Ibuprofen Reduces Testosterone Level in Women With Polycystic Ovary Syndrome

Discussion

The present study demonstrates that a short 3-week course of a nonsteroidal anti-inflammatory agent, ibuprofen, led to a statistically significant reduction of circulating testosterone level in women with PCOS. This observation sheds new light on the understanding of the mechanism regulating androgen production and may provide the basis for a search for new therapeutic approaches aimed at control of hyperandrogenism. We are not aware of previous publications describing the effects of nonsteroidal anti-inflammatory on the reproductive aspects of female physiology; however, a previous study in men revealed that ibuprofen administration led to "compensated hypogonadism".^[22] In that study, LH and ibuprofen plasma levels were positively correlated and the ratio of testosterone to LH was reduced.

Current concepts describing the regulation of ovarian androgen production focus on direct actions of LH on ovarian theca cells resulting in upregulated expression of key enzymes, including Cyp11a1 and Cyp17a1.^[28–30] Another well-recognized endocrine stimulator of androgen synthesis is insulin either acting alone or in synergy with LH.^[31,32] In the present study, decline of testosterone level following ibuprofen treatment was not associated with statistically significant changes in LH or insulin levels, suggesting that ibuprofen actions are not mediated by these hormones and may be due to direct actions at the level of the ovary. Indeed, in our previous experiments on rat theca-interstitial cells, we found that ibuprofen profoundly reduces androgen production and inhibits RNA expression of Cyp11a1 and Cyp17a1.^[21]

Ibuprofen is a nonselective inhibitor of cyclooxygenases COX1 and COX 2, the enzymes responsible for conversion of arachidonic acid to active prostaglandins, including proinflammatory prostaglandin E₂ (PGE2), an important paracrine mediator in the ovary. Indeed, granulosa cells of women with PCOS produce and release greater amounts of PGE2 than cells from women without PCOS.^[33] In animal studies, PGE2 was shown to stimulate testosterone production.^[28] In view of the aforementioned considerations and the present findings, we hypothesize that ibuprofen directly inhibits ovarian PGE2 production and hence reduces androgen synthesis. In view of the side effects of ibuprofen, its long-term use in hyperandrogenic patients cannot be recommended. Furthermore, since the process of ovulation involves the activation of inflammatory pathways,^[34] the administration of nonsteroidal anti-inflammatory drugs should be avoided in women desiring ovulation. However, the present findings point to the potential for novel treatments of excessive androgen production by the development of novel treatments targeting inflammation, or possibly selective inhibition of production and/or action of PGE2.

Another potentially clinically relevant observation is the relationship of ISI with the response to ibuprofen treatment (see Table 3), whereby women with the greatest insulin sensitivity experienced a greater decline of testosterone. In other words, those with insulin resistance, and hence compensatory hyperinsulinemia, were less likely to respond to ibuprofen, suggesting that insulin-mediated androgen synthesis is less sensitive to inhibition of proinflammatory pathways.

The present study, while presenting interesting findings, has notable limitations including a small number of relatively young participants with, on average, only modestly elevated BMI. Consequently, further larger clinical trials on more diverse populations of women with PCOS are warranted. In summary, this pilot study supports the concept that hyperandrogenism may be reduced by the suppression of proinflammatory pathways.

J Endo Soc. 2022;6(10) © 2022 Endocrine Society