Danish Headache Center, Department of Neurology, Glostrup Research Institute, Rigshospitalet-Glostrup, University of Copenhagen, Denmark; Translational Research Centre, Rigshospitalet, Denmark.
Danish Headache Center, Department of Neurology, Glostrup Research Institute, Rigshospitalet-Glostrup, University of Copenhagen, Denmark; Translational Research Centre, Rigshospitalet, Denmark.
Toxicol Appl Pharmacol. 2024 May;486:116919. doi: 10.1016/j.taap.2024.116919. Epub 2024 Apr 3.
Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues.
Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA.
Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands.
These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.
特发性颅内高压（IIH）是一种以颅内压升高为特征的疾病，是一种年轻女性的疾病。一线药物治疗包括乙酰唑胺和托吡酯，鉴于 IIH 患者的性质和这些药物的给药方案，评估它们对内分泌系统的影响很重要。我们旨在评估乙酰唑胺和托吡酯对相关内分泌组织中类固醇谱的影响。
雌性 Sprague Dawley 大鼠通过口服灌胃接受慢性临床等效剂量的乙酰唑胺或托吡酯，并在发情期处死。通过定量靶向 LC-MS/MS 评估侧脑室 CP、第四脑室 CP、CSF、血清、子宫角和子宫底、卵巢、肾上腺和垂体中组织特异性类固醇谱。我们通过 ELISA 测定配对血清中的黄体生成素（LH）和卵泡刺激素（FSH）水平。
托吡酯增加了侧脉络丛中的雌二醇浓度并降低了 DHEA 的浓度。此外，它降低了垂体中的雄烯二酮浓度。托吡酯增加了血清 LH。乙酰唑胺降低了血清和子宫底的孕酮水平，并增加了肾上腺的皮质甾醇水平。
这些结果表明，乙酰唑胺和托吡酯在大鼠中均具有内分泌干扰作用。托吡酯主要针对脉络丛和垂体，而乙酰唑胺具有更广泛的全身作用。此外，托吡酯主要靶向性激素，而乙酰唑胺广泛影响所有类别的激素。在人类中尚未记录到类似的影响，但这些令人担忧的发现需要进一步研究。
