“Luteal Analgesia”: Progesterone Dissociates Pain Intensity and Unpleasantness by Influencing Emotion Regulation Networks

Abstract

Background: Pregnancy-induced analgesia is known to occur in association with the very high levels of estradiol and progesterone circulating during pregnancy. In women with natural ovulatory menstrual cycles, more modest rises in these hormones occur on a monthly basis. We therefore hypothesized that the high estradiol high progesterone state indicative of ovulation would be associated with a reduction in the pain experience.Methods: We used fMRI and a noxious thermal stimulus to explore the relationship between sex steroid hormones and the pain experience. Specifically, we assessed the relationship with stimulus-related activity in key regions of networks involved in emotion regulation, and functional connectivity between these regions.Results: We demonstrate that physiologically high progesterone levels are associated with a reduction in the affective component of the pain experience and a dissociation between pain intensity and unpleasantness. This dissociation is related to decreased functional connectivity between the inferior frontal gyrus and amygdala. Moreover, we have shown that in the pre-ovulatory state, the traditionally “male” sex hormone, testosterone, is the strongest hormonal regulator of pain-related activity and connectivity within the emotional regulation network. However, following ovulation the traditionally “female” sex hormones, estradiol and progesterone, appear to dominate.Conclusions: We propose that a phenomenon of “luteal analgesia” exists with potential reproductive advantages.

Menstrual and oral contraceptive cycle phases do not affect submaximal and maximal exercise responses

“…It was suggested that differences in the responses between groups may be a result of less variability in hormones across the hormonal contraceptive cycle . Because RPE may be difficult to differentiate from pain, another explanation could be that RPE values at the end of the MLSS trial may have been affected by a decreased perception of pain in the mid‐luteal phase compared with the late‐follicular phase (known as the “luteal analgesia” effect) . Although it is unclear why perception of effort was different when all physiological responses remained the same, it would be interesting to know how this elevated RPE in the mid‐follicular phase would have affected performance during a longer ride.…”

“…40 Because RPE may be difficult to differentiate from pain, another explanation could be that RPE values at the end of the MLSS trial may have been affected by a decreased perception of pain in the mid-luteal phase compared with the late-follicular phase (known as the "luteal analgesia" effect). 41 Although it is unclear why perception of effort was different when all physiological responses remained the same, it would be interesting to know how this elevated RPE in the mid-follicular phase would have affected performance during Table 3 and results section for statistical significances a longer ride. For example, if the MLSS ride was prolonged until volitional exhaustion, it is possible that these women not using oral contraceptives may disengage from the exercise trial earlier due to the greater perception of effort.…”

Menstrual cycle-associated modulations in neuromuscular function and fatigability of the knee extensors in eumenorrheic women

“…Indeed, it has recently been postulated that "luteal analgesia" occurs in eumenorrheic females when progesterone is elevated, where the affective response to nociceptive pain is reduced due to alterations in functional connectivity in the emotional regulation network (69). Thus, it could be possible that the analgesic effects of enhanced GABAergic neurotransmission permitted participants to continue exercising for a longer period due to a lower perception of pain.…”

Caesarean delivery: Bringing more than just a bundle of joy

“…Studies of the impact of menstrual hormone changes on pain perception have found that high levels of progesterone, in the presence of high estradiol, produce a dissociation of the subjective pain rating and its unpleasantness such that, although pain is recognized, it is perceived as less distressing. 12 Investigation of this effect using functional magnetic resonance imaging techniques reveals a decreased connectivity between the inferior frontal gyrus (IFG), a region of the prefrontal cortex, and the amygdala. 12 The IFG has been found to modulate pain unpleasantness and links both to the nucleus accumbens, generating positive reappraisal of emotion, and to the amygdala, generating negative appraisals.…”

“…12 Investigation of this effect using functional magnetic resonance imaging techniques reveals a decreased connectivity between the inferior frontal gyrus (IFG), a region of the prefrontal cortex, and the amygdala. 12 The IFG has been found to modulate pain unpleasantness and links both to the nucleus accumbens, generating positive reappraisal of emotion, and to the amygdala, generating negative appraisals. 13 This uncoupling of the IFG to the amygdala in the high-progesterone, high-estradiol state thus reduces the negative emotional bias applied to painful stimuli.…”