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Parallel Diurnal Fluctuation of Testosterone, Androstenedione

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Parallel Diurnal Fluctuation of Testosterone, Androstenedione Clin Chem Lab Med 2017; 55(9): 1315–1323 Marco Mezzullo, Alessia Fazzini, Alessandra Gambineri, Guido Di Dalmazia, Roberta Mazza, Carla Pelusi, Valentina Vicennati, Renato Pasquali, Uberto Pagotto and Flaminia Fanelli* Parallel diurnal fluctuation of testosterone, androstenedione, dehydroepiandrosterone and 17OHprogesterone as assessed in serum and saliva: validation of a novel liquid chromatography-tandem mass spectrometry method for salivary steroid profiling DOI 10.1515/cclm-2016-0805 by a four paired collection protocol (8 am, 12 am, 4 pm and Received September 7, 2016; accepted November 22, 2016; 8 pm) in 19 healthy subjects. previously published online January 11, 2017 Results: The assay allowed the quantitation of T, A, DHEA Abstract and 17OHP down to 3.40, 6.81, 271.0 and 23.7 pmol/L, respectively, with accuracy between 83.0 and 106.1% for Background: Salivary androgen testing represents a valu- all analytes. A parallel diurnal rhythm in saliva and serum able source of biological information. However, the proper was observed for all androgens, with values decreasing measurement of such low levels is challenging for direct from the morning to the evening time points. Salivary immunoassays, lacking adequate accuracy. In the last few androgen levels revealed a high linear correlation with years, many conflicting findings reporting low correlation serum counterparts in both sexes (T: R > 0.85; A: R > 0.90; with the serum counterparts have hampered the clinical DHEA: R > 0.73 and 17OHP: R > 0.89; p < 0.0001 for all). application of salivary androgen testing. Liquid chroma- Conclusions: Our LC-MS/MS method allowed a sensitive tography-tandem mass spectrometry (LC-MS/MS) makes it evaluation of androgen salivary levels and represents an possible to overcome previous analytical limits, providing optimal technique to explore the relevance of a compre- new insights in endocrinology practice. hensive androgen profile as measured in saliva for the Methods: Salivary testosterone (T), androstenedione (A), study of androgen secretion modulation and activity in dehydroepiandrosterone (DHEA) and 17OHprogesterone physiologic and pathologic states. (17OHP) were extracted from 500 µL of saliva, separated in Keywords: androstenedione; dehydroepiandrosterone 9.5 min LC-gradient and detected by positive electrospray (DHEA); liquid chromatography-tandem mass spectro- ionization – multiple reaction monitoring. The diurnal metry; 17OHProgesterone; saliva; testosterone. variation of salivary and serum androgens was described aPresent address: Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany Introduction *Corresponding author: Flaminia Fanelli, PhD, Endocrinology Unit, Department of Medical and Surgical Sciences, Centre for Applied Androgens are key regulators of many physiologic func- Biomedical Research (C.R.B.A.), S. Orsola-Malpighi Hospital, Alma tions and their measurement represents an essential Mater University of Bologna, via Massarenti 9 – 40138 Bologna, Italy, Tel.: +390512143950, E-mail: [email protected]. diagnostic step in clinical practice. Serum testosterone http://orcid.org/0000-0003-2601-2694 (T) level has long been used as a diagnostic parameter Marco Mezzullo, Alessia Fazzini, Alessandra Gambineri, Guido Di both in male and female disorders. In males, total T frac- Dalmazi, Roberta Mazza, Carla Pelusi, Valentina Vicennati, Renato tion is strictly associated with hypogonadic states [1] and Endocrinology Unit, Department Pasquali and Uberto Pagotto: with age-related metabolic impairment [2]. Though a diag- of Medical and Surgical Sciences, Centre for Applied Biomedical Research (C.R.B.A.), S. Orsola-Malpighi Hospital, Alma Mater nostic cut-off of 12.1 nmol/L for serum T insufficiency is University of Bologna, Bologna, Italy. largely accepted [1], considerable heterogeneity has been http://orcid.org/0000-0001-6748-3041 (M. Mezzullo) described in the association between T levels and clinical 1316 Mezzullo et al.: Analytical and biological validation of a LC-MS/MS method for salivary androgen profiling presentations, mostly explained by the intra- and inter- quantitation, LC-MS/MS represents the optimal technique individual variability in sex hormone binding globulin to explore the relevance of a comprehensive androgen levels [1]. Moreover, co-morbidities or concurring condi- profile as measured in saliva for the study of androgen tions such as aging, obesity, diabetes, hyperthyroidism, secretion modulation and activity. estrogen and glucocorticoid treatment, alter the propor- In this paper, we developed and validated a LC-MS/ tion between total and free T fraction, making the former MS method dedicated to the assessment of salivary T, A, a poor indicator of androgen activity. In females, elevated DHEA and 17OHP. We also provided a biological valida- serum T levels can be associated with classic and non- tion by investigating the relationship between salivary classic adrenal hyperplasia, Cushing syndrome, ovarian and circulating levels along the daytime both in male and and adrenal androgen secreting tumors, ovarian hyper- female healthy adults. thecosis, severe insulin resistance and chiefly to the var- iegated frame of the polycystic ovary syndrome (PCOS) [3]. Recent evidence contributed to a reconsideration of the relevance of total T testing as a biomarker of androgen Materials and methods imbalance, suggesting an important and specific role for Chemicals serum free T [4] and for other androgens such as andros- tenedione (A) [5] and dihydrotestosterone (DHT) [6]. The Gradient-grade methanol, N-hexane, ethyl-acetate, acetonitrile, gold standard methodologies for a reliable assessment of formic acid and granular food-grade activated charcoal were pur- circulating free hormones are the equilibrium dialysis and chased from Merck (Darmstadt, Germany). Ultrapure water was the ultrafiltration combined with isotopic dilution mass obtained by a MilliQ Gradient A10 System (Merck). T, A, DHEA and spectrometry [7], but both techniques are time consum- 17OHP pure standards were from Steraloids (Newport, RI, USA), testosterone-[2,2,4,6,6-2H ] (deuterium content 98.7%, d5-T) and ing and impracticable in a routine setting. Immunoassays 5 17OHProgesterone-[2,2,4,6,6,21,21,21-2H ] (deuterium content 98.7%, based on the analog displacement fit the high-throughput 8 d8-17OHP) were from CDN Isotopes (Pointe-Claire, Canada), andros- necessity of large clinical laboratories, although they have 2 tenedione-[2,2,4,6,6- H5] (deuterium content 98%, d5-A) was pur- been shown to be fairly inaccurate [8]. For these reasons, chased from Cambridge Isotope Laboratories (Tewksbury, MA, USA), 2 free T is usually calculated by the Vermeulen formula [9]. DHEA-[2,2,3,4,4,6- H6] (deuterium content 97.0%, d6-DHEA) was from Salivary hormone testing has often been postulated Sigma-Aldrich (St. Louis, MO, USA). as a valid alternative to serum free fraction measurement [10]; however, sensitivity and specificity limitations of available immunoassays have hampered the diffusion of Specimens salivary T testing in clinical settings [11], mostly because of the derived lack of harmonization among different assays Nineteen healthy drug free, normal weight (body mass index range: 18.0–25.0 kg/m2) volunteers, twelve males (25–65 years) and seven results [12–15]. As for female hyperandrogenism, specific- females (30–45 years) were recruited from the hospital staff after giv- ity and sensitivity issues explain the conflicting findings ing their informed consent. The study was approved by the Local Ethics on the subsistence of a correlation between very low sali- Committee. Exclusion criteria were the presence of any oral inflamma- vary and circulating T [16, 17]. To date, only a few studies tory processes with or without evident bleeding and/or any dental care focusing on salivary T testing in females have been con- treatment within 30 days before the collection. Subjects were asked to avoid drinking, eating and brushing their teeth in the 30 min before ducted by using the liquid chromatography-tandem mass saliva collection. Subjects underwent a paired blood and saliva collec- spectrometry (LC-MS/MS) technique [18, 19]. The monitor- tion at 8 am, 12 am, 4 pm and 8 pm on a working day. The lunch time was ing of salivary A and 17OHProgesterone (17OHP) levels was scheduled between 12:30 am and 1 pm. Blood was withdrawn in Vacu- shown to be useful in the evaluation of hydrocortisone ette Z serum beads clot activator tubes (Greiner Bio-One, Kremsmun- replacement therapy for congenital adrenal hyperplasia ster, Germany), allowed to settle for 20 min and centrifuged (2000 g, (CAH), both in pediatric [20] and in adult patients [21, 22]. 10 min, room temperature (RT). About 2 mL of saliva were collected by direct spitting in 15 mL polypropylene tubes (Sarstedt, Nümbrecht, Ger- Salivary dehydroepiandrosterone (DHEA) potential was many). Samples were transferred to 1.5 mL tubes (Eppendorf, Hamburg, explored in the monitoring of aging and stress [23]. With Germany) and stored at − 80 °C until analysis. the exception of T, the relationship between salivary A, DHEA and 17OHP levels and the serum counterparts has not been investigated using LC-MS/MS. In particular, it Calibrators and in house quality control (QCs) has not been clarified whether salivary levels duly reflect the circadian fluctuation observed in serum androgens Gravimetrically determined stock solutions were prepared in metha- [24, 25]. By allowing sensitive and selective multi-analyte
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