title: Modeling Testosterone Circadian Rhythm in Hypogonadal Males: Effect of Age and Circannual Variations.
abstract: The objective of this study was to characterize the baseline circadian rhythm of testosterone levels in hypogonadal men. A total of 859 baseline profiles of testosterone from hypogonadal men were included in this analysis. The circadian rhythm of the testosterone was described by a stretched cosine function. Model parameters were estimated using NONMEM(®) 7.3. The effect of different covariates on the testosterone levels was investigated. Model evaluation was performed using non-parametric bootstrap and predictive checks. A stretched cosine function deeply improved the data goodness of fit compared to the standard trigonometric function (p < 0.001; ΔOFV = -204). The effect of the age and the semester, defined as winter and spring versus summer and fall, were significantly associated with the baseline levels of testosterone (p < 0.001, ΔOFV = -15.6, and p < 0.001, ΔOFV = -47.0). Model evaluation procedures such as diagnostic plots, visual predictive check, and non-parametric bootstrap evidenced that the proposed stretched cosine function was able to model the time course of the diurnal testosterone levels in hypogonadal males with accuracy and precision. The circadian rhythm of the testosterone levels was better predicted by the proposed stretched cosine function than a standard cosine function. Testosterone levels decreased by 5.74 ng/dL (2.4%) every 10 years and were 19.3 ng/dL (8.1%) higher during winter and spring compared to summer and fall.
authors.affiliation: Université de Montréal, Montréal, Canada.|inVentiv Health Clinical, 5160 Décarie, Montréal, Canada , H3X 2H9.
authors.forename: Mario
authors.initials: M
authors.lastname: González-Sales
authors.affiliation: inVentiv Health Clinical, 5160 Décarie, Montréal, Canada , H3X 2H9. olivier.barriere@inventivhealth.com.
authors.forename: Olivier
authors.initials: O
authors.lastname: Barrière
authors.affiliation: inVentiv Health Clinical, 5160 Décarie, Montréal, Canada , H3X 2H9.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Tremblay
authors.affiliation: Université de Montréal, Montréal, Canada.
authors.forename: Fahima
authors.initials: F
authors.lastname: Nekka
authors.affiliation: inVentiv Health Clinical, 5160 Décarie, Montréal, Canada , H3X 2H9.
authors.forename: Julie
authors.initials: J
authors.lastname: Desrochers
authors.affiliation: inVentiv Health Clinical, 5160 Décarie, Montréal, Canada , H3X 2H9.
authors.forename: Mario
authors.initials: M
authors.lastname: Tanguay
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000097:blood*; D000465:Algorithms; D002940:Circadian Rhythm; D006801:Humans; D007006:Hypogonadism / Q000097:blood*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D012621:Seasons; D012984:Software; D013739:Testosterone / Q000097:blood*; D055815:Young Adult
chemical_list: D013739:Testosterone
keywords: NONMEM®; circadian rhythm; stretched cosine function; testosterone