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Expert Critique

FROM THE ASCO Reading Room

Aiza Tariq, MD Doctor of Medicine, Resident Physician Icahn School of Medicine at Mount Sinai Beth Israel

The difference in epidemiology of fibromyalgia and chronic fatigue syndrome has long led researchers to postulate that sex hormones may play a role in the perception of pain in fibromyalgia. Fibromyalgia tends to affect women more commonly than men. It is widely know that sex hormones affect pain perception; animal studies have shown that females are more sensitive to pain and that their pain levels can be altered by changing hormone levels.

This effect is more prominent after females reach puberty, further feeding into the hypothesis that sex hormones must modulate some nociceptive pain response. Different studies have shown that sex hormones not only affect the activity of pain receptors, but also of the pain processing pathway in the nervous system and in the microglial cells in the brain.

This study, though with a small sample size and short follow-up period, is the first to look at daily pain measurements in patients in correlation with hormone fluctuations. Testosterone and progesterone were shown to have pain diminishing properties in outside studies while progesterone has long been thought to have anti-inflammatory effects. I found the cortisol and progesterone interaction fascinating, further emphasizing the role stress plays in pain modulation. This study showing an inverse relationship between testosterone levels and fibromyalgia is important as it can help us better evaluate and treat these patients. Hormone specific therapies can be important in helping modulate pain for this select subset of patients. The downside though is the long-term effects of altering hormone levels, for example: hot flashes, hair loss, changes in sleep etc, which can be just as debilitating for patients. Further research is needed into this field to allow rheumatologists and endocrinologists a chance to help better treat FM pain.

Full Critique

The normal fluctuations of sex hormones can have corresponding effects on pain in fibromyalgia patients, according to new study results.

Authors of the study, which was published in the April issue of , said the new findings could help patients better understand or predict their own pain, and could even help inform treatment decisions.

"The normal circulation levels of sex hormones do have a clinically significant impact on fibromyalgia pain," said lead study author Jarred Younger, PhD, director of the Neuroinflammation, Pain and Fatigue Laboratory at the University of Alabama at Birmingham. "There's literature going back 100 years that sex hormones have an effect on pain ... We tracked women over a month and saw the ups and downs of their pain, then tracked when something in the blood also went up or down."

After a 2-week baseline, the small longitudinal study followed eight women with fibromyalgia over 25 days, during which time researchers analyzed daily blood samples and self-reported pain levels. All the women had normal menstrual cycles.

Day-to-day changes in progesterone (P=.002) as well as testosterone (P=.015) were significantly and inversely correlated with pain severity. There was no statistically significant relationship between estradiol and pain (P=.551) or cortisol and pain (P=.633).

Participants reported daily fibromyalgia pain severity on a scale of 0 to 100, with 0 being "no pain" and 100 being "severe pain."

Across the 25-day study period, average progesterone was 4.11 ± 5.64 ng/mL, estradiol 92.56 ± 65.62 pg/mL, and testosterone 42.36 ± 17.49 ng/mL. The pain level across all days was 56.49 ± 26.54. Average cortisol was 12.92 ± 6.4 µg/dL.

This constituted interassay variations in progesterone of 2.26%, estradiol of 1.42%, testosterone of 7.49%, and cortisol of 2.46%. Respective intra-assay variations were 1.04%, 2.31%, 11.05%, and 5.19%. Minimum detection values were .10 ng/mL, 25.0 pg/mL, 10 ng/mL, and .2 µg/dL, respectively.

The study results found a significant and inverse relationship between reported pain severity and fluctuations in these hormones. Progesterone had the most significant effect (F= -9.76, P=.002), followed by testosterone (F= -6.01, P=.015).

The relationship between pain and cortisol was not statistically significant (F=.23, P=.633), and estradiol was not associated with pain at all (F=.36, P=.551).

Younger and colleagues also analyzed pain for the low and high points in progesterone variation. The average pain score was 66.5 when progesterone was lowest and 50.4 when progesterone was highest. That constitutes a 25.6% decrease in pain (F=9.1, P=.005).

"We conclude that this research adds to the strong literature showing a relationship between sex hormones and pain, and suggest that those relationships have real-world consequences for individuals with chronic pain disorders," Younger and colleagues wrote in the study. "Sex hormones may be an important target for successfully managing some chronic pain conditions."

Clinical Implications

According to Younger, the findings suggest the need for new studies into the role of sex hormones in pain, specifically in patients with fibromyalgia, as well as the biological underpinnings of the phenomenon and, ultimately, new fibromyalgia therapies.

In the meantime, the existing body of evidence points to several hypotheses and potential applications that could help inform care strategies in patients with fibromyalgia -- a notoriously difficult condition to predict and treat.

The exact relationship is not known, but possible connections between hormones and pain include effects on peripheral nociceptors or nociceptive processing, spinal inflammation, central microglia, brain systems that control pain, or opioid systems.

Sex hormones have long been believed to play a role in fibromyalgia, given that women are twice as likely as men to have the condition, according to statistics from the . Sexual dysfunction also is a associated with fibromyalgia.

Additionally, links exist between sex hormones and many different pain conditions, such as migraine headaches. So-called stress hormones like cortisol also are involved, and the interplay among them is often complex.

"Pain conditions are much more common in women than men," said Akiko Okifuji, PhD, a pain specialist and researcher at the University of Utah, in a . "When it comes down to pain, we do not know what [female sex hormones] do. We do know that estrogen tends to suppress stress reactivity, and that stress reactivity seems to have pain effects, and fibromyalgia is associated with [stress] hyporeactivity."

The recent study sheds new light on these relationships. Although cortisol had a negligible direct effect on fibromyalgia pain, high cortisol levels appeared to amplify the impact that low progesterone levels could have on pain. This could suggest that stress does play a role in fibromyalgia pain.

"Having [higher] pain when progesterone is low and cortisol is high, that might suggest someone is really stressed, didn't get enough sleep," Younger said. "It's true especially at some points in the cycle. [Progesterone] dips around menstruation so it can be hard to tell someone to manage that, but cortisol and stress are something that could be involved."

Using targeted hormone-based therapies to help manipulate sex hormones might also be a way of modulating pain response.

"Women with fibromyalgia can expect to have differences in pain," Younger said. "Maybe there's an oral contraceptive that could smooth things out. Using low-dose testosterone could be good. The next step here is exploring potential treatment options to help manage these fluctuations."

This can also add some measure of predictability to a disease that is essentially unpredictable. The lack of predictability adds to the debilitating nature of the disorder, because planning future activities can be difficult for fibromyalgia patients. Understanding more about the pain fluctuations can offer peace of mind.

"They should just expect that to occur," Younger said. "With the predictability of fibromyalgia, just knowing more can help. Patients have good days and bad days. On Monday they may feel OK but on Thursday they might feel horrible. This will help them with that."