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Cushing's syndrome in pregnancy: a diagnostic conundrum.

Introduction

Cushing's syndrome was named after Harvey Cushing who described it in 1912. William Osler described the syndrome in 1898 but he wrongfully attributed it to myxedema. (1) Cushing's syndrome is a rare entity with an incidence of 1 case per 2 to 3 million people. (2) It usually poses diagnostic uncertainty because of the common prevalence of its signs and symptoms. Cushing's syndrome in pregnancy, described by Hunt and McConahey in 1953, is very rare with only 126 cases previously reported. (3) Cushing's syndrome may prevent conception because the associated hypercortisolism and hyperandrogenism affect normal follicular and endometrial development.

During normal pregnancy there is increased production of corticosteroid binding globulins by the liver and increased placental production of cortisol releasing hormone (CRH) and adrenocorticotropic hormone (ACTH); this causes elevated levels of total and free cortisol which may result in increased salivary and urinary free cortisol levels (Table-1). (4) These physiologic and biochemical changes make the diagnosis of Cushing's syndrome in pregnancy an intriguing challenge. We present a woman who had Cushing's syndrome of pregnancy that resulted from an adrenal adenoma.

Case Presentation

A 31 year old gravida 5, para1 woman, who was 16 weeks pregnant, was admitted to the hospital because of headache, blurred vision, excessive weight gain and hirsutism. Past medical history included gestational diabetes, gestational hypertension and a left adrenal mass (2.7 cm) noted on CT scan 6 months earlier. A low serum ACTH and normal serum cortisol levels were noted 6 months ago when the mass was first discovered. Physical examination showed facial plethora, prominent supraclavicular fat pads, wide abdominal purple striae, and multiple bruises in the lower extremities. Laboratory tests done at our facility are detailed in Table 1. Magnetic resonance imaging (MRI) showed the left adrenal mass (3.2 cm) with features suggestive of an adrenal adenoma.

She was diagnosed with Cushing's syndrome secondary to an adrenal adenoma. The patient was treated with robotic left adrenalectomy. Histopathology confirmed the diagnosis of adrenal adenoma. The patient was started on physiologic dose of corticosteroids (hydrocortisone 20 mg in the morning and 10 mg in the evening). The plasma ACTH level increased to normal by 4 months after surgery (Table 2). The patient had an uncomplicated delivery of a healthy boy after 37 weeks of gestation. After the delivery, the oral corticosteroids were tapered and discontinued.

Discussion

Cushing's syndrome is hypercortisolism due to any cause, most commonly from exogenous administration of glucocorticoids. Cushing's disease is hypercortisolism due to excess production of ACTH by the pituitary. (5) Cushing's syndrome in pregnancy is rare and the etiology is different from the non-pregnant patient. Adrenal adenomas cause 40 to 50% of cases of Cushing's syndrome in pregnancy but only 15% cases of Cushing's syndrome in non-pregnant patients. Cushing's disease is also rare in pregnancy; most patients with Cushing's disease are unlikely to become pregnant because of associated hyperandrogenism. (4)

Cushing's syndrome is rarely diagnosed before 12 to 26 weeks of gestation because the typical symptoms of weight gain, bruising and hirsutism are attributed to pregnancy. (3) Some women may not show signs of Cushing's syndrome despite increased cortisol levels because they may have increased cortisol binding globulin (CBG) levels or decreased sensitivity to cortisol. (6) Maternal mortality and morbidity may be associated with untreated Cushing's syndrome in pregnancy because of associated hypertension (68%), diabetes (25%), preeclampsia (14%), osteoporosis (5%) and psychiatric disorders (4%). (3) Although the fetus is protected by the cortisol degrading enzyme in the placenta, complications may include prematurity (60%), IUGR (26.2%), still birth (6%) and spontaneous abortions (5%). Rare cases of cleft palate, patent ductus arteriosus, coarctation of the aorta, transient hypertrophic obstructive cardiomyopathy have been reported. (7) Spontaneous bruising, facial plethora and wide purple abdominal striae have the highest diagnostic predictive value for Cushing's syndrome. (8)

Physiologic changes in pregnancy include elevated ACTH, serum and urinary cortisol, CRH, and plasma and urinary aldosterone levels and blunted responses to ACTH, CRH and dexamethasone. (4) These may alter the interpretation of tests to diagnose Cushing's syndrome as detailed in Table 3.

Urinary free cortisol levels and midnight salivary cortisol levels are recommended as the diagnostic tests for Cushing's syndrome in pregnancy. Plasma ACTH levels may help in determining the etiology. A low ACTH level suggests adrenal etiology and imaging with either ultrasonography or MRI without gadolinium is recommended. (3)

Cushing's syndrome resulting from an adrenal tumor in pregnancy usually is treated with adrenalectomy, optimally during the second trimester. Patients treated with adrenalectomy have a live birth rate of 87%. (9) Medical treatment, most commonly with metapyrone is an alternative for women who decline surgery or who are diagnosed in the third trimester. (10) Ketoconazole may be teratogenic. Cyproheptadine is not efficacious and aminoglutethimide is not recommended because it may cause fetal masculinization. (3)

Conclusion

Cushing's syndrome in pregnancy is a diagnostic challenge. The clinical signs and laboratory tests of Cushing's syndrome may be similar to those of pregnancy. Physicians need to have a high index of suspicion for this condition in order to initiate the appropriate work up and arrive at the diagnosis.

References

(1.) De P, Evans LM, Scanlon MF, Davies JS. "Osler's phenomenon": misdiagnosing Cushing's syndrome. Postgrad Med J. 2003;79(936):594-596.

(2.) Steffensen C, BakAM, Rubeck KZ, Jorgense JO. Epidemiology of Cushing's syndrome. Neuroendocrinology. 2010;92(Suppl 1):1-5.

(3.) Vilar L, FreitasMda C, Lima LH, Lyra R, Kater CE. Cushing's syndrome in pregnancy: an overview. Arq Bras Endocrinol Metabol. 2007;51(8):1293-1302.

(4.) Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocr Rev. 2005;26(6):775-799.

(5.) Guaraldi F, Salvatori R. Cushing syndrome: maybe not so uncommon of an endocrine disease. J Am Board Fam Med. 2012;25(2):199-208.

(6.) Cook DJ, Riddell, Boo JD. Cushing's syndrome in pregnancy. CMAJ, 1989; 141: 1059-1061.

(7.) Fayol L, Masson P, Millet V, Simeoni U. Cushing's syndrome in pregnancy and neonatal hypertrophic obstructive cardiomyopathy. ActaPaediatr. 2004;93(10):1400-1402.

(8.) Stewart PM. The adrenal cortex. In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, eds. Williams Textbook of Endocrinology. 11 ed. Philadelphia, PA: WB Saunders; 2008:445-503.

(9.) Aron DC, Schnall AM, Sheeler LR. Cushing's syndrome and pregnancy. Am J Obstet-Gynecol. 1990;162(1):244-252.

(10.) 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(2):164-167.

Vishnu Garla, MD

Reem Kheetan, MD

Tipu Saleem, MD

Department of Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington WV

Corresponding Author: Vishnu Garla MD, 1600 Medical Center Drive, Huntington, WV 25701; vishnu.garla@gmail.com
Table 1: Laboratory studies on admission to hospital.

Test                                          Level   Reference
                                                      range

Adrenocorticotropic hormone (ACTH) (pg/ml)    <1.1    7.2 to 63.3
Cortisol, serum ([micro]g/dL)                 24.5    3.1 to 16.7
Cortisol, serum (after overnight 1 mg DXT)    24      (<5)
  ([micro]g/dL)
Cortisol, urinary free ([micro]g/24 h)        442     0 to 50
Aldosterone, serum (ng/dL)                    1.2     0 to 30
Renin, plasma (ng/ml/hr)                      1.6     0.15 to 2.33
Metanephrines, urinary ([micro]g/24 h)        109     35 to 460
Metanephrines, plasma (pg/ml)                 14      0 to 62
Dehydroepiandrosterone (DHEA) (ng/dl)         40      31 to 701
Vanillylmandelic acid, urinary (mg/24 h)      6       0 to 7.5
Epinephrine, urinary ([micro]g/24 h)          12      0 to 20
Norepinephrine, urinary ([micro]g/24 h)       124     0 to 135
Dopamine, urinary ([micro]g/24 h)             276     0 to 510

Table 2:--Laboratory studies for the patient before
and after resection of the adrenal tumor

Test                  Preoperative      Postoperative     Reference
                                                          range

Adrenocorticotropic   <1.1              10.8              7.2 to
  hormone (ACTH)                                            63.3
  (pg/mL)
Cortisol, urinary     442               69                0 to 50
  ([micro]g/24h)

Table 3: Comparison of laboratory studies with
adrenal Cushing's syndrome and normal pregnancy

Test                  Adrenal           Normal
                      Cushing's         pregnancy
                      syndrome

Morning serum         Increased         Increased
  cortisol
Diurnal rhythm        Midnight          Midnight
  of cortisol           nadir lost        nadir
                                          preserved
Salivary              Increased         Increased
  cortisol
Urinary free          > 4 fold          3 fold
  cortisol              increase          increase in
                                          third
                                          trimester
Low dose              After test        Blunted
  dexamethasone         cortisol > 5      response
  suppression           ([micro]g/dL)
  test
High dose             < 50%             Blunted
  dexamethasone         suppression       response
  suppression           of cortisol
  test
Adrenocorticotropic   Decreased         Increased
  hormone (ACTH)                          because of
                                          placental
                                          cortisol
                                          releasing
                                          hormone (CRH)
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Article Details
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Title Annotation:Scientific Article
Author:Garla, Vishnu; Kheetan, Reem; Saleem, Tipu
Publication:West Virginia Medical Journal
Article Type:Report
Geographic Code:1U5WV
Date:Nov 1, 2013
Words:1386
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