A novel animal model to study hot flashes: no effect of gonadotropin-releasing hormone

Abstract

Objective: Menopausal hot flashes compromise the quality of life for most women. The physiological mechanisms underlying hot flashes remain poorly understood, and the absence of an animal model to investigate hot flashes hinders investigations in this field.

Methods: We first developed the sheep as a model to study peripheral skin temperature changes using fever-inducing lipopolysaccharide (LPS; 200 microg/kg) administered to ovary-intact ewes. Because a strong correlation between luteinizing hormone pulses and hot flashes has previously been reported, we then determined whether intravenous gonadotropin-releasing hormone (GnRH; 1 mg), a dose sufficient to elevate cerebrospinal fluid-GnRH concentrations, could modulate ear skin temperature in both ovariectomized and low-estrogen-replaced ovariectomized ewes.

Results: Some ewes responded to LPS in heart rate and abdominal temperature, but there was no significant effect on either parameter or cheek temperature for the group. In contrast, LPS injection caused a significant (P < 0.001) change in skin temperature at the ear. Ear temperature showed no significant change in response to GnRH relative to control injections in both ovariectomized and low estrogen ewes.

Conclusions: We developed a model animal system in the ewe that can accurately detect small changes in peripheral skin temperature. This system has the potential to be extremely useful in future studies investigating the pathology of hot flashes and holds several advantages over previous model systems developed for this research. GnRH per se does not seem to be involved in thermoregulatory events.

Figure 1

The sheep as a model for studying peripheral temperature changes. The locations of the thermocouples on the ear, cheek and abdomen are shown.

Figure 2

Changes in (A) heart rate, (B) abdomen temperature, (C) ear temperature and (D) cheek temperature in two representative ewes after an intravenous injection of 0.9% saline (vehicle; n=6; left) or LPS (n=6; right).

Figure 3

Mean (+SEM) changes in abdomen, cheek and ear temperature and heart rate in 6 ewes after an intravenous injection of 0.9% saline (solid columns) or LPS (open columns). A significant effect (p<0.001) of LPS was evident on ear temperature.

Figure 4

Representative ewes showing no change in ear temperature following vehicle (0.9% saline; left panels A and B; n=6) and either a 1mg GnRH injection to ovariectomized ewes (A right panel; n=6) or a 1mg GnRH injection to ovariectomized ewes bearing subcutaneous estradiol implants (B right panel; n=6). This was confirmed in the group analysis for both the ovariectomized (C left panel) and the ovariectomized+estradiol (C right panel) groups following 0.9% saline (solid columns) or 1mg GnRH (open columns).