Journal of Obstetrics and Gynaecology, 2014; Early Online: 1–2 © 2014 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online
A decision dilemma: Cushing syndrome during pregnancy M. Darocas1, N. Ruiz1, M. T. Bergoglio2 & A. Cano1,3 1Obstetrics and Gynaecology Service, 2Endocrinology Unit, University Hospital Dr Peset and 3Department of Paediatrics, Obstetrics and Gynaecology, University of Valencia, Valencia, Spain
J Obstet Gynaecol Downloaded from informahealthcare.com by University of Connecticut on 10/10/14 For personal use only.
DOI: 10.3109/01443615.2014.937329 Correspondence: A. Cano, Department of Pediatrics, Obstetrics and Gynecology, Facultad de Medicina, Av Blasco Ibáñez 15, 46010 Valencia, Spain. E-mail: [email protected]
Introduction The rare presentation of Cushing syndrome during pregnancy prevents the use of established guidelines for management. A three-step dilemma challenges clinicians making this diagnosis: surveillance, medical or surgical treatment in the case of intervention, or open surgery or laparoscopy in the case of surgery. A critical analysis of each option is presented here, based on the clinical case of a woman who was diagnosed with Cushing syndrome during pregnancy and who underwent laparoscopic excision of a functional adrenal adenoma. Cushing syndrome is rare during pregnancy because frequent anovulation adds to an already uncommon process (5–25 cases per million/ year). Most of the sparse cases are due to adrenocortical tumours. Hypercortisolism has been implicated in maternal complications, including hypertension (66%), diabetes (25%) and even death (2%). The related fetal complications are preterm labour (60%), intrauterine growth restriction (26%) and perinatal death (15%) (Lindsay et al. 2005). The low incidence of Cushing syndrome has impaired the formulation of management guidelines. Recently, advances in laparoscopy have offered alternatives to inhibitors of steroidogenic enzymes and to surveillance for management. Thus, a three-step dilemma challenges clinicians who diagnose Cushing syndrome during pregnancy: whether to intervene, whether to administer medical or surgical treatment in the case of intervention and whether to perform open surgery or laparoscopy in the case of surgery. These challenges are analysed in the following case.
Case report A 21-year-old pregnant woman was referred to our centre at the 25th gestational week because of sudden hirsutism and acne, obvious red-coloured abdominal striae, oedema and asthenia. Her hypercortisolism (urinary free cortisol: 1,200 μg/24 h), undetectable ACTH, mild anaemia, hypokalaemia and gestational diabetes were consistent with Cushing syndrome. ACTH-independent hypercortisolism was confirmed by magnetic resonance, which detected a 45 mm left mass without lymph nodes or metastases. After consultation with an endocrinologist and a surgeon, laparoscopic excision was planned. Further complications, pneumonia and severe pre-eclampsia, occurred over the following days. The patient’s blood pressure was normalised with i.v. labetalol and rescue hydralazine, and subsequently controlled with oral alpha-methyldopa (500 mg/8 h). Laparoscopic excision at the 29th week confirmed an adrenal adenoma. Replacement therapy with oral glucocorticoids was then initiated. At 1 week after discharge, the patient returned with uterine contractions and a shortened (12 mm) cervix. Tocolysis with i.v. atosiban stopped labour and, within days, her hypertension and proteinuria disappeared. Premature membrane rupture was followed by vaginal delivery of a healthy 2,270 g male at the
33rd week. Replacement therapy with glucocorticoids (prednisone: 5/0/2.5 mg/day) was maintained for 2 months and then reduced to 5 mg/day. This dosage was maintained for 15 additional months because of persistent low levels of urinary free cortisol when the replacement therapy was interrupted. The fatigue, acne and hirsutism vanished 2 months post-surgery.
Discussion The exceptionality of Cushing syndrome during pregnancy creates uncertainties about appropriate management. The surveillance-only option implies the risk of complacence up to a poorly-defined stage, with risks affecting the mother and fetus. Although this conservative approach prevents any potential risk associated with medical or surgical management, the favourable trend in the live birth rate (Lindsay et al. 2005) supports intervention. Medical treatment includes the anti-steroidogenic agents metyrapone or ketoconazole to delay surgery or until postpartum. Both drugs are considered as FDA category C, although limited prior experience (13 cases for metyrapone and four cases for ketoconazole) has not produced fetal malformations (Lim et al. 2013; Boronat et al. 2011). Prior experience with metyrapone has been concentrated in cases without tumours, in which an aberrant expression of the LH/hCG receptor has been postulated (Achong et al. 2012). The 9% rate of carcinoma (Homer et al. 2012; Kotteas et al. 2012) has led to a preference for adrenalectomy. Open surgery has been the traditional approach, but the growing experience with laparoscopy, with 11 cases previously reported (Tejura et al. 2005; De Nobrega et al. 2011; Sammour et al. 2012), is appealing. Concerns about laparoscopy derive from the technical difficulties entailed by an enlarged uterus, which reduces the space for manipulating instruments, and by the risks associated with unintended lesions on such a vascularised organ. Concerns have also arisen about potential harm due to increased intra-abdominal pressure, which might affect uterine blood flow or due to the effect of carbon dioxide insufflations on fetal physiology. An additional strength of surgery during pregnancy is the rapid improvement of pathologies in the mother, as in the present case and other cases (Schiemer et al. 2011). In contrast, preterm birth occurred in 7/12 previous laparoscopic cases, although this rate is comparable with the 4/6 cases with adrenal tumours treated medically (Sammour et al. 2012; Boronat et al. 2011). There is no clear explanation for this unsatisfactory outcome, although surgery itself has been considered a risk factor for preterm birth. This is an important issue, because gestational age at delivery is crucial for a newborn’s prognosis, and the risk of such an effect must be considered when deliberating any intervention during pregnancy. Glucocorticoid replacement must follow because of the inoperative contralateral adrenal gland, but the treatment length is uncertain, with published intervals varying from 1 week (De Nobrega et al. 2011) to more than 5 years (Sammour et al. 2012). In conclusion, hypercortisolism should be controlled in Cushing syndrome during pregnancy. Laparoscopy seems to be well tolerated, and medical treatment seems adequate in cases without tumours or as an adjunct to surgery. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References Achong N, D’Emden M, Fagermo N et al. 2012. Pregnancy-induced Cushing’s syndrome in recurrent pregnancies: case report and literature
2
M. Darocas et al.
J Obstet Gynaecol Downloaded from informahealthcare.com by University of Connecticut on 10/10/14 For personal use only.
review. Australian and New Zealand Journal of Obstetrics and Gynaecology 52: 96–100. Boronat M, Marrero D, López-Plasencia Y et al. 2011. Successful outcome of pregnancy in a patient with Cushing’s disease under treatment with ketoconazole during the first trimester of gestation. Gynecological Endocrinology 27:675–677. De Nobrega-Correa H, Aragón-Charris J, Torres-Cepeda D et al. 2011. Cortical adrenal adenoma as a cause of Cushing’s syndrome during pregnancy. Endocrinología y Nutrición 58:248–249. Homer L, Viatge M, Gayet FX et al. 2012. Cushing syndrome and pregnancy: a propos of a malignant adrenocortical carcinoma. Gynecologie Obstetrique and Fertiliteé 40:e1–e4. Kotteas E, Ioachim E, Pavlidis N. 2012. A pregnant patient with adrenocortical carcinoma: case report. Onkologie 35:517–519.
Lim WH, Torpy DJ, Jeffries WS. 2013. The medical management of Cushing’s syndrome during pregnancy. European Journal of Obstetrics, Gynecology, and Reproductive Biology 168:1–6. Lindsay JR, Jonklaas J, Oldfield EH et al. 2005. Cushing’s syndrome during pregnancy: personal experience and review of the literature. Journal of Clinical Endocrinology and Metabolism 90:3077–3083. Sammour RN, Saiegh L, Matter I et al. 2012. Adrenalectomy for adrenocortical adenoma causing Cushing’s syndrome in pregnancy: a case report and review of literature. European Journal of Obstetrics, Gynecology, and Reproductive Biology 165:1–7. Schiemer R, Latibeaudiere M, Close C et al. 2011. Type 2 diabetes identified in pregnancy secondary to Cushing’s syndrome. Journal of Obstetrics and Gynaecology 31:541. Tejura H, Weiner J, Gibby O et al. 2005. Cushing’s syndrome in pregnancy. Journal of Obstetrics and Gynaecology 25:713–714.
A decision dilemma: Cushing syndrome during pregnancy M. Darocas1, N. Ruiz1, M. T. Bergoglio2 & A. Cano1,3 1Obstetrics and Gynaecology Service, 2Endocrinology Unit, University Hospital Dr Peset and 3Department of Paediatrics, Obstetrics and Gynaecology, University of Valencia, Valencia, Spain
J Obstet Gynaecol Downloaded from informahealthcare.com by University of Connecticut on 10/10/14 For personal use only.
DOI: 10.3109/01443615.2014.937329 Correspondence: A. Cano, Department of Pediatrics, Obstetrics and Gynecology, Facultad de Medicina, Av Blasco Ibáñez 15, 46010 Valencia, Spain. E-mail: [email protected]
Introduction The rare presentation of Cushing syndrome during pregnancy prevents the use of established guidelines for management. A three-step dilemma challenges clinicians making this diagnosis: surveillance, medical or surgical treatment in the case of intervention, or open surgery or laparoscopy in the case of surgery. A critical analysis of each option is presented here, based on the clinical case of a woman who was diagnosed with Cushing syndrome during pregnancy and who underwent laparoscopic excision of a functional adrenal adenoma. Cushing syndrome is rare during pregnancy because frequent anovulation adds to an already uncommon process (5–25 cases per million/ year). Most of the sparse cases are due to adrenocortical tumours. Hypercortisolism has been implicated in maternal complications, including hypertension (66%), diabetes (25%) and even death (2%). The related fetal complications are preterm labour (60%), intrauterine growth restriction (26%) and perinatal death (15%) (Lindsay et al. 2005). The low incidence of Cushing syndrome has impaired the formulation of management guidelines. Recently, advances in laparoscopy have offered alternatives to inhibitors of steroidogenic enzymes and to surveillance for management. Thus, a three-step dilemma challenges clinicians who diagnose Cushing syndrome during pregnancy: whether to intervene, whether to administer medical or surgical treatment in the case of intervention and whether to perform open surgery or laparoscopy in the case of surgery. These challenges are analysed in the following case.
Case report A 21-year-old pregnant woman was referred to our centre at the 25th gestational week because of sudden hirsutism and acne, obvious red-coloured abdominal striae, oedema and asthenia. Her hypercortisolism (urinary free cortisol: 1,200 μg/24 h), undetectable ACTH, mild anaemia, hypokalaemia and gestational diabetes were consistent with Cushing syndrome. ACTH-independent hypercortisolism was confirmed by magnetic resonance, which detected a 45 mm left mass without lymph nodes or metastases. After consultation with an endocrinologist and a surgeon, laparoscopic excision was planned. Further complications, pneumonia and severe pre-eclampsia, occurred over the following days. The patient’s blood pressure was normalised with i.v. labetalol and rescue hydralazine, and subsequently controlled with oral alpha-methyldopa (500 mg/8 h). Laparoscopic excision at the 29th week confirmed an adrenal adenoma. Replacement therapy with oral glucocorticoids was then initiated. At 1 week after discharge, the patient returned with uterine contractions and a shortened (12 mm) cervix. Tocolysis with i.v. atosiban stopped labour and, within days, her hypertension and proteinuria disappeared. Premature membrane rupture was followed by vaginal delivery of a healthy 2,270 g male at the
33rd week. Replacement therapy with glucocorticoids (prednisone: 5/0/2.5 mg/day) was maintained for 2 months and then reduced to 5 mg/day. This dosage was maintained for 15 additional months because of persistent low levels of urinary free cortisol when the replacement therapy was interrupted. The fatigue, acne and hirsutism vanished 2 months post-surgery.
Discussion The exceptionality of Cushing syndrome during pregnancy creates uncertainties about appropriate management. The surveillance-only option implies the risk of complacence up to a poorly-defined stage, with risks affecting the mother and fetus. Although this conservative approach prevents any potential risk associated with medical or surgical management, the favourable trend in the live birth rate (Lindsay et al. 2005) supports intervention. Medical treatment includes the anti-steroidogenic agents metyrapone or ketoconazole to delay surgery or until postpartum. Both drugs are considered as FDA category C, although limited prior experience (13 cases for metyrapone and four cases for ketoconazole) has not produced fetal malformations (Lim et al. 2013; Boronat et al. 2011). Prior experience with metyrapone has been concentrated in cases without tumours, in which an aberrant expression of the LH/hCG receptor has been postulated (Achong et al. 2012). The 9% rate of carcinoma (Homer et al. 2012; Kotteas et al. 2012) has led to a preference for adrenalectomy. Open surgery has been the traditional approach, but the growing experience with laparoscopy, with 11 cases previously reported (Tejura et al. 2005; De Nobrega et al. 2011; Sammour et al. 2012), is appealing. Concerns about laparoscopy derive from the technical difficulties entailed by an enlarged uterus, which reduces the space for manipulating instruments, and by the risks associated with unintended lesions on such a vascularised organ. Concerns have also arisen about potential harm due to increased intra-abdominal pressure, which might affect uterine blood flow or due to the effect of carbon dioxide insufflations on fetal physiology. An additional strength of surgery during pregnancy is the rapid improvement of pathologies in the mother, as in the present case and other cases (Schiemer et al. 2011). In contrast, preterm birth occurred in 7/12 previous laparoscopic cases, although this rate is comparable with the 4/6 cases with adrenal tumours treated medically (Sammour et al. 2012; Boronat et al. 2011). There is no clear explanation for this unsatisfactory outcome, although surgery itself has been considered a risk factor for preterm birth. This is an important issue, because gestational age at delivery is crucial for a newborn’s prognosis, and the risk of such an effect must be considered when deliberating any intervention during pregnancy. Glucocorticoid replacement must follow because of the inoperative contralateral adrenal gland, but the treatment length is uncertain, with published intervals varying from 1 week (De Nobrega et al. 2011) to more than 5 years (Sammour et al. 2012). In conclusion, hypercortisolism should be controlled in Cushing syndrome during pregnancy. Laparoscopy seems to be well tolerated, and medical treatment seems adequate in cases without tumours or as an adjunct to surgery. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References Achong N, D’Emden M, Fagermo N et al. 2012. Pregnancy-induced Cushing’s syndrome in recurrent pregnancies: case report and literature
2
M. Darocas et al.
J Obstet Gynaecol Downloaded from informahealthcare.com by University of Connecticut on 10/10/14 For personal use only.
review. Australian and New Zealand Journal of Obstetrics and Gynaecology 52: 96–100. Boronat M, Marrero D, López-Plasencia Y et al. 2011. Successful outcome of pregnancy in a patient with Cushing’s disease under treatment with ketoconazole during the first trimester of gestation. Gynecological Endocrinology 27:675–677. De Nobrega-Correa H, Aragón-Charris J, Torres-Cepeda D et al. 2011. Cortical adrenal adenoma as a cause of Cushing’s syndrome during pregnancy. Endocrinología y Nutrición 58:248–249. Homer L, Viatge M, Gayet FX et al. 2012. Cushing syndrome and pregnancy: a propos of a malignant adrenocortical carcinoma. Gynecologie Obstetrique and Fertiliteé 40:e1–e4. Kotteas E, Ioachim E, Pavlidis N. 2012. A pregnant patient with adrenocortical carcinoma: case report. Onkologie 35:517–519.
Lim WH, Torpy DJ, Jeffries WS. 2013. The medical management of Cushing’s syndrome during pregnancy. European Journal of Obstetrics, Gynecology, and Reproductive Biology 168:1–6. Lindsay JR, Jonklaas J, Oldfield EH et al. 2005. Cushing’s syndrome during pregnancy: personal experience and review of the literature. Journal of Clinical Endocrinology and Metabolism 90:3077–3083. Sammour RN, Saiegh L, Matter I et al. 2012. Adrenalectomy for adrenocortical adenoma causing Cushing’s syndrome in pregnancy: a case report and review of literature. European Journal of Obstetrics, Gynecology, and Reproductive Biology 165:1–7. Schiemer R, Latibeaudiere M, Close C et al. 2011. Type 2 diabetes identified in pregnancy secondary to Cushing’s syndrome. Journal of Obstetrics and Gynaecology 31:541. Tejura H, Weiner J, Gibby O et al. 2005. Cushing’s syndrome in pregnancy. Journal of Obstetrics and Gynaecology 25:713–714.
