Not all flushing is hormonal

I recently saw a 78-year-old male in consultation for “flushing.” He had a pre-existing diagnosis of hypogonadism managed with daily transdermal testosterone gel. He also had essential hypertension and was taking triamterene/hydrochlorothiazide, metoprolol, enalapril and felodipine. His blood pressure was 128/60 mmHg, which is his baseline.

Over the past several years, he experienced episodes he described as “burning up inside.” These last up to three or four hours but are never associated with headache, elevated BP, tachycardia, palpitations, sweating, diarrhea or any other specific symptoms. He does not have any visible dermatologic changes with these episodes. The question was whether his dose of testosterone replacement therapy was adequate and/or whether there might be another endocrine explanation of his symptoms.

Prior to coming to see me, he had the following laboratory studies: urine 5-hydroxyindoleacetic acid 16 mg/24 hr (normal <6). Plasma free metanephrine <0.20 nmol/L (<0.49), plasma free normetanephrine 0.56 nmol/L (<0.89). Twenty-four hour fractionated urine catecholamines: norepinephrine 243 ug/24 hr (normal <80), epinephrine 7.2 ug/24 hr (<20), dopamine 455 ug/24 hr (<400), 24 hour urine metanephrine 423 ug/24 hr (normal in hypertensive individual <400), 24 hour urine normetanephrines 2047 ug/24 hr (normal in hypertensive individual <900). These were obtained while taking his antihypertensive and other medications including acetaminophen.

I ordered additional laboratory studies: total testosterone 564 ng/dL (240 to 950), free testosterone 15.2 ng/dL (9 to 30), TSH 0.91, plasma free metanephrine <0.20 nmol/L (<0.50), plasma free normetanephrine 0.49 nmol/L (<0.90). I also repeated the 24 hour urine fractionated catecholamines, normetanephrines and metanephrines after all medications had been withheld. They were well within the normal laboratory reference ranges.

I explained to the patient that his symptoms are not due to hypogonadism as his testosterone is optimal. My suspicion for a neuroendocrine tumor syndrome is low. The highly sensitive tests for pheochromocytoma, plasma free metanephrines and normetaphrines, were negative on two occasions. I assume the abnormal first 24 hour urine catecholamine collection was a false positive.

Dihydropyridine calcium channel blockers, including felodipine, have been associated with flushing. Typically the flushing is minor and self-limited. However, vasodilatory side effects have been reported in as many as 10% to 20% of individuals on this class of antihypertensive.

Therefore, we stopped the felodipine to determine if that might be the culprit. Indeed, the flushing episodes disappeared immediately and have not recurred.

The patient since asked whether or not he should continue taking the transdermal testosterone gel. He said he was started on the testosterone primarily because of flushing. Because I do not have access to the original evaluation and laboratory studies performed before initiation of testosterone replacement therapy, I do not know for certain. We decided to stop the testosterone gel and observe. In the future, I will repeat the morning total and free testosterone to determine if he requires long term testosterone replacement therapy or not.

Not all flushing is hormonal in origin.