CYP3A7*1C allele is associated with reduced levels of 2-hydroxylation pathway oestrogen metabolites.

BACKGROUND: Endogenous sex hormones are well-established risk factors for breast cancer; the contribution of specific oestrogen metabolites (EMs) and/or ratios of specific EMs is less clear. We have previously identified a CYP3A7*1C allele that is associated with lower urinary oestrone (E1) levels in premenopausal women. The purpose of this analysis was to determine whether this allele was associated with specific pathway EMs. METHODS: We measured successfully 12 EMs in mid-follicular phase urine samples from 30 CYP3A7*1C carriers and 30 non-carriers using HPLC-MS/MS. RESULTS: In addition to having lower urinary E1 levels, CYP3A7*1C carriers had significantly lower levels of four of the 2-hydroxylation pathway EMs that we measured (2-hydroxyestrone, P=1.1 × 10-12; 2-hydroxyestradiol, P=2.7 × 10-7; 2-methoxyestrone, P=1.9 × 10-12; and 2-methoxyestradiol, P=0.0009). By contrast, 16α-hydroxylation pathway EMs were slightly higher in carriers and significantly so for 17-epiestriol (P=0.002). CONCLUSIONS: The CYP3A7*1C allele is associated with a lower urinary E1 levels, a more pronounced reduction in 2-hydroxylation pathway EMs and a lower ratio of 2-hydroxylation:16α-hydroxylation EMs in premenopausal women. To further characterise the association between parent oestrogens, EMs and subsequent risk of breast cancer, characterisation of additional genetic variants that influence oestrogen metabolism and large prospective studies of a broad spectrum of EMs will be required.

Predicted endurance times during overhead work: influences of duty cycle and tool mass estimated using perceived discomfort.

A need for overhead work remains in several industries and such work is an important risk factor for shoulder musculoskeletal problems. In this study, we evaluated the effects of duty cycle and tool mass on endurance times during overhead work. A psychophysical approach was used, via a new methodology that was implemented to more efficiently estimate endurance times (rather than through direct measurements). Participants performed a simulated overhead task in specified combinations of tool mass and duty cycle. Both duty cycle and tool mass have substantial effects on the development of fatigue and estimated endurance times, though the former was more substantial and an interactive effect was evident. Gender differences were not substantial, except when using the largest tool mass. We recommend that, for two-hour periods of overhead work, tool masses greater than 1.25 kg should be avoided, as should duty cycles greater than 50%. Practitioner Summary: The current results may facilitate enhanced design and evaluation of overhead work tasks. In addition, the new estimation approach that was employed may enhance the efficiency of future studies using a psychophysical approach (ie using extrapolation of patterns of reported discomfort to predict longer term outcomes).

Fatigue during prolonged intermittent overhead work: reliability of measures and effects of working height.

Shoulder pain is prevalent among industrial workers and existing evidence supports that overhead work is an important specific risk factor. Existing guidelines are limited, with overhead work typically recommended to be avoided, and research on overhead work has been mixed in terms of the effects of increasing arm reach. A laboratory-based simulation of overhead work was conducted, at three working heights, in order to facilitate improved guidelines and to identify potential non-linear effects of overhead work height. Several indicators of shoulder fatigue served as outcome measures and a preliminary study was performed to assess the reliability of several of these measures. Fatigue measures based on electromyography (EMG) generally had low reliability, whereas excellent reliability was exhibited for ratings of perceived discomfort (RPD). Consistent with this, no effects of overhead work height were found on EMG-based measures, yet clear non-linear effects were found on RPD and task performance. The source of the effects of work height appeared to be related to a combination of muscle activation levels and demands on precision/control at the highest location. These results support the utility of subjective measures for relatively low-level intermittent exertions and demonstrate increasingly detrimental fatigue and performance effects at extremes in reach during overhead work.