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A Unique Androgen Excess Signature in Idiopathic Intracranial Hypertension Is Linked to Cerebrospinal Fluid Dynamics

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A Unique Androgen Excess Signature in Idiopathic Intracranial Hypertension Is Linked to Cerebrospinal Fluid Dynamics A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics Michael W. O'Reilly, … , Wiebke Arlt, Alexandra J. Sinclair JCI Insight. 2019. https://doi.org/10.1172/jci.insight.125348. Research In-Press Preview Endocrinology Neuroscience Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison to sex-, body mass index- and age- matched control groups with either simple obesity and PCOS, i.e. obesity and androgen excess. IIH women showed a pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum testosterone, and increased CSF testosterone and androstenedione. Human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We show that in a rat choroid plexus cell line testosterone significantly enhanced the activity of Na+/K+ ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in IIH. Find the latest version: https://jci.me/125348/pdf 1 A unique androgen excess signature in idiopathic intracranial hypertension is linked to 2 cerebrospinal fluid dynamics 3 Michael W. O’Reilly1,2*, Connar S. J. Westgate1*, Catherine Hornby1*, Hannah Botfield1,2*, Angela E. 4 Taylor1,2, Keira Markey1,2,3, James L. Mitchell1,2,3, William J. Scotton1,2,3, Susan P. Mollan4, Andreas 5 Yiangou1,2,3, Carl Jenkinson1, Lorna C. Gilligan1, Mark Sherlock5, James Gibney5, Jeremy W. 6 Tomlinson6, Gareth G. Lavery1,2, David J. Hodson1,2,7, Wiebke Arlt1,2, Alexandra J. Sinclair1,2,3. 7 *Contributed equally to this work 8 1. Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, 9 Birmingham, B15 2TT, UK 10 2. Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Edgbaston, 11 Birmingham, B15 2TH, UK 12 3. Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, B15 2TH, 13 Birmingham, UK 14 4. Birmingham Neuro-Ophthalmology Unit, Ophthalmology Department, University Hospitals 15 Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK 16 5. Department of Endocrinology and Diabetes Mellitus, Tallaght Hospital, Tallaght, Dubin, 17 Republic of Ireland 18 6. Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Biomedical Research 19 Centre, University of Oxford, Churchill Hospital, Oxford, UK, OX3 7LE, UK 20 7. Centre for Membrane Proteins and Receptors (COMPARE), University of Birmingham, and 21 University if Warwick, Birmingham, B15 2TT, UK 22 Abbreviated title: Androgen excess in IIH 23 Key words: Idiopathic intracranial hypertension, pathogenesis, androgen excess, 24 Word count: 5,278 25 Number of figures: 3 Number of tables: 1 26 Supplementary Information: 1 figure; 2 tables 1 27 Correspondence: 28 Dr. Alexandra Sinclair 29 Institute of Metabolism and Systems Research, 30 University of Birmingham, 31 Edgbaston, Birmingham 32 B15 2TT, UK 33 Phone: +441214158586 Email: [email protected] 34 Creative Commons CC-BY licence required as per funding bodies – MRC/NIHR/WT 35 Conflict of interest statement 36 The authors declare that no conflict of interest exists. 37 Abstract 38 Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated 39 intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to 40 polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In 41 this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen 42 metabolome in women with IIH in comparison to sex-, body mass index- and age-matched control 43 groups with either simple obesity and PCOS, i.e. obesity and androgen excess. IIH women showed a 44 pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum 45 testosterone, and increased CSF testosterone and androstenedione. Human choroid plexus expressed 46 the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We 47 show that in a rat choroid plexus cell line testosterone significantly enhanced the activity of Na+/K+ 48 ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of 49 androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid 50 plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in 51 IIH. 2 52 INTRODUCTION 53 Idiopathic intracranial hypertension (IIH) is a chronic and disabling condition characterized by 54 elevated intracranial pressure (ICP) (1). Patients have reduced quality of life due to chronic headaches 55 and papilledema-induced visual loss (permanent in 25% patients) (2, 3). Predominantly occurring in 56 areas of socioeconomic deprivation, IIH incidence is rising rapidly in line with the global epidemic of 57 obesity (2 per 100,000 in 2002 to 5 per 100,000 in 2016), driving escalating healthcare costs (predicted 58 at £450 Million per year by 2030) (4). IIH is overwhelmingly a disease of obese women of reproductive 59 age (5, 6), and endocrine disturbances have been hypothesized to play a pathogenic role (7, 8). 60 However, IIH etiology remains unexplained (3); identifying the cause of IIH has been determined as 61 the most important research questions by IIH patients in a recent research priority setting exercise (3). 62 IIH shares phenotypic characteristics with polycystic ovary syndrome (PCOS), in which 63 androgen excess is a defining feature (9). Studies have suggested that the prevalence of PCOS is 64 increased in IIH, as compared to the background population (10, 11), and case reports have described 65 the onset of IIH in patients receiving androgen treatment when undergoing female-to-male gender 66 reassignment (12). Hyperandrogenism has been identified in younger onset cases of IIH (13). However, 67 the androgen phenotype of women with IIH has not been studied in detail or compared to the androgen 68 profile in PCOS. Androgen receptors are noted in the choroid plexus (14, 15), but there are no 69 mechanistic studies examining their potential impact on cerebrospinal fluid (CSF) secretion. 70 We aimed to delineate the androgen phenotype of women with active IIH, and to explore the 71 potential role of androgens in disease pathogenesis. To this end, we have performed complementary in 72 vivo and ex vivo investigations, comprehensively examining the androgen metabolome in serum, urine 73 and CSF in a large cohort of women with active IIH (papilledema and lumbar puncture pressure >25 74 cm CSF on the day of sample collection) compared to sex-, age- and BMI-matched women with PCOS 75 and simple obesity. We used state-of-the-art mass spectrometry-based analysis and employed cell 76 models to investigate the functional role of androgens in CSF secretion. 3 77 RESULTS 78 Women with IIH have a distinct androgen excess profile compared to PCOS and simple obesity 79 Age and BMI were not significantly different between the three groups comprising women with 80 IIH (n=70), simple obesity (n=40), and PCOS (n=60) (Table 1). We measured serum androgens by 81 liquid chromatography-tandem mass spectrometry (LC-MS/MS) (Table 1, Figure 1). Serum 82 concentrations of the active androgen testosterone (Figure 1B) were significantly higher in patients 83 with IIH compared to controls with PCOS and simple obesity (all p<0.001). Conversely, the androgen 84 precursor androstenedione (Figure 1C) was significantly lower in IIH than in PCOS (p<0.001) and 85 obese controls (p<0.05). In keeping with previous studies, serum androstenedione was higher in PCOS 86 than in obese controls (p<0.01) and IIH (p<0.001). 11-oxygenated androgens are adrenal-derived and 87 have recently been shown to be the major contributor to androgen excess in PCOS (16), therefore, we 88 also determined their concentrations. Serum concentrations of the 11-oxygenated androgen precursors 89 11-hydroxyandrostenedione (11OH4, Figure 1F) and 11-ketoandrostenedione (11KA4, Figure 1G) 90 were only increased in PCOS (all p<0.001) compared to IIH and obese controls. 91 Systemic steroid metabolism in 24-h urine samples was profiled using gas chromatography- 92 mass spectrometry (GC-MS) in the three study groups (Table 1 and Figure 1H-I). The ratios of 93 androsterone/etiocholanolone (An/Et) and 5α-tetrahydrocortisol/tetrahydrocortisol (5α-THF/THF) 94 determine net systemic 5α-reductase activity, an important reaction in androgen activation (17), which 95 was significantly increased in IIH as compared to PCOS and obese controls (p<0.05). 96 Active androgens are elevated in CSF from women with IIH compared to controls 97 We measured CSF androgen concentrations in 55 IIH women, 19 healthy volunteer controls 98 with obesity and no known comorbidities, and 31 lean controls (indications for lumbar puncture: 99 headache n=9, demyelination n=6, cerebrovascular disease n=3, normal investigations
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