Adrenal Cushing’s syndrome during pregnancy

in European Journal of Endocrinology
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  • 1 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
  • 2 Department of Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
  • 3 IJsselland Hospital, Capelle aan den IJssel, The Netherlands
  • 4 Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands

Correspondence should be addressed to C E Andreescu; Email: Corina.Andreescu@uzbrussel.be

Cushing syndrome (CS) during pregnancy is a rare condition with only a few cases reported in the literature. Misdiagnosis of CS is common because of overlapping features like fatigue, weight gain, striae and emotional changes that can occur during normal pregnancy. Changes in maternal hormones and their binding proteins complicate assessment of glucocorticoid hormone levels during gestation. CS during pregnancy is most frequently due to an adrenal adenoma and to a lesser degree to adrenocorticotropic hormone (ACTH) hypersecretion by a pituitary adenoma. Furthermore, aberrant expression of luteinizing hormone (LH) receptors in the adrenal cortex has been suggested to be involved in the pathogenesis of adrenal CS during pregnancy. We report three pregnant women with ACTH-independent Cushing’s syndrome and an adrenal tumor. After uncomplicated delivery, patient 1 underwent in vivo testing for aberrant hormone receptor expression by the adenoma. Cortisol responses were found after administration of luteinizing hormone-releasing hormone (LHRH), human chorionic gonadotropin (hCG), glucagon, vasopressin and a standard mixed meal. All patients were treated with laparoscopic adrenalectomy. Adrenal tumor tissue of two patients showed positive immunohistochemical staining of LH receptors. Considering the cortisol responses to LHRH and hCG, and the development of CS during pregnancy in these patients, it is likely that ACTH-independent hypercortisolism was induced by the pregnancy-associated rise in hCG levels that activated aberrantly expressed LH receptors in the adrenal adenoma. Remarkably, adrenal adenomas may simultaneously express multiple aberrant receptors and individual ligands may play a role in the regulation of cortisol production in CS during pregnancy.

Abstract

Cushing syndrome (CS) during pregnancy is a rare condition with only a few cases reported in the literature. Misdiagnosis of CS is common because of overlapping features like fatigue, weight gain, striae and emotional changes that can occur during normal pregnancy. Changes in maternal hormones and their binding proteins complicate assessment of glucocorticoid hormone levels during gestation. CS during pregnancy is most frequently due to an adrenal adenoma and to a lesser degree to adrenocorticotropic hormone (ACTH) hypersecretion by a pituitary adenoma. Furthermore, aberrant expression of luteinizing hormone (LH) receptors in the adrenal cortex has been suggested to be involved in the pathogenesis of adrenal CS during pregnancy. We report three pregnant women with ACTH-independent Cushing’s syndrome and an adrenal tumor. After uncomplicated delivery, patient 1 underwent in vivo testing for aberrant hormone receptor expression by the adenoma. Cortisol responses were found after administration of luteinizing hormone-releasing hormone (LHRH), human chorionic gonadotropin (hCG), glucagon, vasopressin and a standard mixed meal. All patients were treated with laparoscopic adrenalectomy. Adrenal tumor tissue of two patients showed positive immunohistochemical staining of LH receptors. Considering the cortisol responses to LHRH and hCG, and the development of CS during pregnancy in these patients, it is likely that ACTH-independent hypercortisolism was induced by the pregnancy-associated rise in hCG levels that activated aberrantly expressed LH receptors in the adrenal adenoma. Remarkably, adrenal adenomas may simultaneously express multiple aberrant receptors and individual ligands may play a role in the regulation of cortisol production in CS during pregnancy.

Introduction

Cushing syndrome (CS) during pregnancy is rare since only a limited number of cases is reported in literature (1, 2, 3, 4, 5). The diagnosis of this condition is difficult because of the overlapping features of fatigue, weight gain, striae and emotional changes that can occur during normal pregnancy. Therefore, a high degree of clinical awareness is required to recognize CS and to avoid maternal and fetal complications.

Hormonal changes in normal pregnancy profoundly affect the hypothalamic-pituitary-adrenal axis. There is a significant estrogen-induced increase in cortisol-binding globulin, coupled with the placental production of corticotropin-releasing hormone, which leads to an increase in measured plasma cortisol levels. In the first and second trimesters there is a two- to threefold increase in both total and free cortisol levels reaching a plateau in the third trimester (1). This is paralleled by a two- to threefold increase in urinary free cortisol (UFC) concentrations. The increase in cortisol and CBG levels results in a disturbed dexamethasone suppression test during pregnancy. One important difference between normal pregnancy and CS is that the cortisol circadian rhythm is preserved in pregnancy, though it may be blunted (5). The fetus is normally protected from the increase in cortisol by the placental enzyme 11β-hydroxysteroid dehydrogenase type 2, which converts active glucocorticoids into inactive metabolites (5).

CS during pregnancy is most frequently due to an adrenal adenoma and to a lesser degree to adrenocorticotropic hormone (ACTH) hypersecretion from a pituitary adenoma (1, 2, 3, 4). Aberrant expression of various hormone receptors in the adrenal glands is thought to play a role in the pathogenesis of this condition, in particular expression of the LH receptor (2, 3, 6, 7). The reported treatment modality of CS during pregnancy is variable and depends on the underling etiology and gestational age, but surgery is usually the recommended treatment option. In this study we describe three pregnant women with ACTH-independent Cushing’s syndrome and an adrenal tumor. One patient underwent a full evaluation for ectopic hormone receptor expression postpartum and adrenal tumor tissue from two patients was evaluated for LH receptor expression.

Subjects and methods

Case reports

Patient 1

Patient 1 is a 31-year-old woman (gravida 2, para 1) who presented in 2013 in a hospital elsewhere, when she was 32 weeks pregnant, with edema and pain in the lumbar region. Her menses had been regular until this pregnancy and her first pregnancy was uncomplicated. Her medical history included a gastric bypass two years after the first pregnancy and vitamin B12 deficiency. After surgery she reached a BMI of 28 (BMI before surgery 38.5) and her weight was stable until the second pregnancy. She had never been treated with glucocorticoids. There was no family history of endocrine disorders. At physical examination, she had a vital pregnancy, mild plethora, purple striae on the abdomen and skin atrophy with several ecchymoses. The patient’s height was 1.62 m, and weight was 80 kg. Blood pressure was 165/90 mmHg, as compared with 120/70 mmHg at the first prenatal visit. Hematological, liver and renal function tests were normal, except for a mild hypokalemia. Serum potassium levels ranged between 3.1 mmol/L and 3.4 mmol/L on different occasions. Urinary dipstick revealed significant proteinuria (+++) making the diagnosis of pre-eclampsia possible.

Fetal ultrasonography showed a single fetus in cephalic presentation and normal amniotic fluid.

Patient’s blood pressure was well controlled with enalapril and labetalol at a dose of 40 mg and 600 mg daily respectively. Hypokalemia was fully corrected with potassium suppletion. Endocrine evaluation revealed ACTH-independent hypercortisolism (Table 1).

Table 1

Results of biochemical screening during pregnancy and after delivery.

PatientDiurnal cortisol rhythm (nmol/L)Salivary cortisol (nmol/L)Urinary free cortisol (nmol/24 h)1 Mg-DST (nmol/L)ACTH (pmol/L)
During pregnancy
 Patient 1690–1070–1030Not measured1380360<1.1
After delivery
 Patient 1320–596–28018–47–64582210<1.1
 Patient 2609–670–701Not measured1131848<1.1
 Patient 3629–615–560Not measured1772604<1.1

At 35 weeks an induced labor resulted in normal vaginal delivery of a healthy girl (birth weight 2340 g). The labor was induced because hypercortisolism in pregnancy is associated with a high risk of spontaneous abortion and stillbirth. Computed tomography (CT) identified a 3.8 cm adenoma of the left adrenal gland (Fig. 1). Further investigation revealed also osteoporosis with compression fractures of the T11 and T12 vertebral bodies. Bone mineral density as analyzed by DEXA showed a T score of −2.7 and −2.6 at the L2–L4 region and at femoral neck respectively.

Figure 1
Figure 1

Abdominal CT (A and C) and MRI (B) showing a left adrenal mass suggestive of adrenal adenoma in patient 1 (A), patient 2 (B) and patient 3 (C).

Citation: European Journal of Endocrinology 177, 5; 10.1530/EJE-17-0263

After delivery features of her Cushingoid phenotype improved but did not resolve completely. In addition, hypertension persisted. Two months after delivery she was referred to our center and four months after delivery she underwent in vivo testing for aberrant hormone receptor expression by the adenoma (see results and Table 2).

Table 2

Peak plasma cortisol levels as percentage of baseline value, in in vivo stimulation tests of patient 1 with pregnancy-induced Cushing syndrome based on adrenal adenoma.

Stimulation testPeak value as % of baseline
LHRH (100 μg)211
hCG (10000 U)155
ACTH (250 ug)213
TRH (200 μg)133
Standard mixed meal292
Glucagon (1 mg)347
Desmopressine (2.5 μg)198

Tests were considered negative if cortisol levels increased by <25%. A partial response was defined as a 25–49% increase, and a positive test was defined as a more than 50% increase in cortisol level.

Subsequently she underwent a laparoscopic adrenalectomy and hydrocortisone replacement was commenced. Macro-pathological examination of the removed adrenal gland showed an adenoma appearing as a well-circumscribed, yellow, lobulated nodule with a diameter of 31 mm.

Signs and symptoms of hypercortisolism further improved and two months after surgery, the patient’s blood pressure was 115/70 mmHg without medication, and all biochemical abnormalities had resolved. For the first 16 months after adrenalectomy patient had insufficient response to 250 µg synthetic ACTH (Synacthen) (<525 nmol/L). Six month later hydrocortisone has been tapered and subsequently ceased. Osteoporosis was treated with a bisphosphonate, calcium and vitamin D supplementation. One year after surgery the bone mineral density as analyzed by DEXA showed a T score of −1.6 and −1.5 at the L2–L4 region and at femoral neck respectively.

Patient 2

Patient 2 is a 28-year-old woman (gravida 2, para 1) who was admitted to the emergency department of another hospital when she was 33 weeks pregnant with hypertension, gestational diabetes and liver tests abnormalities. Her menses had been regular until this pregnancy and during her first pregnancy there were no complications or Cushingoid symptoms.

She reported fatigue, weight gain, easy bruisability and proximal muscle weakness. Physical examination revealed a blood pressure of 140/86 mmHg, hirsutism, facial plethora, purple abdominal striae, and dorsocervical fat pads. The blood pressure was well controlled with labetalol 400 mg daily and the diabetes mellitus was treated with novorapid and lantus.

At the time of admission liver tests abnormalities were noticed: alanine aminotransferase (ALAT) 73 IU/L, asparagine aminotransferase (ASAT) 52 IU/L, gamma glutamyl transpeptidase (gGT) 49 IU/L, lactate dehydrogenase (LDH) 303 IU/L, alkaline phosphatase (AF) 109 IU/L. Thrombocyte number and hemoglobin level were normal, 213 × 109/L and 9 mmol/L, respectively.

Initially there was suspicion of HELLP syndrome but this was ruled out as thrombocyte level and protein level in the urine were normal. An ultrasonography showed an intrauterine fetus without abnormalities and a normal placenta. No further investigation was performed during the pregnancy. At 38 weeks a spontaneous labor resulted in normal vaginal delivery of a healthy boy (birth weight 2740 g). Labor induction was not performed. After delivery the patient was referred to our center and four months after delivery underwent endocrine evaluation which revealed ACTH-independent hypercortisolism (see results and Table 1). Magnetic resonance imaging showed a 3.3 cm nodule in her left adrenal gland (see results, Fig. 1). The adrenal gland was removed laparoscopically and appeared as a well-circumscribed, yellow, lobulated nodule with a diameter of 3.6 cm. After surgery hydrocortisone replacement was started and continued for 12 months until the cortisol response to 250 µg Synacthen (after stopping hydrocortisone) was sufficient (>525 nmol/L). Menses went back to being regular 2 month after the surgery. The clinical phenotype of Cushing’s syndrome as well as the hypertension and diabetes mellitus disappeared within several months thereafter.

Patient 3

Patient 3 is, a 25-year-old woman, gestational age 28 weeks, who was seen in another hospital because of gestational diabetes and recurrent episodes of depression that were progressively difficult to treat (paroxetine, daily 20 mg). There was no family history of endocrine abnormalities. She had no relevant medical history and she had not been treated with glucocorticoids. Her menstrual cycle had been regular until pregnancy. The patient’s height was 1.63 m, and her weight was 73 kg. She had facial plethora, increased dorsocervical fat pads, mild facial hirsutism, a few non-pigmented abdominal striae, and bruises. The fundal height was consistent with gestational age. Patient was not referred for further investigation because of the mildness of complaints and advanced pregnancy.

At 38 weeks a spontaneous labor resulted in normal vaginal delivery of a healthy boy (birth weight 3755 g).

Laboratory investigations, six months after delivery, revealed ACTH-independent hypercortisolism (see results and Table 1). CT showed a 3.4 cm adenoma in the left adrenal gland (see results Fig. 1). The adrenal gland was removed by laparoscopic surgery. The adrenal gland appeared as a well-circumscribed nodule with a diameter of 3.6 cm. After the surgery hydrocortisone replacement was started and continued for 12 months until cortisol response to 250 µg Synacthen was sufficient (>525 nmol/L). The clinical phenotype of Cushing’s syndrome as well as the depressive complaints disappeared within several months thereafter.

Methods

All studies were performed according to the rules of the hospital medical ethics committee. Informed consent was obtained from all patients.

Assays

Serum cortisol (8:00, 22:00 and 12:00 h; reference value, 200–700 nmol/L), UFC (determined in unextracted urine; upper limit, 850 nmol/24 h) and plasma ACTH-(1–39) concentrations (detection limit, 1.1 pmol/L) were measured by a fluorescent immunoassay (Diagnostic Products, Los Angeles, CA, USA). To screen for ectopic and aberrant eutopic hormone receptor expression (after cessation of all medication 4 days before testing), the following tests were performed: LHRH (100 μg i.v.), hCG (10000 U i.m), TRH (200  μg i.v.), glucagon (1  mg i.v.), desmopressin (dDAVP, 2.5  μg s.c), metoclopramide (10 mg), a standard mixed meal (116  g carbohydrates, 27 g proteins, and 14 g fat) and a 2-h upright posture test. All tests except the standard mixed meal were performed in the morning, and the standard mixed meal test was performed during lunch time. A positive response was defined by a >50% increase in plasma cortisol levels as defined by Lacroix et al. (6, 7). Plasma LH (premenopausal reference value, 1–50 IU/L; postmenopausal, 15–90 IU/L) and FSH (premenopausal, 1–25 IU/L; postmenopausal, 35–150 IU/L) concentrations were determined by an immunofluorometric assay (Diagnostic Products). Blood samples were collected 60 and 30 min before starting the test and then every 30 min until the test was completed (7).

Immunohistochemistry

Directly after laparoscopic removal, adrenal tissue of the major part of the adrenals was prepared as described previously (4, 6). The mouse MAB (20C3 provided by Dr A. Funaro) was used for LH receptor immunohistochemistry on formalin-fixed paraffin-embedded tissue. Normal adult testis was used as a positive control. Tissue sections of 3 μm thickness were deparafinized and incubated with the antibody (dilution 1:1000  in PBS containing 1% BSA) overnight at 4°C. Rabbit anti-mouse secondary biotinylated antibodies (DAKO, Glostrup, Denmark) were used in a 1:200 dilution and incubated for 30 min at room temperature. Antibody complex was visualized by avidin–biotin conjugated with HRP using 3,3-diaminobenzidine as chromogen and H2O2 as substrate. All slides were counterstained with hematoxylin.

Results

Hypercortisolism

Patient 1

The initial endocrine evaluation during pregnancy revealed an absent cortisol diurnal rhythm, an increased UFC excretion and insufficient suppression of cortisol after 1 mg dexamethasone. Basal ACTH concentrations were below the detection limit of 1.1 pmol/L (Table 1).

After delivery, all tests were repeated and showed similar results (Table 1).

Patient 2

Endocrine evaluation after delivery demonstrated absence of cortisol diurnal rhythm, an increased UFC excretion. Basal ACTH concentrations were undetectable (Table 1). Serum cortisol concentrations were not suppressed after the oral administration of 1 mg dexamethasone.

Patient 3

Endocrine evaluation after delivery demonstrated the absence of cortisol diurnal rhythm and an increased UFC excretion. Serum cortisol concentrations were not suppressed after the oral administration of 1 mg dexamethasone. Basal ACTH concentrations were undetectable (see for results Table 1).

Screening for aberrant cortisol responses

Patient 1 was screened for the presence of abnormal cortisol responses due to aberrant adrenal receptor expression, according to the protocol of Lacroix et al. (7) (Table 2).

Administration of 100 µg LHRH iv resulted in an increase in LH levels from 0.7 U/L to a peak level after 60 min of 12.4 U/L directly followed by a rapid increase in cortisol concentrations from 455 nmol/L to peak levels after 120 min of 963 nmol/L. FSH levels rose more slowly from 6.1 to 26.9 U/L after 160 min.

Administration of hCG induced a comparable increase in plasma cortisol levels from 437 nmol/L to a peak level of 930 nmol/L. Administration of glucagon induced an increase in plasma cortisol levels from 593 nmol/L to a peak level after 240 min of 875 nmol/L.

After a standard mixed meal, cortisol concentrations rose from 178 nmol/L to a peak level of 698 nmol/L.

No increase was observed in serum cortisol concentrations after oral administration of 10 mg metoclopramide and during the posture test (2 h, supine position), followed by a 2-h ambulatory period.

LH receptor studies

Immunohistochemical examination demonstrated the presence of LH receptor expression in adrenal adenoma tissue of patients 1 and 2, as well as in control Leydig cells (Fig. 2). Adrenal adenoma tissue of patient 3 was not tested.

Figure 2
Figure 2

Representative illustration of LH/hGC-R immunohistochemistry. (A) adrenal adenoma from patient 1. (B) Adrenal adenoma from patient 2. (C) Adult human testis in which the Leydig cells are positive (dark staining, Left central area image). Magnification 20×.

Citation: European Journal of Endocrinology 177, 5; 10.1530/EJE-17-0263

Discussion

In all our patients, development of Cushing’s syndrome during pregnancy was caused by an adrenal adenoma and was in one of them characterized by in vivo responsiveness of cortisol production to LHRH, hCG, glucagon, vasopressin and a standard mixed meal. Considering the tumor size, the adrenal mass in our patients could have been present before pregnancy, whether or not accompanied by subtle hypercortisolism. However, all three patients developed overt clinical CS during pregnancy. The cortisol response to LHRH and hCG, the suppressed ACTH levels and the presence of LH receptors in the adrenal adenomas of two patients suggest that LH/hCG regulates, at least in part, cortisol production in these patients directly at the adrenal level and could be responsible for the exacerbation of a preexisting subclinical CS.

Our first patient underwent bariatric surgery at a very young age and developed severe osteoporosis during pregnancy indicating possible longstanding subclinical hypercortisolism before pregnancy. Another argument for prolonged subclinical hypercortisolism is the persistent insufficiency of the remaining adrenal gland. All patients needed hydrocortisone replacement after the surgery.

To date, only a few patients with pregnancy-induced CS have been described (2, 3, 4, 5, 8, 9, 10, 11, 12, 13, 14). Pregnancy is uncommon in women with CS, as hyperandrogenism and hypercortisolism suppress gonadotrophin secretion (9, 10). Oligomenorrhea and amenorrhea, which are directly associated with infertility, are reported in approximately 75% of women of reproductive age diagnosed with CS (11, 15). The diagnosis of CS during gestation is difficult. First, there are many overlapping symptoms and signs in normal pregnancy such as obesity, abdominal striae and the increased tendency to develop hyperglycemia and hypertension. However, the presence of ecchymoses, myopathy, dark striae and difficult to control blood pressure and diabetes mellitus should alert the clinician. The frequency of hypertension and gestational diabetes is much higher than during normal pregnancy. Hyperglycemia and hypertension were also noticed in our patients.

Maternal morbidity occurs in about 70% of cases, although maternal mortality is very low (8). In addition preeclampsia, eclampsia, infection and congestive heart failure seem to occur more frequently (9, 16). Bone loss leading to fractures occurs less often in women with CS during pregnancy because pregnancy is a hyperestrogenic state in which bone resorption is inhibited (17). However, osteoporosis can be present in CS during pregnancy and can present with pain in the back and hips in the third trimester (12). One of our patients developed multiple pathological fractures of thoracic vertebra during pregnancy that were associated with back pain. A possible preexisting subclinical hypercortisolism might have played a role in the development of the osteoporosis in this young patient. One year after the surgery, her bone mineral density was normal.

The risk for the fetus depends on the effects of glucocorticoids on both the fetus directly and the maternal-placental unit. The fetus itself is relatively protected from (excess) glucocorticoids due to placental degradation of cortisol by 11β-hydroxysteroid dehydrogenase type 2 (13). Nevertheless, fetal mortality is as high as 25%–40% due to spontaneous abortion, stillbirth and early neonatal death due to prematurity. There are little data on an increased risk of congenital anomalies (14). In all our cases, healthy babies were born.

The most common cause of CS in pregnant women is an adrenal adenoma, in contrast to non-pregnant women in whom a pituitary adenoma is the most common cause of CS. This may be attributed to the fact that patients with an adrenal adenoma are most likely to be purely cortisol producing, thus their ovulatory function remains unaffected (15, 18, 19). Alternatively, pregnancy-induced hCG levels might have triggered a preexisting subclinical CS in these patients due to the aberrant expression of LH receptors in adrenocortical cells of an adrenal adenoma, whereas pre-pregnancy LH levels might be insufficient for the development of CS. All our patients were ultimately diagnosed with an adrenal adenoma.

For adrenal tumors, unilateral adrenalectomy can be been performed safely during pregnancy even into the early third trimester, although surgery is usually performed between 6 and 28 weeks of gestation (5). Because of the late presentation of all our patients and lack of CS diagnosis during the pregnancy in two of the cases, surgery was not performed during pregnancy. There were no complications during labor and all three children were born healthy. Only in one case, the labor was induced. In this case, the diagnosis of CS was made during pregnancy, while in the other two cases, only after delivery. When the diagnosis of CS is made late in the third semester, it seems safe to postpone the testing and surgery until after delivery. In case of difficult-to-treat complications related to hypercortisolism one might choose to induce labor.

Medical treatment of CS in pregnancy is usually avoided to minimize the potential for teratogenesis and induction of fetal adrenal insufficiency. Medical therapy can be applied for preparation or as a substitute for surgery for those patients with persistent disease postoperatively and for those who are not good surgical candidates (20). If medical treatment is needed, metyrapone or ketoconazole can be used during pregnancy. Metyrapone has been shown to be effective in some patients and has been used most frequently. Its side effects can include hypertension and worsening of preeclampsia. However, metyrapone crosses the placenta and may affect fetal adrenal steroid synthesis (11, 21). Ketoconazole has been shown to be effective in some patients as well, but it can cause intrauterine fetal growth retardation. However one case report describes use of ketoconazole in pregnancy resulting in a birth of a normal male infant without genital abnormalities (5).

Generally, a cesarean section should be avoided because hypercortisolism can impair wound healing. If cesarean section is performed, stress dose steroids are not recommended (16).

CS during pregnancy is a rare phenomenon with only a few cases reported in the literature. The adrenal manifestations include simple adenoma and mild bilateral diffuse hyperplasia (2, 3, 4, 11, 21, 22). Although the exact etiology is unknown, the most commonly postulated mechanism involves aberrant LH/hCG receptor expression by adrenal tumor tissue, which is coupled to steroidogenesis. The association between the LH/hCG receptor and pregnancy-induced CS was first postulated by Lacroix et al. (23) who described a patient with bilateral macronodular hyperplasia (BMAH) and transient CS during pregnancy and constant CS during menopause. In vivo, cortisol production was stimulated by GnRH, hCG, LHRH and a 5HT4 agonist. This patient was treated with the GnRH analog leuprolide acetate, resulting in suppression of LH levels, followed by normalization of cortisol production. This implies that the cortisol response to LH indeed plays a pathogenetic role in this form of CS. Previous published cases suggest that a minimum LH/hCG, concentration threshold, reached during pregnancy and after menopause, is needed in order to induce hypercortisolism (2, 4). Furthermore, Chui et al. (24) described a patient who developed CS with each pregnancy, leading to multiple miscarriages, with resolution of symptoms post-partum. Adrenal tissue showed increased expression of LH/hCG mRNA secondary to duplication of the LH/hCG gene (24). We previously documented two patients with non-pregnancy-induced CS and BMAH, who showed an in vivo cortisol response to GnRH, hCG, LH, ACTH and a 5HT4 agonist (29). LH receptor mRNA and protein expression was found in the adrenal tissue of both patients. Remarkably, one of the patients developed CS under premenopausal LH levels. In the largest series of BMAH to date, aberrant responses to LH were seen in 33% of patients (25).

Increased expression of the LH receptor gene as well as the mutation of the LH receptor are also possible explanations for the adrenal responsiveness to LH/hCG (4, 7). Interestingly, some cases of pregnancy-induced CS spontaneously resolve after delivery (2, 10, 11, 30). However, CS prevailed in our patients up to 6 months after delivery suggesting that a preexisting adrenal adenoma may be necessary for the persistence of CS after delivery. Considering the cortisol responses to LHRH and hCG in one of our patients, and the development of CS during pregnancy in these patients, it is likely that the LH/hCG concentration threshold that was reached during the pregnancy initiated a process of increased autonomous cortisol secretion that persisted in the adrenal adenoma even after the end of pregnancy. Increased hCG secretion during pregnancy might upregulate LHCGR, GATA4 and ZFMP2 expression and induce the hCG-responsive cells to differentiate into adrenal steroid-producing cells (2).

Furthermore, hCG may stimulate dehydroepiandrosterone sulfate production by stimulating LH receptors (26, 27). However, not all patients with CS during pregnancy respond to hCG administration, indicating alternative pathogenic mechanisms (27). It is known that adrenal adenomas or hyperplasia can present aberrant GIP receptor expression (28). Although the GIP receptor expression was not tested in our patients, a positive cortisol response to standard meal test was present in one of them. Moreover, this patient responded to other multiple stimuli, which also may have played a role in the regulation of cortisol production during pregnancy.

In conclusion, CS during pregnancy is a rare condition and is predominantly caused by adrenal neoplasia. Aberrant LH receptor expression by the adrenal adenoma or hyperplasia seems to play an important role in the pathogenesis and exacerbation of CS. Furthermore, aberrant LH receptors expression could be responsible for the development of autonomous secretion that persists even after the pregnancy when the LH/hCG concentration has decreased. Early recognition is important for maternal and fetal outcome.

Declaration of interest

All authors declare that no support from any organization was received for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contribution statement

All authors provided critical discussion and contributed in the preparation of the manuscript. C E-A design study, data collection, analyzed the data and drafted and revised the paper; R A-A, J-H, L H G-L analyzed the data and revised the draft paper; W W-H and L J-H revised the drafted the paper and R A F designed the study and revised the draft paper.

Acknowledgements

The research team would like to thank all patients who participated in this study.

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    Abdelmannan D & Aron DC. Adrenal disorders in pregnancy. Endocrinology Metabolism Clinics of North America 2011 40 779794.

  • 17

    Liel Y, Atar D & Ohana N. Pregnancy-associated osteoporosis: preliminary densitometric evidence of extremely rapid recovery of bone mineral density. Southern Medical Journal 1998 91 3335. (doi:10.1097/00007611-199801000-00006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Chico A, Manzanares JM, Halperin I, Martínez de Osaba MJ, Adelantado J & Webb SM Cushing’s disease and pregnancy: report of six cases. European Journal of Obstetrics and Gynecology and Reproductive Biology 1996 64 143146. (doi:10.1016/0301-2115(95)02258-9)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Murakami S SM, Kubo T, Kawakami Y & Yamashita K. A case of mid-trimester intrauterine fetal death with Cushing's syndrome. Journal of Obstetrics and Gynaecology Research 1998 24 153156. (doi:10.1111/j.1447-0756.1998.tb00067.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Sonino N & Boscaro M. Medical therapy for Cushing’s disease. Endocrinology Metabolism Clinics of North America 1999 28 211222. (doi:10.1016/S0889-8529(05)70064-5)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Close CF, Mann MC, Watts JF & Taylor KG ACTH-independent Cushing’s syndrome in pregnancy with spontaneous resolution after delivery: control of the hypercortisolism with metyrapone. Clinical Endocrinology 1993 39 375379. (doi:10.1111/j.1365-2265.1993.tb02380.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Lacroix A, Bourdeau I, Lampron A, Mazzuco TL, Tremblay J & Hamet P Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clinical Endocrinology 2010 73 115.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Lacroix A, Hamet P & Boutin JM. Leuprolide acetate therapy in luteinizing hormone--dependent Cushing’s syndrome. New England Journal of Medicine 1999 341 15771581. (doi:10.1056/NEJM199911183412104)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Chui MH, Ozbey NC, Ezzat S, Kapran Y, Erbil Y & Asa SL Case report: adrenal LH/hCG receptor overexpression and gene amplification causing pregnancy-induced Cushing’s syndrome. Endocrine Pathology 2009 20 256261. (doi:10.1007/s12022-009-9090-2)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Hofland J, Hofland LJ, van Koetsveld PM, Steenbergen J, de Herder WW, van Eijck CH, de Krijger RR, van Nederveen FH, van Aken MO & de Groot JW ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11beta-hydroxylase. Orphanet Journal of Rare Diseases 2013 8 142. (doi:10.1186/1750-1172-8-142)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Seron-Ferre M, Lawrence CC & Jaffe RB. Role of hCG in regulation of the fetal zone of the human fetal adrenal gland. Journal of Clinical Endocrinology and Metabolism 1978 46 834837. (doi:10.1210/jcem-46-5-834)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    O’Connell Y, McKenna TJ & Cunningham SK. The effect of prolactin, human chorionic gonadotropin, insulin and insulin-like growth factor 1 on adrenal steroidogenesis in isolated guinea-pig adrenal cells. Journal of Steroid Biochemistry and Molecular Biology 1994 48 235234.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Albiger NM, Occhi G, Mariniello B, Iacobone M, Favia G, Fassina A, Faggian D, Mantero F & Scaroni C Food-dependent Cushing’s syndrome: from molecular characterization to therapeutical results. European Journal of Endocrinology 2007 157 771778. (doi:10.1530/EJE-07-0253)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    de Groot JW, Links TP, Themmen AP, Looijenga LH, de Krijger RR, van Koetsveld PM, Hofland J, van den Berg G, Hofland LJ & Feelders RA Aberrant expression of multiple hormone receptors in ACTH-independent macronodular adrenal hyperplasia causing Cushing’s syndrome. European Journal of Endocrinology 2010 163 293299. (doi:10.1530/EJE-10-0058)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Wieland RG, Shaffer MB Jr & Glove RP. Cushing’s syndrome complicating pregnancy. A case report. Obstetrics and Gynecology 1971 38 841843.

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  • View in gallery

    Abdominal CT (A and C) and MRI (B) showing a left adrenal mass suggestive of adrenal adenoma in patient 1 (A), patient 2 (B) and patient 3 (C).

  • View in gallery

    Representative illustration of LH/hGC-R immunohistochemistry. (A) adrenal adenoma from patient 1. (B) Adrenal adenoma from patient 2. (C) Adult human testis in which the Leydig cells are positive (dark staining, Left central area image). Magnification 20×.

  • 1

    Lindsay JR & Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocrine Reviews 2005 26 775799. (doi:10.1210/er.2004-0025)

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  • 2

    Plockinger U, Chrusciel M, Doroszko M, Saeger W, Blankenstein O, Weizsacker K, Kroiss M, Hauptmann K, Radke C & Pollinger A Functional implication of LH/hCG receptors in pregnancy-induced Cushing syndrome Journal of the Endocrine Society 2017 1 5771

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  • 3

    Rask E, Schvarcz E, Hellman P, Hennings J, Karlsson FA & Rao CV Adrenocorticotropin-independent Cushing’s syndrome in pregnancy related to overexpression of adrenal luteinizing hormone/human chorionic gonadotropin receptors Journal of Endocrinological Investigation 2009 32 313. (doi:10.1007/BF03345718)

    • Crossref
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  • 4

    Trinh A, Chan I, Alexiadis M, Pell M, Kumar B & Fuller PJ Adrenal Cushing’s syndrome in pregnancy: clinical and molecular characterisation of a case Obstetric Medicine 2016 9 4345. (doi:10.1177/1753495X15618542)

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  • 5

    Lindsay JR, Jonklaas J, Oldfield EH & Nieman LK Cushing’s syndrome during pregnancy: personal experience and review of the literature. Journal of Clinical Endocrinology and Metabolism 2005 90 30773083. (doi:10.1210/jc.2004-2361)

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  • 6

    Feelders RA, Lamberts SW, Hofland LJ, van Koetsveld PM, Verhoef-Post M, Themmen APN, de Jong FH, Bonjer HP, Clark AJ & van der Lely AJ Luteinizing hormone (LH)-responsive Cushing’s syndrome: the demonstration of LH receptor messenger ribonucleic acid in hyperplastic adrenal cells, which respond to chorionic gonadotropin and serotonin agonists in vitro. Journal of Clinical Endocrinology and Metabolism 2003 88 230237. (doi:10.1210/jc.2002-020621)

    • Crossref
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  • 7

    Lacroix A, Ndiaye N, Tremblay J & Hamet P Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocrine Reviews 2001 22 75110. (doi:10.1210/edrv.22.1.0420)

    • PubMed
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  • 8

    Vilar L, Freitas Mda C, Lima LH, Lyra R & Kater CE Cushing’s syndrome in pregnancy: an overview. Arquivos Brasileiros de Endocrinologia and Metabologia 2007 51 12931302.

    • Crossref
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    • Export Citation
  • 9

    Sheeler LR. Cushing’s syndrome and pregnancy. Endocrinology Metabolism Clinics of North America 1994 23 619627.

  • 10

    Kita M, Sakalidou M, Saratzis A, Ioannis S & Avramidis A Cushing’s syndrome in pregnancy: report of a case and review of the literature. Hormones 2007 6 242246.

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    Aron DC, Schnall AM & Sheeler LR. Spontaneous resolution of Cushing’s syndrome after pregnancy. American Journal of Obstetrics and Gynecology 1990 162 472474. (doi:10.1016/0002-9378(90)90413-2)

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  • 12

    Tajika T, Shinozaki T, Watanabe H, Yangawa T & Takagishi K Case report of a Cushing’s syndrome patient with multiple pathologic fractures during pregnancy. Journal of Orthopaedic Science 2002 7 498500. (doi:10.1007/s007760200087)

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  • 13

    Hillman DA & Giroud CJ. Plasma cortisone and cortisol levels at birth and during the neonatal period. Journal of Clinical Endocrinology and Metabolism 1965 25 243248. (doi:10.1210/jcem-25-2-243)

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  • 14

    Fitzsimons R, Greenberger PA & Patterson R. Outcome of pregnancy in women requiring corticosteroids for severe asthma. Journal of Allergy and Clinical Immunology 1986 78 34953. (doi:10.1016/S0091-6749(86)80088-4)

    • Crossref
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  • 15

    Buescher MA, McClamrock HD & Adashi EY. Cushing syndrome in pregnancy. Obstetrics and Gynecology 1992 79 130137.

  • 16

    Abdelmannan D & Aron DC. Adrenal disorders in pregnancy. Endocrinology Metabolism Clinics of North America 2011 40 779794.

  • 17

    Liel Y, Atar D & Ohana N. Pregnancy-associated osteoporosis: preliminary densitometric evidence of extremely rapid recovery of bone mineral density. Southern Medical Journal 1998 91 3335. (doi:10.1097/00007611-199801000-00006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Chico A, Manzanares JM, Halperin I, Martínez de Osaba MJ, Adelantado J & Webb SM Cushing’s disease and pregnancy: report of six cases. European Journal of Obstetrics and Gynecology and Reproductive Biology 1996 64 143146. (doi:10.1016/0301-2115(95)02258-9)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Murakami S SM, Kubo T, Kawakami Y & Yamashita K. A case of mid-trimester intrauterine fetal death with Cushing's syndrome. Journal of Obstetrics and Gynaecology Research 1998 24 153156. (doi:10.1111/j.1447-0756.1998.tb00067.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Sonino N & Boscaro M. Medical therapy for Cushing’s disease. Endocrinology Metabolism Clinics of North America 1999 28 211222. (doi:10.1016/S0889-8529(05)70064-5)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Close CF, Mann MC, Watts JF & Taylor KG ACTH-independent Cushing’s syndrome in pregnancy with spontaneous resolution after delivery: control of the hypercortisolism with metyrapone. Clinical Endocrinology 1993 39 375379. (doi:10.1111/j.1365-2265.1993.tb02380.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Lacroix A, Bourdeau I, Lampron A, Mazzuco TL, Tremblay J & Hamet P Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clinical Endocrinology 2010 73 115.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Lacroix A, Hamet P & Boutin JM. Leuprolide acetate therapy in luteinizing hormone--dependent Cushing’s syndrome. New England Journal of Medicine 1999 341 15771581. (doi:10.1056/NEJM199911183412104)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Chui MH, Ozbey NC, Ezzat S, Kapran Y, Erbil Y & Asa SL Case report: adrenal LH/hCG receptor overexpression and gene amplification causing pregnancy-induced Cushing’s syndrome. Endocrine Pathology 2009 20 256261. (doi:10.1007/s12022-009-9090-2)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Hofland J, Hofland LJ, van Koetsveld PM, Steenbergen J, de Herder WW, van Eijck CH, de Krijger RR, van Nederveen FH, van Aken MO & de Groot JW ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11beta-hydroxylase. Orphanet Journal of Rare Diseases 2013 8 142. (doi:10.1186/1750-1172-8-142)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Seron-Ferre M, Lawrence CC & Jaffe RB. Role of hCG in regulation of the fetal zone of the human fetal adrenal gland. Journal of Clinical Endocrinology and Metabolism 1978 46 834837. (doi:10.1210/jcem-46-5-834)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    O’Connell Y, McKenna TJ & Cunningham SK. The effect of prolactin, human chorionic gonadotropin, insulin and insulin-like growth factor 1 on adrenal steroidogenesis in isolated guinea-pig adrenal cells. Journal of Steroid Biochemistry and Molecular Biology 1994 48 235234.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Albiger NM, Occhi G, Mariniello B, Iacobone M, Favia G, Fassina A, Faggian D, Mantero F & Scaroni C Food-dependent Cushing’s syndrome: from molecular characterization to therapeutical results. European Journal of Endocrinology 2007 157 771778. (doi:10.1530/EJE-07-0253)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    de Groot JW, Links TP, Themmen AP, Looijenga LH, de Krijger RR, van Koetsveld PM, Hofland J, van den Berg G, Hofland LJ & Feelders RA Aberrant expression of multiple hormone receptors in ACTH-independent macronodular adrenal hyperplasia causing Cushing’s syndrome. European Journal of Endocrinology 2010 163 293299. (doi:10.1530/EJE-10-0058)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Wieland RG, Shaffer MB Jr & Glove RP. Cushing’s syndrome complicating pregnancy. A case report. Obstetrics and Gynecology 1971 38 841843.