Oral Contraception Linked to Smaller Hypothalamus

Ingrid Hein

December 05, 2019


Women who take the birth control pill have a smaller hypothalamus than those who do not, and report anger and depression more often, report researchers.

Michael Lipton

"The mean difference in volume of hypothalamus was about 6%, about 60 μL," said Michael Lipton, MD, PhD, from the Albert Einstein College of Medicine in Bronx, New York.

"It was very surprising to us that oral contraceptive use would have this degree of effect on the actual structure of a central part of the brain," he told Medscape Medical News.

The study did not show that oral contraceptives cause the difference, he pointed out, "but it is a very strong association."

Lipton and his colleagues became interested in studying the effect oral contraception on the brain after they found that women were more susceptible than men to head injury when "heading" a soccer ball. That study showed that alteration in microstructural white matter was greater in women than men who purposefully used their head to deflect the ball during play, "suggesting preliminary support for a biologic divergence of brain response to repetitive trauma."

It was very surprising to us that oral contraceptive use would have this degree of effect on the actual structure of a central part of the brain.

The team wanted to know why this was true, which led them to research various factors. "We thought one of the explanations may be different sex hormones; this is one of the testable aspects of that variation," Lipton said. They hypothesized that prescribed hormones might cause a baseline difference in men and women, so focused their study "on the effects of current oral contraceptive use."

To do that, they used 3 Tesla MRI to look at the brains of 50 women, 21 of whom were taking oral contraception, Lipton explained at the Radiological Society of North America 2019 Annual Meeting in Chicago.

The group was "small and pretty homogeneous," he acknowledged. Mean age was 23.0 years in the oral contraceptive group and 21.4 years in the non-oral contraceptive group.

Brain MRI depicting hypothalamus in red.

Using ITK-SNAP, the researchers manually segmented the hypothalamus and used FreeSurfer to determine total intracranial volume.

"The hypothalamus segmentation was reliable," with an intraclass correlation coefficient of 0.86, Lipton reported.

The degree of difference was higher than expected. Those taking birth control pills had a smaller hypothalamus (b, –63.4; P = .006).

And participants with a smaller hypothalamus reported more anger (P = .02) and depression (P = .09), but there was no correlation with cognitive performance.

"It's not surprising, when you think about it," he said. It is known that sex steroids — "of which estrogen and progesterone are two types" — have a trophic effect. "They get in the central nervous system and can affect cell growth."

"The mechanism of action of the oral contraceptive pill is not well understood," said Lipton, but it should be. Of the approximately 47 million women 15 to 49 years of age who used contraception in the United States from 2015 to 2017, 12.6% used oral contraception, according to a 2018 report from the National Center for Health Statistics.

In animal studies, sex steroids have shown alterations in the growth of neurons and other supporting cells in the brain.

Lipton pointed out that this study provides evidence of the need to differentiate male from female participants in scientific studies so that the biologic differences in response to disease and treatment can be better understood. "Historically, we have been overwhelmingly doing studies in male subjects," he pointed out.

"It shouldn't be a surprise that oral contraceptives have an effect. This is another piece of evidence that tells us that when you look at a disease or the efficacy of a treatment, you need to take a broad look at confounders," he said, including hormones.

However, "I would not tell people that their hypothalamus might shrink if they take the pill, given that this is a cross-sectional comparison," he explained.

"This is something we certainly need to research more," he added.

It might not be a permanent change.

"This is the first time anyone has looked at the hypothalamus; it’s always been a difficult area to measure," said Vincent Mathews, MD, from the Medical College of Wisconsin in Milwaukee. But new technologies have made it easier to measure volumes of brain structure.

"This is an area of the brain that's involved in the control of hormone release and production, so an anatomic change, as well as a physiologic change, that results from contraceptives makes sense," he told Medscape Medical News.

But "it might not be a permanent change," Mathews pointed out. In fact, other studies have shown that oral contraceptives are associated with portions of the brain that are larger. "And certain types of memory are actually enhanced, for people that take these drugs."

Is this positive? Is this negative? "You can’t say either way," he explained.

Radiological Society of North America (RSNA) 2019 Annual Meeting. Presented December 4, 2019.

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