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Oligohydramnios in a Pregnant Woman With Cushing’s Syndrome Caused By an Adrenocortical Adenoma

June 14, 2007

By de Groot, Pieter C M van Kamp, Inge L; Zweers, Evert J K; de Kroon, Cor D; van Wijngaarden, Willem J

Abstract A 28-year-old primigravida with severe oligohydramnios and pre-eclamptic symptoms was found to have Cushing’s syndrome caused by an adrenocortical tumor. After meternal therapy the amniotic volume normalised, but the fetus succumbed. As clinical features of pre-eclampsia and Cushing’s syndrome may overlap, diagnosis can be delayed or even missed.

Keywords: Cushing’s syndrome, oligohydramnios, pregnancy, adrenocortical adenoma, hypertension

Introduction

Oligohydramnios is a complication seen in 0.5-8.2% of pregnancies [1,2]. The cause can be of maternal, placental, fetal, or idiopathic origin. We describe herein a case of oligohydramnios with a rare maternal cause: Cushing’s syndrome resulting from an adrenocortical adenoma. To our knowledge this has not been reported before. This case illustrates the observation that hypertension and oligohydramnios may not always be preeclamptic and placental in origin.

Case report

A 28-year-old primigravida was referred by her midwife because of hypertension at a gestational age of 21 weeks. She complained of edema of the arms and legs. She had no medical history of note apart from bulimia for which she had been treated six years before. She did not use any medication. All antenatal checks in the first trimester had been normal.

Her blood pressure was 150/85 mmHg and there was slight albuminuria (+). Blood tests were normal except for a serum potassium level of 2.5 mmol/L, a high fasting blood sugar level and an abnormal glucose tolerance (Table I). She was admitted, and potassium supplementation was started. An ultrasound scan showed an anhydramnios without any structural fetal abnormalities. The estimated fetal weight (EFW) was 448 g (18th centile for gestational age) and Doppler examination showed notches of both uterine arteries. Both the umbilical artery pulsatility index (PI) and midcerebral artery PI were normal. Normal fetal movements were present. Chorionic villous sampling was performed which revealed a normal female karyotype.

Two days later the patient complained of blurred vision and lack of concentration. Multiple subcutaneous ecchymoses developed spontaneously and blood pressure increased to 165/105 mmHg. Methyldopa was started and because of elevated blood sugar levels refractory to dietary adjustments, insulin therapy was commenced. Psychiatric advice was requested for increasing anxiety.

Despite oral supplementation, the serum potassium level dropped to 1.6 mmol/L. Electrocardiography showed U-waves with an increased QT-segment, typical for low serum potassium levels. She was transferred to the coronary care unit for close monitoring and intravenous potassium supplementation. Treatment with spironolactone was commenced. The combination of hypertension and a 0.89 g/24 h urinary albumin excretion warranted the diagnosis of preeclampsia. However, the atypical constellation of symptoms and clinical findings urged further investigation. Additional blood tests showed hypercortisolism (2365 nmol/L) without a normal circadian rhythm, an increased 24-hour urinary cortisol excretion, and a positive dexamethasone suppression test, which confirmed the suspicion of Cushing’s syndrome (Table I). To find the cause for the high cortisol levels, an ultrasound and magnetic resonance imaging scan of the pituitary and adrenal glands were performed. A smooth surfaced tumor of the right adrenal gland with a diameter of 5 cm was found (Figure 1). Potassium levels increased to become low- normal under continuing potassium supplementation and spironolactone therapy.

Table I. Laboratory test results.

At 23 weeks of gestation, fetal growth was found to be symmetrically reduced (EFW 479 g, P10). The thoracic circumference (TC) was 12.94 cm (P95). There was an increase in amniotic fluid volume with an amniotic fluid index of 5.7 cm. No structural abnormalities were seen, apart from chubby cheeks (Figure 2) and a borderline myocardial hypertrophy, however with a normal heart-thorax ratio (0.5). Surgery to remove the right adrenal gland and tumor was planned.

Despite improvement of the maternal condition the fetus died at a gestational age of 25+6 weeks. After induction of labor, a female baby of 590 g (PlO) was born without dysmorphic features. The chubby cheeks were prominent. Consent for autopsy was not given. Histopathological examination of the placenta did not reveal any abnormalities.

Two weeks after delivery a right adrenalectomy was performed followed by cortisol supplementation. Histopathologic investigation showed a benign adrenocortical adenoma. Two weeks after surgery the patient was in good health and discharged from hospital care. At outpatient follow-up at one, three and six months after surgery no problems were noted, and hydrocortisone supplementation was gradually reduced.

Figure 1. Ultrasound scan of the adrenocortical tumor of the right adrenal gland.

Figure 2. Chubby cheeks of the fetus (arrow).

Discussion

Pregnancy in a woman with untreated Cushing’s syndrome is rare because of the high incidence of infertility secondary to the disorder. The most likely mechanism through which ovulation is suppressed in these patients is by inhibition of pituitary gonadotropin production secondary to excessive production of adrenal androgens [3,4].

Cushing’s syndrome can be either adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent. ACTH can be produced by the pituitary gland or by ectopic sources, mostly steroid-producing tumors. In the general population ACTH-independent Cushing’s syndrome is usually caused by adrenal hyperplasia (59.3%), an adrenal adenoma (15.7%), or an adrenal carcinoma (9.3%) [4]. In pregnant women, however, adrenal adenoma is reported to have a much higher incidence (50%) [4]. This is supported by a large observational study of 122 pregnancies with Cushing’s syndrome including 56 cases with an adrenal adenoma and 12 with an adrenal carcinoma [5]. In none of the studies on pregnancy and Cushing’s syndrome to date, has either oligo- or anhydramnios been mentioned explicitly as a specific complication.

In our patient, the severity of the disease increased during pregnancy. All checks during the first trimester were normal and no problems were apparent. In the second trimester, however, hypertension and ecchymoses developed, the serum potassium level deteriorated to abnormal low levels secondary to increased urinary potassium loss, and sleeping problems and complaints of anxiety increased. All these symptoms were secondary to the hypercortisolism as classical features of Cushing’s syndrome. After specific questioning, our patient told us that she had seen her general practitioner one year previously because of her face becoming increasingly round and because she was having sleeping problems; this had lead to a period off work because of’stress’. This would suggest that the actual onset of the disease took place well before conception. As adrenal tumors may respond to luteinizing hormone (LH) and human chorionic gonadotropin (hCG) through specific hormonal receptor expression [6], the physiological high levels of hCG in the second trimester may well explain the worsening of the disease during this gestational stage.

In the normal population, hypertensive disorders complicate 5- 10% and gestational diabetes mellitus 3-5% of all pregnancies. Gestational diabetes is more common in women with pregnancy-induced hypertension (PIH) or preeclampsia (3.9-4.5%) compared to controls without PIH or preeclampsia (2.7%) [7]. Pregnancies with Cushing’s syndrome are complicated by hypertension in 65-68%, diabetes or impaired glucose tolerance in 25-32%, and preeclampsia in 9-14% of cases [4,5]. As pregnant women with preeclampsia may develop some of the classical features of Cushing’s syndrome, the latter diagnosis may easily be missed or delayed. There should be clinical suspicion in the case of any pregnant woman who develops a combination of hyperglycemic, hypertension or evidence of androgen excess [3].

The anhydramnios in our case could not be explained by either abnormalities of the fetal urinary system, premature rupture of the membranes or severe placental insufficiency. The apparent reversibility of the anhydramnios after maternal potassium supplementation and spironolactone therapy would appear to support a maternal origin.

Maternal cortisol crosses the placenta and can, in high doses, affect the fetus and carry a poor prognosis [3]. Not only the development of the anhydramnios, but also fetal hypertension with thickening of the cardiac muscle and facial Cushing’s appearance may be explained by supraphysiological cortisol levels in the fetus. Through the mineralocorticoid action of cortisol, urinary potassium excretion is enhanced and sodium is retained. With the retention of osmotically active sodium ions, water is retained as well. In adults, this would invoke an escape mechanism involving a decreased re-absorption of sodium in the proximal tubules accompanied by the passive excretion of water. In fetuses, however, the surplus of sodium ions and water can be dealt with by the placenta without the need to resort to this escape mechanism. Continued exposure to high levels of mineralocorticoid substances may, in fetuses, thus lead to the reduction of urine production and result in oligo- or anhydramnios. Spironolactone crosses the placenta and acts on the fetal kidneys counteracting the mineralocorticoid action of cortisol. This will lead to the retention of potassium and the excretion of sodium ions and is accompanied by the excretion of water leading to an increase in fetal urine production and amniotic fluid volume. Why exactly the fetus died whilst maternal therapy appeared to take effect remains unclear. Despite a possible cardiomyopathy, there were no ultrasound features of cardiac decompensation. Unfortunately a post-mortem examination was refused. It is well known that prolonged anhydramnios at this gestational age carries a very poor prognosis in fetal outcome [1]. We can now only speculate on the long-term effects of an anhydramnios existing for at least three weeks, followed by normalization of the amount of amniotic fluid at this gestational age.

To our knowledge this is the first report of maternal Cushing’s syndrome leading to anhydramnios early in the second trimester. Both Cushing’s syndrome during pregnancy and prolonged anhydramnios early in the second trimester carry a poor fetal prognosis, which is reflected in our case. An anhydramnios, in combination with the other associated symptoms as listed, may prompt suspicion of Cushing’s syndrome and further evaluation.

References

1. Peipert JF, Donnenfeld AE. Oligohydramnios: A review. Obstet Gynecol Surv 1991;46:325-339.

2. Rutherford SE, Phelan JP, Smith CV, Jacobs N. The four- quadrant assessment of amniotic fluid volume: An adjunct to antepartum fetal heart rate testing. Obstet Gynecol 1987;70: 353- 356.

3. Aron DC, Schnall AM, Sheeler LR. Cushing’s syndrome and pregnancy. Am J Obstet Gynecol 1990; 162:244-252.

4. Buescher MA, McClamrock HD, Adashi EY. Gushing syndrome in pregnancy. Obstet Gynecol 1992;79:130-137.

5. Lindsay JR, Jonklaas J, Oldfield EH, Nieman LK. Cushing’s syndrome during pregnancy: Personal experience and review of the literature. J CHn Endocrinol Metab 2005;90:3077-3083.

6. Wy LA, Carlson HE, Kane P, Li X, Lei ZM, Rao CV. Pregnancy- associated Cushing’s syndrome secondary to a luteinizing hormone/ human chorionic gonadotropin receptorpositive adrenal carcinoma. Gynecol Endocrinol 2002; 16:413-417.

7. Bryson CL, Ioannou GN, Rulyak SJ, Critchlow C. Association between gestational diabetes and pregnancy-induced hypertension. Am J Epidemiol 2003;158:1148-1153.

PIETER C. M. DE GROOT1, INGE L. VAN KAMP1, EVERT J. K. ZWEERS2, COR D. DE KROON1, & WILLEM J. VAN WIJNGAARDEN3

1 Department of Obstetrics and Gynaecology, Leiden University Medical Centre, Postbus 9600, 2300 RC Leiden, The Netherlands, 2 Department of Internal Medicine, Ziekenhuis Bronovo, Bronovolaan 5, 2597 AX The Hague, The Netherlands, and * Department of Obstetrics and Gynecology, Ziekenhuis Bronovo, Bronovolaan 5, 2597 AX The Hague, The Netherlands

(Received 27 December 2006; revised 16 January 2007; accepted 16 January 2007)

Correspondence: P. C. M. de Groot, Department of Obstetrics and Gynaecology, Leiden University Medical Centre, Postbus 9600, 2300 RC Leiden, The Netherlands. Tel: +31 648072684/71526911. E-mail: pcmdegroot@yahoo.co.uk

Copyright Taylor & Francis Ltd. May 2007

(c) 2007 Journal of Maternal – Fetal & Neonatal Medicine. Provided by ProQuest Information and Learning. All rights Reserved.




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