al. Virilization of a female infant by a maternal adrenocortical carcinoma. Endocr Pract 2011;17(2):e26-31.
72. Albiger NM, Sartorato P, Mariniello B, et al. A case of primary aldosteronism in pregnancy: do LH and GNRH receptors have a potential role in regulating aldo- sterone secretion? Eur J Endocrinol 2011;164(3):405-12.
73. Okawa T, Asano K, Hashimoto T, et al. Diagnosis and management of primary aldosteronism in pregnancy: case report and review of the literature. Am J Peri- natol 2002; 19(1):31-6.
74. Ehrlich EN, Lindheimer MD. Effect of administered mineralocorticoids or ACTH in pregnant women. Attenuation of kaliuretic influence of mineralocorticoids dur- ing pregnancy. J Clin Invest 1972;51(6): 1301-9.
75. Messina M, Biffignandi P, Ghigo E, et al. Possible contraindication of spironolac- tone during pregnancy. J Endocrinol Invest 1979;2(2):222.
76. Groves TD, Corenblum B. Spironolactone therapy during human pregnancy. Am J Obstet Gynecol 1995;172(5): 1655-6.
77. Young WF Jr. Adrenal causes of hypertension: pheochromocytoma and primary aldosteronism. Rev Endocr Metab Disord 2007;8(4):309-20.
78. Cabassi A, Rocco R, Berretta R, et al. Eplerenone use in primary aldosteronism during pregnancy. Hypertension 2012;59(2):e18-9.
79. Morton A, Panitz B, Bush A. Eplerenone for Gitelman syndrome in pregnancy. Nephrology (Carlton) 2011;16(3):349.
80. Girling J, Martineau M. Thyroid and other endocrine disorders in pregnancy. Ob- stet Gynaecol Reprod Med 2010;20(9):265-71.
81. Lenders JW. Pheochromocytoma and pregnancy: a deceptive connection. Eur J Endocrinol 2012; 166(2): 143-50.
82. Keely E. Endocrine causes of hypertension in pregnancy-when to start looking for zebras. Semin Perinatol 1998;22(6):471-84.
83. Salazar-Vega JL, Levin G, Sanso G, et al. Pheochromocytoma associated with pregnancy: unexpected favourable outcome in patients diagnosed after deliv- ery. J Hypertens 2014;32(7): 1458-63 [discussion: 1463].
84. Dong D, Li H. Diagnosis and treatment of pheochromocytoma during preg- nancy. J Matern Fetal Neonatal Med 2014;27(18): 1930-4.
85. Gebhart VM, Jirikowski GF. Estrogen dependent expression of sex hormone binding globulin in PC 12 cells. Steroids 2014;81:26-30.
86. Kamari Y, Sharabi Y, Leiba A, et al. Peripartum hypertension from pheochro- mocytoma: a rare and challenging entity. Am J Hypertens 2005;18(10): 1306-12.
87. Refaat MM, Idriss SZ, Blaszkowsky LS. Case report: an unusual case of adrenal neuroblastoma in pregnancy. Oncologist 2008; 13(2): 152-6.
88. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromo- cytoma: which test is best? JAMA 2002;287(11):1427-34.
89. Oliva R, Angelos P, Kaplan E, et al. Pheochromocytoma in pregnancy: a case series and review. Hypertension 2010;55(3):600-6.
90. Golden SH, Robinson KA, Saldanha I, et al. Clinical review: Prevalence and inci- dence of endocrine and metabolic disorders in the United States: a comprehen- sive review. J Clin Endocrinol Metab 2009;94(6): 1853-78.
91. Kebebew E, Reiff E, Duh QY, et al. Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress? World J Surg 2006;30(5):872-8.
92. Allolio B, Fassnacht M. Clinical review: Adrenocortical carcinoma: clinical up- date. J Clin Endocrinol Metab 2006;91(6):2027-37.
93. Crucitti F, Bellantone R, Ferrante A, et al. The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 1996;119(2): 161-70.
94. Luton JP, Cerdas S, Billaud L, et al. Clinical features of adrenocortical carci- noma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 1990;322(17):1195-201.
95. Fassnacht M, Libe R, Kroiss M, et al. Adrenocortical carcinoma: a clinician’s up- date. Nat Rev Endocrinol 2011;7(6):323-35.
96. Abiven-Lepage G, Coste J, Tissier F, et al. Adrenocortical carcinoma and preg- nancy: clinical and biological features and prognosis. Eur J Endocrinol 2010; 163(5):793-800.
97. Wajchenberg BL, Albergaria Pereira MA, Medonca BB, et al. Adrenocortical car- cinoma: clinical and laboratory observations. Cancer 2000;88(4):711-36.
98. Murakami S, Saitoh M, Kubo T, et al. A case of mid-trimester intrauterine fetal death with Cushing’s syndrome. J Obstet Gynaecol Res 1998;24(2): 153-6.
99. Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical carcinoma. J Clin En- docrinol Metab 2013;98(12):4551-64.
100. Gomes DC, Leal LF, Mermejo LM, et al. Sonic hedgehog signaling is active in human adrenal cortex development and deregulated in adrenocortical tumors. J Clin Endocrinol Metab 2014;99(7):E1209-16.
101. Elsayes KM, Mukundan G, Narra VR, et al. Adrenal masses: MR imaging fea- tures with pathologic correlation. Radiographics 2004;24(Suppl 1):S73-86.
102. Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev 2014; 35(2):282-326.
103. Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adreno- cortical carcinoma. N Engl J Med 2007;356(23):2372-80.
104. Kojori F, Cronin CM, Salamon E, et al. Normal adrenal function in an infant following a pregnancy complicated by maternal adrenal cortical carcinoma and mitotane exposure. J Pediatr Endocrinol 2011;24(3-4):203-4.
105. Tripto-Shkolnik L, Blumenfeld Z, Bronshtein M, et al. Pregnancy in a patient with adrenal carcinoma treated with mitotane: a case report and review of literature. J Clin Endocrinol Metab 2013;98(2):443-7.