Stroke: Higher lifetime estrogen levels tied to 13% lower risk

• Researchers investigated the effects of lifetime estrogen exposure on stroke risk.
• They found that higher levels of lifetime estrogen exposure in women were associated with a lower risk of stroke.
• Further research is needed to understand how higher estrogen exposure confers protection from stroke.

A stroke occurs when blood is blocked from reaching the brain or a blood vessel in the brain bursts.

Stroke is the second-leading cause of death around the world, and its incidence increased substantially between 1990 and 2019 globally, including a 70% increase in the number of incident, or first-ever, strokes.

Some studies suggest that higher estrogen levels may protect against stroke. Research shows, for example, that young women have a lower stroke risk than men, and that this risk increases after menopause, when estrogen production reduces.

Understanding more about stroke risk factors could improve preventative care and lead to improved treatment options.

Recently, researchers examined the link between lifetime cumulative estrogen exposure and stroke risk among postmenopausal women in China.

They found that women with the highest lifetime estrogen exposure had the lowest stroke risk.

The study appeared in Neurology.

What they did 

For the study, researchers examined healthcare data from 122,939 postmenopausal women without prior stroke at baseline from the China Kadoorie Biobank study. Participants were aged between 40 and 79 years and were followed for an average of 8.9 years.

They were asked to provide information about their reproductive history, including the age of puberty onset, the age at which menopause started, and the number of pregnancies they had. They also provided information on their use of contraceptive pills.

The women were then split into four groups according to their reproductive lifespan (RL), or the number of years between puberty onset and menopause. Those in the shortest RL group had up to 31 reproductive years, whereas those in the longest RL group had 36 years or more.

The researchers also collected data on stroke incidence. During the study, they recorded 15,139 cases of new-onset stroke.

The researchers found that 13.2% of women in the longest RL group had a stroke, compared to 12.6% of women in the shortest RL group.

However, after adjusting for factors including smoking, age, and physical activity, they found that, in fact, participants in the longest RL group had a 5% lower risk for all types of stroke than those in the shortest group.

In particular, when they looked at different stroke subtypes, they found that those in the longest RL group had a 13% lower risk for intracerebral hemorrhage compared to those in the shortest RL group. Intracerebral hemorrhage is the most fatal kind of stroke which occurs when blood vessels burst in the brain.

Women in the longest RL group also had a 5% lower risk for ischemic stroke — when the blood supply to the brain is interrupted or reduced — compared to the shortest group.

The researchers also found that oral contraceptive pill use duration, which is linked to increased estrogen levels, was associated with a lower risk of stroke.

Those with fewer stillbirths, miscarriages, and terminations were also less likely to develop stroke.

Estrogen and stroke risk 

“The link between reproductive lifespan, endogenous/ exogenous estrogens and risk of stroke in women is poorly understood,” Dr. Bharti Manwani, assistant professor of vascular neurology with McGovern Medical School at UTHealth Houston, not involved in the study, told Medical News Today.

“Preclinical studies have shown estrogen to be a profound neuroprotective agent, while clinical trials of estrogen replacement therapy in postmenopausal women failed to show benefit,” she noted.

Dr. Alex Polyakov, associate professor and gynecologist at the University of Melbourne in Australia, also not involved in the study, agreed that the exact mechanisms behind estrogen’s effects on stroke risk are not fully understood.

He added that: “Further research is needed to better understand the biological, behavioral, and social factors that may contribute to the link. Some potential mechanisms include the ability of estrogen to influence blood flow and the formation of blood clots, which can play a role in stroke risk.”

“Estrogen may also have protective effects on the brain and cardiovascular system. Estrogen is known to have a number of beneficial effects on the cardiovascular system, such as improving blood lipid levels, decreasing oxidative stress, and promoting blood vessel health. The relationship between estrogen levels and stroke risk is complex and can vary depending on various factors such as age, genetics, lifestyle, and hormone replacement therapy.”

– Dr. Alex Polyakov

In the Neurology paper, the researchers concluded that cumulative estrogen exposure from reproductive factors could be a useful indicator of a woman’s risk of different types of stroke after menopause.

Study limitations 

We asked study author Dr. Peige Song of the School of Public Health at Zhejiang University School of Medicine, Hangzhou, China, about the study’s limitations.

She told us that “[s]ome limitations of the study include potential recall bias in the collection of reproductive factor information, and the inability to control for other factors that may impact estrogen exposure and stroke risk, such as genetics, early life experiences, and diet.”

“The major limitation of this study is that estrogen exposure was measured indirectly rather than through direct blood levels,” Dr. Adi Iyer, a neurosurgeon and neurointerventional surgeon at the Pacific Neuroscience Institute at Providence Saint John’s Health Center in Santa Monica, CA, not involved in the study, also told MNT.

Dr. Polyakov added as the study is observational, it can only establish a correlation and not causation. He further noted that the study was conducted only on Chinese patients, and so its findings may not apply to people from other populations.

Implications 

“The implications of this study for the future of women’s health are very intriguing, and more studies regarding the cerebrovascular protection value of a higher lifetime estrogen exposure is needed,” Dr. George B. Branning, board-certified physician specializing in obstetrics and gynecology, from Biote Medical Faculty, not involved in the study, told MNT.

“Although hormone replacement therapy [HRT] is usually suggested for patients who want relief of their symptoms such as hot flashes, night sweats, weight gain, and mood changes, studies have shown that HRT is essential to lifetime functional bone health, sexual health, and cognitive protection. These new study results indicate we can perhaps add stroke protection to this growing list of benefits,” he added.

Dr. Manwani agreed that it is essential to know that longer cumulative estrogen exposure decreases stroke risk in postmenopausal women. She noted, however, that age at puberty onset or menopause is beyond a woman’s control.

“Therefore, it is important for clinicians to risk-stratify women with decreased estrogen exposure/ lower reproductive lifespan and work on controlling/ treating their other modifiable vascular risk factors aggressively, for example, hypertension, hyperlipidemia, atrial fibrillation, diabetes mellitus, smoking,” she explained.

“[These findings] also open up another debate about the role of estrogen in stroke. Is it good or bad? More studies on estrogen replacement therapy are needed to identify if increasing the estrogen exposure by use of hormone therapy would be beneficial,” she concluded.

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