Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism

Diabetes/metabolic syndrome, renal damage, impaired bone mineral density, and osteoporosis have been reported more prevalent in AI patients with PA.

“Diabetes mellitus/metabolic syndrome (278,279), renal damage (280), impaired bone mineral density (81), and osteoporosis (264,281,282) have also been reported to be more prevalent in AI patients with PA.”

Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess in patients with primary hyperaldosteronism.

“Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess, indeed, postoperative evidence of adrenal insufficiency as evidenced by a suboptimal cortisol response to synacthen testing was found in 29% of patients despite a normal preoperative dexamethasone suppression test.”

Results from panels of multiple steroids are increasingly analyzed using novel statistical techniques including machine learning, revealing a personalized "urinary steroid metabolome."

“Increasingly, the results from panels of multiple steroids are being analyzed using novel statistical technical techniques including machine learning (which allows for the discovery of diagnostic and disease-specific patterns) revealing a personalized “urinary steroid metabolome.””

Patients with primary hyperaldosteronism had significantly increased cortisol and total glucocorticoid metabolite excretion.

“Patients with primary hyperaldosteronism had significantly increased cortisol and total glucocorticoid metabolite excretion.”

Arlt et al. used GC-MS analysis to reveal previously unrecognized significant glucocorticoid excess in patients with primary hyperaldosteronism, labeled "Connshing" syndrome.

“Arlt et al. have used GC-MS analysis to reveal previously unrecognized significant glucocorticoid excess in patients with primary hyperaldosteronism, labeled “Connshing” syndrome (281).”

Several surrogate parameters of metabolic risk (BMI, waist-hip ratio, fasting insulin, HOMA-IR, HDL cholesterol) correlated significantly with glucocorticoid but not mineralocorticoid output in patients with primary hyperaldosteronism.

“Several surrogate parameters of metabolic risk (including BMI, waist–hip ratio, fasting insulin, HOMA-IR, and high-density lipoprotein cholesterol) correlated significantly with glucocorticoid but not mineralocorticoid output.”

Postoperative evidence of adrenal insufficiency as evidenced by suboptimal cortisol response to synacthen testing was found in 29% of patients despite a normal preoperative dexamethasone suppression test.

“Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess, indeed, postoperative evidence of adrenal insufficiency as evidenced by a suboptimal cortisol response to synacthen testing was found in 29% of patients despite a normal preoperative dexamethasone suppression test.”

This approach has been used for some time for diagnosing inborn errors of steroidogenesis such as CAH but has recently been developed for evaluation of functionality and malignant potential of patients with adrenal nodules.

“This approach has been used for some time for diagnosing inborn errors of steroidogenesis such as CAH but has recently been developed for the evaluation of functionality and malignant potential of patients with adrenal nodules (281).”

The urine steroid metabolome of patients with overt Cushing syndrome is characterized by excessive excretion of glucocorticoid and mineralocorticoid precursor metabolites, although androgen metabolites tend to be suppressed in adrenal Cushing but increased in ACTH-dependent Cushing syndrome.

“The urine steroid metabolome of patients with overt Cushing syndrome is characterized by excessive excretion of glucocorticoid and mineralocorticoid precursor metabolites, although androgen metabolites tend to be suppressed (148, 149) in adrenal Cushing but increased in ACTH-dependent Cushing syndrome (150, 151) [Fig. 8A and 8B (1, 148–155)].”

Similar, albeit less pronounced, steroid metabolome changes are observed in patients with mild autonomous cortisol excess.

“Similar, albeit less pronounced changes are observed in patients with MACE (148) (Fig. 8C).”

Immunohistochemical expression of CYP11B1 in aldosterone-producing adenoma tissue correlated with the corresponding excretion of glucocorticoid and 11-oxygenated androgen metabolites.

“Both the conversions of 11-deoxycortisol to cortisol and A4 to 11OHA4 are catalyzed by the adrenal enzyme CYP11B1, and a recent study showed that the immunohistochemical expression of CYP11B1 in APA tissue correlated with the corresponding excretion of glucocorticoid and 11-oxygenated androgen metabolites (148).”

The prevalent cosecretion of both cortisol and aldosterone in primary aldosteronism, termed "Connshing syndrome," is likely to explain the reported increased risk of type 2 diabetes, osteoporosis, and depression in PA.

“This prevalent cosecretion of both cortisol and aldosterone in PA, termed “Connshing syndrome” (148, 174), is likely to explain the reported increased risk of type 2 diabetes, osteoporosis, and depression in PA (153, 175–183), which have no intuitive link to mineralocorticoid activity, but represent commonly noted consequences of cortisol excess.”

A large proportion of primary aldosteronism patients demonstrate excessive urinary excretion of glucocorticoid metabolites, as well as of the 11-oxygenated androgen metabolite 11β-OHAn.

“Until recently, PA had been regarded as a disorder of mineralocorticoid biosynthesis only; however, it has now been shown that a large proportion of PA patients also demonstrate excessive urinary excretion of glucocorticoid metabolites, as well as of the 11-oxygenated androgen metabolite 11β-OHAn (148) (Fig. 8D).”