Circadian variation in systemic hormone levels in healthy men

Sjöberg, Bertil; Torre, B. de la; Hedman, M.; Falkay, G.; Diczfalusy, E.

doi:10.1007/bf03349304

Cited by 43 publications

(25 citation statements)

References 36 publications

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“…It is well known that in young men androstenedione and testosterone, but not DHEAS, have a circadian rhythm (54,55), although the daily variation in hormone concentration appears to decrease with age (56,57). Because of the high mean age of our population and the large number of subjects, we believe that differences in sampling time did not have a major influence on the results.…”

Section: Dheas Stratummentioning

confidence: 73%

A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women

et al. 2005

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Objective: The origin of oestrogens in men is only partly understood. From infusion studies with radioactively labelled hormones, we know that oestradiol (E2) and oestrone (E1) are either directly secreted by the testes and adrenal glands or peripherally produced from testicular or adrenal androgens. Design and methods: We determined E2, E1, androstenedione, testosterone and dehydroepiandrosterone sulphate (DHEAS) in 292 elderly men and 367 postmenopausal women. We considered postmenopausal women as men without testes, assuming that the postmenopausal ovary is not endocrinologically active and that the testes do not contribute to circulating levels of DHEAS. Subjects were stratified by DHEAS levels to adjust for differences in DHEAS levels between sexes. For men and women separately, mean levels of E2, E1, androstenedione and testosterone were calculated per DHEAS stratum. The relative direct and indirect contributions of the testes to steroid levels in men were calculated by the formula [(C m -C f )/C m ] £ 100%, in which C m and C f represent the mean concentrations of the steroid in men and women respectively. Results: The relative contributions (%) of the testes to hormone levels per DHEAS stratum (, 2, 2-4, 4 -6 and .6 mmol/l) respectively were, for E2, 72%, 60%, 52% and 44%; for E1, 54%, 47%, 35% and 34%; for androstenedione, 14%, 4%, 12% and 0%; and, for testosterone, 88%, 88%, 87% and 83%. Conclusions: We conclude that in elderly men dependent on DHEAS levels, 44-72% of E2 and 34-54% of E1 originate directly or indirectly from the testes.European Journal of Endocrinology 152 261-268

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Section: Dheas Stratummentioning

confidence: 73%

A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women

et al. 2005

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“…8) Furthermore, circadian rhythm in plasma levels of DHT was reported in healthy men: the peak time of DHT occurred in the early evening. 10,11) In fact, some of % DHT levels at 4 h were higher concentrations than baseline DHT levels in spite of administration of TF-505 (Fig. 6).…”

Section: Discussionmentioning

confidence: 90%

Section: (ϫ)-(S )-4-[1-[4-[1-(4-isobutylphenyl)butoxymentioning

confidence: 99%

“…19) The limit of quantification was set at 50 pg tube Ϫ1 with intraand inter-assay coefficients of variation below 20 and 25%, respectively. Taking into account the circadian rhythm-related changes in plasma DHT concentrations, 10,11) values after administration of TF-505 were compared to those at the same times before administration (basal values). Changes in plasma DHT concentrations were expressed as percentages of the basal values.…”

Section: Volunteers and Study Designmentioning

confidence: 99%

“…In addition, there has been reported a circadian rhythm in plasma levels of DHT. 10,11) Therefore, the present study used the E max model with an extended indirect response model by incorporating a circadian rhythm in order to fit the model to the data.Population PK-PD studies and modeling are considered useful in drug development for assessment of efficacy/safety in relation to drug plasma concentrations and defining an optimum dosage regimen in the target population. Many population PK-PD analysis studies have been reported during the development of drugs such as an antineoplastic, 12) an anesthetic, 13) a lactate reducing agent, 14) a platelet inhibitor, 15) a thrombin inhibitor, 16) and a 11-b-hydroxysteroid dehydrogenase inhibitor.…”

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Population Pharmacokinetic-Pharmacodynamic Modeling of TF-505 Using Extension of Indirect Response Model by Incorporating a Circadian Rhythm in Healthy Volunteers

Matsumoto

Fujita

Ishida

et al. 2005

Biological & Pharmaceutical Bulletin

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4-Isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyric acid ,TF-505, is a novel nonsteroidal and non-competitive inhibitor of type I and type II 5a-reductase. 5a-Reductase, a nuclear membrane-bound enzyme, consists of two isozymes. Type I is expressed in extraprostatic tissues such as skin and liver and type II is detected in male accessory sex glands, prostate and liver.2) The physiological function of 5a-reductase is the conversion of testosterone into dihydrotestosterone (DHT). As high activities of 5a-reductases were shown in patients with benign prostate hyperplasia [3][4][5] and a defect of the type II 5a-reductase gene was associated with male pseudohermaphroditism with a small or absent prostate, 6,7) it is considered that 5a-reductases play an important role in the development of benign prostate hyperplasia. Thus, TF-505 has been developed as a therapeutic drug for benign prostatic hyperplasia.We have previously reported the results of tolerability and single-and multiple-dose studies of TF-505 in healthy volunteers. In that study, concentration-effect analysis of TF-505 was also carried out using an indirect response model. However, the modeling was conducted in each group of studies so that the parameters obtained from that model could not reflect those from a population, but a small size of individuals. 8) In the present study, the pharmacokinetic (PK) and pharmacodynamic (PD) data from both single-and multipledose studies were combined to evaluate parameters in the generalized population and retrospective analysis was conducted using mixed-effect modeling (NONMEM). 9) In the process of the modeling, a surrogate marker of the effect of TF-505, an inhibition of plasma DHT levels, tended to increase 4 h after administration of TF-505 in all single-dose studies. In our simulation based on the present model, plasma DHT levels reached to a maximum level in the early evening and declined with time. In addition, there has been reported a circadian rhythm in plasma levels of DHT. 10,11) Therefore, the present study used the E max model with an extended indirect response model by incorporating a circadian rhythm in order to fit the model to the data.Population PK-PD studies and modeling are considered useful in drug development for assessment of efficacy/safety in relation to drug plasma concentrations and defining an optimum dosage regimen in the target population. Many population PK-PD analysis studies have been reported during the development of drugs such as an antineoplastic, 12) an anesthetic, 13) a lactate reducing agent, 14) a platelet inhibitor, 15) a thrombin inhibitor, 16) and a 11-b-hydroxysteroid dehydrogenase inhibitor.17) Although such population approaches in clinical trials are mostly performed on the patient population, some studies were also performed on healthy volunteers in phase I studies.14-17) The aim of the present study was to define the population PK-PD model of TF-505 in an early human study. The parameters thus obtained would more reflect population mean than those obtained from t...

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Endocrinology of Male Infertility and Fertility

Wu¹

1983

Clinical Practice in Urology

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Circadian variation in systemic hormone levels in healthy men

Cited by 43 publications

References 36 publications

A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women

A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women

Population Pharmacokinetic-Pharmacodynamic Modeling of TF-505 Using Extension of Indirect Response Model by Incorporating a Circadian Rhythm in Healthy Volunteers

Endocrinology of Male Infertility and Fertility

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