Elsevier

Maturitas

Volume 53, Issue 2, 20 January 2006, Pages 210-216
Maturitas

Estrogenic control of thermoregulation in ERαKO and ERβKO mice

https://doi.org/10.1016/j.maturitas.2005.04.006Get rights and content

Abstract

Objective

Estrogen is the most effective treatment for preventing the vasomotor symptoms in women. The ability of estrogen to control tail skin temperature (TST) in rats is used as an animal model for the studies of estrogens on menopausal hot flushes. Today, we know that estrogen can mediate its actions via the interaction with two different estrogen receptors: ERα and ERβ. To elucidate the function of each estrogen receptor subtype control of thermoregulation, we developed an animal model demonstrating estrogen control of TST in mice.

Methods and results

We determined that estrogen depletion by ovariectomy (OVX) of mice causes an elevation of basal tail skin temperature. Administration of estradiol cypionate suppressed this increase in TST in a dose dependent manner. Estrogen depletion by OVX in either ERα-knockout (ERαKO) or ERβ-knockout (ERβKO) mice resulted in an increase in TST that could be suppressed by estrogen treatment.

Conclusion

We show that mice serve as a suitable animal model for estrogen-controlled thermoregulation and that the expression of either ERα or ERβ alone in mice is sufficient to maintain control TST by estrogen.

Introduction

Estrogen deficiency in women caused by oophorectomy, treatment with a GnRH agonist, or the onset of menopause, induces vasomotor symptoms or “hot flushes”, characterized by transient episodes of sweating, palpitations and feelings of heat that can be physically measured as an increase in skin temperature [1], [2], [3]. Long-term estrogen deprivation causes osteoporosis that leads to debilitating bone fractures. In most cases, hormone replacement therapy (HRT) by estrogen alleviates the vasomotor symptoms and prevents osteoporosis. However, the findings in the Women's Health Initiative (WHI) studies that HRT causes an increase in breast cancer and cardiovascular risk led to the recommendation to limit the use of HRT to vasomotor symptoms [4], [5]. Currently, alternative therapies with bisphosphonates, PTH and selective estrogen receptor modulators (SERMs) are available for use in women for the treatment and the prevention of osteoporosis [6], [7], but none address vasomotor symptoms and the current SERMs (e.g. raloxifene and tamoxifen) exacerbate rather than relieve the climacteric symptoms.

Monitoring tail skin temperatures (TST) of ovariectomized rats has generally been used as an animal model for the evaluation of agents to control menopausal hot flashes [8], [9], [10]. The ability of estrogenic compounds was evaluated for their ability to repress elevation of rat TST that is induced by naloxone withdrawal in the morphine-dependent rat [11], [12]. Ovariectomy, itself, has been shown to elevate tail skin temperature, which was suppressed by estrogen treatment [13], [14], [15]. Recently, we showed that rats fed on chow devoid of soy and alfalfa exhibited significantly higher TST than rats maintained on normal chow [15]. Similarly, as in women, treatments with either a GnRH agonist or tamoxifen in intact rats induced an increase in TST. Overall, it is well established that estrogen in both women and rats can control skin temperature. There are two related estrogen receptors ERα and ERβ that belong to the nuclear receptor superfamily [16], [17]. Both ERα and ERβ bind 17β-estradiol with high affinity and activate transcription through bindings to similar estrogen response elements. However, these receptors differ in their tissue distributions, their actions in various transcription assays, as well as their phenotype of the corresponding knockout mice [17], [18]. To address this question, we established a mouse model for estrogen-controlled TST and tested the effects of estrogen on TST in mice in which either ERα or ERβ genes were inactivated.

Section snippets

Animals

Wild type mice: C57BL/6 mice were obtained from Taconic (Germantown, NY).

ERα-knockout mice: Male and female mice, heterozygous for the disrupted estrogen receptor alpha (ERα), were obtained from the National Institute of Environmental Health Sciences [19]. A breeding colony composed of five heterozygous ERα(+/−) male and female mice was established at an external vendor (Taconic). The ERα genotype was established using the established PCR method. ERα(+/−) mice were used to maintain and expand

Estrogen controlled TST in mice

Estrogen depletion of wild type mice via ovariectomy resulted in an elevation of basal tail skin temperature. The onset of elevated temperature in wild type C57BL/6 mice was similar in timing to the profile observed in rats in that increased TST was reached by 3–5 weeks post-ovariectomy (data not shown). TST temperature increased to an average of 26.3 ± 0.2 °C (±S.E.M.; n = 10) (Fig. 1). ECP was administered subcutaneously to half of these mice delivering calculated dose of 0.1 mg/(kg day) which

Discussion

The availability of mice in which either ERα or ERβ genes are inactivated allows the determination of the contribution of each receptor subtype for many of the actions of estradiol. To elucidate the relative contribution of each estrogen receptor in the control of thermoregulation, we first determined whether, similar to rats, mice could be used for the studies of estrogen-controlled TST. Kai et al. reported that the increase in mouse TST induced by nifedipine, a calcium channel antagonist, is

References (34)

  • B.L. Marrone et al.

    Physiol Behav

    (1976)
  • J.W. Simpkins et al.

    Life Sci

    (1983)
  • I. Merchenthaler et al.

    Maturitas

    (1998)
  • M.J. Katovich et al.

    Maturitas

    (1986)
  • E.E. Opas et al.

    Maturitas

    (2004)
  • M. Kai et al.

    Eur J Pharmacol

    (2003)
  • M. Osterlund et al.

    Brain Res Mol Brain Res

    (1998)
  • D. Barton et al.

    Drugs Aging

    (2001)
  • J.S. Carpenter

    Cancer

    (1998)
  • R.R. Freedman

    Am J Human Biol

    (2001)
  • L.M. Morimoto

    Cancer Causes Control

    (2002)
  • A.D. Pradhan

    JAMA

    (2002)
  • E. Seeman

    J Bone Miner Metab

    (2001)
  • V.C. Jordan et al.

    J Natl Cancer Inst

    (2001)
  • M.J. Fregly et al.

    Proc Soc Exp Biol Med

    (1978)
  • T. Hosono et al.

    Am J Physiol Regul Integr Comp Physiol

    (2001)
  • T. Kobayashi et al.

    Am J Physiol Regul Integr Comp Physiol

    (2000)
  • Cited by (28)

    • Long-term oral administration of a novel estrogen receptor beta agonist enhances memory and alleviates drug-induced vasodilation in young ovariectomized mice

      2021, Hormones and Behavior
      Citation Excerpt :

      However, DPN (0.05 mg/kg) and EGX358 (0.5 mg/kg) treatment did not alter TSkin relative to vehicle treatment at this time point. These findings contrast with previous studies demonstrating that ERβ-selective phytoestrogen diets and DPN injections can reduce increases in TSkin compared to vehicle treatment following OVX in both rats and mice (Bowe et al., 2006; Opas et al., 2006; Zhao et al., 2011). However, the long-term design of our study, in addition to the relatively low dosage of both DPN and EGX358, may have contributed to these contrasting results.

    • Gonadectomy prior to puberty decreases normal parental behavior in adult mice

      2014, Hormones and Behavior
      Citation Excerpt :

      The only significant effect of EB treatment in the current study was found in the duration of nest building, in the number of times tested mice initiated nest building and in the time spent crouching over pups, suggesting that EB treatment in adulthood mainly affects non-pup oriented behavior, while EB is not necessary to provoke the onset of parental behavior directed directly towards pups even in gonadectomized mice. Interestingly, estrogens have been implicated in the thermoregulation and perhaps nest building behavior reflects some effects of estrogens on this mechanism, especially as two previous studies have suggested that in mice and rats, estrogens lower tail skin temperature (Opas et al., 2004, 2006). It has to be noted that the mice in the present study were treated only with EB, while during normal pregnancy mice are exposed to both progesterone and estradiol.

    • Estrogen in the medial preoptic nucleus of the hypothalamus modulates cold responses in female rats

      2010, Brain Research
      Citation Excerpt :

      We also assessed the effect of local estrogen administration to the MPO on heat loss response by estimating tail surface temperature in Experiment 2 because the tail is the main effecter organ for heat dissipation in rats (Gordon, 1990). Previous studies show that systemic administration of estrogen decreased Ttail in rats (Bowe et al., 2006; Hosono et al., 2001) and mice (Opas et al., 2006) at a Ta of 24–25 °C. However, in the present study, no such response was observed.

    View all citing articles on Scopus
    View full text