http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(5): 345–349 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2013.879857
CUSHING’S SYNDROME IN PREGNANCY
Cushing’s syndrome in pregnancy: a case report and mini review of the literature K. Katulski1, A. Podfigurna-Stopa1, M. Maciejewska-Jeske1, M. Ruchala2, E. Gurgul2, M. Szymankiewicz3, G. H. Breborowicz4, K. Karmelita-Katulska5, M. Stajgis5, M. Biczysko6, M. Gryczynska2, A. R. Genazzani7, and B. Meczekalski1 1
Department of Gynecological Endocrinology, 2Department of Endocrinology, Metabolism and Internal Medicine, 3Department of Neonatology, Department of Perinatology and Gynaecology, 5Department of Radiology, 6Department of General, Gastroenterological and Endocrine Surgery, Poznan University of Medical Sciences, Poznan, Poland, and 7Department of Reproductive Medicine and Child Development, Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy
4
Abstract
Keywords
Adrenal diseases in pregnant women are diagnosed relatively rarely. The main cause of hypercortisolemia during pregnancy is Cushing’s syndrome related to adrenal adenoma. It is important to diagnose Cushing’s syndrome in pregnant women because it can lead to significant maternal and foetal complications and morbidity. However, due to physiological endocrine changes and symptoms in pregnant women the diagnosis of this disorder can be a challenge. One current case describes a 38-year-old pregnant woman with hypertension, oedema and an adrenal tumour. At the beginning, Conn syndrome was suspected, but after careful analysis Cushing’s syndrome (with an adenoma of the right adrenal gland) was diagnosed. After delivery and 5 weeks of pharmacological treatment the patient underwent right side adrenalectomy by laparoscopy.
Adrenal tumour, Cushing’s syndrome, hypertension, pregnancy
Cushing’s syndrome was described for the first time by Harvey Cushing in 1932 [1]. It includes signs and symptoms related to prolonged exposure to high cortisol levels [2]. Women with hypercortisolemia are subfertile, because high cortisol level causes anovulation [2]. Therefore, Cushing’s syndrome occurs relatively rarely in pregnant women [3]. To date, approximately 150 cases of Cushing’s syndrome in pregnancy have been reported with 18 weeks being the mean gestational age [4,5]. It is important to diagnose Cushing’s syndrome in pregnant women because it can lead to significant maternal and foetal morbidity [6]. However, due to physiological endocrine changes and symptoms in pregnant women, the diagnosis of this disorder can be a challenge [6]. Symptoms typical for Cushing’s syndrome in pregnant women include central weight gain, oedema, hypertension, fatigue, mood changes and glucose intolerance [7]. Additionally, interpretation of hormonal assay and hormonal tests in these women is difficult [7]. Maternal complications are related to hypertension, pre-eclampsia, diabetes mellitus, infections and premature labour [8]. The foetus may experience intrauterine growth restriction, prematurity, miscarriage and stillbirth [9].
Case report A 38-year-old woman (gravida 1, para 1) at 19 weeks of pregnancy with the suspicion of Conn syndrome was admitted
Address for correspondence: B. Me˛czekalski, Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland. E-mail: [email protected]
Received 1 October 2013 Accepted 30 December 2013 Published online 24 January 2014
to the Department of Gynaecological Endocrinology, Poznan University of Medical Sciences in Poland. The patient suffered from hypertension and was taking methyldopa 250 mg four times a day. The daily average blood pressure readings during her stay in the Department were 120/80, 120/80 and 115/75 mmHg. She suffered from hypothyroidism and was taking 50 mg of levothyroxine. During hospitalization the serum concentrations of thyroxin was 0.69 ng/dl with normal ranges between 0.83 and 1.7 ng/dl and thyrotropin was 0.15 mIU/ ml with normal ranges between 0.27 and 4.2 mIU/ml. During hospitalization a low serum potassium level was revealed – 3.5 mmol/l – and potassium chloride was administered. We diagnosed gestational diabetes type 2 and ordered a diabetic diet. Urinary metanephrine concentrations were 513.0 mg/l and normetanephrine 56.5 mg/l. The metanephrine 24-h urinary excretion was 46 mg with normal concentrations below 350 mg/ 24 h, normetanephrine 201 mg with normal concentrations below 5600 mg/24 h and vanillylmandelic acid 12.3 mg with normal concentrations below 13.6 mg/24 h. Serum cortisol concentration after morning awakening was 805.8 nmol/l with an normal range between 171 and 536 nmol/l and in the afternoon 933.2 nmol/l. Ultrasonography of the abdomen performed at 18 weeks of gestation revealed in the pregnant woman, around the right adrenal hypoechogenic, a round tumour with a diameter of 35 mm. During the patient’s stay at the Department of Gynaecological Endocrinology, magnetic resonance imaging (MRI) of the adrenal glands was performed (in the Department of Radiology, Poznan University of Medical Sciences, Poznan, Poland) on a 1.5 T scanner (Magnetom Avanto, Simens, Erlangen, Germany) using a
20 14
Introduction
History
346
K. Katulski et al.
matrix phased-array coil. The system has a maximum gradient amplitude of 60 mT/m and a slew rate of 200 mT/m/ms. We did not use contrast during the examination. The length of time of scanning was 15 min. The MRI revealed a round lesion in the right adrenal gland with diameter of 30 mm. The lesion was hypointense in the T2 images and demonstrated a loss of signal intensity on the out-of-phase images. Adrenal masses that contain intracellular fat have been shown to lose signal intensity on chemical shift out-of-phase images compared with in-phase images owing to the presence of intracellular lipid benign lesions. We recognized the adrenal adenoma (Figures 1 and 2). Afterwards, the patient was hospitalized and monitored at the Department of Gynecological Endocrinology three times (at 22, 25 and 28 weeks of gestation). At 25 weeks of gestation plasma, renin activity was 1.9 ng/ml/ h in a lying down position with normal range between 0.5 and 1.9 and 3.48 ng/ml/h in the sitting position with normal range between 1.9 and 6.0 ng/ml/h. At 28 weeks of gestation, the plasma adrenocorticotropic hormone (ACTH) concentration was 1.8 pg/ml with normal concentrations below 60 pg/ml. The 24-h urinary cortisol concentration was 1018 nmol/l and 24-h urinary cortisol excretion was 2901 nmol, which were extremely increased. Serum cortisol
Figure 1. TSE coronal T2-weighted image performed during a single breath hold arrow rounded lesion in right adrenal gland.
Gynecol Endocrinol, 2014; 30(5): 345–349
concentration after morning awakening was 840.3 nmol/l and in the afternoon 929.5 nmol/l. The female neonate was born by caesarean section at 35 week of gestation in a good condition, and the Apgar score at 1 and 5 min was nine points at both times. Birth weight was 2660 g and was appropriate for the gestational age. Due to the mother’s diseases, the newborn was admitted for observation to the Neonatology Department, Poznan University of Medical Sciences in Poland. In the first day of the child’s life, the child developed hypoglycaemia (blood glucose levels ranged from 12 to 45 mg%), which was compensated by an intravenous 10% glucose supplementation. We also observed disturbances in the newborn’s electrolytes in the form of hyperkalemia (potassium level in the blood ranged from 6.1 to 6.8 meq/l) and hypercalcemia (the serum total blood calcium was between 2.3 and 2.4 meq/l, and ionized calcium range from 13 to 1.5 meq/l). An abdominal ultrasound examination showed no abnormalities. From the third day of life there were no signs of adrenal dysfunction of the neonate. Electrolyte disorders were never clinically manifested and disappeared completely on the third day of life. Blood pressure and heart rate were normal during all the neonatal stay at the hospital. Other additional laboratory tests, such as sodium, chloride, magnesium and inorganic phosphorus, were normal throughout the child’s stay in the department. The values of serum thyroid hormones (T3, T4) and TSH in the blood of the newborn were normal. Due to the transient food intolerance, during the first 3 days of life the baby was on total parental nutrition. Then, on the fourth day we started enteral feeding with good tolerance and a normal body weight gain. Mild neonatal jaundice occurred between the third and fifth day of life and did not require treatment other than phototherapy. Routine screening tests (for hypothyroidism, phenylketonuria, cystic fibrosis) were carried out and their results were normal. On the 18th day of life the newborn was discharged home in a good general condition, with a body weight of 3030 g. After childbirth, we decided to perform a CT examination on the mother using the standard protocol (GE multidetector scanner), which confirmed an adenoma of the right adrenal gland. To exclude any pathology in the pituitary gland, we performed an MRI of the head using the standard protocol and no pathologies were found. On the 25th day after delivery, the patient was admitted to the Endocrinology Clinic, Poznan University of Medical Sciences in Poland. At that time, the patient’s major complaint was muscle weakness, which severely decreased her mobility. Her blood pressure tended to rise up to 160/100 mmHg. The patient suffered also from headaches, hair loss, mood changes and
Figure 2. GRE T1-weighted chemical shift images: (A) in-phase axial image, arrow – adrenal adenoma and (B) out-of-phase axial image, arrow – lipid rich adrenal adenoma (a loss of signal in out-of-phase images).
DOI: 10.3109/09513590.2013.879857
insomnia. Cortisol concentration after morning awakening was increased: 737.4 nmol/l. She presented with a round ‘‘moon face’’, central obesity (persistent large waistline after delivery), abdominal purple striate, muscle atrophy in the upper and lower extremities, ankle oedema, multiple petechie and ecchymoses, facial acne and multiple verrucae on her neck (which appeared during pregnancy). The patient’s serum morning cortisol level was slightly increased 588–620 nmol/l with normal ranges between 171 and 536 nmol/l. However, the diurnal cortisol rhythm was disturbed (at 6 pm 556–703 nmol/l, at 11 pm 491–609 nmol/l) and 24-h urinary cortisol excretion was markedly increased (up to 1206 nmol; normal range between 100 and 379 nmol/24 h). The dehydroepiandrosterone–sulphate level was low (6 mg/dl; normal range between 61 and337). The ACTH secretion was suppressed (0.7–2.3 pg/ml; normal range between 0 and 60 pg/ml). Therefore, an adrenaldependent cause of hypercortisolism was the most probable diagnosis (with the tumour in the right adrenal gland revealed in previous MRI and CT). Sodium and potassium levels were within normal ranges (Na 143 mmol/l, normal range between 136 and 145; K 3.88 mmol/l, normal range between 3.5 and 5.1). Ketoconazole was administered orally at an initial dose of 3 400 mg. Due to a rapid decrease of the cortisol level on the sixth day of treatment (90 nmol/l), the ketoconazole dose was reduced to 3 200 mg. The drug tolerance was good. However, the therapy caused an increase of aminotraspherases concentration (alanine aminotransferase from 42 to 92 U/l, aspartate aminotransferase from 20 to 38 U/l). The patient was treated also with (1) ramipril 5 mg for hypertension, (2) spironolactone 50 mg for hypertension and peripheral oedema, (3) potassium and calcium to prevent electrolyte disturbances, (4) paracetamol and ketoprophen for headaches and (5) hydroxyzine 25 mg as a tranquillizer. The glucose level was efficiently controlled by the diabetic diet. The patient continued L-thyroxine substitution at the dose of 75 mg. Her TSH level was decreased (0.03 mU/ml; normal range between 0.27 and 4.20), free triiodothyronine (fT3) maintained low (3.13 pmol/l; normal range between 3.93 and 7.70) and the free thyroxine (fT4) level was normal (16.53 pmol/l; normal range between 11.5 and 21.0). Antithyroid antibodies were negative (anti-thyroglobulin510 IU/l, anti-thyroid peroxidase 9 IU/l, thyrotropin receptor antibody 0.33 IU/l). A thyroid ultrasound did not reveal any focal lesions. Thyroid echogenicity was irregular and decreased. Her chest X-ray was normal. In abdominal ultrasound, there were no other abnormalities other than the right adrenal tumour. The femoral neck bone density was decreased (0.690 g/cm2; T-score – 2.5, Z-score – 2.0). Ketoconazole treatment resulted in a noticeable decrease of cortisol release (24-h cortisol excretion was reduced to 370 nmol/24 h). The patient was consulted by a surgeon and anaesthesiologist and qualified for a right adrenalectomy.
Surgical treatment of the patient After short pharmacological preparation a laparoscopic right sided, transperitoneal lateral adrenalectomy was performed in the Department of General, Gastroenterological and Endocrine Surgery, Poznan University of Medical Sciences, Poznan, Poland. Directly after the procedure, a hydrocortisone substitution was introduced. After surgery no complications were observed. The patient was dismissed from hospital on the fifth postoperative day as proper hydrocortisone substitution doses were established. The patient was referred to the Endocrinology Outpatient Clinic for later follow-up. The histopathological result after surgery revealed a cortical adenoma of the right adrenal gland (diameter 3.2 cm).
Cushing’s syndrome
347
Discussion and mini-review of the literature During pregnancy, Cushing’s syndrome is manifested extremely rarely – to date, less than 150 cases have been recorded [5]. Patients suffering from Cushing’s syndrome often have procreation problems due to the negative influence of corticotrophinreleasing hormone (CRH) and ACTH on GnRH on gonadotropin secretion. The aetiology of Cushing’s syndrome diagnosed in a group of pregnant women and in the general population is different – while adrenal gland tumours are its most frequent cause in pregnant women, the pituitary gland is its major cause in the general population [4]. This disproportion is mainly caused by the fact that pregnancy is rare in Cushing’s syndrome patients, as mentioned above. It can also be caused by the presence of LH/hCG receptors (LHCGRs) in the adrenal gland tumours, which are active during pregnancy [10]. The concentration of cortisol and other adrenal steroids in the serum of a pregnant woman is a result of placental hormonal activity and increased function of the adrenal cortex. The placenta produces a hormone which acts like the CRH, stimulating synthesis and release of proopiomelanocortin and its derivatives: corticotrophin and beta-endorphin. Placental corticoliberin levels are high in the serum of both the foetus and the mother. ACTH levels in the serum of the mother increase in the third trimester and are highest around the time of the delivery. Adrenal steroids synthesis is significantly elevated; the higher concentrations of cortisol in the serum are responsible for stretch marks and may lead to insulin resistance in the third trimester [11]. ACTH-dependent and ACTH-independent Cushing’s syndrome developing during pregnancy and spontaneously resolving after delivery is an exceptional case. A high concentration of oestradiol and hCG during pregnancy in women manifesting an abnormal reactivity of adrenal cortex cells to these hormones are listed as etiological factors of the ACTH-independent form of Cushing’s syndrome [12]. Since hypercortisolemia symptoms are similar to those which can be found during pregnancy, diagnosis of Cushing’s syndrome in pregnant women is difficult. These symptoms include: central weight gain, stretch marks, swelling, arterial hypertension (68%), glucose intolerance or gestational diabetes (25%) and pre-eclampsia (14%). Other symptoms (less frequently observed) include osteoporotic fractures (5%), and mental disorders (2%). In 2% of cases, the disease led to the death of the patient [12]. Our patient presented with hypertension, hypothyroidism, gestational diabetes, muscle weakness and mood changes. A similar situation has been described by Borna et al. [13], who treated a 33-year-old patient in the 30th week of gestation. The patient suffered from hypertension, gestational diabetes and foetal tachycardia. Abdominal MR imaging showed a right adrenal gland tumour and laboratory tests revealed an elevated cortisol level, low ACTH and potassium levels. The patient was treated conservatively. A caesarean section was performed in the 32nd week of gestation and afterwards a right adrenalectomy was carried out. A similar case was recorded by Kim and co-workers, who described a patient with severe pre-eclampsia and gestational diabetes. In the 30th week of gestation, a caesarean section was performed. Five weeks after delivery, a laparoscopic right adrenalectomy was performed [14]. Bednarek-Tupikowska et al. [15] described a case of a pregnant patient with an adrenal cortex adenoma who underwent a left adrenalectomy 3 weeks following delivery by caesarean section in the 35th week of gestation. Achong et al. [16] described an interesting case of a patient suffering from CS who was treated conservatively during her five pregnancies. They emphasized that, in rare cases, pregnancyinduced CS occurs. So far, only nine cases like this one have been
348
K. Katulski et al.
recorded. The first report of nine such cases was described by Vilar et al. [17]. The results of imaging of the adrenal glands and histopathological results varied in these nine cases. No abnormalities were revealed in six cases, bilateral micronodular hyperplasia was found in one case, and one bilateral macronodular hyperplasia (MAH) and one adenoma. Although the exact aetiology is unknown, the most commonly postulated mechanism involves aberrant LHCGR expression. The ACTH receptor is a member of the G-protein-coupled receptor family. Normally, ACTH binding to the receptor stimulates adenylyl cyclase, resulting in cortisol production. However, in some forms of ACTH-independent MAH and adrenal adenomas, other G-protein-coupled receptors are aberrantly coupled to the adenylyl cyclase pathway, resulting in cortisol production in response to other ligands, for example, gastric inhibitory peptide, vasopressin, catecholamines, oestrogen and serotonin. Therefore, LH/hCG-induced CS may be due to an upregulation of a normally weakly expressed eutopic receptor [12]. The association between the LHCGR and pregnancy-induced CS was first suggested by Lacroix et al. who described a patient with ACTH-independent MAH and CS associated with pregnancy and menopause. In vivo, cortisol was stimulated by GnRH, hCG and rhLH as well as 5HT4R receptor agonists, and a response to leuprolide (a long-acting GnRH analogue) occurred. Other reports of pregnancy-induced CS demonstrate a response to hCG post-partum [16]. Pregnancy-induced CS is possible given the clear temporal relationship with pregnancy and resolution of the hypercortisolism (clinically and biochemically) in the post-partum period. In six/nine cases reported, the adrenal imaging was normal, as it was in our patient. As the postulated mechanism for pregnancyinduced CS involves aberrant LHCGR expression or function, failure to identify a mutation in the ACTH receptor does not exclude this diagnosis [18]. Undiagnosed and untreated Cushing’s Syndrome during pregnancy leads to severe foetal complications. These include spontaneous abortion, pre-term birth (46%), foetal death and intrauterine dystrophy. However, approximately 80% of pregnancies end with the delivery of a healthy child [10]. Regarding our patient, the foetus and newborn suffered from transient electrolyte disorders and transient hypoglycaemia. The newborn was discharged home in good general condition after 18 days. Laboratory diagnostics of Cushing’s syndrome is significantly impeded by the presence of hypercortisolemia, pre-eclampsia and glucose intolerance. During pregnancy, the concentration of total and free cortisol is two or three times higher than in the non-gestational period. A regular circadian rhythm of cortisol and ACTH is preserved. Results of the Dexamethasone Supression Test and urinary free cortisol excretion levels are difficult to interpret. An increased percentage of false positive results has been observed. In diagnostics, it is advised to mark the levels of free cortisol in a 24-h sample of urine, along with the concentration of cortisol in saliva in the late evening hours. Differential diagnosis of hypercortisolemia can cause a series of problems, too. In the general population, low concentration of ACTH is recorded in ACTH-independent Cushing’s syndrome, which is not the case during pregnancy. An 8 mg dexamethasone test can be helpful, as long as it is analysed along with other noninvasive tests, such as the CRF test or desmopressin test in the event of cortisol suppression reaching over 80% [18]. In the case of our patient, critical for diagnosis was the improper concentration of serum cortisol in the blood and urine and the round tumour of 35 mm which was found around the right adrenal hypoechogenic during ultrasonographic examination.
Gynecol Endocrinol, 2014; 30(5): 345–349
The use of imaging tests during pregnancy is limited and based mostly on ultrasonographic imaging and MRI. Worthy of notice, MRI tests should only be carried out after the 32nd week of the pregnancy and contrast agents belonging to class C. Interpretation of MRI results of the pituitary gland may be difficult due to its physiological enlargement during pregnancy [19]. Therapy for Cushing’s syndrome during pregnancy is significantly limited depending on its presentation and development, it can be treated pharmacologically and surgically. Pharmacological treatment aims to prepare the patient to a planned surgery (preferably laparoscopic) in the second trimester or post-delivery. In such cases, Metyrapone (1.5 g to 3 g/24 h) is the medication of choice. As opposed to Ketoconazole and Mitotan, Metyrapone is not teratogenic in nature, and it decreases cortisol levels through inhibiting adrenal cortical 11 beta-hydroxylase. In the case referred to here, the pregnant patient was treated symptomatically with swelling reduction medicine and blood pressure medicine. Surgical treatment was completed post-partum [17]. Some authors recommend surgical treatment of the adrenal glands during pregnancy. Blanco et al. [20] reported an interesting case of a patient with an adrenal gland tumour which was diagnosed before pregnancy. The patient was treated conservatively and in the 16th week of gestation an adrenalectomy was performed. Spontaneous delivery occurred in the 30th week of gestation. Toutounchi et al. [21] described a case of a 21-year-old female who was treated laparoscopically in the 24th week of gestation, with a left adrenalectomy. Spontaneous delivery occurred in the 38th week of gestation. Tejura et al. [18] recorded a 23-year-old patient suffering from CS, whose right adrenal gland tumour was treated surgically in the 30th week of gestation. The patient gave birth by caesarean section in the 38th week of gestation. However, not all patients accept surgical treatment during pregnancy. Delibasi et al. [22] described a case of a 22-year-old female whose pregnancy was terminated in the 11th week of gestation due to a high risk of death of the mother. Earlier in the pregnancy, the patient had refused to undergo surgical treatment of her right adrenal gland tumour (a 3 cm tumour was diagnosed in CT). In conclusion, it is obvious, that the best outcome is achieved by a multidisciplinary approach consisting of an endocrinologist, obstetrician, anaesthetist, neonatologist and endocrine surgeon.
Declaration of interest The authors report no conflicts of interest.
References 1. Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 1932;50:137–95. 2. Lekarev O, New M. Adrenal disease in pregnancy. Best Pract Res Clin Endocrinol Metab 2011;25:959–73. 3. Abdelmannan D, Aron DC. Adrenal disorders in pregnancy. Endocrinol Metab Clin North Am 2011;40:779–94. 4. Buescher MA, McClamrock HD, Adashi EY. Cushing syndrome in pregnancy. Obstet Gynecol 1992;79:130–7. 5. Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing’s syndrome during pregnancy: personal experience and review of the literature. J Clin Endocrinol Metab 2005;90:3077–83. 6. Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocr Rev 2005;26:775–99. 7. Kita M, Sakalidou M, Saratzis A, et al. Cushing’s syndrome in pregnancy: report of case and review of literature. Hormones (Athens) 2007;6:242–6.
DOI: 10.3109/09513590.2013.879857
8. Meczekalski B, Katulski K, Podfigurna-Stopa A, Czyzyk A. Nadnercza. In: Meczekalski B, ed. Endokrynologia ciazy. [Endocrinology of pregnancy] Warszawa: PZWL; 2012:46–58. 9. Vilar L, Freitas Mda C, Lima LH, et al. Cushing’s syndrome in pregnancy: an overview. Arq Bras Endocrinol Metabol 2007;51: 1293–302. 10. Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushings syndrome during pregnancy: personal Experience and review of the literature. J Clin Endocrinol Metab 2005;90:3077–83. 11. Feedlers RA, Lamberts SWJ, Hofland LJ, et al. Luteinizing hormone (LH)-responsive Cushing syndrome: the demonstration of LH receptor messenger ribonucleic acid in hyperplastic adrenal cells, which respond to chorionic gonadotropin and serotonin agonists in vitro. J Clin Endocrinol Metab 2003;88:230–7. 12. Lindsay JR, Nieman LK. The hypothalamic–pituitary–adrenal axis in pregnancy: challenges in disease detection and treatment. Endocrinol Rev 2005;26:775–99. 13. Borna S, Akbari S, Eftekhar T, Mostaan F. Cushing’s syndrome during pregnancy secondary to adrenal adenoma. Acta Med Iran 2012;50:76–8. 14. Kim HG, Lee KH, Je GH, Han MS. A case of Cushing s syndrome in pregnancy secondary to an adrenal cortical adenoma. J Korean Med Sci 2003;18:444–6.
Cushing’s syndrome
349
15. Bednarek-Tupikowska G, Kubicka E, Sicin´ska-Werner T, et al. A case of Cushing’s in pregnancy. Endokrynol Pol 2011;62:181–5. 16. Achong N, d’Emden M, Fagermo M, Mortimer R. Pregnancyinduced Cushing’s syndrome in recurrent pregnancies: case report and literature reviews. Aust NZ J Obstret Gynaecol 2012;52:96–100. 17. Vilar L, Freitas Mda C, Lima LH, et al. Cushings syndrome in pregnancy: an overview. Arq Bras Endocrinol Metabol 2007;51: 1293–302. 18. Tejura H, Weiner J, Gibby O, et al. Cushing’s syndrome in pregnancy. J Obstret Gynaecol 2005;25:713–8. 19. Karmelita-Katulska K, Katulski K, Meczekalski B, et al. Application of new Imaging methods in the evaluation of the fetal chest. Arch Perinatal Med 2012;18:200–5. 20. Blanco C, Maqueda E, Rubio JA, Rodriguez A. Cushing’s syndrome during pregnancy secondary to an adrenal adenoma: metyrapone treatment and laparoscopic adrenalectomy. J Endocrinol Invest 2006;29:164–7. 21. Toutounchi S, Makowska A, Krajewska E, et al. Laparoscopic treatment of Cushing’s syndrome in a woman in late pregnancy – a case presentation. Videosurg Other Miniinvasive Tech 2011;6:261–3. 22. Delibasi T, Ustun I, Aydin Y, et al. Early severe pre-eclamptic findings in patient with Cushing’s syndrome. Gynecol Endocrinol 2006;22:710–2.
Copyright of Gynecological Endocrinology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
CUSHING’S SYNDROME IN PREGNANCY
Cushing’s syndrome in pregnancy: a case report and mini review of the literature K. Katulski1, A. Podfigurna-Stopa1, M. Maciejewska-Jeske1, M. Ruchala2, E. Gurgul2, M. Szymankiewicz3, G. H. Breborowicz4, K. Karmelita-Katulska5, M. Stajgis5, M. Biczysko6, M. Gryczynska2, A. R. Genazzani7, and B. Meczekalski1 1
Department of Gynecological Endocrinology, 2Department of Endocrinology, Metabolism and Internal Medicine, 3Department of Neonatology, Department of Perinatology and Gynaecology, 5Department of Radiology, 6Department of General, Gastroenterological and Endocrine Surgery, Poznan University of Medical Sciences, Poznan, Poland, and 7Department of Reproductive Medicine and Child Development, Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy
4
Abstract
Keywords
Adrenal diseases in pregnant women are diagnosed relatively rarely. The main cause of hypercortisolemia during pregnancy is Cushing’s syndrome related to adrenal adenoma. It is important to diagnose Cushing’s syndrome in pregnant women because it can lead to significant maternal and foetal complications and morbidity. However, due to physiological endocrine changes and symptoms in pregnant women the diagnosis of this disorder can be a challenge. One current case describes a 38-year-old pregnant woman with hypertension, oedema and an adrenal tumour. At the beginning, Conn syndrome was suspected, but after careful analysis Cushing’s syndrome (with an adenoma of the right adrenal gland) was diagnosed. After delivery and 5 weeks of pharmacological treatment the patient underwent right side adrenalectomy by laparoscopy.
Adrenal tumour, Cushing’s syndrome, hypertension, pregnancy
Cushing’s syndrome was described for the first time by Harvey Cushing in 1932 [1]. It includes signs and symptoms related to prolonged exposure to high cortisol levels [2]. Women with hypercortisolemia are subfertile, because high cortisol level causes anovulation [2]. Therefore, Cushing’s syndrome occurs relatively rarely in pregnant women [3]. To date, approximately 150 cases of Cushing’s syndrome in pregnancy have been reported with 18 weeks being the mean gestational age [4,5]. It is important to diagnose Cushing’s syndrome in pregnant women because it can lead to significant maternal and foetal morbidity [6]. However, due to physiological endocrine changes and symptoms in pregnant women, the diagnosis of this disorder can be a challenge [6]. Symptoms typical for Cushing’s syndrome in pregnant women include central weight gain, oedema, hypertension, fatigue, mood changes and glucose intolerance [7]. Additionally, interpretation of hormonal assay and hormonal tests in these women is difficult [7]. Maternal complications are related to hypertension, pre-eclampsia, diabetes mellitus, infections and premature labour [8]. The foetus may experience intrauterine growth restriction, prematurity, miscarriage and stillbirth [9].
Case report A 38-year-old woman (gravida 1, para 1) at 19 weeks of pregnancy with the suspicion of Conn syndrome was admitted
Address for correspondence: B. Me˛czekalski, Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland. E-mail: [email protected]
Received 1 October 2013 Accepted 30 December 2013 Published online 24 January 2014
to the Department of Gynaecological Endocrinology, Poznan University of Medical Sciences in Poland. The patient suffered from hypertension and was taking methyldopa 250 mg four times a day. The daily average blood pressure readings during her stay in the Department were 120/80, 120/80 and 115/75 mmHg. She suffered from hypothyroidism and was taking 50 mg of levothyroxine. During hospitalization the serum concentrations of thyroxin was 0.69 ng/dl with normal ranges between 0.83 and 1.7 ng/dl and thyrotropin was 0.15 mIU/ ml with normal ranges between 0.27 and 4.2 mIU/ml. During hospitalization a low serum potassium level was revealed – 3.5 mmol/l – and potassium chloride was administered. We diagnosed gestational diabetes type 2 and ordered a diabetic diet. Urinary metanephrine concentrations were 513.0 mg/l and normetanephrine 56.5 mg/l. The metanephrine 24-h urinary excretion was 46 mg with normal concentrations below 350 mg/ 24 h, normetanephrine 201 mg with normal concentrations below 5600 mg/24 h and vanillylmandelic acid 12.3 mg with normal concentrations below 13.6 mg/24 h. Serum cortisol concentration after morning awakening was 805.8 nmol/l with an normal range between 171 and 536 nmol/l and in the afternoon 933.2 nmol/l. Ultrasonography of the abdomen performed at 18 weeks of gestation revealed in the pregnant woman, around the right adrenal hypoechogenic, a round tumour with a diameter of 35 mm. During the patient’s stay at the Department of Gynaecological Endocrinology, magnetic resonance imaging (MRI) of the adrenal glands was performed (in the Department of Radiology, Poznan University of Medical Sciences, Poznan, Poland) on a 1.5 T scanner (Magnetom Avanto, Simens, Erlangen, Germany) using a
20 14
Introduction
History
346
K. Katulski et al.
matrix phased-array coil. The system has a maximum gradient amplitude of 60 mT/m and a slew rate of 200 mT/m/ms. We did not use contrast during the examination. The length of time of scanning was 15 min. The MRI revealed a round lesion in the right adrenal gland with diameter of 30 mm. The lesion was hypointense in the T2 images and demonstrated a loss of signal intensity on the out-of-phase images. Adrenal masses that contain intracellular fat have been shown to lose signal intensity on chemical shift out-of-phase images compared with in-phase images owing to the presence of intracellular lipid benign lesions. We recognized the adrenal adenoma (Figures 1 and 2). Afterwards, the patient was hospitalized and monitored at the Department of Gynecological Endocrinology three times (at 22, 25 and 28 weeks of gestation). At 25 weeks of gestation plasma, renin activity was 1.9 ng/ml/ h in a lying down position with normal range between 0.5 and 1.9 and 3.48 ng/ml/h in the sitting position with normal range between 1.9 and 6.0 ng/ml/h. At 28 weeks of gestation, the plasma adrenocorticotropic hormone (ACTH) concentration was 1.8 pg/ml with normal concentrations below 60 pg/ml. The 24-h urinary cortisol concentration was 1018 nmol/l and 24-h urinary cortisol excretion was 2901 nmol, which were extremely increased. Serum cortisol
Figure 1. TSE coronal T2-weighted image performed during a single breath hold arrow rounded lesion in right adrenal gland.
Gynecol Endocrinol, 2014; 30(5): 345–349
concentration after morning awakening was 840.3 nmol/l and in the afternoon 929.5 nmol/l. The female neonate was born by caesarean section at 35 week of gestation in a good condition, and the Apgar score at 1 and 5 min was nine points at both times. Birth weight was 2660 g and was appropriate for the gestational age. Due to the mother’s diseases, the newborn was admitted for observation to the Neonatology Department, Poznan University of Medical Sciences in Poland. In the first day of the child’s life, the child developed hypoglycaemia (blood glucose levels ranged from 12 to 45 mg%), which was compensated by an intravenous 10% glucose supplementation. We also observed disturbances in the newborn’s electrolytes in the form of hyperkalemia (potassium level in the blood ranged from 6.1 to 6.8 meq/l) and hypercalcemia (the serum total blood calcium was between 2.3 and 2.4 meq/l, and ionized calcium range from 13 to 1.5 meq/l). An abdominal ultrasound examination showed no abnormalities. From the third day of life there were no signs of adrenal dysfunction of the neonate. Electrolyte disorders were never clinically manifested and disappeared completely on the third day of life. Blood pressure and heart rate were normal during all the neonatal stay at the hospital. Other additional laboratory tests, such as sodium, chloride, magnesium and inorganic phosphorus, were normal throughout the child’s stay in the department. The values of serum thyroid hormones (T3, T4) and TSH in the blood of the newborn were normal. Due to the transient food intolerance, during the first 3 days of life the baby was on total parental nutrition. Then, on the fourth day we started enteral feeding with good tolerance and a normal body weight gain. Mild neonatal jaundice occurred between the third and fifth day of life and did not require treatment other than phototherapy. Routine screening tests (for hypothyroidism, phenylketonuria, cystic fibrosis) were carried out and their results were normal. On the 18th day of life the newborn was discharged home in a good general condition, with a body weight of 3030 g. After childbirth, we decided to perform a CT examination on the mother using the standard protocol (GE multidetector scanner), which confirmed an adenoma of the right adrenal gland. To exclude any pathology in the pituitary gland, we performed an MRI of the head using the standard protocol and no pathologies were found. On the 25th day after delivery, the patient was admitted to the Endocrinology Clinic, Poznan University of Medical Sciences in Poland. At that time, the patient’s major complaint was muscle weakness, which severely decreased her mobility. Her blood pressure tended to rise up to 160/100 mmHg. The patient suffered also from headaches, hair loss, mood changes and
Figure 2. GRE T1-weighted chemical shift images: (A) in-phase axial image, arrow – adrenal adenoma and (B) out-of-phase axial image, arrow – lipid rich adrenal adenoma (a loss of signal in out-of-phase images).
DOI: 10.3109/09513590.2013.879857
insomnia. Cortisol concentration after morning awakening was increased: 737.4 nmol/l. She presented with a round ‘‘moon face’’, central obesity (persistent large waistline after delivery), abdominal purple striate, muscle atrophy in the upper and lower extremities, ankle oedema, multiple petechie and ecchymoses, facial acne and multiple verrucae on her neck (which appeared during pregnancy). The patient’s serum morning cortisol level was slightly increased 588–620 nmol/l with normal ranges between 171 and 536 nmol/l. However, the diurnal cortisol rhythm was disturbed (at 6 pm 556–703 nmol/l, at 11 pm 491–609 nmol/l) and 24-h urinary cortisol excretion was markedly increased (up to 1206 nmol; normal range between 100 and 379 nmol/24 h). The dehydroepiandrosterone–sulphate level was low (6 mg/dl; normal range between 61 and337). The ACTH secretion was suppressed (0.7–2.3 pg/ml; normal range between 0 and 60 pg/ml). Therefore, an adrenaldependent cause of hypercortisolism was the most probable diagnosis (with the tumour in the right adrenal gland revealed in previous MRI and CT). Sodium and potassium levels were within normal ranges (Na 143 mmol/l, normal range between 136 and 145; K 3.88 mmol/l, normal range between 3.5 and 5.1). Ketoconazole was administered orally at an initial dose of 3 400 mg. Due to a rapid decrease of the cortisol level on the sixth day of treatment (90 nmol/l), the ketoconazole dose was reduced to 3 200 mg. The drug tolerance was good. However, the therapy caused an increase of aminotraspherases concentration (alanine aminotransferase from 42 to 92 U/l, aspartate aminotransferase from 20 to 38 U/l). The patient was treated also with (1) ramipril 5 mg for hypertension, (2) spironolactone 50 mg for hypertension and peripheral oedema, (3) potassium and calcium to prevent electrolyte disturbances, (4) paracetamol and ketoprophen for headaches and (5) hydroxyzine 25 mg as a tranquillizer. The glucose level was efficiently controlled by the diabetic diet. The patient continued L-thyroxine substitution at the dose of 75 mg. Her TSH level was decreased (0.03 mU/ml; normal range between 0.27 and 4.20), free triiodothyronine (fT3) maintained low (3.13 pmol/l; normal range between 3.93 and 7.70) and the free thyroxine (fT4) level was normal (16.53 pmol/l; normal range between 11.5 and 21.0). Antithyroid antibodies were negative (anti-thyroglobulin510 IU/l, anti-thyroid peroxidase 9 IU/l, thyrotropin receptor antibody 0.33 IU/l). A thyroid ultrasound did not reveal any focal lesions. Thyroid echogenicity was irregular and decreased. Her chest X-ray was normal. In abdominal ultrasound, there were no other abnormalities other than the right adrenal tumour. The femoral neck bone density was decreased (0.690 g/cm2; T-score – 2.5, Z-score – 2.0). Ketoconazole treatment resulted in a noticeable decrease of cortisol release (24-h cortisol excretion was reduced to 370 nmol/24 h). The patient was consulted by a surgeon and anaesthesiologist and qualified for a right adrenalectomy.
Surgical treatment of the patient After short pharmacological preparation a laparoscopic right sided, transperitoneal lateral adrenalectomy was performed in the Department of General, Gastroenterological and Endocrine Surgery, Poznan University of Medical Sciences, Poznan, Poland. Directly after the procedure, a hydrocortisone substitution was introduced. After surgery no complications were observed. The patient was dismissed from hospital on the fifth postoperative day as proper hydrocortisone substitution doses were established. The patient was referred to the Endocrinology Outpatient Clinic for later follow-up. The histopathological result after surgery revealed a cortical adenoma of the right adrenal gland (diameter 3.2 cm).
Cushing’s syndrome
347
Discussion and mini-review of the literature During pregnancy, Cushing’s syndrome is manifested extremely rarely – to date, less than 150 cases have been recorded [5]. Patients suffering from Cushing’s syndrome often have procreation problems due to the negative influence of corticotrophinreleasing hormone (CRH) and ACTH on GnRH on gonadotropin secretion. The aetiology of Cushing’s syndrome diagnosed in a group of pregnant women and in the general population is different – while adrenal gland tumours are its most frequent cause in pregnant women, the pituitary gland is its major cause in the general population [4]. This disproportion is mainly caused by the fact that pregnancy is rare in Cushing’s syndrome patients, as mentioned above. It can also be caused by the presence of LH/hCG receptors (LHCGRs) in the adrenal gland tumours, which are active during pregnancy [10]. The concentration of cortisol and other adrenal steroids in the serum of a pregnant woman is a result of placental hormonal activity and increased function of the adrenal cortex. The placenta produces a hormone which acts like the CRH, stimulating synthesis and release of proopiomelanocortin and its derivatives: corticotrophin and beta-endorphin. Placental corticoliberin levels are high in the serum of both the foetus and the mother. ACTH levels in the serum of the mother increase in the third trimester and are highest around the time of the delivery. Adrenal steroids synthesis is significantly elevated; the higher concentrations of cortisol in the serum are responsible for stretch marks and may lead to insulin resistance in the third trimester [11]. ACTH-dependent and ACTH-independent Cushing’s syndrome developing during pregnancy and spontaneously resolving after delivery is an exceptional case. A high concentration of oestradiol and hCG during pregnancy in women manifesting an abnormal reactivity of adrenal cortex cells to these hormones are listed as etiological factors of the ACTH-independent form of Cushing’s syndrome [12]. Since hypercortisolemia symptoms are similar to those which can be found during pregnancy, diagnosis of Cushing’s syndrome in pregnant women is difficult. These symptoms include: central weight gain, stretch marks, swelling, arterial hypertension (68%), glucose intolerance or gestational diabetes (25%) and pre-eclampsia (14%). Other symptoms (less frequently observed) include osteoporotic fractures (5%), and mental disorders (2%). In 2% of cases, the disease led to the death of the patient [12]. Our patient presented with hypertension, hypothyroidism, gestational diabetes, muscle weakness and mood changes. A similar situation has been described by Borna et al. [13], who treated a 33-year-old patient in the 30th week of gestation. The patient suffered from hypertension, gestational diabetes and foetal tachycardia. Abdominal MR imaging showed a right adrenal gland tumour and laboratory tests revealed an elevated cortisol level, low ACTH and potassium levels. The patient was treated conservatively. A caesarean section was performed in the 32nd week of gestation and afterwards a right adrenalectomy was carried out. A similar case was recorded by Kim and co-workers, who described a patient with severe pre-eclampsia and gestational diabetes. In the 30th week of gestation, a caesarean section was performed. Five weeks after delivery, a laparoscopic right adrenalectomy was performed [14]. Bednarek-Tupikowska et al. [15] described a case of a pregnant patient with an adrenal cortex adenoma who underwent a left adrenalectomy 3 weeks following delivery by caesarean section in the 35th week of gestation. Achong et al. [16] described an interesting case of a patient suffering from CS who was treated conservatively during her five pregnancies. They emphasized that, in rare cases, pregnancyinduced CS occurs. So far, only nine cases like this one have been
348
K. Katulski et al.
recorded. The first report of nine such cases was described by Vilar et al. [17]. The results of imaging of the adrenal glands and histopathological results varied in these nine cases. No abnormalities were revealed in six cases, bilateral micronodular hyperplasia was found in one case, and one bilateral macronodular hyperplasia (MAH) and one adenoma. Although the exact aetiology is unknown, the most commonly postulated mechanism involves aberrant LHCGR expression. The ACTH receptor is a member of the G-protein-coupled receptor family. Normally, ACTH binding to the receptor stimulates adenylyl cyclase, resulting in cortisol production. However, in some forms of ACTH-independent MAH and adrenal adenomas, other G-protein-coupled receptors are aberrantly coupled to the adenylyl cyclase pathway, resulting in cortisol production in response to other ligands, for example, gastric inhibitory peptide, vasopressin, catecholamines, oestrogen and serotonin. Therefore, LH/hCG-induced CS may be due to an upregulation of a normally weakly expressed eutopic receptor [12]. The association between the LHCGR and pregnancy-induced CS was first suggested by Lacroix et al. who described a patient with ACTH-independent MAH and CS associated with pregnancy and menopause. In vivo, cortisol was stimulated by GnRH, hCG and rhLH as well as 5HT4R receptor agonists, and a response to leuprolide (a long-acting GnRH analogue) occurred. Other reports of pregnancy-induced CS demonstrate a response to hCG post-partum [16]. Pregnancy-induced CS is possible given the clear temporal relationship with pregnancy and resolution of the hypercortisolism (clinically and biochemically) in the post-partum period. In six/nine cases reported, the adrenal imaging was normal, as it was in our patient. As the postulated mechanism for pregnancyinduced CS involves aberrant LHCGR expression or function, failure to identify a mutation in the ACTH receptor does not exclude this diagnosis [18]. Undiagnosed and untreated Cushing’s Syndrome during pregnancy leads to severe foetal complications. These include spontaneous abortion, pre-term birth (46%), foetal death and intrauterine dystrophy. However, approximately 80% of pregnancies end with the delivery of a healthy child [10]. Regarding our patient, the foetus and newborn suffered from transient electrolyte disorders and transient hypoglycaemia. The newborn was discharged home in good general condition after 18 days. Laboratory diagnostics of Cushing’s syndrome is significantly impeded by the presence of hypercortisolemia, pre-eclampsia and glucose intolerance. During pregnancy, the concentration of total and free cortisol is two or three times higher than in the non-gestational period. A regular circadian rhythm of cortisol and ACTH is preserved. Results of the Dexamethasone Supression Test and urinary free cortisol excretion levels are difficult to interpret. An increased percentage of false positive results has been observed. In diagnostics, it is advised to mark the levels of free cortisol in a 24-h sample of urine, along with the concentration of cortisol in saliva in the late evening hours. Differential diagnosis of hypercortisolemia can cause a series of problems, too. In the general population, low concentration of ACTH is recorded in ACTH-independent Cushing’s syndrome, which is not the case during pregnancy. An 8 mg dexamethasone test can be helpful, as long as it is analysed along with other noninvasive tests, such as the CRF test or desmopressin test in the event of cortisol suppression reaching over 80% [18]. In the case of our patient, critical for diagnosis was the improper concentration of serum cortisol in the blood and urine and the round tumour of 35 mm which was found around the right adrenal hypoechogenic during ultrasonographic examination.
Gynecol Endocrinol, 2014; 30(5): 345–349
The use of imaging tests during pregnancy is limited and based mostly on ultrasonographic imaging and MRI. Worthy of notice, MRI tests should only be carried out after the 32nd week of the pregnancy and contrast agents belonging to class C. Interpretation of MRI results of the pituitary gland may be difficult due to its physiological enlargement during pregnancy [19]. Therapy for Cushing’s syndrome during pregnancy is significantly limited depending on its presentation and development, it can be treated pharmacologically and surgically. Pharmacological treatment aims to prepare the patient to a planned surgery (preferably laparoscopic) in the second trimester or post-delivery. In such cases, Metyrapone (1.5 g to 3 g/24 h) is the medication of choice. As opposed to Ketoconazole and Mitotan, Metyrapone is not teratogenic in nature, and it decreases cortisol levels through inhibiting adrenal cortical 11 beta-hydroxylase. In the case referred to here, the pregnant patient was treated symptomatically with swelling reduction medicine and blood pressure medicine. Surgical treatment was completed post-partum [17]. Some authors recommend surgical treatment of the adrenal glands during pregnancy. Blanco et al. [20] reported an interesting case of a patient with an adrenal gland tumour which was diagnosed before pregnancy. The patient was treated conservatively and in the 16th week of gestation an adrenalectomy was performed. Spontaneous delivery occurred in the 30th week of gestation. Toutounchi et al. [21] described a case of a 21-year-old female who was treated laparoscopically in the 24th week of gestation, with a left adrenalectomy. Spontaneous delivery occurred in the 38th week of gestation. Tejura et al. [18] recorded a 23-year-old patient suffering from CS, whose right adrenal gland tumour was treated surgically in the 30th week of gestation. The patient gave birth by caesarean section in the 38th week of gestation. However, not all patients accept surgical treatment during pregnancy. Delibasi et al. [22] described a case of a 22-year-old female whose pregnancy was terminated in the 11th week of gestation due to a high risk of death of the mother. Earlier in the pregnancy, the patient had refused to undergo surgical treatment of her right adrenal gland tumour (a 3 cm tumour was diagnosed in CT). In conclusion, it is obvious, that the best outcome is achieved by a multidisciplinary approach consisting of an endocrinologist, obstetrician, anaesthetist, neonatologist and endocrine surgeon.
Declaration of interest The authors report no conflicts of interest.
References 1. Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 1932;50:137–95. 2. Lekarev O, New M. Adrenal disease in pregnancy. Best Pract Res Clin Endocrinol Metab 2011;25:959–73. 3. Abdelmannan D, Aron DC. Adrenal disorders in pregnancy. Endocrinol Metab Clin North Am 2011;40:779–94. 4. Buescher MA, McClamrock HD, Adashi EY. Cushing syndrome in pregnancy. Obstet Gynecol 1992;79:130–7. 5. Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing’s syndrome during pregnancy: personal experience and review of the literature. J Clin Endocrinol Metab 2005;90:3077–83. 6. Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocr Rev 2005;26:775–99. 7. Kita M, Sakalidou M, Saratzis A, et al. Cushing’s syndrome in pregnancy: report of case and review of literature. Hormones (Athens) 2007;6:242–6.
DOI: 10.3109/09513590.2013.879857
8. Meczekalski B, Katulski K, Podfigurna-Stopa A, Czyzyk A. Nadnercza. In: Meczekalski B, ed. Endokrynologia ciazy. [Endocrinology of pregnancy] Warszawa: PZWL; 2012:46–58. 9. Vilar L, Freitas Mda C, Lima LH, et al. Cushing’s syndrome in pregnancy: an overview. Arq Bras Endocrinol Metabol 2007;51: 1293–302. 10. Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushings syndrome during pregnancy: personal Experience and review of the literature. J Clin Endocrinol Metab 2005;90:3077–83. 11. Feedlers RA, Lamberts SWJ, Hofland LJ, et al. Luteinizing hormone (LH)-responsive Cushing syndrome: the demonstration of LH receptor messenger ribonucleic acid in hyperplastic adrenal cells, which respond to chorionic gonadotropin and serotonin agonists in vitro. J Clin Endocrinol Metab 2003;88:230–7. 12. Lindsay JR, Nieman LK. The hypothalamic–pituitary–adrenal axis in pregnancy: challenges in disease detection and treatment. Endocrinol Rev 2005;26:775–99. 13. Borna S, Akbari S, Eftekhar T, Mostaan F. Cushing’s syndrome during pregnancy secondary to adrenal adenoma. Acta Med Iran 2012;50:76–8. 14. Kim HG, Lee KH, Je GH, Han MS. A case of Cushing s syndrome in pregnancy secondary to an adrenal cortical adenoma. J Korean Med Sci 2003;18:444–6.
Cushing’s syndrome
349
15. Bednarek-Tupikowska G, Kubicka E, Sicin´ska-Werner T, et al. A case of Cushing’s in pregnancy. Endokrynol Pol 2011;62:181–5. 16. Achong N, d’Emden M, Fagermo M, Mortimer R. Pregnancyinduced Cushing’s syndrome in recurrent pregnancies: case report and literature reviews. Aust NZ J Obstret Gynaecol 2012;52:96–100. 17. Vilar L, Freitas Mda C, Lima LH, et al. Cushings syndrome in pregnancy: an overview. Arq Bras Endocrinol Metabol 2007;51: 1293–302. 18. Tejura H, Weiner J, Gibby O, et al. Cushing’s syndrome in pregnancy. J Obstret Gynaecol 2005;25:713–8. 19. Karmelita-Katulska K, Katulski K, Meczekalski B, et al. Application of new Imaging methods in the evaluation of the fetal chest. Arch Perinatal Med 2012;18:200–5. 20. Blanco C, Maqueda E, Rubio JA, Rodriguez A. Cushing’s syndrome during pregnancy secondary to an adrenal adenoma: metyrapone treatment and laparoscopic adrenalectomy. J Endocrinol Invest 2006;29:164–7. 21. Toutounchi S, Makowska A, Krajewska E, et al. Laparoscopic treatment of Cushing’s syndrome in a woman in late pregnancy – a case presentation. Videosurg Other Miniinvasive Tech 2011;6:261–3. 22. Delibasi T, Ustun I, Aydin Y, et al. Early severe pre-eclamptic findings in patient with Cushing’s syndrome. Gynecol Endocrinol 2006;22:710–2.
Copyright of Gynecological Endocrinology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
