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Hypothalamus should be viewed as a target for migraine treatment

SAN FRANCISCO — Although it comprises a relatively small area of the brain, the hypothalamus has an extremely important function and there’s growing evidence that suggests it plays a pivotal role in various forms of headache, including migraines and cluster headaches, according to Andrew C. Charles, MD, director of headache research and treatment program and professor of neurology at the David Geffen School of Medicine at UCLA.

“The hypothalamus is kind of the regulator of all hormonal function in the body,” Charles told Healio Internal Medicine. “It’s really the ultimate master and controller of the sleep-wake cycle, the reproductive endocrine pathways, as well as energy metabolism which includes hunger, regulation of temperature and regulation of fluid balance in the body. Even though it is small, it is a structure that regulates a huge number of biological functions in the body, many of which are altered in migraine patients.”

Charles, who was a presenter during a plenary session about therapeutic targets of the future at the American Headache Society Annual Scientific Meeting, said recent functional imaging studies have implicated the hypothalamus in migraine attacks.

“Hours before a headache begins, [physicians] can actually see the hypothalamus lighting up as an indication that it is being activated even well before the pain begins within a migraine attack,” he said.

This “lighting up” function presents itself as an appealing therapeutic target “because it may be fundamentally involved in the very earliest stages of a migraine attack.”

Hormonal functions

The hypothalamus produces a variety of hormones and is sensitive to feedback from other hormones, Charles noted.

The reason this is important, Charles said, is because when hormone modulation in migraine is discussed, it mostly involves estrogen or progesterone. That matters because those hormones are ultimately controlled by the hypothalamus and when a patient is given exogenous estrogen and progesterone, that directly feeds back to the hypothalamus.

“Part of the challenge with dealing with hormone therapy in migraine patients is [that how the therapy affects] the hypothalamus may be different in different patients,” he said. “The other critically important point is that it is a part of the brain that has multiple cycles. For the hormonal cycle, there’s basically this release of a gonadotropin-releasing hormone (GnRH) every hour in every person, which is one of the most robust clocks in the brain.”

How hormones given to a patient as therapy may affect them may, in many instances, depend on when in the different cycles of hormonic function they are receiving treatment.

“It’s not just ‘more estrogen good, less estrogen bad and vice versa’, it’s more, ‘how do we target this cycling process appropriately at different times to be able to effectively manage these patients?’”

Understanding migraines

The hypothalamus should be thought about as a possible target for various current therapies, Charles said.

Additionally, considering the involvement of the hypothalamus helps expand understanding migraine not as a simple headache, but rather as a whole-body phenomenon.

“Most clinicians know that it is, we know about hormones and we know about issues with diet and energy metabolism, but we really haven’t had a context for thinking about that based on simplistic ideas of migraine as a blood vessel problem,” he said.

Primary care physicians and other physicians should not get frustrated when looking at hormone replacement or birth control therapy in patients with migraines because the complexity of the endocrine system increase the likelihood that not all patients will react the same way to treatment, Charles said.

Targeted therapeutics

The current understanding of targeting therapeutics to the hypothalamus is relatively limited, Charles said.

There have been instances where inhaled oxytocin has been tried as a migraine therapy.

“In terms of implementing other approaches, I would tell physicians to acknowledge the complexity of the system and the role of the hypothalamus and try not to be frustrated that simple interventions, especially on the hormonal side, don’t work,” he said.

This idea has the potential to be appealing for patients who don’t always understand why sleep, diet and hormonal function impact their migraine attacks.

For instance, CGRP-targeted therapy and other pituitary adenylate cyclase-activating peptides are involved in the function of the hypothalamus.

Physicians can now start to study patient responses to these therapies and take them back to a laboratory and understand how they work and consider the hypothalamus as a target for some newer therapies, according to Charles.

“There are CGRP receptors all over the hypothalamus and it’s quite possible that one of the mechanisms by which these new treatments are working is by modulating that function,” he said. “We don’t know that yet, but I think that’s something that definitely will be worth paying attention to.” – by Ryan McDonald

Reference:

Charles AC. Plenary – Part 2: Therapeutic Targets of the Future. Presented at: American Headache Society Annual Scientific Meeting; June 28-July 1, 2018; San Francisco.

Disclosures: Charles reports consulting for Amgen, Biohaven, Eli Lilly and eNeura.