(CNN) — People who use estrogen-only pills during menopause were more likely to be diagnosed with high blood pressure than those using patches or creams, a new study found. However, doctors who treat menopause say estrogen-only pills are rarely prescribed for high-risk patients, and the overall benefits of hormone replacement therapy far outweigh the risks for many patients.
Hormone replacement therapy, or HRT, can be given as estrogen only, progesterone only or estrogen plus progesterone to combat symptoms of menopause such as hot flashes, chills, night sweats, sleep problems, mood changes and vaginal dryness and pain during sex. Most of the time, the dual formation uses progestin, a synthetic version of progesterone.
People taking estrogen-only pills during menopause were 14% more likely to be diagnosed with high blood pressure than those using estrogen-only patches, the study found. When compared to people using estrogen-only vaginal creams or suppositories, those taking the hormone orally were 19% more likely to diagnosed with hypertension.
“This is the biggest study that’s only looked at women who are only taking estrogen and have never taken a progestin as HRT,” said senior study author Dr. Sofia Ahmed, a professor at the Cumming School of Medicine at the University of Calgary, Canada.
When taken as a pill, estrogen is predominately metabolized in the liver, where the hormone is turned inactive and then passes from the body via urine and feces. When applied as a patch on the skin, estrogen enters the blood stream and bypasses the liver, while vaginal creams and suppositories are absorbed locally.
Still, it’s all estrogen, so why would taking it orally make a difference?
Physicians who treat menopause “almost never use oral estrogen anymore because it goes through the liver and increases blood clot proteins and triglycerides and is associated with slight increases in blood pressure,” said Dr. Stephanie Faubion, director of the Mayo Clinic’s Center for Women’s Health in Jacksonville, Florida, who was not involved in the study.
“But we already knew this from the Women’s Health Initiative Study, which found blood pressure rises to the degree of 1 to 1.5 millimeters of mercury. That’s like blood pressure rising from 128 to 129,” said Faubion, also serves as the medical director for The North American Menopausal Society, a professional association providing certification for menopause practitioners.
“The North American Menopause Society recommends, again and again, that for symptomatic women who are under 60 and within 10 years of menopause, the benefits still outweigh the risks,” Faubion said. “And for women with risk factors, we would try to minimize risk by using transdermal instead of oral to avoid first pass metabolism through the liver.”
Significant study limitations
The study, published Monday in the journal Hypertension, looked at the medical records of over 112,000 Canadian women, ages 45 years and older, who used at least six months of estrogen-only hormone therapy between 2008 and 2019. The majority of people in the study used estrogen for more than three years.
Routes of administration included oral, transdermal, vaginal and intramuscular. Very few study participants used intramuscular estrogen, so that delivery route was dropped from the study.
A synthetic version of estradiol was used by 55% of the study participants. Estradiol is the most potent and prevalent female sex hormone throughout a woman’s life, according to the Cleveland Clinic.
The other are two are estetrol, which is produced only during pregnancy, and estrone, a weak estrogen that continues to be produced after menopause. Only 5% of people in the study used estrone as a method of hormone replacement.
Conjugated equine estrogen, one of the oldest forms of estrogen therapy, was used by 40% of people in the study. The 10 or more estrogens in this version are isolated from the urine of pregnant horses — either naturally or synthetically — and have been sold since the 1940s under the brand name Premarin (PREgnant MARes’ urINe). Today, there are a number of other brands on the market.
Researchers then analyzed medical records to see which study participants developed high blood pressure within two years. Not only did people taking oral estrogen have a greater risk than transdermal or vaginal delivery — those taking conjugated equine estrogen had an 8% higher risk of being diagnosed with high blood pressure than people taking estradiol, the study found.
“We also found that the longer a person was on oral estrogen, the more likely they were to be diagnosed with high blood pressure or hypertension,” said Ahmed, the senior study author. Taking a higher dose was also associated with greater risk, she noted.
Because the study used medical records, researchers could only analyze information captured by the attending physicians, Ahmed said, which led to some significant limitations in the study.
“We didn’t know if they were smokers or not, if they were sedentary or quite physically active, and we didn’t know what their BMI (body mass index) was and if people were obese,” Ahmed said. “All of those factors play a role in determining one’s risk of developing high blood pressure.”
The lack of information on weight was especially significant, said Samar El Khoudary, a professor of epidemiology at the University of Pittsburgh School of Public Health, who was not involved in the study.
“Body mass index is the biggest risk factor for hypertension. It may be that the differences that they found in blood pressure is simply due to excess weight,” said El Khoudary, who is lead author on the American Heart Association’s 2020 guidelines on menopause and cardiovascular risk.
“In younger women, we know obesity would actually shut down the ovaries. In older women, fat tissue produces more estrogen by transforming testosterone into estrogen,” she said.
However, the biggest issue with the study, she said, is the failure to compare pill, patch and vaginal administration to women of similar ages that took no estrogen at all.
“Because this study did not have a no-estrogen group that served as a control for comparison, you cannot conclude that oral estrogen-only use was associated with an increased risk of hypertension in women, period,” El Khoudary said. “You cannot say that.”
There is a need for large, randomized studies “factoring in all the complexities of hormone therapy around this important transition period in the female lifecycle,” Ahmed said. “At the end of the day, it’s an individualized decision about what is best for the person going through menopause and should include open dialogue with their physician or health care team.”
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