Cerebrospinal fluid sex steroid excess in newly diagnosed patients with idiopathic intracranial hypertension activates choroid plexus

Abstract Background Idiopathic intracranial hypertension (IIH) is a neurometabolic disorder most commonly affecting young females with obesity. The disease presents with daily headaches and papilledema caused by raised intracranial pressure (ICP). Although hormonal dysfunction has been implicated in IIH, the connection between altered steroid hormones and choroid plexus (CP) physiology is unclear. The objective of this translational study was to define the steroid hormone profile in newly diagnosed, treatment naïve patients with IIH and identify the influence of steroid hormones on CP functionality. Methods A case-control study of prospectively recruited cohort of female patients with newly diagnosed treatment naïve IIH ( n = 56) and age, sex and body mass index matched healthy controls ( n = 34) had comprehensive steroid profiling of paired serum and cerebrospinal fluid (CSF) via liquid chromatography tandem mass-spectrometry, assessing 18 steroids. Steroid profiles in 10 patients in remission, with matching samples at time of diagnosis, were also assessed. Complementary preclinical studies in rat and mice were performed to examine the effects of sex steroid hormones on CP function. In CP, mRNA-sequencing and calcium dynamics were assessed after sex steroid hormone exposure. Results Patients displayed a distinct steroid profile, with six and three differential steroids in the CSF and serum, respectively. The progestins, pregnenolone (q < 0.01) and progesterone (q < 0.05), as well as the androgens testosterone (q < 0.01) and dehydroepiandrosterone-sulphate (q < 0.001), were higher in the CSF of patients compared to controls. In the serum, progesterone (q < 0.01) was higher, with the androgens, dehydroepiandrosterone (q < 0.01) and dihydrotestosterone (q < 0.001) lower. At remission, CSF pregnenolone (q < 0.05) and testosterone (q < 0.05) normalized. Progesterone ( P < 0.0001 ) , and testosterone ( P < 0.0001) increased intracellular calcium levels. Conclusions We demonstrate profound steroid hormone deviation in patients where steroid dysfunction normalizes at remission. Our findings suggest that progesterone and testosterone can activate CP. This potential link between steroid hormones and CP dynamics could influence CSF secretion and contribute to a raised intracranial pressure, making it an interesting future study target in IIH pathophysiology.