Overuse of analgesics can affect the fertility biomarker Anti-Müllerian Hormone in females. A translational study.

Background: Medication overuse headache is a prevalent secondary headache due to the overuse of analgesics, mainly over-the-counter analgesics. Over-the-counter analgesics have been associated with disrupted male endocrinology, while the effects on female endocrinology remain nearly unknown. The aim was to understand the effect of long-term analgesic exposure in females with medication overuse headache on Anti-Müllerian hormone, a surrogate measure of female fertility.
Methods: Using a translational approach, an observational prospective clinical study was conducted to determine the effect of withdrawal therapy in females with medication overuse headache on Anti-Müllerian hormone levels, in combination with pre-clinical investigation of primary granulosa cells to understand the effects of analgesics on granulosa cell function.
Results: We included 21 females (mean-age 30.0 years; SD (7.3)) for Anti-Müllerian hormone -measurement. Anti-Müllerian Hormone increased by 21% from baseline (mean 20.1 pmol/L; SD (8.7)) after withdrawal of analgesics ((mean 24.3 pmol/L; SD (12.0)); p  = 0.0023). Exposing primary granulosa cells to analgesics (acetaminophen (100 and 200 µM, n = 9-10) and ibuprofen (150 and 200 µM, n = 12-13)) did not reduce Anti-Müllerian hormone levels. In contrast, de novo DNA synthesis in GCs (n = 6) exposed to acetaminophen was reduced by 78% ( p  = 0.0036) compared to controls, suggesting that cellular proliferation was restricted.
Conclusion: We found that frequent use of over-the-counter analgesics was associated with repressed Anti-Müllerian Hormone levels, likely through disruption of granulosa cell proliferation. Further research is crucial to investigate a potential effect of analgesics on adult female reproductive endocrinology. Trial registration : ClinicalTrials.gov Identifier NCT04090333.
Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.N.C. has received funding from the TrygFoundation. L.N.C. has also given lectures for Novartis, Allergan and TEVA, and has provided consulting advice to Lundbeck. C.R. has received a 12-month scholarship from Novo Nordisk Foundation. R.H.J. received grants from ATI, Lundbeck Foundation, The Medical Society in Copenhagen, Novo Nordisk Foundation, TrygFoundation and University of Copenhagen. R.H.J. has also conducted clinical trials for ATI, Electrocore, and Eli-Lilly; given lectures for Allergan, ATI, Merck, Novartis, Pfizer, and TEVA; has been trustee in International Headache Society, Director of Lifting Thetherden, and current Director of the Danish Headache Center. D.M.K. has received a grant from the Lundbeck Foundation. B.S.N., M.R.P., C.H.L., A.M.K., C.S.J.W., J.V., L.B.J., S.G.K., S.Z. have nothing to declare. The authors declare that all research conducted, its contents and results are free and independent from the funders.