A disease that causes chronic headaches and even blindness in women, and has puzzled researchers for more than 100 years, may be caused by excess androgens, particularly testosterone, that modulate secretion of cerebrospinal fluid (CSF), UK investigators have discovered.
Although a rare condition, idiopathic intracranial hypertension (IIH), which is characterized by increased intracranial pressure, is becoming more common, in line with the global obesity epidemic.
With the worldwide incidence of IIH more than doubling between 2002 and 2016, from 2 per 100,000 to 5 per 100,000, it is estimated that the associated healthcare costs could reach as high $450 million per year by 2030.
Michael W. O'Reilly, PhD, Institute of Metabolism and Systems Research, University of Birmingham, UK, and colleagues studied 70 women with the condition, alongside 60 women with polycystic ovary syndrome (PCOS) and 40 obese but otherwise healthy controls.
They found that testosterone levels in the blood were significantly increased in women with IIH, as was the activity of enzymes involved in androgen activation.
The research, recently published online in JCI Insight, also showed that women with IIH had significantly increased levels of testosterone and an androgen precursor in the CSF compared with healthy control women.
Senior author Alexandra J. Sinclair, MBChB, PhD, also of the University of Birmingham, said: "These findings mark a key step forward; for the first time we have found a pattern of androgen dysregulation that is unique to IIH and potentially a driver of abnormal brain pressure in people with the condition."
"Taken together, this provides the first evidence that IIH may be a manifestation of female androgen excess," she said in a press release from her university.
Compelling Data but More Work Needed to Uncover Therapeutics
Wiebke Arlt, MD, DSc, director of the Institute of Metabolism and Systems Research at the University of Birmingham, also an author on the study, described the findings as "a significant step forward."
"Understanding the cause of a disease is a vital step to ultimately refine treatments which improve patient care and outcomes," Arlt added.
And Michelle Williamson, chair of the patient charity IIH UK, said that a recent survey had identified uncovering the cause of IIH as "the number one priority" for patients and physicians alike.
Saying that the charity is "delighted" by the findings, she continued: "It is vital for the patients to see that progress is being made."
Approached for comment, Andrea Dunaif, MD, system chief, Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York City, who was not involved in the study, described the data as "compelling."
She told Medscape Medical News that, as IIH is not a particularly common condition, it is notable that the researchers were able to identify such a large patient population.
Dunaif said that she was "surprised that androgens could be implicated in causing this disorder," adding: "It's not that often that you have a novel disease mechanism discovered."
"You just wouldn't think about testosterone regulating CSF production."
She pointed out, however, that it remains to be seen whether testosterone production, or action, could be a therapeutic target in IIH.
Dunaif added: "It might be possible to test the hypothesis with available agents that could suppress ovarian androgen production."
IIH Associated With Obesity but Androgen Excess Seems to Play a Role
O'Reilly and colleagues note that IIH is principally seen in obese women of reproductive age and, although the condition remains unexplained, it is suggested that endocrine disturbance may be involved in the pathogenesis.
To investigate further, they recruited 70 women with IIH aged 18-45 years, alongside 60 women diagnosed with PCOS, which is characterized by androgen excess, and 40 obese but otherwise healthy controls.
The median age of women with IIH was 34 years and median body mass index (BMI) was 37.9 kg/m2. The two comparison groups were matched for age and BMI.
Serum concentrations of testosterone were significantly higher in patients with IIH than in patients with PCOS or controls (P < .001 for both), and levels of the androgen precursor androstenedione were significantly lower in patients with IIH than patients with PCOS (P < .001) or controls (P < .05).
Examining systemic steroid metabolism in 24-hour urine samples, the team also found that net systemic 5 alpha-reductase activity, which is involved in androgen activation, was significantly increased in patients with IIH versus patients with PCOS and controls (P < .05).
They then went on to look at androgen concentrations in the CSF in 55 women with IIH, 19 healthy obese controls, and a further 31 lean control women.
Testosterone levels in the CSF were significantly higher in patients with IIH than in the two control groups (P < .001), as were androstenedione concentrations (P < .0001).
Although serum levels of both testosterone and androstenedione were significantly correlated with levels in the CSF (P = .03), there were no significant correlations between serum or CSF androgen levels and BMI or markers of IIH disease activity.
Recent Guidelines Emphasized Weight Loss
These new results follow the publication in October 2018 of the first guidelines on the management of IIH, published in the Journal of Neurology, Neurosurgery and Psychiatry, which emphasized weight loss as the best way to modify the disease and induce remission.
The recommendations, which were developed by a team of UK and German researchers — including Sinclair and other scientists involved in the current study — also underline the importance of protecting the vision of patients with surgery, such as CSF diversion and optic nerve sheath fenestration, the first choice for acute management if vision is declining.
The target audience "includes neurologists, ophthalmologists, neurosurgeons, radiologists, emergency medicine specialists, ear nose and throat specialists, and other clinicians who investigate and manage IIH. It also contains information that will be of interest to those in primary care and other healthcare professionals."
The study was funded by the National Institute of Health Research UK, Medical Research Council UK, and Wellcome Trust, as well as the European Research Council under the EU's Horizon 2020 research and innovation program.
JCI Insight. 2019;4:e125348. Full text
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Cite this: Testosterone May Underlie Rare Blindness Condition in Women - Medscape - Apr 02, 2019.