Page 1 of 18 Accepted Preprint first posted on 14 April 2015 as Manuscript EJE-14-1130

1 Management of the pregnant patient with Cushings syndrome

2
3 Bronstein MD1, Machado MC1, Fragoso MCBV1,2
4
5 Neuroendocrine Unit1, Adrenal Unit2, Division of Endocrinology and Metabolism
6 Hospital das Clinicas, University of Sao Paulo Medical School, Sao Paulo, Brazil
7
8 Corresponding authors: Marcello D. Bronstein MD, PhD1
9
10 Sao Paulo Medical School, Av Enas de Carvalho Aguiar, 155 80 andar bloco 03, So
11 Paulo, SP, 05403-000, Brazil
12 Email: mdbronstein@uol.com.br
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14
15
16
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18 Keywords: Cushings syndrome, pregnancy, hypercortisolism.
19 The word count 3289
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21
22
23 Abstract: The progress in diagnosis and treatment of endocrine diseases turned
24 pregnancy into reality for women with such medical disorders, including Cushings
25 syndrome (CS). Nevertheless, despite its rarity, pregnancy in patients with CS can be
26 troublesome due to maternal-fetal complications. Therefore hipercortisolism, if present,
27 should be surgically or medically controlled in most cases. Moreover, changes in the
28 hypothalamic-pituitary-adrenal axis during normal pregnancy may mislead the
29 diagnosis of CS during this period, as many laboratory assessments suggestive of CS
30 may be present in normal pregnancy, in a setting of clinical features mimicking those
31 seen in patients with CS. The aim of this review is to update the diagnostic approach to
32 this medical condition, mainly for pregnant women without previous diagnosis of CS,
33 and to describe the therapeutic strategies for CS during pregnancy in order to minimize
34 complications for both mother and fetus.
35
36

37

38 Introduction

39 The progress in diagnosis and treatment of endocrine diseases has led to an

40 increase in the ovulation rate and consequently turned pregnancy into reality for women

41 with such medical disorders. These achievements include patients with Cushings

42 syndrome (CS), a condition where high serum cortisol and androgen levels usually

43 impair the gonadotropic axis. Nevertheless, pregnancy in a setting of hypercortisolism

Copyright 2015 European Society of Endocrinology.

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44 brings risk for both mother and fetus, becoming a concern for endocrinologists,

45 gynecologists and pediatricians. This review intends: 1) To describe the changes in the

46 hypothalamic-pituitary-adrenal axis during normal pregnancy, which may mislead the

47 diagnosis of CS during this period; 2) To update the diagnostic approach to this medical

48 condition, mainly for pregnant women without previous diagnosis of CS; 3) To describe

49 the therapeutic strategies for CS during pregnancy in order to minimize complications

50 for both mother and fetus.

51
52 I. Hypothalamic-pituitary-adrenal axis of binary complex maternal-fetus

53
54 The physiological activation of the hypothalamic-pituitary-adrenal axis (HPA)

55 during pregnancy has been proposed to act as a biological clock that times labor and

56 delivery (Figure 1).

57 The corticotropin-releasing hormone (CRH), one the most important modulators

58 of the HPA, is not only produced in the hypothalamus but has been detected in theca
1
59 and in stromal cells as well as in cells of the ovarian corpora lutea In addition, the

60 epithelial cells of the endometrium encompass CRH and have shown specific CRH
2,3
61 receptors This peptide has effects on maturation of fetal adrenal, on fetal-placental

62 unit circulation and also paracrine effects on the placenta. Its molecular structure is

63 identical to the hypothalamic form 4.

64 During pregnancy, CRH and ACTH plasma levels exponentially increase in the

65 first trimester of gestation due to CRH and ACTH placenta production (Figure 2).

66 Nevertheless, the HPA axis is protected by a physiological concurrent increase of CRH-

67 binding protein 5. The physiological increase of CRH/ACTH during pregnancy causes a

68 slight elevation of cortisol levels (serum, salivary and urinary). Nonetheless, the cortisol
Page 3 of 18

69 secretion maintains a pulsatile and circadian rhythm even in the third trimester when

70 cortisol attains maximal levels 6.

71 Another aspect to be considered concerns the increase of corticosteroid-binding

72 globulin (CBG) production secondary to high levels of estradiol in pregnancy. The

73 CBGs increase reaches its highest levels at the end of pregnancy, leading to a serum

74 cortisol overestimation by commercial assays that generally measure total serum

75 cortisol levels, which mainly represent the bound fraction with CBG 7. Nevertheless,

76 serum-free cortisol levels also rise around 1.6 fold by the eleventh week of pregnancy

77 due to the pregnancy-induced HPA activation 6. Consequently, urinary free cortisol

78 increases up to threefold the normal range 8. Interestingly enough, the placenta

79 expresses 11 hydroxysteroid dehydrogenase 2, which converts cortisol to cortisone,

80 therefore protecting the fetus from the high maternal cortisol levels9 . As a consequence

81 of the HPA changes, the stimulation test with exogenous CRH in pregnancy fail to
10
82 increase ACTH and cortisol which recovers in few weeks after delivery . However,

83 higher doses of CRH can produce an increase of ACTH and cortisol starting from the

84 third trimester 11. Moreover the suppression of cortisol after dexamethasone suppression

85 test is attenuated compared to non-pregnant state 9.

86 Due to ACTH-induced cell proliferation during pregnancy, maternal adrenal

87 glands gradually become hypertrophic. The circulating fetal CRH is almost exclusively

88 of placental origin and ACTH can be detectable in fetal plasma at 12 weeks of gestation
10
89 . The CRH-binding protein is elevated in the first two trimesters of pregnancy and

90 decreases considerably in the last trimester with consequent elevation of bioavailable

91 plasmatic CRH. The increase of CRH plays a role in the labor process and in fetal lung
12
92 maturation . Fetal adrenals are huge compared to the adult adrenal glands and the

93 major steroid produced is DHEAS, in contrast to the preponderance of cortisol detected

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94 in the fetal circulation, which appears to come from maternal source 13. In addition the

95 fetal adrenal converts placental progesterone to cortisol. Another origin of cortisol is the

96 amniotic fluid where cortisone is converted into cortisol by choriodecidua.

97 Around the fourth day postpartum, maternal plasma CRH, ACTH, and cortisol

98 gradually decline to basal levels. The adrenal glands are slightly suppressed similarly to

99 early stages of successfully operated patients with Cushing disease (CD), normalizing at
13
100 12 weeks . This transient period of CRH suppression might be related to mood

101 disorders and autoimmune diseases frequently observed in postpartum women.

102
103 II. Pregnancy in Cushings syndrome

104
105 Pregnancy is considered a transient physiologic state of hypercortisolism,

106 however lacking specific clinical manifestations of CS. Despite its higher prevalence in

107 women of reproductive age, pregnancy in CS is extremely rare due to infertility

108 associated with hypogonadotrophic hypogonadism secondary to cortisol and androgens

109 excess 14.

110 There is a significant difference between the frequency of etiologies of CS in

111 pregnancy and in non-pregnant women. In pregnancy the incidence of adrenal disorders

112 (particularly adenomas) and CD is 60% and 33% respectively, in contrast to non-

113 pregnant patients where the incidence is 15% for adrenal adenoma and 70% for

114 Cushings disease1. This preponderance is probably related to the exclusive cortisol

115 production from adrenal adenomas, as compared to CD with its mixed secretion of

116 cortisol and androgens 15. Linday1 et al. , reviewing 136 pregnancies in 122 women with

117 CS, described the following etiologies: CD (n = 40); adrenal adenoma (n = 56); adrenal

118 carcinoma (n = 12); ectopic ACTH secretion (EAS) (n = 4), Carneys complex (n = 1);
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119 and ACTH-independent hyperplasia (AIH) (n = 4) possibly due to aberrant receptor

120 stimulation.

121
122 III. Diagnosis

123
124 The diagnosis of CS during pregnancy is often a challenge, as we need to cope

125 with three situations: 1) Patients who become pregnant with previously diagnosed CS

126 (the easiest scenario); 2) Patients who develop CS during pregnancy, and 3) Women

127 with clinical features of CS, as striae, hypertension and diabetes, which are prevalent in

128 normal pregnancy. Concerning clinical differential diagnosis, features such as muscular

129 weakness, larger purple striae (mainly in regions outside of abdomen) (Figure 3), and

130 osteoporosis are clues that point to CS instead of normal pregnancy. Hirsutism,

131 resulting from hyperandrogenism, is not a common sign in CS associated to pregnancy

132 since most cases are pure benign adrenal adenomas usually with isolated cortisol
16
133 secretion . Nevertheless, differential diagnosis on clinical basis is often misleading

134 and therefore needs the additional support of laboratory and imaging procedures.

135 Hormonal diagnosis of CS during pregnancy may also be a challenge, as high

136 serum and urinary cortisol levels and an abnormal cortisol dexamethasone suppression

137 test frequently occur in normal pregnancy 4,17. Thus, high urinary free cortisol, mainly if

138 lower than 3 times the upper limit normal range, usually cannot differentiate normal

139 pregnancy from CS, especially during the second and third trimester. The absence of

140 circadian rhythm is probably the best test as it is preserved during normal pregnancy,

141 pointing to salivary cortisol as one of the best tools. Nevertheless, to date, threshold

142 values for the diagnosis of CS in pregnancy are not well validated.

143 Once the diagnosis of CS is confirmed or highly suspected, we must proceed to

144 discover its etiology. Although adrenal adenomas account for 60% of cases of
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145 Cushings pregnancy, the expected ACTH suppression of this condition, albeit

146 confirmatory, is often not observed, probably due to pituitary ACTH stimulation by
17,18
147 placental CRH or by placental ACTH itself . Patients with CD diagnosed during

148 pregnancy present ACTH levels in the upper half of the normal range or even higher 17.

149 High-dose dexamethasone suppression test could be a clue for differential

150 diagnosis, since, if positive, an adrenal tumor should be unlikely. Nevertheless, lack of

151 suppression does not rule-out ACTH-dependent Cushings, due to the elevated levels of

152 bound cortisol 18.

153 A distinctive feature of adrenal Cushings syndrome caused by aberrant LH

154 receptor is the disappearance of hypercortisolism after delivery in coincidence with

155 cessation of HCG placental production. Of course, this feature is of no diagnostic aid

156 while pregnancy is in course (Figure 4)19.

157 Concerning the distinction between pituitary and ectopic ACTH secretion,

158 pituitary etiology can be safely confirmed by either of the commonly used tests. In fact,

159 high dose dexamethasone suppression test correctly identified almost all reported cases

160 using the 50% cortisol decrease threshold, and stimulation with 100 g CRH evoked
20
161 marked ACTH and cortisol responses in patients with CD . Inferior petrosal sinus
21
162 sampling has been carried out in a few pregnant women with suspected CD but

163 should be employed sparingly in order to avoid unnecessary radiation and possible

164 thrombotic events 17. Non-gadolinium enhanced MRI itself may not be informative for
1,22
165 microadenomas , and, further, the physiological enlargement of the pituitary gland

166 during pregnancy may mask a small tumor 1. Imaging should be performed only if

167 surgery is planned prior to birth and, obviously, adrenal CT scans should be avoided.

168 Therefore adrenal imaging should be initially performed by ultrasound, leaving non-
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169 gadolinium contrasted MRI for non-diagnosed cases. Nonetheless, the issue of adrenal

170 incidentalomas should be taken into account for the differential diagnosis.

171
172 IV. Treatment of pregnancies with Cushings syndrome

173
174 Approximately 150 cases of pregnancy and endogenous CS were reported in the

175 literature. Of those, treatment was performed in a subset of patients but many cases,

176 especially when discovered late in pregnancy, were managed conservatively, just trying

177 to control comorbidities such as hypertension and diabetes mellitus.

178 Nonetheless, uncontrolled CS during pregnancy is associated with a high rate of

17
179 maternal complications . Even in treated cases some patients develop complications

180 such as preeclampsia and premature delivery.

181 The most common described maternal morbidities are: hypertension (68%),

182 diabetes or glucose intolerance (25%), preeclampsia (14%), osteoporosis and fractures

183 (5%), cardiac failure (3%), psychiatric disorders (4%), wound infections (2%) and

184 maternal death (2%) 17.

185 Concerning newborns, a tendency for higher live birth rate was observed in

186 women treated during pregnancy. The more frequent fetal morbidity is prematurity

187 occurring in about 43% of pregnancies. Other described complications are: intrauterine

188 growth retardation (21%), stillbirths (6%), spontaneous abortion or intrauterine death

189 (5%) and hypoadrenalism (2%) 17.

190 Similarly to non-pregnant women, surgery usually is the first treatment option in
1,17,23,24
191 pregnant CS patients . On the other hand, further options to treat

192 hypercortisolism as radiotherapy and mitotane are contraindicated in this period due to
25
193 the potential harmful or teratogenic effect and delayed outcome .
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194 In patients with CD and pregnancy, 42.5% were not submitted to specific

195 treatment of hypercortisolism17. The treated ones were equally submitted to

196 transsphenoidal surgery, medical treatment or bilateral adrenalectomy. Surgical

197 treatment has been done in ACTH secreting pituitary adenomas ideally between the end

198 of first trimester and early second trimester (12-29 weeks of gestation), a period

199 associated with a lower rate of maternal and fetal complications. Several factors

200 influence surgical decision as the etiology, severity, stage of gestation and therapeutic

201 risk-benefit for the maternal-fetal outcomes 24.

202 Adrenalectomy for adrenal etiologies of CS, such as adrenal adenomas and

203 carcinomas, was performed with good results both for hypercortisolim resolution and
23
204 birth rate (87%) . Additionally, bilateral adrenalectomy can be performed in other

205 situations, especially in non-controlled CD or severe ectopic ACTH syndrome.

206 Medical therapy, generally initiated during the second or third trimesters, is the

207 second treatment option. Of these, treatment with steroidogenesis inhibitors was the

208 most used option, particularly with metyrapone 26 (Table 1). This drug was used in 69%

209 of cases showing good control of hypercortisolism in most of them, with one report of

210 adrenal insufficiency 17,27. The most worrisome side effect of metyrapone is the increase

211 of precursors such as 11-deoxycorticosterone, worsening hypertension and increasing

212 preeclampsia frequency. Although it crosses the placental membrane in animal studies,
28,29
213 no neonatal abnormalities have been reported in human patients . Ketoconazole, the

214 most used steroidogenesis inhibitor in non-pregnant CS patients, has been less utilized

215 in pregnancy due to potential side effects such as anti-androgenic effect and
17,30,31
216 teratogenicity (only in animal studies) . Other adrenal steroidogenesis blockers as

217 aminoglutethimide and mitotane, were rarely used, being contraindicated due to fetal

218 masculinization and teratogenicity, respectively 16. Concerning pituitary tumor directed
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219 drugs, in spite of the increasing use of cabergoline for CD, only one patient treated with

220 this dopamine agonist during pregnancy was reported, to date32.

221 In conclusion, despite its rarity, pregnancy in patients with CS can be

222 troublesome due to maternal-fetal complications. The achievements in the physiology of

223 the corticotrophic axis during pregnancy applied to laboratorial assays, the improvement

224 of imaging methods and of pituitary and adrenal surgical approaches, favorably

225 contributed for the differential diagnosis with normal pregnancy as well as for the

226 reduction of maternal and fetal morbidity and mortality.

227
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229 This research did not receive any specific grant from any funding agency in the public,
230 commercial or not-for-profit sector. The authors fully declare any potential conflict of
231 interest.
232
233
234
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236 References:
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309 24. Bronstein MD, Paraiba DB, Jallad RS. Management of pituitary tumors in
310 pregnancy. Nature reviews. Endocrinology. May 2011;7(5):301-310.
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337 32. Woo I, Ehsanipoor RM. Cabergoline therapy for Cushing disease throughout
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341 Australian & New Zealand journal of obstetrics & gynaecology. Feb
342 2012;52(1):96-100.
343 34. Mundra V SC, DeSantis P, . Cushing syndrome: a rare ocurrence in pregnancy.
344 Endocrinologist. 2010;20:165-167.
345
346
347
348 Figure 1. Hypothalamic-pituitary-adrenal axis in normal pregnancy. The production of
349 cortisol linked of corticosteroid-binding globulin is increased as well as the free
350 fraction. The concentration of ACTH is high and the adrenal cortex is responsible to
351 stimulus. Abbreviations: 16 alpha-OH-4A, 16 alpha hydroxyandrostenedione; CRH,
352 corticotropin-releasing hormone; DHEA, dehydroepiandrosterone; DHEAS,
353 dehydroepiandrosterone sulphate.
354 From: Ref 24: Bronstein MD, Paraiba DB, Jallad RS. Management of pituitary tumors
355 in pregnancy. Nature reviews endocrinology. May 2011;7(5):301-310.
356
357
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358 Figure 2. Serial increases in serum cortisol (B) and ACTH (C) during pregnancy in
359 normal controls throughout pregnancy 4
360 From ref 4: Carr BP, CR Jr, Madden JD, MacDonald PC, Porter JC. Maternal plasma
361 adrenocorticotropin and cortisol relationships throughout human pregnacy. Am J Obstet
362 Gynecol 1981;139(4):416-422.
363
364
365 Figure 3. Non-pregnant woman with Cushings disease exhibiting large striae in the
366 abdomen and arm (HC/FMUSP)
367
368
369 Figure 4. Illustration of aberrant receptors expression (LH/hCGR) in adrenal cortex
370 causing bilateral macronodular adrenal hyperplasia in patient with Cushings syndrome
371 developed during pregnancy
372 From Ref 19: Lacroix A, Ndiaye N, Tremblay J, Hamet P. Ectopic and abnormal
373 hormone receptors in adrenal Cushing's syndrome. Endocrine reviews. Feb
374 2001;22(1):75-110.
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1 Table 1. Reports of medications used to treat patients with Cushings syndrome and
2 pregnancy.
3
Medication n=26 % Dose Comments
Metyrapone 17,26,27,30,33,34 16 61% 0.5-3.0 g/day Systemic hypertension
and preeclampsia risk
Ketoconazole17,30,31 4 15% 0.6-1.0 g/day Teratogenicity (only in
animal studies)
Cyproheptadine17 3 11% - Lack of efficacy

Aminoglutethimide17 1 4% 2.5 g/day Fetal masculinization

Mitotane17 1 4% - Teratogenic

Cabergoline31,32 1 4% _ -

4 n (number of patients); % percentage of total of patients treated

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Figure 1. Hypothalamic-pituitary-adrenal axis in normal pregnancy. The production of cortisol linked of

corticosteroid-binding globulin is increased as well as the free fraction. The concentration of ACTH is high
and the adrenal cortex is responsible to stimulus. Abbreviations: 16 alpha-OH-4A, 16 alpha
hydroxyandrostenedione; CRH, corticotropin-releasing hormone; DHEA, dehydroepiandrosterone; DHEAS,
dehydroepiandrosterone sulphate.
From: Ref 24: Bronstein MD, Paraiba DB, Jallad RS. Management of pituitary tumors in pregnancy. Nature
reviews endocrinology. May 2011;7(5):301-310.

251x208mm (72 x 72 DPI)

Page 15 of 18

Figure 2. Serial increases in serum cortisol (B) and ACTH (C) during pregnancy in normal controls
throughout pregnancy 4
From ref 4: Carr BP, CR Jr, Madden JD, MacDonald PC, Porter JC. Maternal plasma adrenocorticotropin and
cortisol relationships throughout human pregnacy. Am J Obstet Gynecol 1981;139(4):416-422.

220x280mm (72 x 72 DPI)

 Page 16 of 18

Figure 3. Non-pregnant woman with Cushings disease exhibiting large striae in the abdomen and arm
(HC/FMUSP)
136x102mm (220 x 220 DPI)
Page 17 of 18

Figure 3. Non-pregnant woman with Cushings disease exhibiting large striae in the abdomen and arm
(HC/FMUSP)
451x338mm (72 x 72 DPI)
 Page 18 of 18

Figure 4. Illustration of aberrant receptors expression (LH/hCGR) in adrenal cortex causing bilateral
macronodular adrenal hyperplasia in patient with Cushings syndrome developed during pregnancy
From Ref 19: Lacroix A, Ndiaye N, Tremblay J, Hamet P. Ectopic and abnormal hormone receptors in adrenal
Cushing's syndrome. Endocrine reviews. Feb 2001;22(1):75-110.

445x389mm (96 x 96 DPI)