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Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males.

ABSTRACT: Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex assembly. Lower doses of the FLAP inhibitor MK886 were required to reduce LTB4 levels in exudates of female versus male mice and rats. Following platelet-activating factor-induced shock, MK886 increased survival exclusively in female mice, and this effect was abolished by testosterone administration. FLAP inhibitors and the novel-type 5-LO inhibitors licofelone and sulindac sulfide exhibited higher potencies in human blood from females, and bioactive 5-LO/FLAP complexes were formed in female, but not male, human and murine leukocytes. Supplementation of female blood or leukocytes with 5?-dihydrotestosterone abolished the observed sex differences. Our data suggest that females may benefit from anti-LT therapy to a greater extent than males, prompting consideration of sex issues in LT modifier development.

SUBMITTER: Pace S

PROVIDER: S-EPMC5531400 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males.

Pace Simona S Pergola Carlo C Dehm Friederike F Rossi Antonietta A Gerstmeier Jana J Troisi Fabiana F Pein Helmut H Schaible Anja M AM Weinigel Christina C Rummler Silke S Northoff Hinnak H Laufer Stefan S Maier Thorsten J TJ Rådmark Olof O Samuelsson Bengt B Koeberle Andreas A Sautebin Lidia L Werz Oliver O

The Journal of clinical investigation 20170724 8

Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex ...[more]

PMID: 28737505

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Project description:Health differences between sexes are relatively well recognized, though less is known about the specificity of women's and men's health responsiveness to medical care. Applying data from Polish regions, this study identifies sex-based differences in medical care efficiency and investigates the reasons for these disparities in the gender bias context.The study estimates sex-specific health production functions for regional data from Poland (1999-2013). Using panel-data regression, male and female life expectancies at ages 0, 15, 30, 45, 60 and 65 are regressed on a set of socioeconomic factors, with the primary interest in medical care proxied by doctor density.The results show that in Poland the association between life expectancy and doctor density was positive for both men and women; however, the coefficients for medical care were insignificant for those at birth and at the age of 30 for both sexes. The magnitude of health care for longevity was higher for men comparing to women at every age, though the difference between sexes was not statistically significant. The sex-based disparities in medical care efficiency were more pronounced at younger ages and they diminished with age. The inspection of data on the health system in Poland shows that male patients seemed to be in an advantageous position: the mean reimbursement per service for men was higher in most medical care areas; men reported less problems with access to health care; and their mortality trend exhibited more favorable evolution over time. Additionally, the association between other socioeconomic factors and health also differed across sexes, and several of these factors were more important for life expectancy than health care.Polish medical care suffers from gender bias, which possibly makes men more responsive to medical care. The disparities in the operation of medical care in Poland should be challenged to achieve more equal access to services between sexes and possibly to gain more health from the treatment of female patients.

Dataset Information

Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males.

Publications

Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males.

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