Abstract and Introduction
Context: Hyperandrogenism is a central feature of polycystic ovary syndrome (PCOS). In vitro studies have demonstrated that inflammatory stimuli promote whereas ibuprofen inhibits androgen production by ovarian theca-interstitial cells.
Objective: This work aimed to determine the effects of nonselective inhibitor of cyclooxygenases COX-1 and COX-2 on testosterone levels.
Methods: A prospective pilot study took place in an academic hospital of women with PCOS defined according to Rotterdam criteria (N = 20). Evaluations were taken at baseline and after 3 weeks of ibuprofen administration (400 mg twice a day or 400 mg 3 times a day, respectively, in women with weight < and ≥ 70 kg). The main outcome measure was total serum testosterone.
Results: Ibuprofen administration was associated with a decline of total testosterone from 0.75 ± 0.06 ng/mL to 0.59 ± 0.05 ng/mL (P = .008). There was no statistically significant change in the levels of other relevant hormones including dehydroepiandrosterone sulfate, gonadotropins, and insulin. Multiple regression analysis identified the greatest decline of testosterone was independently predicted by baseline testosterone level (P = .004) and by baseline insulin sensitivity index (P = .03).
Conclusion: Nonselective inhibition of COX-1 and COX-2 leads to selective reduction of testosterone consistent with direct inhibitory effect on ovarian steroidogenesis.
Polycystic ovary syndrome (PCOS), the most common endocrine disorder among women of reproductive age, is associated with hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology.[1–4] While the pathophysiology of this syndrome is still poorly understood, the central feature of PCOS is excessive production of androgens by ovarian theca cells. Over the last 2 decades, accumulated evidence has demonstrated that PCOS is associated with low-grade systemic inflammation characterized by increased concentration of leukocytes, C-reactive protein, and several proinflammatory cytokines.[6–10] Our recent studies have revealed that women with PCOS have elevated serum markers of endotoxemia: lipopolysaccharides (LPS) and LPS-binding protein, possibly due to increased gut wall permeability and/or altered gut microbiome.
In vitro experiments indicate that proinflammatory stimuli may contribute to increased synthesis of androgens; indeed, in studies of isolated rat theca-interstitial cells, we found that LPS and interleukin 1β directly stimulate androgen production by increasing expression of the key gene regulating androgen synthesis: Cyp17a1. Furthermore, molecules with pronounced anti-inflammatory properties, such as statins and resveratrol, inhibit expression of Cyp17a1 and reduce androgen production in theca-interstitial cells.[14,15] In clinical trials, statins and resveratrol reduced testosterone levels in women with PCOS.[16–20]
More recently we found that a nonsteroidal anti-inflammatory drug, ibuprofen, inhibited androgen production by rat theca-interstitial cells abrogating stimulatory actions of LPS and interleukin 1β. These effects were observed at a pharmacologic concentration of ibuprofen (0.1 mM; human studies of individuals taking 600 mg of ibuprofen twice a day for 6 weeks).[22,23]
In view of the aforementioned observations, we carried out a pilot trial in women with PCOS evaluating effects of ibuprofen on serum testosterone and other relevant hormones.
J Endo Soc. 2022;6(10) © 2022 Endocrine Society