Non Steroidal Anti-inflammatory Drug Use and Levels of Oestrogens and Androgens in Men

Margaret A. Gates; Andre B. Araujo; Susan A. Hall; Gary A. Wittert; John B. McKinlay

Disclosures

Clin Endocrinol. 2012;76(2):272-280. 

In This Article

Discussion

Our results do not provide strong support for an association between prescription or over-the-counter NSAID use and sex steroid hormone levels in men. Individuals who used prescription NSAIDs within 4 weeks prior to blood collection had lower levels of several hormones, when compared to those with no NSAID use, but none of the associations reached statistical significance in analyses of all men combined. However, in stratified analyses, there was evidence of interactions with BMI and physical activity, including significant associations between prescription NSAID use and lower levels of free testosterone, estradiol, free estradiol and estrone among obese men and between prescription NSAID use and lower levels of free testosterone and DHEAS among inactive men. Although our results suggest that prescription NSAID use may affect hormone levels in certain subgroups of men, additional studies are needed to confirm these results and explore potential mechanisms.

To our knowledge, no large, population-based studies have examined associations between NSAID use and sex steroid hormone levels in men. In three studies of analgesic use and hormone levels in postmenopausal women, two studies reported significant associations between use of aspirin or nonaspirin NSAIDs and lower oestrogen levels,[1,2] while the third study reported no association between regular NSAID use and levels of oestrogens or androgens.[21] Several small clinical investigations and one small observational study have examined NSAID use and androgen levels in men. In a study of 12 male athletes, a 10-day course of aspirin treatment was associated with a borderline significant increase in plasma testosterone but no change in DHEAS or free testosterone.[22] In contrast, an observational study of 34 healthy young men reported no association between aspirin use and plasma testosterone.[23] In a study of five sedentary men, treatment with a single 400-mg dose of propyphenazone was associated with decreased urinary excretion of several testosterone metabolites, but no association was observed for treatment with other NSAIDs.[24] Another study of eight healthy young men reported that aspirin inhibited the increase in plasma testosterone levels typically caused by the administration of human chorionic gonadotrophin.[25] These studies suggest a possible association between NSAID use and androgen levels in men but are limited by inconsistent results, small sample sizes and the inclusion of a small number of different NSAIDs and hormones.

In the current analysis, we observed evidence of lower oestrogen levels but no difference in testosterone levels among prescription NSAID users overall and significantly lower levels of both androgens and oestrogens among obese users of prescription NSAIDs. In contrast, aromatase inhibition attributable to NSAID-induced inhibition of COX and prostaglandin E2 would be expected to result in lower oestrogen and higher androgen levels.[26] In a study of 12 severely obese men, weekly treatment with 2·5 mg of the aromatase inhibitor letrozole was associated with increased testosterone and decreased estradiol levels,[27] suggesting that the differences in our results could be due to a mechanism other than aromatase inhibition. The enzyme AKR1C3 preferentially transforms androstenedione to testosterone,[3,28] but interestingly in the prostate appears to inactivate DHT.[29] AKR1C3 also reduces estrone to the more potent oestrogen estradiol and catalyses the production of pro-inflammatory prostaglandins.[3] AKR1C3 expression is elevated in adipose tissue and reduced by weight loss[30] and is strongly inhibited by NSAIDs,[3,31] which may have contributed to our results. The disparate results by obesity status and activity level also could be due to differences in the hormonal profiles, the rate of catabolism of testosterone and estradiol, sensitivity to NSAIDs in certain subgroups of men, or larger amounts of adipose tissue and higher levels of peripheral aromatization in obese and inactive men. However, it is also possible that the associations observed may be due to nonhormonal mechanisms. For example, lower hormone levels among prescription NSAID users, in particular those who are obese or inactive, may be due to confounding by health status or other characteristics of these individuals. There was no evidence of variation in the NSAIDs/hormones association by arthritis history in our analysis, although it is possible that other pre-existing conditions may have influenced both NSAID use and hormone levels. The results for LH and FSH were generally consistent with the expected negative feedback between gonadotrophins and testosterone.

In addition to the potential for uncontrolled confounding, other limitations of our data include the lack of information on the duration, frequency and recency of NSAID use. Although our exposure variables capture NSAID use within the past 4 weeks, use within a few days prior to blood collection may be most relevant for hormone levels. In addition, a relatively small number of men reported current or recent use of prescription NSAIDs, and we were unable to examine associations with different prescription NSAID classes. In our analysis, we observed associations between prescription NSAID use and lower levels of several hormones, particularly among obese and inactive men, but no association with the use of over-the-counter NSAIDs. The lack of an association with over-the-counter NSAID use could be due to differences in the COX inhibitory activity of prescription vs over-the-counter NSAIDs or more frequent use among individuals with an indication for prescription NSAIDs. Further, use of over-the-counter NSAIDs may be reported with less accuracy than prescription NSAIDs. Although medication use was assessed by both self-report and direct observation of medication labels, over-the-counter NSAIDs may be used sporadically and their use may therefore be more difficult to recall. Users of over-the-counter NSAIDs were more likely to report a history of arthritis or cardiovascular disease than nonusers, however, suggesting some degree of reliability of their reporting. The cross-sectional nature of our analysis is also a limitation, as it is impossible to determine the temporal relationship between NSAID use and hormone levels and the potential impact of pre-existing conditions or other factors. We also do not have data on acute illness, which can influence levels of certain hormones. In addition, blood was collected from participants at different times of the day, which may have influenced the results owing to diurnal variation in hormone levels. In sensitivity analyses, the results were essentially unchanged when adjusted for time of blood collection, but the inverse associations between NSAID use and levels of certain hormones appeared to be stronger when restricted to men with blood collection before 10 am. Finally, testosterone levels were assessed by a platform-based immunoassay that is known to underestimate testosterone levels across the range of concentrations in men and women.[32] Such measurement error likely resulted in an underestimate of testosterone levels for both users and nonusers of NSAIDs but little change in the per cent difference for users vs nonusers.

Our analysis also has several strengths, such as the large number of men included, the use of community-based sampling and the racial and socioeconomic diversity of our population. In addition, we have data on multiple hormones of interest and detailed covariate data assessed at the time of blood collection, which allowed us to carefully control for confounding by these variables.

In summary, although we did not observe an association between NSAID use and levels of oestrogens or androgens overall, our results suggest a possible association between prescription NSAID use and hormone levels in obese and inactive men. However, additional research is needed to confirm these results and to explore potential mechanisms. If NSAIDs do in fact modulate hormone levels, this could have a large public health impact owing to the common use of NSAIDs and the high prevalence of potentially hormone-related diseases such as type 2 diabetes,[6] cardiovascular disease[8] and prostate cancer.[5,33,34]

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