Cutaneous microvascular response during local cold exposure - the effect of female sex hormones and cold perception
Introduction
Raynaud's phenomenon, which is characterized by intense cold-induced constriction of cutaneous arteries, is more common in women compared with men. The fluctuations of symptoms according to menstrual cycle were also observed which implies an important role of sex hormones in its pathogenesis (Bakst et al., 2008, Eid et al., 2007). The cold pressure testing where one hand is immersed in the cold water is commonly used as a diagnostics procedure. Researchers have also described the differences between men and women in the response of their cardiovascular system to cold pressure testing (Tousignant-Laflamme and Marchand, 2009a). In spite of the general knowledge that differences in sensitivity to cold exist between males and females (Cankar et al., 2000, Cankar and Finderle, 2003, Fillingim et al., 2009, Meh and Denislic, 1994, Tousignant-Laflamme and Marchand, 2009a) Despite above mentioned both sexes are regarded as a homogenous group during the test results interpretation.
Similarly women have greater sensitivity to pain with lower thresholds and tolerance to painful stimuli (Alabas et al., 2012). Although the pain conditions are more common in women within reproductive age and demonstrate cyclical exacerbations in accordance with menstrual cycle indicating the role of sex hormones in pain perception, the underlying mechanisms are unclear. The net effect of progesterone and estrogen on pain perception depends on the sum of their pronociceptive and antinociceptive effects at many levels of neuroaxis (Aloisi and Bonifazi, 2006, Iacovides et al., 2015, Nag and Mokha, 2014, de Tommaso, 2011, Traub and Ji, 2013, Wiesenfeld-Hallin, 2005). Nevertheless, it is still unclear whether the absolute hormone level values or their fluctuation determine the pronociceptive or antinociceptive direction of their action (Traub and Ji, 2013, Iacovides et al., 2015).
In addition, both estrogen and progesterone might directly influence microvascular reactivity involved in microvascular response to cold. First, both female sex hormones augment cold induced vasoconstriction mediated by α2 adrenoceptors in vessel walls (Colucci et al., 1982, Eid et al., 2007, Mercuro et al., 1999, Sita and Miller, 1996). In addition, estrogen also regulates microvascular function via stimulation of non-genomic signaling, resulting in rapid nitric oxide release (Kim et al., 2014, Huang and Kaley, 2004) which might attenuate microvascular cold-induced vasoconstriction (Hodges, 2006). Despite that, the study of Matsuda-Nakamura and coworkers did not confirm an effect of body core temperature changes during the menstrual cycle phases on cold perception or on the cardiovascular system response to whole body cooling (Matsuda-Nakamura et al., 2015).
Our previous study showed that differences exist between males and females in their microvascular response to local cooling. In addition, females exhibit intra-menstrual cycle variability in their microvascular response to local cooling (Cankar and Finderle, 2003). In females, sensitivity to cold is presumed to depend on the phase of the menstrual cycle (Kowalczyk et al., 2006). Therefore, the perception of cold and cold pain might influence the results of local cold provocation testing.
In addition, there is no general consensus on the temperature that should be used for cold provocation testing. A great range of cooling temperatures is commonly used both for males and females (Minson, 2010), in spite of the well-known fact that at different cooling temperatures distinct cold and/or cold pain receptors are activated (Campero et al., 2001, Caterina, 2003, Lötsch et al., 2015, Morrison et al., 2008, Schepers and Ringkamp, 2009, Tominaga and Caterina, 2004). At cooling temperatures below 15 °C receptors other than thermoreceptors are activated (Adriaensen et al., 1983, Saumet et al., 1985).
To date there is no study comparing quantitatively determined individual thermal sensations with cutaneous microvascular response during cooling test in women who are in the follicular and luteal phases of their menstrual cycle.
The aim of present study is to determine specific differences in the microvascular response to local cooling in women who are in each of the two phases of the menstrual cycle and to determine the correlative relationship between quantitatively determined perception of cold stimuli and estradiol and progesterone levels on the one hand, and cutaneous microvascular response to local cold exposure at different cooling temperatures commonly used in cold provocation testing on the other. We hypothesized that both female sex hormones and cold perception threshold influence cutaneous microvascular response to local cold exposure in women with a regular menstrual cycle.
Section snippets
Subjects
The measurements were performed on eighteen healthy female volunteers (mean age 31.5 ± 5.7) with no chronic illnesses and no prescribed medication, including pharmacological contraception to insure normal progesterone and estrogen levels fluctuations. All participants kept dairies of their menstrual cycles to ensure that measurements were performed at comparable intervals of both menstrual cycle phases.
The subjects were not allowed to consume any drinks containing alcohol, caffeine, or theine 12 h
Baseline values of cardiovascular parameters
There was no statistically significant difference in the baseline arterial pressure, heart rate, laser-Doppler flux, or skin temperature between the follicular and luteal phases of the menstrual cycle (Table 2).
Cold perception and cold pain perception thresholds
Data regarding the cold perception and cold pain perception thresholds in the follicular and in the luteal phase of the menstrual cycle are presented in Table 3. The cold pain perception threshold value was significantly higher for females in the luteal phase compared to the values
Discussion
The main findings of the present study are: the laser-Doppler flux decrease during cooling is more pronounced during the luteal phase of menstrual cycle than during the follicular phase; the laser-Doppler flux decrease correlates with absolute estradiol and progesterone level in the follicular phase, while in the luteal phase it correlates only with absolute progesterone level; and finally, the cold perception threshold correlates with the cutaneous microvascular response to local cooling in
Conclusions
The correlations among the variables of cold perception and cold pain perception thresholds, sex hormone levels, and microvascular response to cold in both phases of menstrual cycle confirm the existence of interplay among these physiological parameters. The effects of individual thermal sensitivity and the phase of the menstrual cycle or even estradiol and progesterone levels should probably be considered in study design as well as in the interpretation of results for studies using local
Conflict of interest
The authors have no conflict of interest.
Author contributions
All authors conception and design of research; M. M. performed experiments; C. K. and M. M. analyzed data; All authors interpreted results of experiments; C. K. prepared figures; C. K. drafted manuscript; M. M. and F. Z. edited and revised manuscript; All authors approved final version of manuscript.
Funding source
The study was supported by Ministry of Higher Education, Science and Technology (grant no.: P3-0019), Slovenia.
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