Elevated Intracranial Pressure Associated With Exogenous Hormonal Therapy Used for Gender Affirmation

Background: Addison disease, corticosteroid withdrawal, and taking synthetic growth hormone have been linked with development of intracranial hypertension, but there is still debate on whether administration of other exogenous hormones plays a role in precipitating elevated pressure. The growing use of hormonal therapy for gender affirmation provides an opportunity to explore this possibility. Methods: All transgender patients taking exogenous hormones for female-to-male (FTM) and male-to-female (MTF) transitions who were diagnosed with intracranial hypertension at Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital and Beth Israel Deaconess Medical Center between August 2014 and November 2018 were included in a retrospective review. Visual acuity, type, and dose of exogenous hormone, visual field testing, clinical exam, results of neuroimaging and lumbar puncture, and treatment modalities were catalogued and analyzed. Results: Six transgender individuals were identified. Five were FTM, with an average hormone treatment time of 18.4 months, and one was MTF who had been treated with hormones for 4 years. The average age of all patients was 23.5 years. The average time between onset of symptoms and presentation was 5 months. Fifty percent of the patients reported pulse-synchronous tinnitus, 83% reported positional headache, 33% reported transient visual obscurations, and 16% reported diplopia. Lumbar punctures performed on 4 of the patients revealed elevated opening pressures and normal cerebrospinal fluid constituents. MRI findings consistent with elevated intracranial pressure (ICP) were present in the other 2 patients in whom lumbar puncture was unsuccessful. Four patients were treated with acetazolamide and one was treated with topiramate, with an average follow-up time of 15.7 months. All patients demonstrated bilateral optic disc swelling, and all maintained normal acuity and color vision. Performance on visual field testing was not significantly affected in any patient. Conclusions: This is the largest reported series to date of gender-transitioning patients with intracranial hypertension, including one novel MTF conversion. These observations warrant further investigation into the possible link of exogenous hormonal therapy and elevated ICP and any mechanisms or confounders underlying this potential association.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Elevated Intracranial Pressure Associated With Exogenous Hormonal Therapy Used for Gender Affirmation Huy V. Nguyen, MD, Aubrey L. Gilbert, MD, PhD, Elizabeth Fortin, MD, Ivana Vodopivec, MD, PhD, Nurhan Torun, MD, Bart K. Chwalisz, MD, Dean M. Cestari, MD, Joseph F. Rizzo III, MD Background: Addison disease, corticosteroid withdrawal, and taking synthetic growth hormone have been linked with development of intracranial hypertension, but there is still debate on whether administration of other exogenous hormones plays a role in precipitating elevated pressure. The growing use of hormonal therapy for gender affirmation provides an opportunity to explore this possibility. Methods: All transgender patients taking exogenous hormones for female-to-male (FTM) and male-to-female (MTF) transitions who were diagnosed with intracranial hypertension at Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital and Beth Israel Deaconess Medical Center between August 2014 and November 2018 were included in a retrospective review. Visual acuity, type, and dose of exogenous hormone, visual field testing, clinical exam, results of neuroimaging and lumbar puncture, and treatment modalities were catalogued and analyzed. Results: Six transgender individuals were identified. Five were FTM, with an average hormone treatment time of 18.4 months, and one was MTF who had been treated with hormones for 4 years. The average age of all patients was 23.5 years. The average time between onset of symptoms and presentation was 5 months. Fifty percent of the patients reported pulse-synchronous tinnitus, 83% reported positional headache, 33% reported transient visual obscurations, and 16% reported diplopia. Lumbar punctures performed on 4 of the patients revealed elevated opening pressures and normal cerebrospinal fluid constituents. MRI findings consistent with elevated intracranial pressure (ICP) were present in the other 2 patients in whom lumbar puncture was unsuccessful. Four patients were treated with acetazolamide and one was treated with topiramate, with an average follow-up time of 15.7 months. All patients demonstrated bilateral optic disc swelling, and all maintained Neuro-Ophthalmology Service, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts. The authors report no conflicts of interest. Address correspondence to Joseph F. Rizzo, MD, NeuroOphthalmology Service, Massachusetts Eye and Ear, Harvard Medical School, 243 Charles St, Boston, MA 02114; E-mail: [e-mail] Nguyen et al: J Neuro-Ophthalmol 2021; 41: 217-223 normal acuity and color vision. Performance on visual field testing was not significantly affected in any patient. Conclusions: This is the largest reported series to date of gender-transitioning patients with intracranial hypertension, including one novel MTF conversion. These observations warrant further investigation into the possible link of exogenous hormonal therapy and elevated ICP and any mechanisms or confounders underlying this potential association. Journal of Neuro-Ophthalmology 2021;41:217–223 doi: 10.1097/WNO.0000000000000926 © 2020 by North American Neuro-Ophthalmology Society T he diagnosis of idiopathic intracranial hypertension (IIH) is based on application of some modification of Dandy’s criteria, which provide evidence of elevated intracranial pressure (ICP) without identification of a secondary cause. Widely accepted secondary causes of elevated ICP include use of tetracycline antibiotics, vitamin A and its analogues, synthetic growth hormone, and withdrawal from corticosteroids. IIH is generally assumed to have a hormonal basis, because the condition is much more prevalent among women and it occurs more commonly among women with polycystic ovarian syndrome (PCOS), a condition in which there is both a hyperestrogen and a hyperandrogen state. Cases of elevated ICP also have been reported among women who receive exogenous hormones for birth control, either as part of an intrauterine device or sub-dermal implant, but this link is not substantiated and is clouded by multiple confounders (1). Five cases have previously been reported of intracranial hypertension occurring in the context of female-to-male (FTM) gender conversion in patients taking exogenous androgens. Although the evidence for intrinsic hormonal imbalance is a compelling risk factor for intracranial hypertension among women, no clear causal relationship with exogenous sex hormones has been 217 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution established to date. The challenge of understanding a possible cause-and-effect relationship between exogenous sex hormones used in gender conversion and intracranial hypertension is partly confounded by the frequent occurrence of weight gain, which is an unequivocal risk factor for IIH. We present 6 cases of intracranial hypertension that developed in the setting of hormone therapy for gender conversion. Our cases, which include both FTM and maleto-female (MTF) transitions, highlight the potential risk for elevated ICP posed by use of exogenous sex hormones. METHODS This retrospective study was approved by the institutional review board of the Massachusetts Eye and Ear. All transgender patients taking exogenous hormones for FTM and MTF transitions who were referred to the NeuroOphthalmology service at Massachusetts Eye and Ear and diagnosed with elevated ICP between August 2014 and November 2018 were reviewed. Table 1 summarizes the findings of the 6 cases, which are discussed in more detail below. All automated (Humphrey) visual fields obtained were deemed to be reliable given that there were fewer than 2/12 fixation losses, and fewer than 11% false positive and false negative responses on any test. Optic disc photographs (Fig. 1) were obtained for all patients except for Patient 3. Patient 1 A 23-year-old patient undergoing FTM gender affirmation was referred for workup of a 3-month history of intermittent binocular horizontal diplopia that was worse at distance. He did not report headaches, pulse-synchronous tinnitus, or transient visual obscurations. He had been taking testosterone over the prior 14 months as part of his gender affirmation. He had no history of vitamin A/ retinoid, tetracycline, steroid, or growth hormone use. He had had a 20-pound weight gain over the prior year, and his body mass index at presentation was 29.05 kg/m2. His examination revealed central visual acuity of 20/20 in both eyes, with normal color vision (Ishihara) and no TABLE 1. Patient characteristics Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Age at presentation 23 29 19 22 23 25 Gender transition FTM FTM FTM FTM FTM MTF Body mass index (kg/m2) 29.1 35.0 31.9 36.1 44.0 Not recorded Time of onset of symptoms to 3 5 7 2 1 12 presentation (months) Follow-up time (months) 9 25 7 2 32 19 Symptoms/Signs Optic disc edema Bilateral Bilateral Bilateral crowding Bilateral Bilateral Bilateral Pulse-synchronous tinnitus No No Yes Yes No Yes Positional headache No Yes Yes Yes Yes Yes Transient visual No Yes No Yes No No obscurations Diplopia Yes No No No No No Risk factors Hormone used (E = estrogen, T T T T T E T = testosterone) Length of hormone use 14 months 2 years 2 years 15 months 15 months 4 years Weight gain 20 lbs in 1 yr No 30 lbs in 1 yr 10 lbs in 1 yr 50 lbs in 2 yrs No Vitamin A use No No No No No No No No D M No No Tetracycline use (D = doxycycline, M = minocycline) Steroid use No No No No No No Retinoid use No No No No No No Examination findings Visual acuity on presentation 20/20 20/20 20/20 20/20 20/20 20/20 Abnormal MRI findings Yes No No MRI was done Yes Yes Yes LP opening pressure (cm 41 11 30 U 37 U H2O) (U = unsuccessful lumbar puncture) Treatment Diamox Diamox Topiramate Diamox Diamox None FTM, female-to-male; MTF, male-to-female. 218 Nguyen et al: J Neuro-Ophthalmol 2021; 41: 217-223 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Available optic disc photos from Patient 1 (A), Patient 2 (B), Patient 4 (C), Patient 5 (D), and Patient 6 (E) at presentation. All patients demonstrated varying degrees of bilateral optic disc edema. relative afferent pupillary defect (RAPD). There was a small, comitant esophoria without abduction deficit. Automated (Humphrey) visual fields were reliable with a mean deviation of 23.53 dB in the right eye and 25.88 dB in the left eye; there was mild bilateral blind spot enlargement. Dilated funduscopy revealed Frisen grade III bilateral optic disc edema. A brain MRI with and without contrast demonstrated a partially empty sella turcica, flattening of the posterior surfaces of the globes, enlarged optic nerve sheaths, and distal tapering of the distal transverse sinuses bilaterally without evidence of thrombosis. Lumbar puncture demonstrated an opening pressure of 41 cm H2O, and the fluid was bland. He was started on 250 mg acetazolamide twice daily with significant improvement in diplopia, papilledema, and visual fields over 5 months. Patient 2 A 29-year-old patient undergoing FTM gender affirmation was referred for workup of a 5-month history of positional headaches and transient visual obscurations. He did not report pulse-synchronous tinnitus or diplopia. He had been taking testosterone for 2 years as part of his gender affirmation. He had no history of recent weight gain, vitamin A/retinoid, tetracycline, steroid, or growth hormone use. His body mass index was 35 kg/m2. Three months before presentation, bilateral optic disc swelling was found by an outside provider. A brain MRI and magnetic resonance venography (MRV) had Nguyen et al: J Neuro-Ophthalmol 2021; 41: 217-223 been interpreted as being normal (these were unavailable for review). A lumbar puncture also performed at an outside institution and in the prone position had revealed an opening pressure of 11 cm H2O and bland constituents. Clinical suspicion was still high enough for elevated ICP for acetazolamide 325 mg daily to be initiated. His symptoms improved after starting the medication, but then recurred when he discontinued it because of nausea. His examination 2 months later revealed central visual acuity of 20/20 in both eyes, with normal color vision (Ishihara) and no RAPD. Automated (Humphrey) visual fields were reliable with mean deviation of 23.29 dB in the right eye and 25.82 dB in the left eye and demonstrated nonspecific depression inferiorly in both eyes. Dilated fundus examination revealed elevated blurred optic disc margins in both eyes. A B-Scan ultrasound did not show optic disc drusen. He was started on topiramate with significant improvement in his headaches and transient visual obscurations. Patient 3 A 19-year-old patient undergoing FTM gender affirmation was referred for many months of worsening positional headaches, occasionally with pulse-synchronous tinnitus. He did not report transient visual obscurations or diplopia. He had been taking testosterone for 2 years as part of his gender affirmation, and he had no history of vitamin A, 219 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution steroid, growth hormone, or retinoid use. His body mass index was 31.9 kg/m2 in the setting of a 30 pound weight gain over the prior year. He had also been on doxycycline for about 4 months, but his symptoms had begun well before starting the medication. His examination revealed central visual acuity of 20/20 in both eyes with normal color vision (Ishihara) and no RAPD. Automated (Humphrey) visual fields were reliable with a mean deviation of 21.93 dB in the right eye and 21.22 dB in the left eye and full in both eyes. Both optic discs were crowded, without disc swelling. A computed tomography (CT) head with and without contrast was interpreted as being normal and a CT venogram did not show venous sinus thrombosis. A lumbar puncture was bland with an elevated opening pressure of 30 mm Hg. The patient was instructed to follow-up in 6 months while continuing topiramate therapy, which improved his headaches. Patient 4 A 22-year-old patient undergoing FTM gender affirmation was referred for workup of incidentally observed bilateral optic disc swelling. He did not report headaches or diplopia, but endorsed a two-month history of pulse-synchronous tinnitus and a one-month history of transient visual obscurations. He had been taking testosterone injections for the prior 15 months as part of his gender affirmation. He had a body mass index of 36.1 kg/m2, and endorsed a 10-pound weight gain over the prior year. He had also been on minocycline 50 mg twice daily for 9 months and this had been increased to 100 mg twice daily 3 months before presentation. He had no history of vitamin A/ retinoid, steroid, or use of synthetic growth hormone. His examination revealed central visual acuity of 20/20 in both eyes with normal color vision (Ishihara) and no RAPD. Automated (Humphrey) visual fields were reliable with a mean deviation of 20.64 dB in the right eye and 22.23 dB in the left eye and full in both eyes. Dilated fundoscopy revealed elevation of both optic discs. A brain MRI and MRV with and without contrast demonstrated a partially empty sella turcica, enlarged optic nerve sheaths, and distal tapering of the transverse sinuses without evidence of thrombosis. A lumbar puncture was attempted, but was unsuccessful. The patient was instructed to stop minocycline. On follow-up 1 month after stopping minocycline, the patient complained of worsening pulse-synchronous tinnitus and transient visual obscurations. He was lost to follow-up following that visit. Patient 5 A 23 year-old patient undergoing FTM gender affirmation was referred for workup of headaches of 5 days duration. He reported that he had been diagnosed with IIH 4 years prior at an outside institution with a lumbar puncture showing high opening pressure, although the exact number could 220 not be obtained. At that time he was prescribed acetazolamide and topiramate, both of which he stopped taking after 1 year. He did not report pulse-synchronous tinnitus, transient visual obscurations, or diplopia. He had been taking testosterone injections over the prior 15 months as part of his gender affirmation. He had no history of vitamin A, tetracycline, steroid, growth hormone, or retinoid use, but had a 50-pound weight gain over the prior 2 years. His body mass index at presentation was 44.0 km/m2. His examination revealed central visual acuity of 20/20 in the right eye and 20/25 in the left eye, with normal color vision (Ishihara) and no RAPD. Automated (Humphrey) visual fields were reliable with a mean deviation of 23.35 dB in the right eye and 22.92 dB in the left eye and revealed only nonspecific defects. Dilated funduscopy revealed bilateral optic disc edema. A brain MRI with and without contrast demonstrated a partially empty sella turcica. He was started on acetazolamide 500 mg twice a day. Over the course of 2 years of follow-up, his medication regimen was increased to acetazolamide 500 mg twice a day and nortriptyline 75 mg nightly. He lost 40 pounds over this time and was doing well at last follow-up. Patient 6 A 25-year-old patient undergoing MTF gender affirmation was referred for workup of incidentally observed bilateral optic disc swelling. She did not report visual changes, but endorsed pulse-synchronous tinnitus and intermittent positional headaches over the past year. She did not report transient visual obscurations or diplopia. She had been taking conjugated estrogen and spironolactone over the past 4 years as part of her gender affirmation. She had no history of weight gain, vitamin A/retinoid, tetracycline, steroid, or growth hormone use. Her examination revealed central visual acuity of 20/20 in both eyes with normal color vision (Ishihara) and no RAPD. Automated (Humphrey) visual fields were reliable with a mean deviation of 21.23 dB in the right eye and 22.33 dB in the left eye and demonstrated questionable enlargement of the blind spot in the left eye. Dilated funduscopy revealed elevation of both optic discs. MRI of the brain with and without contrast demonstrated partially empty sella turcica and flattening of the posterior surfaces of the globes. MRV showed distal transverse venous sinus stenosis, but did not reveal venous sinus thrombosis. A lumbar puncture was not performed. Follow-up examinations were stable at 3 months, including repeat automated visual fields, and at 1 year. DISCUSSION The exact mechanism by which the endogenous metabolic profile of female gender, obesity, and/or recent weight gain trigger IIH remains elusive. Here, we present 6 cases of patients who developed evidence of elevated ICP in the Nguyen et al: J Neuro-Ophthalmol 2021; 41: 217-223 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution context of taking exogenous hormones for gender conversion. These cases add evidence to the risk of developing elevated ICP when the typical equilibrium among sex hormones is altered. One of our cases reveals for the first time that patients who undergo MTF conversion are also susceptible to developing elevated ICP. The lack of a clear perspective on the relationship between endogenous hormones and elevation of ICP is evident by the long list of putative hormonal factors, including: the effect of androgens, progestins and estrogens and their metabolites; leptins 11b-hydroxysteroid dehydrogenase and glucagon-like-peptide-1, among others. Curious observations regarding adiposity include the fact that the mass of truncal fat correlates with opening pressure on lumbar puncture for patients with IIH, but weight itself (as measured by the BMI) does not, although it does in patients without IIH (2). Fat distribution may also be relevant, with lower body adiposity increasing risk of IIH (3). In addition, the effect of BMI is not as relevant a risk factor for prepubertal pediatric patients and it was also found not to differ between a male IIH cohort and a healthy male cohort (4). Extraglandular production of estrogen from the aromatization of androstenedione to estrone by adipocytes is an important contributor to serum estradiol levels, which may underlie the link of IIH to obesity (5). This suspicion is perhaps supported by a case report of Donaldson and Binstock of an obese young woman with Turner syndrome who developed IIH, because in Turner syndrome, all nonexogenously administered estrogen is produced by adipocytes (6). High levels of estrone and low levels of androstenedione have been measured in the cerebrospinal fluid (CSF) of patients with IIH (7), and it has been hypothesized that estrone stimulates the secretory cells of the choroid plexus to produce more CSF (8). Estrogen also decreases tight junctional resistance and remodeling of occludin, which decreases the paracellular permeability of CSF (9) and which may plausibly be relevant to IIH. However, despite the potential role of estrogens in the causation of elevated ICP, there is no statistically significant evidence that exogenous hormones, either estrogens or progestins as are commonly delivered in pharmacological forms of birth control, or the elevated levels of estrogen that occur during pregnancy, increase the risk of IIH (1,10). Additional cues regarding hormone regulation can be gleaned from the relatively high prevalence of PCOS in patients with IIH (11,12). Although there is a lack of adequate age- and weight-matched controls, the reported increase in prevalence is perhaps roughly twice that found in women without IIH (13). Assuming that the metabolic dysregulation in PCOS is in some way an added risk factor for development of IIH, the distinctive hyperandrogenic state of PCOS is potentially relevant. In women, androgens are produced primarily by the ovaries and adrenal glands, but a substantial fraction of testosterone is produced from peripheral conversion of metabolites, especially adipose tissue, which also converts Nguyen et al: J Neuro-Ophthalmol 2021; 41: 217-223 weaker androgens into more potent androgens (14). The efficiency of this conversion is greater in obese women (15), and increased levels of circulating androgens, including androstenedione, testosterone, and bioavailable testosterone, are associated with earlier age of onset of IIH in women (16). Sex hormone-binding globulin (SHBG) may also be a relevant factor because obesity significantly decreases the amount of circulating SHBG, which can affect the amount of free, direct acting androgen hormones (17,18). Of further intrigue is the fact that the effect of androgen in men may be inverse to that in women, as men with reduced serum androgen levels seem to be at higher risk for developing IIH (19). The 6 cases that we present here, in addition to the 5 previously reported cases (20–24), add relevance to the role of androgens in the development of elevated ICP. Five of our 6 patients were undergoing FTM transition, and had been taking testosterone for an average time period of 23.3 months. The one patient who was undergoing MTF transition had been taking conjugated estrogen for 51 months. The average age of our 6 patients was 23.5 years. Five of 6 of our patients reported headaches; 3 of 6 reported pulsesynchronous tinnitus; 2 of 6 reported transient visual obscurations; and one of 6 reported diplopia. Five of the 6 patients demonstrated bilateral optic disc swelling, with the last having crowding of both discs. Lumbar punctures were performed successfully in 4 of the 6 patients, and 3 of the 4 revealed an elevated opening pressure (the lumbar puncture for our second patient was performed in the prone position, which likely yielded a spuriously low measurement). MRI findings consistent with IIH, including partially empty sella turcica, flattening of the posterior surface of the globes, enlarged optic nerve sheaths, and distal transverse sinus tapering were found in 4 of 6 patients, including the 2 in whom lumbar puncture was unsuccessful. Four patients were treated with acetazolamide and one with topiramate, each with benefit over an average follow-up time of 15.7 months. All of our patients had relatively mild clinical features of elevated ICP, with little to no visual loss. These cases offer potential evidence of elevation of ICP within the context of taking exogenous hormones for gender affirmation. For our 5 FTM cases, we recognize that elevated ICP may have been triggered by an increase in weight, which often occurs in association with androgen therapy (25,26). However, IIH is relatively uncommon in men, and weight gain of the amount experienced by our patients is exceedingly common among men of this age group who only rarely develop IIH. Although none of these arguments is definitive, we still suspect that hormonal supplementation associated with gender conversion may be an independent risk factor for the development of elevated ICP. Our one patient who was undergoing MTF conversion had taken conjugated estrogen. This is the first such case to be reported in the literature. It is perhaps surprising that there are not more reported cases of IIH in MTF 221 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution transgender patients, who often take high doses of estrogen. This observation may point toward the possibility that female biologic sex also is an independent and fundamental genetic risk factor for IIH, because post-hoc hormonal manipulations to convert to male sex seem to carry a higher risk of developing elevated ICP than MTF conversion. We recognize that there are several weaknesses to our study. We recognize that we were unable to obtain CSF in some, or serum hormone levels in any of our patients, although all of our patients had already started exogenous hormonal therapy for at least several months and we had no baseline values to which we could compare their present levels, had we obtained them. Nevertheless, we believe it is important to raise awareness that exogenous hormone use could potentially increase the risk of developing increased ICP. Some of our patients had confounding details, including lumbar puncture with incorrect weight gain or the concurrent use of tetracycline antibiotics. Finally, given that the reported patients came from different institutions, and that we do not know the total numbers of IIH patients seen at these institutions during this time period, we cannot make any comments about incidence or prevalence. Future studies are necessary to definitively correlate gender affirmation hormonal therapy with increased ICP, but we believe that our present series provides evidence for a putative association. Given that interactions with health care systems can be complicated, especially for patients undergoing gender affirmation, it would not be surprising if the true genetic sex of patients may not be known to their ophthalmologist, who often participates more peripherally in health care (27). Given that each of our patients reported at least one classic symptom of elevated ICP, routine questioning for symptoms such as positional headache, transient visual obscurations, pulse-synchronous tinnitus, and diplopia by physicians managing the hormonal therapy for these patients may uncover more cases of elevated ICP in patients undergoing gender conversion, including MTF conversion. CONCLUSIONS This is the largest reported case series of elevated ICP in gender-affirming patients, and it is the first to report such a presentation in the context of MTF gender conversion. All our patients presented with clinical signs and symptoms of increased ICP after initiating gender affirmation hormonal therapy. Our clinical observations, together with the 5 previously reported cases, may offer clues to the genesis of idiopathic intracranial hypertension. Although there are caveats to some of our cases, we believe that there is at least suggestive evidence that exogenous hormone therapy may play a role in increasing ICP, at least in the context of gender affirmation therapy given that induced perturbations of hormonal levels and 222 their metabolites may create novel biochemical challenges that disrupt homeostasis. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: H. V. Nguyen, A. L. Gilbert, and J. F. Rizzo; b. Acquisition of data: A. L. Gilbert, E. Fortin, I. Vodopivec, N. Torun, B. K. Chwalisz, D. M. Cestari, and J. F. Rizzo; c. Analysis and interpretation of data: H. V. Nguyen, A. L. Gilbert, B. K. Chwalisz, and J. F. Rizzo. Category 2: a. Drafting the manuscript: H. V. Nguyen, A. L. Gilbert, E. Fortin, I. Vodopivec, N. Torun, B. K. Chwalisz, D. M. Cestari, and J. F. Rizzo; b. Revising it for intellectual content: H. V. Nguyen, A. L. Gilbert, B. K. Chwalisz, and J. F. Rizzo. Category 3: a. Final approval of the completed manuscript: H. V. Nguyen, A. L. Gilbert, E. Fortin, I. Vodopivec, N. Torun, B. K. Chwalisz, D. M. Cestari, and J. F. Rizzo. REFERENCES 1. Kilgore KP, Lee MS, Leavitt JA, Frank RD, McClelland CM, Chen JJ. A population-based, case-control evaluation of the association between hormonal contraceptives and idiopathic intracranial hypertension. Am J Ophthalmol. 2019;197:74–79. 2. Hornby C, Botfield H, O’Reilly MW, Westgate C, Mitchell J, Mollan SP, Manolopoulos K, Tomlinson J, Sinclair A. Evaluating the fat distribution in idiopathic intracranial hypertension using dual-energy X-ray absorptiometry scanning. Neuroophthalmology. 2018;42:99–104. 3. Kesler A, Kliper E, Shenkerman G, Stern N. Idiopathic intracranial hypertension is associated with lower body adiposity. Ophthalmology. 2010;117:169–174. 4. Schwartz R, Kliper E, Stern N, Dotan G, Berliner S, Kesler A. The obesity pattern of idiopathic intracranial hypertension in men. Graefes Arch Clin Exp Ophthalmol. 2013;251:2643–2646. 5. Donaldson JO. Endocrinology of pseudotumor cerebri. Neurol Clin. 1986;4:919–927. 6. Donaldson JO, Binstock ML. Pseudotumor cerebri in an obese woman with Turner syndrome. Neurology. 1981;31:758–760. 7. Toscano V, Sancesario G, Bianchi P, Cicardi C, Casilli D, Giacomini P. Cerebrospinal fluid estrone in pseudotumor cerebri: a change in cerebral steroid hormone metabolism? J Endocrinol Invest. 1991;14:81–86. 8. Donaldson JO, Horak E. Cerebrospinal fluid oestrone in pseudotumour cerebri. J Neurol Neurosurg Psychiatry. 1982;45:734–736. 9. McGeeney BE, Friedman DI. Pseudotumor cerebri pathophysiology. Headache. 2014;54:445–458. 10. Etminan M. Revised disproportionality analysis of Mirena and benign intracranial hypertension. Ther Adv Drug Saf. 2017;8:299–300. 11. Shin SH, Kim YM, Kim HY, Lee YJ, Nam SO. Idiopathic intracranial hypertension associated with polycystic ovarian syndrome. Pediatr Int. 2014;56:411–413. 12. Cosar E, Cosar M, Köken G, Sahin FK, Caliskan G, Haktanir A, Eser O, Yaman M, Yilmazer M. Polycystic ovary syndrome is related to idiopathic intracranial hypertension according to magnetic resonance imaging and magnetic resonance venography. Fertil Steril. 2008;89:1245–1246. 13. Avisar I, Gaton DD, Dania H, Stiebel-Kalish H. The prevalence of polycystic ovary syndrome in women with idiopathic intracranial hypertension. Scientifica (Cairo). 2012;2012:708042–708044. 14. Cadagan D, Khan R, Amer S. Female adipocyte androgen synthesis and the effects of insulin. Mol Genet Metab Rep. 2014;1:254–263. 15. Quinkler M, Sinha B, Tomlinson JW, Bujalska IJ, Stewart PM, Arlt W. Androgen generation in adipose tissue in women with simple obesity—a site-specific role for 17beta-hydroxysteroid dehydrogenase type 5. J Endocrinol. 2004;183:331–342. Nguyen et al: J Neuro-Ophthalmol 2021; 41: 217-223 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 16. Klein A, Stern N, Osher E, Kliper E, Kesler A. Hyperandrogenism is associated with earlier age of onset of idiopathic intracranial hypertension in women. Curr Eye Res. 2013;38:972–976. 17. Akin F, Bastemir M, Alkis E, Kaptanoglu B. Associations between sex hormone binding globulin and metabolic syndrome parameters in premenopausal obese women. Indian J Med Sci. 2008;62:407–415. 18. Cikim AS, Ozbey N, Sencer E, Molvalilar S, Orhan Y. Associations among sex hormone binding globulin concentrations and characteristics of the metabolic syndrome in obese women. Diabetes Nutr Metab. 2004;17:290–295. 19. Fraser JA, Bruce BB, Rucker J, Fraser LA, Atkins EJ, Newman NJ, Biousse V. Risk factors for idiopathic intracranial hypertension in men: a case-control study. J Neurol Sci. 2010;290:86–89. 20. Mowl AD, Grogg JA, Klein J. Secondary pseudotumour cerebri in a patient undergoing sexual reassignment therapy. Clin Exp Optom. 2009;92:449–453. 21. Park S, Cheng CP, Lim LT, Gerber D. Secondary intracranial hypertension from testosterone therapy in a transgender patient. Semin Ophthalmol. 2014;29:156–158. Nguyen et al: J Neuro-Ophthalmol 2021; 41: 217-223 22. Sheets C, Peden M, Guy J. Idiopathic intracranial hypertension in a transgender man. J Neuroophthalmol. 2007;27:313–315. 23. Hornby C, Mollan SP, Mitchell J, Markey KA, Yangou A, Wright BLC, O’Reilly MW, Sinclair AJ. What do transgender patients teach us about idiopathic intracranial hypertension? Neuroophthalmology. 2017;41:326–329. 24. Buchanan I, Hansen K, Bedolla J. Idiopathic intracranial hypertension in a transgender male on hormone therapy. Arch Emerg Med Crit Care. 2017;2:1019–2021. 25. Velho I, Fighera TM, Ziegelmann PK, Spritzer PM. Effects of testosterone therapy on BMI, blood pressure, and laboratory profile of transgender men: a systematic review. Andrology. 2017;5:881–888. 26. Fernandez JD, Tannock LR. Metabolic effects of hormone therapy in transgender patients. Endocr Pract. 2017;22:383– 388. 27. Chisolm-Straker M, Jardine L, Bennouna C, MorencyBrassard N, Coy L, Egemba MO, Shearer PL. Transgender and gender nonconforming in emergency departments: a qualitative report of patient experiences. Transgend Health. 2017;2:8–16. 223 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.