Results of this functional neuroimaging study indicate a neurobiological predisposition to developing hot flashes on endocrine therapies. Our findings suggest that metabolic activity in the insula and hypothalamus is a biomarker for susceptibility to hot flashes, representing a preexisting trait that precedes and is independent of the perception of hot flashes. Women developing hot flashes had lower rCMRglu before AET in the insula as well as in thermoregulatory and GnRH subregions of the hypothalamus. In response to AET, women reporting hot flashes also had a further decrease in rCMRglu levels in the insula, but not the hypothalamus. Pretreatment rCMRglu levels in the insula and hypothalamus were correlated. Finally, intermediate, relative to extensive, CYP2D6 metabolizers had lower pretreatment rCMRglu levels, suggesting that genetic variability in CYP2D6 enzyme activity may underlie the predisposition to hot flashes among women taking tamoxifen as well as other AET.
The role of the insula in interpreting bodily sensations is divided between the posterior insula, which is primarily responsible for the perception of bodily sensations, and the anterior insula, which integrates emotional awareness of and response to bodily sensations (26
). We observed resting-state pretreatment differences in rCMRglu in both the anterior and posterior insula, whereas others (6
) have found that only the anterior insula is activated on functional MRI during the perception of hot flashes. These results suggest that susceptibility to hot flashes is predicted by decreased metabolic activity in the parts of the insula responsible for both perception and emotional response, whereas the dynamic response of the anterior insula during the experience of hot flashes reflects emotional integration of the bodily sensation.
Insula activity differs between depressed (29
) and anxious (30
) patients and healthy controls. Because depression and anxiety can precede and increase the risk for subsequent development of hot flashes during the menopause transition and in breast cancer patients (31
), we hypothesize that lower rCMRglu underlies a propensity to both psychological symptoms and heightened awareness of bodily sensations, such as hot flashes. We are unable to test this hypothesis in the current study because, by design, our study was restricted to women who did not have depression, and anxiety symptom levels were not measured.
Our results link resting-state differences in hypothalamic activity to the perception of subjective hot flashes in humans, as previously hypothesized (34
). These findings are consistent with animal studies showing that nuclei in anterior preoptic and midhypothalamic regions control thermoregulation (8
) and with studies showing alterations in peripheral markers of thermoregulation in women with hot flashes (37
). Because prior functional MRI studies report no activation of the hypothalamus during hot flashes (6
), hypothalamic activity may predispose to hot flashes but may not be perturbed during the hot flash experience. Results of connectivity analysis between hypothalamic functional subregions and between the insula and hypothalamus raise the possibility that these regions are involved in the generation of hot flashes independently or through a shared neural circuit.
The link between metabolic activity levels in the insula before AET and the development of hot flashes on AET is not explained by menopause status or by the type of AET that was used. Menopause status and type of AET confounded the association of AET-induced hot flashes with changes in metabolic activity levels in the insula in response to AET and in the hypothalamus before AET was started. Subgroup analyses for pre- and postmenopausal women and for each specific AET used are not feasible due to sample size limitation. Further investigation in larger samples is warranted to examine the mechanism through which menopause status and the specific AET used may explain these associations.
We observed important associations between resting-state metabolic activity, CYP2D6
metabolizer status, and hot flashes. IM had lower metabolic activity than EM, which in turn predicts hot flashes. Our findings are consistent with tamoxifen studies reporting more hot flashes in IM than EM (14
). Comparisons with studies reporting fewer hot flashes in PM cannot be made because we had no PM in our study (13
). Because PM comprise a small proportion (5–15%) of the overall population (38
), studies enrolling a much larger number of women would be required to obtain a large enough sample of PM to address questions applicable to this maximally reduced CYP2D6
metabolizer group. In addition to CYP2D6
metabolizer status, the occurrence of hot flashes on tamoxifen may relate to levels of the tamoxifen metabolite endoxifen and the functionality of the P-glycoprotein membrane transporter, which controls the amount of endoxifen that penetrates across the blood-brain barrier into the brain (39
), neither of which was measured in this study.
Our results suggest that CYP2D6 enzyme activity may play a role in hot flashes on tamoxifen as well as AI and leuprolide. Although CYP2D6
associations with hot flashes have been hypothesized to occur secondary to hepatic metabolism of tamoxifen to endoxifen (13
), CYP2D6 enzyme activity in the liver and brain has not been differentiated, nor have CYP2D6
polymorphisms previously been examined in women on AI or leuprolide. Alterations in CYP2D6 activity in serotonin-rich brain regions (40
) suggest that the CYP2D6 enzyme may play a role in serotonin metabolism and that serotonergic tone may be decreased when CYP2D6 function is reduced. The link between CYP2D6
polymorphisms and susceptibility to hot flashes may therefore involve reduced serotonergic tone, consistent with evidence that selective serotonin reuptake inhibitors alleviate hot flashes (41
Our findings in the insula by subjective hot flash status are consistent with our findings for the objective hot flash groups. In the hypothalamus, we found differences in metabolic activity before AET in the anterior preoptic thermoregulatory and inferior tuberal GnRH subregions when data were analyzed using subjective hot flash classifications but not using objective hot flash classifications. Any explanation for this discrepancy is speculative.
Analyses were conducted in parallel using subjective and objective hot flash groupings because of discordance between hot flash classifications, which is expected in ambulatory populations (22
). Hot flashes are more likely to be measured objectively and not subjectively if they are mild or if a woman is distracted by other activities at the time of the flash, whereas hot flashes are more likely to be reported subjectively and not measured objectively if a woman misattributes sweating to a hot flash or if she has negative mood symptoms preceding a hot flash (23
). Additional analyses focused specifically on women whose hot flashes were both reported subjectively and measured objectively or who did not have subjectively or objectively measured hot flashes are not feasible because of the small number of women in such subgroups.
Because we studied hot flashes induced by AET, the generalizability of our results to menopause-related hot flashes is unknown. Other limitations relate to inclusion of women taking different types of AET. Although the mechanism through which each AET blocks estradiol synthesis or action differs, women using different types of AET were included because we hypothesized a common pathway through which estrogen-deprivation therapies result in hot flashes. Because of the limited number of women taking each specific AET, we are unable to conduct analyses within each AET subgroup. However, our analyses confirmed that the prediction of hot flashes by pretreatment rCMRglu levels was not restricted to a specific AET.
In conclusion, our results show that specific neurobiological characteristics confer susceptibility to hot flashes and that genetic variability in CYP2D6 may underlie this predisposition. Hot flashes are an important adverse consequence of AET. Understanding the neural basis of hot flashes will help to identify pretreatment clinical characteristics that correlate with neurobiological biomarkers that are associated with the development of hot flashes on AET. Such approaches will permit the development of early-intervention strategies for hot flashes, with the goal of limiting their adverse impact on quality of life and improving adherence to endocrine therapies.