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Free access

Testosterone and cardiometabolic risk in the general population – the impact of measurement method on risk associations: a comparative study between immunoassay and mass spectrometry

Robin Haring, Sebastian E Baumeister, Matthias Nauck, Henry Völzke, Brian G Keevil, Georg Brabant, and Henri Wallaschofski

Objective

Low total testosterone (TT) serum concentrations in men have been associated with various cardiometabolic risk factors. But given error-prone immunoassays used for TT assessment, upcoming mass spectrometry methods question the validity of these risk associations. Thus, we performed the first comparative study quantifying potential differences in the association of TT with cardiometabolic risk factors between the two methods.

Methods

We used data from 1512 men aged 20–81 years, recruited for the cross-sectional population-based Study of Health in Pomerania (SHIP), Germany. TT concentrations were repeatedly measured by chemiluminescent immunoassay (CLIA, Immulite 2500) and liquid chromatography–tandem mass spectrometry (LC–MS/MS). We tested for significant differences between coefficients from CLIA- and LC–MS/MS-based multiple linear regression models associating TT with major cardiometabolic risk factors including adiposity, lipid metabolism, blood pressure, diabetic status, and inflammation.

Results

TT measurements by CLIA and LC–MS/MS yielded a Pearson correlation coefficient of 0.84. Only three of the ten tested associations for TT with cardiometabolic risk factor showed significant differences between the two measurement methods: in comparison to LC–MS/MS, CLIA-based TT assessment significantly underestimated risk associations of TT with waist circumference (β: −0.54 vs −0.63), BMI (β: −0.19 vs −0.22), and serum glucose levels (β: −0.006 vs −0.008).

Conclusion

In this comparative study, the CLIA platform showed a reasonable measurement error and yielded comparable risk associations, providing little support to measure TT concentrations in men from the general population exclusively by LC–MS/MS.

Open access

11-Oxygenated androgens are not secreted by the human ovary: in-vivo data from four different cases of hyperandrogenism

Matthias K Auer, James M Hawley, Christian Lottspeich, Martin Bidlingmaier, Andrea Sappl, Hanna F Nowotny, Lea Tschaidse, Marcus Treitl, Martin Reincke, Brian G Keevil, and Nicole Reisch

Objective

Differentiation of an adrenal from an ovarian source of hyperandrogenemia can be challenging. Recent studies have highlighted the importance of 11-oxygenated C19 steroids to the androgen pool in humans. The aim of this study was to confirm the origin of 11-oxygenated androgens in females and to explore their potential use in the diagnostics of hyperandrogenic disorders.

Methods

We measured testosterone and its precursors (dehydroepiandrosterone-sulfate and androstenedione) and 11-oxygenated androgens (11β-hydroxyandrostenedione (11-OHA4) and 11-ketotestosterone (11-KT)) in the periphery, adrenal and ovarian veins in four different cases of hyperandrogenism in females (polycystic ovary syndrome (PCOS), primary bilateral macronodular adrenal hyperplasia, Sertoli–Leydig cell tumor and ovarian steroid cell tumor).

Results

Two patients demonstrate excessive testosterone secretion in neoplastic ovarian tumors which was not paralleled by a significant secretion of 11-oxygenated androgens as determined by adrenal and ovarian vein sampling. In androgen-secreting bilateral adrenal macronodular hyperplasia, steroid profiles were characterized by elevated 11-KT and 11-OHA4 concentrations in adrenal veins and the periphery. In the patient with PCOS, peripheral 11-KT concentrations were slightly elevated in comparison to the other patients, but the 11-KT and 11-OHA4 concentrations were comparable in ovarian veins and in the periphery.

Conclusion

This study confirms that 11-OHA4 and 11-KT are not biosynthesized by the ovary. We propose that the testosterone/11-KT ratio as well as 11-OHA4 could help identify predominant adrenal androgen excess and distinguish neoplastic and non-neoplastic ovarian androgen source.

Significance statement

This study confirms that 11β-hydroxyandrostenedione (11-OHA4) and 11-ketotestosterone (11-KT) are not biosynthesized by the human ovary. We propose that the testosterone/11-KT ratio as well as 11-OHA4 could help to identify predominant adrenal androgen excess and distinguish neoplastic and non-neoplastic ovarian androgen source.

Free access

The androgen receptor gene CAG repeat 
in relation to 4-year changes in 
androgen-sensitive endpoints in 
community-dwelling older European men

Robert J A H Eendebak, Ilpo T Huhtaniemi, Stephen R Pye, Tomas Ahern, Terence W O’Neill, György Bartfai, Felipe F Casanueva, Mario Maggi, Gianni Forti, Robert D Alston, Aleksander Giwercman, Thang S Han, Krzysztof Kula, Michael E J Lean, Margus Punab, Neil Pendleton, Brian G Keevil, Dirk Vanderschueren, Martin K Rutter, Gindo Tampubolon, Royston Goodacre, Frederick C W Wu, and for the EMAS Group

Context

The androgen receptor (AR) gene exon 1 CAG repeat length has been proposed to be a determinant of between-individual variations in androgen action in target tissues, which might regulate phenotypic differences of human ageing. However, findings on its phenotypic effects are inconclusive.

Objective

To assess whether the AR CAG repeat length is associated with longitudinal changes in endpoints that are influenced by testosterone (T) levels in middle-aged and elderly European men.

Design

Multinational European observational prospective cohort study.

Participants

A total of 1887 men (mean ± s.d. age: 63 ± 11 years; median follow up: 4.3 years) from centres of eight European countries comprised the analysis sample after exclusion of those with diagnosed diseases of the hypothalamic–pituitary–testicular (HPT) axis.

Main outcome measures

Longitudinal associations between the AR CAG repeat and changes in androgen-sensitive endpoints (ASEs) and medical conditions were assessed using regression analysis adjusting for age and centre. The AR CAG repeat length was treated as both a continuous and a categorical (6–20; 21–23; 24–39 repeats) predictor. Additional analysis investigated whether results were independent of baseline T or oestradiol (E2) levels.

Results

The AR CAG repeat, when used as a continuous or a categorical predictor, was not associated with longitudinal changes in ASEs or medical conditions after adjustments. These results were independent of T and E2 levels.

Conclusion

Within a 4-year time frame, variations in the AR CAG repeat do not contribute to the rate of phenotypic ageing, over and above, which might be associated with the age-related decline in T levels.