Sitch, Alice J

Abstract Objective 11-oxygenated androgens significantly contribute to the circulating androgen pool. Understanding the physiological variation of 11-oxygenated androgens and their determinants is essential for clinical interpretation, for example, in androgen excess conditions. We quantified classic and 11-oxygenated androgens in serum and saliva across the adult age and body mass index (BMI) range, also analyzing diurnal and menstrual cycle-dependent variation. Design Cross-sectional. Morning serum samples were collected from 290 healthy volunteers (125 men, 22-95 years; 165 women, 21-91 years). Morning saliva samples were collected by a sub-group (51 women and 32 men). Diurnal saliva profiles were collected by 13 men. Twelve women collected diurnal saliva profiles and morning saliva samples on 7 consecutive days during both follicular and luteal menstrual cycle phases. Methods Serum and salivary steroids were quantified by liquid chromatography–tandem mass spectrometry profiling assays. Results Serum classic androgens decreased with age-adjusted BMI, for example, %change kg/m2 for 5α-dihydrotestosterone: men −5.54% (95% confidence interval (CI) −8.10 to −2.98) and women −1.62% (95%CI −3.16 to −0.08). By contrast, 11-oxygenated androgens increased with BMI, for example, %change kg/m2 for 11-ketotestosterone: men 3.05% (95%CI 0.08-6.03) and women 1.68% (95%CI −0.44 to 3.79). Conversely, classic androgens decreased with age in both men and women, while 11-oxygenated androgens did not. Salivary androgens showed a diurnal pattern in men and in the follicular phase in women; in the luteal phase, only 11-oxygenated androgens showed diurnal variation. Conclusions Classic androgens decrease while active 11-oxygenated androgens increase with increasing BMI, pointing toward the importance of adipose tissue mass for the activation of 11-oxygenated androgens. Classic but not 11-oxygenated androgens decline with age.

BACKGROUND. Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess. METHODS. We performed mass spectrometry–based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis. RESULTS. Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients. CONCLUSION. Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism. FUNDING. Medical Research Council UK, Wellcome Trust, European Commission.