Elevated sex hormone progesterone in women tied to NMOSD risk
Having disease appeared to lower testosterone, increase SHBG protein
Women with elevated blood levels of the sex hormone progesterone have an increased risk of developing neuromyelitis optica spectrum disorder (NMOSD), according to a study that analyzed genetic variants associated with sex hormone levels.
In a reverse analysis, having NMOSD appeared to lower testosterone and increase the sex hormone-binding globulin (SHBG), a protein that helps control the amount of sex hormones in the body.
“Further research is needed to enhance our understanding of the effects of sex hormones on NMOSD onset and to develop potential treatment strategies,” the researchers wrote in “Sex hormones and neuromyelitis optica spectrum disorder: a bidirectional Mendelian randomization study,” which was published in Neurological Sciences.
NMOSD is a rare autoimmune disease wherein inflammation of the spinal cord and optic nerve, which sends and receives signals from the eye, leads to problems with movement and vision. The disease is more common in women, at a ratio of nearly 3:1 in the U.S., and is up to 10 times more prevalent in women with antibodies against aquaporin-4 (AQP4), the self-reactive antibody that drives inflammation in most NMOSD cases.
The findings suggest sex-related factors such as sex hormones, which affect immune responses, may influence whether NMOSD develops.
Exploring link between developing NMOSD, sex hormones
Here, researchers at Central South University, China investigated a possible link between sex hormones and developing NMOSD. Hormones analyzed included estradiol and progesterone, the main female sex hormones, testosterone, the main male sex hormone, and SHBG.
Similar analyses assessed whether the age at menarche, that is, when menstruation begins, and the age when menstruation ends, or menopause, were linked to NMOSD.
The researchers collected data from genome-wide association studies (GWAS), which are designed to detect associations between genetic variants and a certain trait or disease.
They then applied Mendelian randomization (MR), a method that uses genetic information to find if a cause and effect exist between an exposure — in this case, each of the sex-related factors — and an outcome, that is, developing NMOSD.
The analysis revealed that women who carry genetic variants associated with elevated progesterone had a 64% higher risk of developing NMOSD. When looking at anti-AQP4 antibody status, high progesterone significantly increased the risk of AQP4-related NMOSD by two times and of disease not associated with anti-AQP4 antibodies by 2.3 times. Older age at menarche tended to increase the risk of developing AQP4-related NMOSD by 75%.
SHBG appeared to play a protective role in developing anti-AQP4-negative NMOSD by reducing the relative risk by 84%. No links were found between estradiol, testosterone, and the age at menopause and NMOSD.
A reverse MR was conducted to explore the influences of NMOSD on sex hormones. Among women, NMOSD significantly reduced testosterone levels and increased SHBG.
NMOSD may also reduce estradiol in women and men and delay the age of menarche, while AQP4-related NMOSD may lower progesterone. AQP4 antibody-negative NMOSD seemed to have no impact on any of the evaluated sex-related factors.
Sensitivity analyses found variability in certain findings, but, while “a cause for concern,” the researchers believe the results of the causal analyses aren’t disturbed. “Findings of this MR analysis revealed mutual causal associations between sex hormones and NMOSD, which provided novel perspectives about the gender-related [mechanisms] of NMOSD,” they said.
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