Test Key to Confirming Cushing’s Linked to Pregnancy, Report Suggests

A stimulation test with human choriogonadotropin (hCG) — a hormone normally produced by the placenta to sustain pregnancy — should be performed very soon after a women suspected of pregnancy-induced Cushing’s syndrome gives birth, to confirm a diagnosis, a case report highlighted.

The case report, “Pregnancy-induced Cushing’s syndrome with an adrenocortical adenoma overexpressing LH/hCG receptors: a case report,” was published in the journal BMC Endocrine Disorders.

In most cases, this is triggered by a tumor causing excessive adrenocorticotropic hormone (ACTH) production. However, in rare cases, the condition may also be associated with hormonal changes taking place during pregnancy.

“Although rare, CS [Cushing’s syndrome] in pregnancy is associated with significant maternal and fetal complications and the management of this disorder remains challenging,” the investigators wrote.

Researchers in China described the rare case of a woman found to have pregnancy-induced Cushing’s syndrome, and whose diagnosis was later confirmed by a hCG stimulation test performed after her delivery.

The woman, 27, arrived at the hospital when she was at 20 weeks of gestation. A physical examination found several of the typical features of Cushing’s, including a moon face, acne, a fat lump on her neck, stretch marks on both legs and swollen legs, and high blood pressure.

Lab tests showed her blood potassium levels were abnormally low, while her blood sugar levels were excessively high — consistent with a diagnosis of gestational diabetes. She also had hypercortisolism, a condition in which the levels of cortisol circulating in the blood and urine are abnormally high, one of the hallmarks of Cushing’s.

Her blood cortisol levels, however, did not drop after an overnight dexamethasone suppression test (ODST). This test, which is usually performed to confirm the presence of hypercortisolism, measures blood levels of cortisol in the morning after patients take a tablet of dexamethasone, a corticosteroid that normally blocks its production.

The lack of cortisol suppression, along with the fact that blood levels of ACTH were practically undetectable, indicated the patient had an ACTH-independent form of Cushing’s.

A MRI scan showed a nodule in her left adrenal gland. Apart from that, no other abnormalities were found.

Physicians decided to adopt a conservative treatment strategy to manage some of her symptoms until delivery was possible.

At 36 weeks of gestation, the woman gave birth to a baby girl by cesarean section. Eight weeks after the birth of her daughter, her blood sugar and potassium levels returned to normal, as did her blood pressure and urinary cortisol levels. However, the woman’s blood ACTH levels remained undetectable, and cortisol suppression continued to fail following ODST.

Six months after giving birth, the patient had a hCG stimulation test that rapidly increased her blood cortisol levels, suggesting a form of pregnancy-induced Cushing’s.

She underwent surgery to remove the tumor in one of her adrenal glands, and began taking routine glucocorticoid supplements. Tumor tissue analyses revealed the presence of a high number of luteinizing hormone/chorionic gonadotropin receptors (LHCGRs). These protein receptors can interact with both hCG, which is produced during pregnancy, and luteinizing hormone (LH), a hormone that regulates a woman’s menstrual cycle.

A similar case of pregnancy-induced Cushing’s reported that activation of a signaling cascade leading to corticol production, following the activation of LHCGR by hCG, was likely the underlying cause of the condition.

Based on these observations, the study’s authors suggested that “persistently increased hCG levels in early pregnancy” may activate LHCGRs, triggering the activation of the signaling cascade that leads to increased cortisol production.

“After delivery, when endogenous [natural] cortisol secretion returned to normal, the significant cortisol increase evoked by exogenous [artificial] hCG during non-pregnancy state indicated the positive response of LHCGR to hCG stimulus,” they wrote.

Altogether, this case highlighted that a “stimulation test with exogenous hCG after [delivery] is necessary for the diagnosis of pregnancy-induced CS” and that “LHCGR plays an essential role in the pathogenesis [development] of this rare condition.”