Low estradiol hormone levels tied to worse brain damage in menopause

Low levels of the estrogen hormone estradiol may be linked to worse brain damage, a new study found, offering a possible explanation as to why multiple sclerosis (MS) often progresses more rapidly in women during menopause, when levels of that sex hormone drop.

However, the use of hormone therapy for menopause in women with MS did not lead to a reduction in neurofilament light chain (NfL) or glial fibrillary acidic protein (GFAP) — two biomarkers of damage to cells in the brain and spinal cord. That indicates a need for further research into the other factors that may be involved, according to the team of researchers, from Finland.

“Our preliminary findings suggest that low estradiol in menopausal women with MS has an age-independent association with more pronounced brain atrophy [shrinkage],” the researchers wrote, saying this and other study data “could provide one potential explanation for the more rapid progression of MS after menopause.”

Titled “The association of menopausal hormone levels with progression-related biomarkers in multiple sclerosis,” the study was published in Multiple Sclerosis and Related Disorders.

“The findings of this study complement several research results in which the transition phase of menopause has been related to the progression of MS,” the researchers wrote.

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Examining estradiol levels in women with, without MS at time of menopause

MS is about two to three times as common in women as among men, although the course of the disease is often more severe in men. In women, the time at which MS becomes progressive — with symptoms worsening — overlaps with the age of entry to menopause.

These patterns are thought to be driven mainly by differences in the levels of sex hormones. As well as driving the physical features of men and women, sex hormones are likely to affect the immune response and how well the nervous system repairs damage.

During menopause, the body lowers its production of estradiol, an estrogen and the main sex hormone in women. Although entering menopause has been linked to worsening disability, if and how low estradiol plays a role is unclear.

To know more, the researchers measured the levels of estradiol and other hormones involved in the control of sexual development in 16 women with MS as well as 15 healthy women who served as controls.

Most of the women were in the perimenopausal period — that is, the transition leading up to menopause — or within five years after menopause. All experienced some symptoms of menopause, with most having hot flashes or night sweats.

Levels of estradiol were lower in women with MS than in controls (0.04 vs. 0.1 nmol/L), but the difference was not significant, the data showed. The researchers also noted that levels of luteinizing hormone and follicle-stimulating hormone, which work together to control reproduction, also tended to be higher in the MS patients.

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Lower estradiol levels in MS women linked to more brain lesions

In women with MS, lower levels of estradiol were linked to a higher number or volume of brain lesions, a sign of the disease. On MRI scans, lesions represent areas of damage caused by the immune system mistakenly attacking myelin, the fatty coating around nerve fibers.

Lower levels of estradiol also were linked to lower whole brain volume, a measure of brain atrophy or shrinkage, and to higher levels of NfL and GFAP in the blood. NfL is a biomarker of damage to nerve cells; GFAP reflects damage to astrocytes, star-shaped cells that support nerve cells in the brain and spinal cord and are known collectively as astroglia.

Importantly, low estradiol was linked to measures of brain atrophy and damage to astroglia independent of age. That means that this didn’t occur simply because older women tend to have lower levels of estradiol.

“An age-independent association between low estradiol and brain atrophy was observed in menopausal women with MS,” the researchers wrote, noting that damage to astroglia may “partially explain the more rapid progression of MS after menopause.”

[These findings may] partially explain the more rapid progression of MS after menopause.

Because it has been suggested that hormone therapy may be useful in menopausal women with MS, the researchers watched for changes in the levels of NfL and GFAP over one year of hormone therapy with estradiol and dydrogesterone, a lab-made version of the sex hormone progesterone.

Hormone therapy did not significantly change these biomarkers in women with MS. In contrast, in healthy women without MS, the levels of GFAP in the blood decreased significantly after three months, returning to initial levels after one year.

Altogether, 14 women with MS (88%) and 13 controls (87%) completed one year of hormone therapy. Side effects like irritability, high blood pressure, and adenomyosis, or the growth of tissue lining the uterus, caused three women to stop hormone therapy. For five, estradiol dosing was adjusted due to side effects or lack of efficacy.

However, “a definite conclusion for or against an effect of [hormone therapy for menopause] on these biomarkers needs longer and larger randomized placebo-controlled studies,” the researchers concluded.

The work was funded in part by the Tampere University Hospital Medical Fund, a grant from Novartis Finland Oy, the Maire Taponen Foundation, and the Academy of Finland.