Testosterone may underlie rare blindness condition in women

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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 researchers have discovered.

Idiopathic intracranial hypertension (IIH), which is characterised by increased intracranial pressure, is becoming more common, in line with the global obesity epidemic. Although still a rare condition, worldwide the incidence of IIH has more than doubled between 2002 and 2016, to 5 per 100,000.

Dr. Michael W. O'Reilly, from the 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. In their paper “A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics”, recently published online in JCI Insight, the researchers 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, Dr. Alexandra J. Sinclair, 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.

Co-author Dr. Wiebke Arlt, director of the Institute of Metabolism and Systems Research at the University of Birmingham, 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," Dr. Arlt added.

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 characterised 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, and levels of the androgen precursor androstenedione were significantly lower in patients with IIH than patients with PCOS or controls.

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.

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, as were androstenedione concentrations.

Although serum levels of both testosterone and androstenedione were significantly correlated with levels in the CSF, there were no significant correlations between serum or CSF androgen levels and BMI or markers of IIH disease activity.

Recent guidelines emphasised 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 emphasised 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."