http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2015; 31(2): 102–104 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.984680

CUSHING’S SYNDROME IN PREGNANCY

Cushing’s syndrome in pregnancy Rossella Nassi1, Cristina Ladu1, Chiara Vezzosi1, and Massimo Mannelli2 Endocrinology Unit, San Donato Hospital, Arezzo, Italy and 2Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

Gynecol Endocrinol Downloaded from informahealthcare.com by University of Connecticut on 04/01/15 For personal use only.

1

Abstract

Keywords

Cushing’s syndrome is a rare condition in the general population and is even less common during pregnancy with only a few cases reported in literature. The diagnosis of Cushing’s syndrome may be difficult during pregnancy because the typical features of the disorder and pregnancy may overlap. However, Cushing’s syndrome results in increased fetal and maternal complications, and diagnosis and treatment are critical. This report describes a case of 26-year-old female at the 19th week of pregnancy with symptoms and signs of hypercortisolism, where ACTH-independent Cushing’s syndrome was diagnosed and treated by robotic laparoscopic adrenalectomy at the 21th week of gestation.

Adrenal adenoma, hirsutism in pregnancy, hormonal change in pregnancy, hypercortisolism, pregnancy

Introduction Cushing’s syndrome during pregnancy is a rare nosology, likely because hypercortisolism inhibits normal follicular development and ovulation. To date, only a few cases have been reported in literature [1,2]. Of the total number of Cushing’s syndrome cases during pregnancy, adrenal adenomas are approximately 40–50%. On the other hand, Cushing’s disease represents only about 30% of cases in pregnant women compared with 58–70% in non pregnant women. In the remaining cases, about 10% are due to adrenal carcinoma, ACTH-independent hyperplasia and ectopic ACTH secretion [3]. The diagnosis of Cushing’s syndrome during pregnancy is very difficult because the typical disorder symptoms and pregnancy could overlap. Therefore a high clinical suspicious is needed for diagnosis [4]. In addition, hormonal analysis and visual imaging in pregnancy are limited. Results of hormonal measurements and dynamic tests are not easy to examine due to the physiological changes in the hypothalamo–pituitary–adrenal axis during pregnancy [5]. Because of the fetal and maternal morbidity, early diagnosis and treatment of Cushing’s syndrome in pregnancy are critical. The decision to treat Cushing’s syndrome during pregnancy and the choice of treatment method needs a case-by-case approach depending on the specific etiology, severity of the disease and time of gestation. We describe a case of Cushing’s syndrome secondary to adrenal adenoma, which was treated by robotic laparoscopic adrenalectomy at the 21th week of gestation.

Case report A 26-year-old female at the 19th week of pregnancy was admitted to our hospital at obstetric unit for generalized weakness, dyspnea,

Address for correspondence: Cristina Ladu, MD, Endocrinology Unit, San Donato Hospital, Via Pietro Nenni 20, 52100, Arezzo, Italy. Tel: +390575255356. Fax: +39-0575254395. E-mail: [email protected]

History Received 10 September 2014 Revised 28 October 2014 Accepted 3 November 2014 Published online 27 November 2014

edema and hypertension with severe hypokalemia. The patient was asymptomatic before pregnancy, she had regular menstrual cycles and had no difficulty in conceiving. She noticed from her second month of pregnancy, hirsutism affecting face, chest and back with a progressive increase and acne appearance. Physical examination showed moon face, acne, hirsutism, edema, proximal muscle weakness and hypertension. Echocardiography examination revealed initial signs of hypertensive cardiomyopathy. The basic biochemical examination was normal except severe hypokalemia (1.9 mmol/L). The hormonal screening was largely consistent with Cushing’s syndrome: 24 h urinary free cortisol excretion (UFC) was extremely high (42070 nmol/24 h, normal range 55–248); diurnal cortisol rhythm was absent; plasmatic cortisol was 1072 nmol/L at 6 am (normal range 171–536 nmol/L) and 1177 nmol/L at 8 pm (normal range 64–327 nmol/L). Plasma ACTH level was 51.6 ng/L (normal range 4.7–48.8). Androgen’s profile revealed high total and free testosterone levels (total testosterone 10.8 nmol/L, normal range 0.3–3.5 nmol/L; free testosterone 4.1 pg/ml, normal range 0.15–2.57), with low levels of DHEAS 1.2 mmol/L (normal range 3.3–9.8) and 17 hydroxyprogesterone. All other factors in blood and urine tests, including plasma aldosterone, renin and urinary metanephrines were normal. Abdominal ultrasonography detected a 34  28  37 mm right adrenal mass confirmed by a magnetic resonance imaging scan (Figure 1). Considering the high testosterone levels and the suspicion of an androgen secreting adrenal mass, a transabdominal ultrasonography was performed to detect fetal sex. The examination showed a male fetus with normal external genitalia. The patient was early treated with anti-hypertensive drugs (methyldopa 1500 mg/d and nifedipine prolonged release 30 mg/d) and with intravenous (i.v.) administration of potassium chloride in high doses (100 mEq/d). Despite intensive potassium supplementation, combined with potassium canrenoate, the serum potassium levels remained low. At 21th week of gestation, a robotic laparoscopic right adrenalectomy was performed under

Hypercortisolism in pregnancy

DOI: 10.3109/09513590.2014.984680

103

Table 1. Frequency of maternal and fetal complication. Maternal morbidity Hypertension (68%) Diabetes or impaired glucose tolerance (25%) Preeclampsia (14%) Osteoporosis and fracture (5%) Cardiac failure (3%) Psychiatric disorders (4%) Wound infection (2%) Maternal death (2%)

Fetal morbidity Prematurity (43%) Stillbirths (6%) Spontaneous abortion (5%) Intrauterine growth retardation (21%) Hypoadrenalism (2%)

Gynecol Endocrinol Downloaded from informahealthcare.com by University of Connecticut on 04/01/15 For personal use only.

Adapted from reference 5.

Figure 1. MRI right adrenal mass.

i.v. replacement of hydrocortisone. Histopathologic examination of the tumor was consistent with a benign adrenocortical adenoma. Steroid replacement therapy was post-operatively carried on because of impaired adrenal function. After surgery, the correction of potassium levels was obtained very slowly, according to the severe potassium intracellular depletion. Serum cortisol and UFC remained high with normalization of cortisol circadian rhythm. The patient improved after adrenalectomy, with gradual resolution of cushingoid facie, acne and hirsutism. Blood pressure decreased requiring a less intensive antihypertensive treatment. The subsequent ultrasound scans showed a regular fetal growth. A cesarean section was scheduled and, at 36th week of gestation, she delivered a healthy male baby with normal external genitalia and palpable testes. The newborn weighed 2550 g, his Apgar score was normal, he had no physical malformation and did not require glucocorticoid during neonatal period. In the post-partum, the patient received again glucocorticoid replacement therapy with gradual dose reduction. Six months after delivery, the ACTH test showed adequate adrenal response.

Discussion Pregnancy rarely occurs in women with Cushing’s syndrome because of the menstrual disturbances and infertility associated with glucocorticoid excess. Oligomenorrhea and amenorrhea are reported in approximately 75% of women in reproductive age diagnosed with Cushing’s syndrome. Benign adrenal adenoma is the most common cause of Cushing’s syndrome in pregnancy. The increased incidence of adrenal Cushing’s syndrome in pregnancy is not understood [1,5–8]. It is possible that women with Cushing’s disease are less ovulatory than those with primary adrenal disease, maybe they are more hyperandrogenic [5]. In our patient, the clinical signs of hypercortisolism became evident during pregnancy. This may be due to misdiagnosis before pregnancy or to the presence of a pregnancy-associated stimulatory factor(s) such as products of the feto-placental unit. There are a few reports of recurrent Cushing’s syndrome in pregnancy spontaneously remitted after delivery [9,10]. The theory is that several placental peptides, such as CRF, placental ACTH or a no yet defined factor, stimulate the adrenals. This could explain the appearance and worsening of symptoms [11]. Moreover, the presence of aberrant adrenal LH/hCG receptors in the adrenal

tumor is a possible explanation for cortisol hypersecretion and tumor growth in Cushing’s syndrome during pregnancy [12–15]. The syndrome may be easily confused with pregnancy complication such as gestational diabetes and pre-eclampsia, thus contributing to delay in the diagnosis. The signs and symptoms that can help in discriminating Cushing’s syndrome from normal physiologic pregnancy include hyperpigmented violaceous striae as opposed to skin-colored striae, easy bruising, as well as the pathologic findings of acne and hirsutism due to a significant elevation of adrenal androgens. Furthermore, the physiological change in the hypothalamic– pituitary axis during pregnancy and the increase of hormone levels interfere with the diagnosis [5,8]. Increasing placental secretion of estrogen stimulates CBG production by the liver, thus stimulating cortisol production and increasing circulating levels of bound cortisol. However, both serum cortisol and UFC levels also increase steadily during gestation, reaching values similar to those found in Cushing’s syndrome [4,5]. During the second and third trimesters of gestation, UFC levels are three times higher than the upper normal limit. Plasma ACTH levels rise throughout pregnancy, reaching a peak during labor and delivery. The cause of ACTH increase during pregnancy is not clear, but may include placental synthesis and release of biologically active CRH and ACTH, pituitary desensitization to cortisol feedback or enhanced pituitary responses to factors such as vasopressin or CRH [5]. In addition, cortisol suppression by dexamethasone may be blunted. However, circadian rhythm of cortisol is preserved in normal pregnancy [5,16]. The increased levels of SHBG in pregnancy cause altered ratio of free and bound testosterone. Feedback set for levels of free testosterone leads to increased production of testosterone so that the total testosterone at the end of the first trimester reaches levels common with men [17]. In this patient, the diagnosis of Cushing’s syndrome was made at the second trimester of pregnancy when the screening for hypercortisolism is more difficult. However, the extremely high UFC levels, the suppression of ACTH levels and the absence of the circadian rhythm of cortisol in addition to the detection of right adrenal mass allowed the diagnosis. The maternal prognosis depends on the complication of Cushing’s syndrome, such as hypertension, pre-eclampsia and diabetes. The fetal prognosis depends on the maternal complication (Table 1). Early treatment of hypercortisolism during pregnancy appears to improve maternal and fetal outcomes [1]. In our patient, the severe hypokalemia and the rapidly evolving clinical frame imposed adrenalectomy at 21th week. Adrenalectomy for patients with adrenal tumors seems to be beneficial, and the birth rate after surgery is approximately 87% [5,6]. Although the ideal timing for adrenalectomy during pregnancy is still a matter of debate, the end of the first trimester and the first half of the second trimester are considered the best time for surgery [18,19]. Concerning medical therapy, metyrapone has been used most

104

R. Nassi et al.

Gynecol Endocrinol Downloaded from informahealthcare.com by University of Connecticut on 04/01/15 For personal use only.

often without evidence of teratogenic effects [9,16]. Moreover, this drug may exacerbate hypertension and favor progression to preeclampsia, which may limit its use [20]. Other adrenal steroid synthesis inhibitor, such as aminoglutethimide, ketoconazole and mitotane are contraindicated because of possible teratogenic effects, although ketoconazole has been used successfully in three pregnancies without adverse event [21]. Pharmacological treatment may be considered when surgical therapy is contraindicated or during preparation for surgery, particularly in patients with serious symptoms of hypercortisolism. In summary, surgery is the treatment of choice for Cushing’s syndrome in pregnancy, except perhaps in the third trimester when conservative treatment and early delivery are preferred [1]. An increased suspicion for diagnosis of this rare disease would likely facilitate early treatment and result in improved outcome for both mother and fetus.

Declaration of Interest There is no conflict of interest for any of the authors.

References 1. 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. 2. Kita M, Sakalidou M, Saratzis A, et al. Cushing’s syndrome in pregnancy: report of a case and review of the literature. Hormones (Athens) 2007;6:242–6. 3. Lekarev O, New MI. Adrenal disease in pregnancy. Best Pract Res Clin Endocrinol Metab 2011;25:959–73. 4. Sheeler LR. Cushing’s syndrome and pregnancy. Endocrinol Metab Clin North Am 1994;23:619–27. 5. Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocr Rev 2005;26:755–99. 6. Aron DC, Schnall AM, Sheeler LR. Cushing’s syndrome and pregnancy. Am J Obst Gynecol 1990;162:472–4. 7. Buescher MA. Cushing’s syndrome in pregnancy. Endocrinologist 1996;6:357. 8. Polli N, Pecori Giraldi F, Cavagnini F. Cushing’s syndrome in pregnancy. J Endocrinol Invest 2003;26:1045–50.

Gynecol Endocrinol, 2015; 31(2): 102–104

9. Wallace C, Toth EL, Lewanczuk RZ, Siminoski K. Pregnancyinduced Cushing’s syndrome in multiple pregnancies. J Clin Endocrinol Metab 1996;81:15–21. 10. Ha´na V, Dokoupilova´ M, Marek J, et al. Recurrent ACTHindependent Cushing’s syndrome in multiple pregnancies and its treatment with metyrapone. Clin Endocrinol (Oxf) 2001;54:277–81. 11. Vilar L, Freitas Mda C, Lima LH, et al. Cushing’s syndrome in pregnancy: an overview. Arq Bras Endocrinol Metabol 2007;51: 1293–302. 12. Wy LA, Carlson HE, Kane P, et al. Pregnancy-associated Cushing’s syndrome secondary to a luteinizing hormone/human chorionic gonadotropin receptor-positive adrenal carcinoma. Gynecol Endocrinol 2002;16:413–17. 13. Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in luteinizing hormone-dependent Cushing’s syndrome. N Engl J Med 1999;341:1577–81. 14. Chui MH, Ozbey NC, Ezzat S, et al. Case report: adrenal LH/hCG receptor overexpression and gene amplification causing pregnancyinduced Cushing’s syndrome. Endocr Pathol 2009;20:256–61. 15. Rask E, Schvarcz E, Hellman P, et al. Adrenocorticotropinindependent Cushing’s syndrome in pregnancy related to overexpression of adrenal luteinizing hormone/human chorionic gonadotropin receptors. J Endocrinol Invest 2009;32:313–16. 16. Blanco C, Maqueda E, Rubio JA, Rodriguez A. Cushing’s syndrome during pregnancy secondary to adrenal adenoma: metyrapone treatment and laparoscopic adrenalectomy. J Endocrinol Invest 2006;29:164–7. 17. Kanˇova´ N, Bicˇ´ıkova´ M. Hyperandrogenic states in pregnancy. Physiol Res 2011;60:243–52. 18. Finkenstedt G, Gasser RW, Ho¨fle G, et al. Pheochromocytoma and sub-clinical Cushing’s syndrome during pregnancy: diagnosis, medical pre-treatment and cure by laparoscopic unilateral adrenalectomy. J Endocrinol Invest 1999;22:551–7. 19. Sammour RN, Saiegh L, Matter I, et al. Adrenalectomy for adrenocortical adenoma causing Cushing’s syndrome in pregnancy: a case report and review of literature. Eur J Obstet Gynecol Reprod Biol 2012;165:1–7. 20. 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. Clin Endocrinol (Oxf) 1993;39:375–9. 21. Berwaerts J, Verhelst J, Mahler C, Abs R. Cushing’s syndrome in pregnancy treated by ketoconazole: case report and review of the literature. Gynecol Endocrinol 1999;13:175–82.

Cushing's syndrome in pregnancy.

Cushing's syndrome is a rare condition in the general population and is even less common during pregnancy with only a few cases reported in literature...
215KB Sizes 2 Downloads 9 Views