Caroline Helwick

February 22, 2016

NEW ORLEANS — In women with multiple sclerosis (MS), ovarian aging is associated with a reduction in gray matter volume and higher levels of disability, independent of chronologic age and disease duration, a new study suggests.

Jennifer S. Graves, MD, from the University of California, San Francisco (UCSF), School of Medicine, reported that lower levels of anti-Müllerian hormone (AMH), a marker of fertility, may herald the onset of disability.

"The advantage of a marker like AMH is that it's starting to capture this biological transition in a very early stage, even before women have perimenopausal symptoms and before they develop progressive disease," she said. "This biomarker could let you know if there are imminent changes in the biology of the disease, and this could help you determine if it's time to change the focus of treatment."

The findings were presented here at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016.

Women "Catch Up" After 50

"We know that females have more relapses and inflammation, but males may have earlier or faster progression. After the age of 50, however, we see less 'dimorphism' and women 'catch up' to men in terms of disability," Dr Graves said.

The age at which disability starts to accelerate, therefore, seems to correspond to the perimenopausal period. The mean age of onset of primary progressive and secondary progressive MS is approximately 45 years, she pointed out.

The effects of age and sex differences are "conspicuous-looking" enough to suggest that "ovarian aging may have a role in the transition of phenotype for women with MS," she said.

Dr Graves and her colleagues, therefore, examined whether ovarian aging might contribute to the development of progressive disease, specifically whether AMH levels were associated with clinical disability or brain atrophy. To do so, they looked at levels of AMH, which explains more than 80% of the variability of age of menopause and serves as a surrogate for ovarian reserve in fertility clinics.

Ovarian reserve is an early marker of the aging process that is more specific than chronologic age. Follicular cells have 10 times the mitochondria and are more sensitive to stress than other cells, she noted.

The study presented here included 412 women with MS and 180 healthy controls from a longitudinal cohort at UCSF. Median age was approximately 44 years, median disease duration was 6 years, and median Expanded Disability Status Scale score (EDSS) was 1.5.

The women had up to 10 years of follow-up, including scoring on the Multiple Sclerosis Functional Composite (MSFC) and the EDSS along with periodic MRI. Their AMH levels were measured on stored plasma samples from baseline, year 3, year 5, and years 8 to 10.

Associations With Parameters of Progression

"We first asked whether AMH behaves the same in MS patients as in healthy controls, and we found no differences after adjusting for age, body mass index [BMI], birth control and smoking," Dr Graves reported.

AMH levels were similar in patients with MS and controls, implying normal follicular reserve and rate of ovarian decline.

"This is what we expected. The results further support the finding that fertility is normal in women with MS," she added.

However, the investigators did find a relatively strong association between AMH levels and the two disability metrics. Decline in ovarian reserve, as determined by a two-fold decrease in AMH level, was significantly associated with both EDSS and MSFC after adjustments for chronologic age, she reported.

Similar associations between baseline ovarian reserve and several MRI metrics were also observed, especially a strong association between gray matter metrics and, to a lesser degree, an association with total brain volume.

Table. Associations Between Ovarian Reserve and Clinical and MRI Parameters

Parameter β P Value
EDSS 0.16 .0002
MSFC z score –0.087 .0001
Cortical gray matter –3.10 .005
Total gray matter –3.67 .0077
Total brain volume –5.81 .005
Total white matter –2.14 .022
T2 lesion volume –397.4 .17

Decrease in ovarian reserve represented by two-fold decrease in AMH level.


When disease duration and BMI were added to these analyses, "slight shifts in the magnitude" of the associations were seen but the patterns were consistent, she said.

For the longitudinal analysis, the investigators constructed a multivariable random-intercept/random-slope model that allowed them to use all observations over time, with both within- and between-subject comparisons, adjusting for age. They observed the same pattern of a strong association between reduced AMH and the clinical metrics of disability and the gray matter metrics on MRI; no association was seen with white matter or T2 lesion volume.

In an interview with Medscape Medical News, Dr Graves emphasized the magnitude of this association. The change in disability associated with ovarian decline, she said, is "three- to four-fold the magnitude of the association we see with disease duration."

"Given that we have a clinical association and an MRI metric that's associated with progression, the findings suggest that decline in ovarian function is associated with increased disability, and central nervous system tissue loss, independent of disease duration or age. It supports our hypothesis that ovarian decline may be playing a role in changing the phenotype in the fourth and fifth decade in women," she commented.

When asked how this information might be applied clinically, Dr Graves said that women wanting to become pregnant might be treated with agents with an established safety record, then could shift to higher efficacy treatments when entering the perimenopausal period, where the onset of disability may be looming.

"The findings may contribute to your decision-making as women face this biological transition," she suggested.

She also maintained that women who enter menopause early may be at risk for earlier progression, based on her data. "Early development of ovarian decline could lead to earlier onset of secondary progression," she said.

Other Causes of Premature Ovarian Decline?

Jerry Wolinsky, MD, interim chair of the Department of Neurology at the University of Texas Health Science Center at Houston, said the findings are important, and he wondered about other situations leading to premature ovarian decline.

"One of the things I would want you to look at with these patients, is women who may have had chemotherapy that can cause ovarian failure. You could determine whether they went into secondary progression earlier, despite drugs that, in the short run, look effective in reducing attack frequency," he suggested.

"We do have some patients exposed to cyclophosphamide, but we may not have lots of power to analyze them," Dr Graves answered. "The other situation is to look at surgical menopause, and there are some ongoing efforts to do this."

"I don't think all the heterogeneity in the disease course is explained by ovarian decline alone because there are women who don't develop secondary progression. We don't know if they are retaining ovarian function longer," she continued.

Dr Wolinsky added that he would also like to understand more about the relationship between in vitro fertilization (IVF) and progression.

"Is this measurement useful in knowing which women are likely to respond to IVF and perhaps run the risk of attack precipitation?" he asked.

Dr Graves indicated that AMH level is highly associated with the ability to conceive.

"These are whole other questions with regard to relapse risk and IVF," she said. "Low AMH may earn you fertility treatment, if pregnancy is the goal, but how this affects long-term outcomes is unknown."

Dr Graves and Dr Wolinsky have disclosed no relevant financial relationships.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016. LBA1.2. Presented February 19, 2016.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.