Metabolic activity in the insular cortex and hypothalamus predicts hot flashes: an FDG-PET study

Hadine Joffe, Thilo Deckersbach, Nancy U Lin, Nikos Makris, Todd C Skaar, Scott L Rauch, Darin D Dougherty, Janet E Hall, Hadine Joffe, Thilo Deckersbach, Nancy U Lin, Nikos Makris, Todd C Skaar, Scott L Rauch, Darin D Dougherty, Janet E Hall

Abstract

Context: Hot flashes are a common side effect of adjuvant endocrine therapies (AET; leuprolide, tamoxifen, aromatase inhibitors) that reduce quality of life and treatment adherence in breast cancer patients. Because hot flashes affect only some women, preexisting neurobiological traits might predispose to their development. Previous studies have implicated the insula during the perception of hot flashes and the hypothalamus in thermoregulatory dysfunction.

Objective: The aim of the study was to understand whether neurobiological factors predict hot flashes.

Design: [18F]-Fluorodeoxyglucose (FDG) positron emission tomography (PET) brain scans coregistered with structural magnetic resonance imaging were used to determine whether metabolic activity in the insula and hypothalamic thermoregulatory and estrogen-feedback regions measured before and in response to AET predict hot flashes. Findings were correlated with CYP2D6 genotype because of CYP2D6 polymorphism associations with tamoxifen-induced hot flashes.

Outcome measures: We measured regional cerebral metabolic rate of glucose uptake (rCMRglu) in the insula and hypothalamus on FDG-PET.

Results: Of 18 women without hot flashes who began AET, new-onset hot flashes were reported by 10 (55.6%) and were detected objectively in nine (50%) participants. Prior to the use of all AET, rCMRglu in the insula (P ≤ 0.01) and hypothalamic thermoregulatory (P = 0.045) and estrogen-feedback (P = 0.007) regions was lower in women who reported developing hot flashes. In response to AET, rCMRglu was further reduced in the insula in women developing hot flashes (P ≤ 0.02). Insular and hypothalamic rCMRglu levels were lower in intermediate than extensive CYP2D6 metabolizers.

Conclusions: Trait neurobiological characteristics predict hot flashes. Genetic variability in CYP2D6 may underlie the neurobiological predisposition to hot flashes induced by AET.

Trial registration: ClinicalTrials.gov NCT00455689.

Figures

Fig. 1.
Fig. 1.
Difference in rCMRglu levels in the insula before initiation of AET between the groups of women who did and did not develop subjective hot flashes. A, Region of peak difference in rCMRglu in the insula before AET between subjective hot flash groups (x = 30, y = 10, z = −16; P < 0.001). B, Box plots (median, interquartile range, and extreme values) for rCMRglu levels from corresponding region of peak difference between subjective hot flash groups before AET (P = 0.004).
Fig. 2.
Fig. 2.
Difference in rCMRglu levels in the insula in response to initiation of AET between the groups of women who did and did not develop objective hot flashes. A, Region of peak difference in rCMRglu in the insula in response to AET between objective hot flash groups (x = −32, y = 10, z = −14; P = 0.001). B, Box plots (median, interquartile range, and extreme values) for rCMRglu levels from corresponding region of peak difference between objective hot flash groups in response to AET (P = 0.003).
Fig. 3.
Fig. 3.
Box plots (median, interquartile range, and extreme values) showing rCMRglu levels before initiation of endocrine therapies in functional hypothalamic regions in women who did and did not report developing subjective hot flashes. A, Anterior preoptic thermoregulatory region (P = 0.045); B, inferior tuberal (medial basal) GnRH region (P = 0.007); and C, superior tuberal thermoregulatory region (P = 0.08). *, Outlier.

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