Adrenal Cushing’s syndrome in pregnancy: Clinical and molecular characterisation of a case

Abstract

Background: Cushing's syndrome is rare during pregnancy and more commonly due to adrenal pathology, in contrast to the non-pregnant population. Increased levels of cortisol-binding globulin and placental production of corticotropin-releasing hormone and adrenocorticotropic hormone complicate the diagnostic strategies usually employed.Case: A 32-year-old G1P0 at 15/40 gestation presented with severe peripheral oedema and excessive weight gain. Examination revealed pitting oedema to the abdominal wall, wide violaceous striae, moon facies and acne. Cortisol excess was confirmed with elevated 24 h urinary free cortisol, raised midnight salivary cortisol and lack of diurnal variation. Adrenocorticotropic hormone ranged between 22 and 36 pg/ml (5-8 pmol/L). Fetal ultrasound confirmed a single live intrauterine gestation with an incidental finding of a maternal left adrenal mass. Magnetic resonance imaging confirmed an adrenal mass measuring 3.0 Â 4.4 Â 4.1 cm. She underwent a laparoscopic left adrenalectomy at 18 weeks' gestation without complication. Her postoperative cortisol level was undetectable. Hydrocortisone replacement was commenced with slow weaning as an outpatient. Histology was consistent with an adrenal adenoma. Immunohistochemistry revealed strong staining for the luteinising hormone/choriogonadotropin receptor, and expression of the luteinising hormone/choriogonadotropin receptor gene was in the range seen in normal ovary. DNA analysis revealed a mutation in GNAS encoding the Ga subunit in the cyclic adenosine monophosphate pathway. Conclusion:Cushing's syndrome may present in pregnancy as a result of hCG acting on the luteinising hormone/choriogonadotropin receptor overexpression by the adenoma amplifying the aberrant cyclic adenosine monophosphate signaling implicated in the development of cortisol-secreting adenomas. KeywordsCushing's, pregnancy, adrenal adenoma, luteinising hormone/choriogonadotropin receptor, GNAS CaseCushing's syndrome (CS) in pregnancy is uncommon; it is associated with high rates of maternal diabetes, fracture, pre-eclampsia, fetal morbidity and fetal mortality. 1 We report a case of Cushing's rapidly progressing in pregnancy and characterise the underlying molecular pathogenesis. This case illustrates the difficulties encountered in the workup of Cushing's in pregnancy and the complications that can ensue.A 32-year-old Chinese woman, gravida 1 para 0, presented at 15 weeks' gestation with severe peripheral oedema and excessive weight gain of 30 kg over two months. She had been previously well, conceived naturally and was on no regular medications.On examination, the most striking feature was pitting oedema to the top of her thighs, which hindered her mobility, with wide violaceous striae over her calves and lower abdomen (Figure 1(a)). She had a moon like facies with acne but no hirsutism.Initial biochemistry revealed hypokalaemia (3.0 nmol/L; RR 3.5-5.0 mmol/L) with hypoalbuminaemia (2.5 g/dL; RR 3.5-4.5 g/dL). An abdominal ultrasound confirmed a single live intraute...

Adrenal Cushing’s syndrome during pregnancy

“…To date, only a few patients with pregnancy-induced CS have been described (2,3,4,5,8,9,10,11,12,13,14). Pregnancy is uncommon in women with CS, as hyperandrogenism and hypercortisolism suppress gonadotrophin secretion (9,10).…”

“…CS during pregnancy is a rare phenomenon with only a few cases reported in the literature. The adrenal manifestations include simple adenoma and mild bilateral diffuse hyperplasia (2,3,4,11,21,22). Although the exact etiology is unknown, the most commonly postulated mechanism involves aberrant LH/hCG receptor expression by adrenal tumor tissue, which is coupled to steroidogenesis.…”

“…Directly after laparoscopic removal, adrenal tissue of the major part of the adrenals was prepared as described previously (4,6). The mouse MAB (20C3 provided by Dr A. Funaro) was used for LH receptor immunohistochemistry on formalin-fixed paraffinembedded tissue.…”

“…Cushing syndrome (CS) during pregnancy is rare since only a limited number of cases is reported in literature (1,2,3,4,5). The diagnosis of this condition is difficult because of the overlapping features of fatigue, weight gain, striae and emotional changes that can occur during normal pregnancy.…”

“…CS during pregnancy is most frequently due to an adrenal adenoma and to a lesser degree to adrenocorticotropic hormone (ACTH) hypersecretion from a pituitary adenoma (1,2,3,4). Aberrant expression of various hormone receptors in the adrenal glands is thought to play a role in the pathogenesis of this condition, in particular expression of the LH receptor (2,3,6,7).…”